Our conference coverage in this issue comes from a meeting on HIV and women’s health, another on HIV persistence and cure research, as well as the European AIDS Conference and ICAAC.

The possibility that the slow momentum from numerous research groups pursuing a cure for HIV is an exciting one and Richard Jefferys both summarises the state-of-the-art in this field and comments on the complexities of interpreting these early results in his report from the persistence workshop.

This issue also highlights serious concerns for treatment access and global health including changes at the Global Fund and responses to the suspension of round 11 grants – that became likely last year when donor pledges failed to meet even the minimum budget.

TB reports include the shocking state of TB in South African prisons, covered by Nathan Geffen who also reports encouraging results from the ZAMSTAR study and more news on two promising MDR TB drugs.

It is very helpful that the meeting organisers have posted most of the slides for the oral presentations online, together with free access to the conference abstract book.

Abstracts and presentations are available at these links:

http://regist2.virology-education.com/abstractbook/2012_1.pdf

http://regist2.virology-education.com/2012/2ndHIV&Women/9_Jan.html

http://www.virology-education.com

Reports in this issue include:

• Similar efficacy and a few gender related differences in side effects with rilpivirine vs efavirenz at 96-weeks
• The effect of BMI on efficacy, safety and tolerability of lopinavir/r in women
• Hormonal contraception and higher risk of non-AIDS-defining events in Nashville cohort
• Poorer adherence and loss to follow up in Kenyan women who are pregnant when enrolled to ART programmes

Rilpivirine (RPV) did not show teratogenicity risk in pre-clinical studies and is therefore FDA pregnancy category B, nor does it interact with the oral contraceptives norethindrone and ethinyl estradiol. For these reasons, it could be a useful option for women of child bearing potential.

RPV was non-inferior to efavirenz (EFV) when combined with a nucleos(ti)de backbone in the pooled 96-week analysis of the phase 3 ECHO and THRIVE trials but only for baseline viral load strata <500,000 copies/mL. The primary endpoint was viral suppression to <50 copies/mL at week 48 by TLOVR analysis, with non inferiority defined by 95% CI compared to control not crossing the lower margin of -12%.

An investigation was conducted to look at safety and efficacy outcomes in women participating in these trials specifically and in comparison to men. This analysis included data from 236 (22%) women and 860 men, of these, 121 women and 429 men were randomised to RPV, and 115 women and 431 men to EFV. The women and men had similar median age of about 35 years, baseline CD4 counts of 243 and 258 cells/mm3 and viral loads of 4.9 and 5.0 log10 copies/mL respectively. Of the participants, a greater proportion of women than men (45% vs 18%) were black, and a smaller proportion (33% vs 70%) were white and Latina/o (16% vs 28%).

At 96 weeks, CD4 increases were similar in women and men in the RPV and EFV groups (approximately 225 cells/mm3).

Overall, 14% vs 6.1% of women failed virologically and/or discontinued treatment in the RPV and EFV arms respectively. The difference between the two arms was greater in the first year of treatment with 11.6% vs 3.5% failing compared to 2.5% vs 2.6% in the second year. These proportions were similar for men participating in the study: overall 14.2% vs 7%, year one 11.4% vs 4.4%, and year two 2.8% vs 2.6%, in the RPV and EFV arms respectively.

Stratification by baseline viral load showed similar rates of virological suppression for women and men with <100, 000 copies/mL receiving RPV or EFV (approximately 80%). Between >100,000 and 500,000 copies/mL, women in the RPV arm did slightly better than those receiving EFV, respectively 81% and 73% had viral loads <50 copies/mL at 96 weeks. The results for men in this viral load stratum were similar across the two arms, 72% and 73% for RPV and EFV. Above 500,000 copies/mL only 30% of women in the RPV arm had viral loads <50 copies/mL but this percentage relied on results for 3/10 women. For women receiving EFV the proportion was 57% (8/140). Of the men 67% (29/43) and 79% (46/58) in the RPV and EFV arms had viral loads <50 copies/mL at 96 weeks.

Of women who reported adherence >95%, both those receiving RPV (n=94) and EFV (n=92) had 78% rates of virological suppression <50 copies/mL. For those reporting <95% adherence suppression rates were lower, 67% and 64% for RPV (n=18) and EFV (n=14) respectively.

For men who reported >95% adherence, 96-week suppression rates with RPV (n=364) and EFV (n= 336) were 82% and 85%. Rates for those reporting <95% adherence were 52% with RPV (n=50) and 68% with EFV (n=59).

Resistance was analysed in a very small subset of women, RPV (n=15) and EFV (n=5). This revealed 20% of virologic failures with wild-type virus and 60% of with NNRTI resistance. There were more NRTI mutations in the women receiving RPV than EFV, 47% vs 0% and the most common were E138K (33%) and M184I (27%).

At week 96, rates of adverse events (AEs) leading to discontinuation of treatment were similar across treatment arms and genders. Incidence of grade 2 to 4 adverse events was significantly lower with RPV than EFV in women, 15.7% vs 34.8% and men, 17.5% vs 32.7%, both p<0.001.

Nausea occurred more frequently in women than men receiving both RPV and EFV, 19% vs 11.2%, 18.3% vs 9.7%, both p<0.05. But the incidence of treatment-related psychiatric adverse events was significantly lower in women than men receiving RPV, 9.1% vs 18.2%, p<0.05). Both these rates were lower than those in women and men receiving efavirenz, 16.5% vs 29.5%, p<0.05).

There were lower rates of abnormal dreams and nightmares in women than men receiving RPV 4.1% versus 11.4%, p<0.05. Women also experienced less of these events than men with EFV, 8.7% vs 17.4%, p<0.05. Rates of diarrhoea were similar in women and men receiving RPV, 13.2% versus 16.3%, but lower in women than men receiving efavirenz, 9.6% vs 18.6%, p< 0.05.

Women and men receiving RPV reported lower incidence of neurologic AEs compared to those receiving EFV, 15.7% vs 34.8%, p<0.05, and 17.5% vs 32.7%, p<0.001, for men and women respectively. There was also lower incidence of dizziness, 12.4% vs 27.8%, p<0.05 and 8.8% vs 28.8%, p<0.0001; and rash, 5.8% vs 16.5%, p<0.05 and 6.8% vs 12.5%, p<0.05.

Women and men receiving RPV had less grade 3 or 4 laboratory abnormalities 7.4% vs 11.5% and 10% vs 18.7% but this only reached statistical significance in men, p<0.05.

There were less grade 1 to 3 elevations in LDL cholesterol with RPV than EFV in women 19.9% vs 49.6%, p< 0.05, and men 19.6% vs 43.1%, p<0.001.

For all groups, there were significant increases from baseline in limb fat at week 96 with no statistical differences between treatment groups. Women receiving RPV appeared to have greater increase than the EFV group, median 1592g vs 641g. For men the two groups had similar median increases 828g vs 835g.

There was a trend towards greater BMD changes in women for both arms, but this was in a small sample size (n=30).

Reference:

Short W et al. Sustained efficacy and safety observed for RPV vs EFV plus FTC/TF and with a few gender differences in pooled 96-week ECHO and THRIVE analysis. 2nd International Workshop on HIV and Women. 9-10 January 2012, Bethesda, MD. Oral abstract O_14A.

Body mass index (BMI) can lead to alterations in pharmacokinetics and pharmacodynamics. Data describing the relationship between BMI and clinical outcomes of ART in women are limited.

Investigators from Abbott conducted a meta-analysis in women taking lopinavir/ritonavir (LPV/r)-based regimens in order to look at the effect of BMI on efficacy, safety, and tolerability. Ashwaq Hermes presented findings from this study.

All prospective randomised controlled trials (RCTs) in the company database in adults receiving LPV/r in regimens with two NRTIs, having BMI data, and baseline to week 48 efficacy, safety, and tolerability data were included.

Women were stratified by baseline BMI (kg/m2) into <18.5, ≥18.5-< 25, ≥25-<30 and ≥30 groups. As the number of women with BMI <18.5 was low (n=28), the investigators selected categories of <25 (normal), ≥25-<30 (overweight) and ≥30 (obese) for the analyses.

The meta-analysis included 485 women from seven RCTs, 258 with normal BMI, 130 were overweight women, and 97 categorised as obese. There were statistically significant differences (p<0.05) among the normal, overweight, and obese groups in baseline demographic characteristics: percentage of white women, 53.9%, 36.9% and 25.8% respectively; percentage of Latina women, 17.4%, 33.8%, and 20.6%, respectively and rate of hepatitis C co-infection, 17.2%, 10.8%, 6.2%, respectively.

There were also statistically significant differences in the three groups in baseline disease characteristics: mean viral load, 4.6, 4.4, and 4.3 log10 copies/mL, respectively, and mean CD4 counts 214, 244, and 278 cells/mm3, respectively.

Efficacy was similar across the groups at week 48. Similar proportions of women had viral load <50 copies/mL, 65.1%, 57.7% and 57.7%, respectively (ITT analysis). Mean increases in CD4 counts were also similar across the normal, overweight, and obese groups, 197, 158, and 172 cells/mm3, respectively.

Incidence of grade 3 and above adverse events (AEs) was also similar across the groups, 29.5%, 29.2%, and 41.2%, respectively, p=0.087. Differences were seen in the incidence of moderate/severe abdominal pain, 0.8%, 0%, 7.2%, respectively and diarrhea 9.3%, 10.8%, and 22.7%, respectively in the normal, overweight and obese groups, both p<0.05. These AEs were significantly higher, p<0.05, in the obese women compared with the other two groups. There was no significant difference in the incidence of nausea and vomiting among the three groups.

The investigators noted that increasing BMI is associated with a greater prevalence of diarrhea and abdominal pain, but not nausea or vomiting, in the general population. Also dietary differences among the BMI groups could be confounding, and this information was not collected or controlled for in the meta-analysis. Furthermore people with high BMI have elevated incidence of non-alcoholic fatty liver disease, which is associated with liver fibrosis and changes in drug metabolism.

They concluded that direct comparisons of dose safety and efficacy by BMI groups are needed to increase the understanding of obesity related changes and the impact on treatment.

comment

As reported in other studies, increased weight did not lead to higher rates of virological failure, suggesting that pharmockinetics for lopinavir do not have a direct association with higher weight, even though the PK data were not available or analysed.

However, although the results were not significantly different, it is unclear whether a formal test of equivalence was performed. There is >7% difference between the normal group and the other two groups and response rates appear lower in heavier groups. It would be interesting to see the confidence intervals for the differences which would have to be to conclude equivalence. The CD4 count increases also seem to be lower.

It would also have been interesting to see whether lopinavir/ritonavir has an impact on BMI in relation to baseline BMI.

Reference:

Hermes A et al. A meta-analysis of the effect of BMI on efficacy, safety, and tolerability of lopinavir/ritonavir in HIV-infected women in randomised clinical trials. 2nd International Workshop on HIV and Women. 9-10 January 2012, Bethesda, MD. Oral abstract O_15.

Studies evaluating the effect of hormonal contraceptives (HC) on HIV disease progression have shown conflicting results. Previous findings have been from resource limited settings (RLS) and have not looked at the effect of HC on non-AIDS defining events (non-ADE).

Mainly observational data from Africa and Asia has shown both higher and lower rates of HIV disease progression in women receiving HC. Observational data in HIV negative women has shown an association between HC and metabolic complications.

Vlada Melekhin presented findings from a retrospective cohort study of HIV-positive women attending the Comprehensive Care Center (Nashville, TN) between 1998-2008. The study investigated the association between HC (oral and injectable methods used >28 days) and AIDS-defining events (ADE), non-ADE (ie cardiovascular, renal, liver, and metabolic diseases and non-AIDS associated malignancies) and death.

Eligible women were <55 years old with no history of pulmonary or deep venous thromboembolism, breast cancer, hysterectomy, or bilateral tubal ligation and not pregnant at first clinic visit. Women with no HC were evaluated from their first clinic visit and those using HC at HC start.

Logistic regression analysis included age, race, baseline CD4 count, viral load, and haemoglobin, CD4 nadir, history of ADE, non-ADE, HCV, antiretroviral (ART and non-ART) use, smoking status, IV and non-IV drug use, year of study start, and year of HC start.

Of 467 HC-eligible women, 112 (24%) were on HC at any time during the follow up. At baseline women on HC were younger, median 28.6 vs 35.6 years. They had higher CD4 count 523 vs 364 cells/mm3 and nadir, 340 vs 280 cells/mm3, and lower median viral load, 3.1 vs 4.1 log10 copies/mL. They were less likely to be coinfected with HCV, 5% vs 15% or inject drugs, 16% vs 27%, both p<0.03.

There was no statistical difference in ART use between the HC and no HC groups, 30.4% vs 26.8%, respectively, nor in prior ADE or non-ADE.

Of the 112 women using HC, 51 used oral and the remaining 61 used injectable for a median duration of 7.6 and 13 months respectively, p=0.26.

HC users had longer follow-up compared to non HC users, median 2.8 vs 1.5 years for ADE, 2.8 vs 1.6 years for non-ADE and 3.8 vs 2.1 years for death.

The investigators reported a lower proportion of deaths in the HC group, 6% vs. 15%, p=0.01. But these women had more new cardiovascular non-ADEs, 12% vs. 5%, p=0.02.

In the adjusted analyses, HC use was associated with a statistically significantly higher risk of non-ADE HR 2.0, (95% CI 1.28, 3.1), p=0.02 and non-ADE/death HR 1.89, (95% CI 1.25, 2.87), p=0.03). Risks of ADE and ADE/death were also higher among HC users but did not reach statistical significance: HR 1.51 (95% CI 0.59, 3.85), p=0.39 and 1.49 (95% CI 0.72, 3.11), p=0.29, respectively. Women using injectable HC were at a higher risk of non-ADE and non-ADE/death, HR 2.0 and 1.9 respectively, both p=0.03 and those using oral HC only non-ADE, HR 1.9, p=0.02.

The investigators plan further analyses from this cohort including looking at the effect of ART and suggested as the number of women with HIV who are of child-bearing age increases, it is important to better understand any negative effect of HC on their health.

comment

Investigations into the use of hormonal contraceptive methods and its effect on disease progression in HIV positive women have led to conflicting results,

One randomised controlled trial conducted in Zambia showed risk of CD4 decline or death with hormonal contraception, compared to use of the copper IUD. [2] But the study was designed to look at the incidence of pregnancy and pelvic inflammatory disease in the IUD users and there was considerable discontinuation and switching between methods. Data from several observational studies do not confirm this effect.

The association with non-AIDS events found by Melekin are interesting but should be interpreted cautiously given that two large trials have reached very different conclusions. Observational data is vulnerable to unmeasured confounding and (as they are in the general population) lifestyles are very different between those that use hormonal contraception and those that do not. These differences could (feasibly) explain differences in incidence of some of these serious events. For example, even smoking and alcohol use may be different in the groups. Whille the researchers may have used propensity scores, these do nothing to tackle unmeasured confounding (and are arguably little better than standard multivariable logistic regression models).

The WHO recently held a stakeholders meeting to review the evidence on hormonal contraception and HIV, not only to consider the effect on disease progression but also female to male HIV transmission and HIV acquisition by negative women. The organisation and partners are producing three systematic reviews and there will be a statement from the consultation.

Currently the WHO medical eligibility criteria for contraceptive use defines hormonal contraceptives as category 1 – ie no restriction on the use of the methods for women with HIV (including AIDS).

References:

1. Melekin V et al. Hormonal contraceptive use is associated with a higher risk of non-AIDS-defining events in HIV-1-infected women. 2nd International Workshop on HIV and Women. 9-10 January 2012, Bethesda, MD. Oral abstract O_13.
2. Stringer EM et al. A randomised trial of the intrauterine contraceptive device vs hormonal contraception in women who are infected with the human immunodeficiency virus. Am J Obstet Gynecol 2007 August; 197 (2):144-148. Free full text:
   http://www.ajog.org/article/S0002-9378(07)00399-7/fulltext

There are concerns that women diagnosed with HIV during pregnancy may have greater difficulty with adherence to ART than those who are already aware of their status. This may lead to increased rates of vertical transmission and the development of drug resistance.

April Bell showed findings from a retrospective analysis of data collected from January 2006 to July 2011 by the United States Agency for International Development-Academic Model Providing Access to Healthcare (USAID-AMPATH) programme in Western Kenya.

The study compared adherence rates and pregnancy outcomes between women enrolled in the programme during pregnancy and those who became pregnant after they were already enrolled. Women from both groups were ART-naïve when their pregnancy was identified. Those meeting the eligibility criteria for treatment in Kenya at the time – CD4 <200 cells/mm3 – started ART immediately and those with CD4 >200 cells/mm3 started at 28 weeks gestation.

The women enrolled during pregnancy were younger, with a median age of 27 (IQR 23.2-31.7) years (n=8926), compared to 30.8 (IQR 26.6 – 35.1) years in the group already enrolled (n=5108). At enrollment a higher proportion were married, 69.6% compared to 52% and had a higher median CD4 count 371.5 (IQR 222 – 543) cells /mm3 compared to 282 (IQR 133-461) cells/mm3 for women who became pregnant when they were already enrolled in the programme. All comparisons, p<0.0001.

The women who were pregnant at enrollment were less adherent, 89.7% compared to 93.2% with perfect adherence, and were more likely to be lost to follow up before delivery, 29.6% compared to 3.4%, both p<0.0001.

Among the women who remained in the programme post-partum, there was no difference in the rate of mother-to-child transmission, 7% compared to 8.8%, p=0.0053, or early infant death, 3.2% compared to 4.2%, p=0.032, in those enrolled during pregnancy or became pregnant after enrollment respectively.

Although this study was limited by incomplete data, the investigators were able to conclude that women who are pregnant at enrollment into an HIV care programme are at higher risk for loss to follow up and poor adherence than those already enrolled in care at the time of pregnancy.

They suggested, “Interventions targeting women newly diagnosed with HIV infection during pregnancy are necessary to improve retention and adherence to therapy”.

Reference:

Bell A et al. Adherence and retention rates: a comparison of women enrolled in an ART programme during pregnancy and those who become pregnant after enrollment. 2nd International Workshop on HIV and women. 9—10 January 2012, Bethesda, MD. Oral abstract O_17.

Introduction

This meeting had a limited numbers of attendees and brought together an impressive group of leading researchers.

The abstract book and late breaker abstracts are available in PDF format from the conference website and links:

http://www.hiv-workshop.com/workshop-2011.htm

http://www.hiv-reservoir.net/index.php/the-news/189-abstract-book-2011-hiv-persistence-workshop.html

The site also contains daily rapid summaries of the workshop that will be followed in the next few weeks by more detailed reports.

Introduction

This meeting had a limited numbers of attendees and brought together an impressive group of leading researchers.

The abstract book and late breaker abstracts are available in PDF format from the conference website and links:

http://www.hiv-workshop.com/workshop-2011.htm

http://www.hiv-reservoir.net/index.php/the-news/189-abstract-book-2011-hiv-persistence-workshop.html

The site also contains daily rapid summaries of the workshop that will be followed in the next few weeks by more detailed reports.

Workshop report and commentary

Inaugurated in 2003, the bi-annual International Workshop on HIV Persistence during Therapy (aka ‘the persistence workshop’) is the brainchild of researcher Alain Lafeuillade. The meeting presaged the recent explosion of interest in pursuing a cure for HIV infection, a pursuit many had considered quixotic until the case of Timothy Brown came to light in 2008.

As has been extensively documented, Brown’s apparent cure resulted from a debilitating odyssey of treatments required for the grim diagnosis of acute myelogenous leukemia, enhanced with a mix of insight and good fortune on the part of his doctor Gero Hutter, who was able to provide a stem cell transplant from a donor lacking the major HIV co-receptor CCR5.

The sea change wrought by this fortuitous ‘proof of concept’ was much in evidence at the 2011 persistence workshop this past December; the tentative forays into basic science that were once emblematic of the field are now mixed together with more ambitious plans for advancing ideas into the clinic. Perhaps most strikingly, two large pharmaceutical companies—Gilead and Janssen/Tibotec—described their use of industrial scale screening to search for compounds that are active against latent HIV; this represents an unprecedented expansion of efforts once confined to under-resourced academic labs.

A number of online resources are available with information on presentations at the 2011 persistence workshop: Lafeuillade runs a website called the Reference Portal on HIV Reservoirs & Eradication Strategies which includes an expanding number of reports, video interviews and commentary. [1]

David Margolis from the University of North Carolina has written a comprehensive report for Jules Levin’s National AIDS Treatment Advocacy Project (NATAP) website. [2] Jon Cohen also covered one the most notable presentations in the journal Science. [3]

This report and commentary represents my subjective take on events.

To try and briefly summarise the top-line stories that emerged from the 2011 meeting:

• A triumvirate of researchers – Courtney Fletcher, Mario Stevenson and Tim Schacker – presented data suggesting that sporadic, very limited rounds of HIV replication may occur in some individuals on ART due to poor penetration of certain drugs into the lymphoid tissues. However, preliminary data were only available from a small number of participants (~4-5) so the implications are still uncertain. According to the clinicaltrials.gov entry for the study, it is now expanding from the original enrollment target of 12 to 40 so additional information should soon be forthcoming. [4] Alain Lafeuillade has posted an interview with Mario Stevenson about the findings, and these presentations were the subject of Jon Cohen’s story in Science. [5]
• An Italian research group led by Andrea Savarino described a retrospective analysis involving 18 rhesus macaques infected with SIVmac251 that participated in various studies combining ART with drugs targeting the viral reservoir. The analysis found an association between the number of ‘anti-reservoir’ drugs animals received and the likelihood of controlling SIV to undetectable levels after ART was interrupted; however only three macaques controlled SIV to this degree so the findings should be considered very preliminary. The workshop organisers issued a press release about the data suggesting that for the first time they show that anti-reservoir drugs may be able to contribute to what is now frequently referred to as a ‘functional cure’ (control of viral load in the absence of ART). In an interview with Alain Lafeuillade, Savarino is careful to note that the findings require confirmation in human studies because they could relate to unknown factors specific to the three macaques that controlled SIV in the experiment. [6] This caveat is underscored by the fact that there are relatively few studies involving ART treatment of SIVmac251 in macaques to provide context, and in those that have been published there appear to be some examples of animals that spontaneously controlled viral load after ART interruption (both in control groups and in recipients of a DNA-based therapeutic SIV vaccine).
• David Margolis from the University of North Carolina presented the first data on the use of a histone deacetylase (HDAC) inhibitor named SAHA (aka vorinostat) in individuals with HIV. HDAC inhibitors are at the forefront of efforts to pharmaceutically urge HIV out of latency, so news from Margolis’s trial has been eagerly awaited. While very preliminary, and derived from just four participants, the results so far suggest that the approach is able to increase HIV expression by latently infected cells. It took Margolis many years to get the trial started due to concerns about the safety of HDAC inhibitors (which are used as cancer treatments and can cause serious toxicities) but no serious side effects have occurred to date. As Margolis stressed, much more work is needed before any conclusions can be drawn about the promise of the approach.
• The burgeoning involvement of the pharmaceutical industry in cure-related research – represented by presentations from Romas G from Gilead and Roger Sutmuller from Janssen/Tibotec – was important news because it promises to transform the drug discovery effort by increasing the number of compounds that are being screened by many orders of magnitude.

The workshop agenda was divided into discrete topic areas spread over three days. The first session addressed the subject of animal models, and was led off by Jeff Lifson from the National Cancer Institute (NCI) at Frederick who has nearly two decades of experience studying SIV infection in rhesus macaques. Lifson outlined some of the considerations in developing an appropriate model for cure-related studies, which include mimicking the degree of viral suppression achieved with ART in humans and developing tools to comprehensively assess the impact of additional interventions on SIV reservoirs.

The models currently in use include:

• Macaques infected with hybrid SIV/HIV viruses encoding HIV reverse transcriptase (SHIV-RT), treated with efavirenz, emtricitabine and tenofovir
• Macaques infected with SIVmac251 or SIVmac239 treated with multi-drug regimens (e.g. tenofovir, emtricitabine, raltegravir and ritonavir-boosted darunavir +/- maraviroc)
• Pigtailed macaques infected with SIV/17E-Fr and SIV/Delta B670 treated with tenofovir, integrase inhibitor, saquinavir, atazanavir (this model is primarily being used to assess issues relating to viral activity in the brain)

Lifson described a study conducted by his laboratory in which macaques were infected with the highly virulent challenge virus SIVmac239 and, after sixteen weeks, treated with a multi-drug antiretroviral regimen comprising an integrase inhibitor, tenofovir, emtricitabine, and ritonavir-boosted darunavir. Suppression of viral load to less than 30 copies/mL was eventually achieved, but Lifson noted that it took longer than is seen with HIV in humans. Like the vast majority of macaque studies, the experiment involved Indian rhesus macaques, and Lifson suggested that viral load suppression might be easier to achieve in Chinese rhesus macaques (this subspecies has been shown to control SIV somewhat better in the absence of ART). Lifson acknowledged that refinement of the SIV/macaque model for cure-related research is ongoing, and he cautioned against the premature adoption of any one approach as a standard. As an example of the pitfalls of premature standardisation, he cited the HIV vaccine field’s mistake in adopting a SHIV89.6p challenge model that turned out to have essentially no relevance to human HIV infection.

One potentially important new technology that Lifson highlighted is called digital PCR, which is vastly superior to traditional PCR for measuring small quantities of nucleic acid in samples. PCR amplifies nucleic acid sequences from a single sample by inducing rounds of copying of the original sequence, then back-calculating how many were originally present using a formula that takes into account the number of rounds of copying; however these calculations can be imprecise for a number of reasons. Digital PCR divides a sample into many discrete ‘microfluidic’ wells and then uses PCR to look for the nucleic acid sequence of interest in each well, providing a readout as to whether the sequence is absent (0) or present (1). The total amount of nucleic acid sequence that was present is then calculated based on the number of negative and positive wells, using an approach called a Poisson distribution. Digital PCR assays have only recently been commercialised and a number of laboratories are now busy using them to measure SIV and HIV in research studies.

The presentations following Lifson illustrated the diversity of animal models in use, and the uncertainties associated with them. Andrea Savarino from the Istituto Superiore di Sanità in Rome provided an update on experiments conducted by his group involving macaques infected with SIVmac251. In a paper published in AIDS last year, Savarino and colleagues reported that the gold-based rheumatoid arthritis drug auranofin reduced the reservoir of SIV-infected cells in animals treated with combination ART. [7]

At the workshop, Savarino presented results of a retrospective analysis of 18 macaques (including those included in the experiments reported in the paper) that have received various combinations of antiretrovirals and ‘anti-reservoir’ drugs including auranofin and buthionine sulfoximine (BSO). The breakdown of the antiretroviral regimens employed was as follows:

• ART: tenofovir, emtricabine, raltegravir
• Intensified ART (iART): tenofovir, emtricabine, raltegravir, ritonavir-boosted darunavir
• Mega-ART: tenofovir, emtricabine, raltegravir, ritonavir-boosted darunavir, maraviroc

Three of the 18 macaques have controlled SIVmac251 to undetectable (<40 copies/mL) levels after interruption of all treatment for several months, and Savarino reported that there was a significant correlation between the number of ‘anti-reservoir’ drugs received and this salutary outcome (for the purposes of this analysis, the CCR5 inhibitor maraviroc was counted as an anti-reservoir drug due to evidence that it reduced the amount of SIV DNA when added to intensified ART and preliminary results from a human study suggesting it may impact reservoirs). Some macaques also received the HDAC inhibitor SAHA, but an impact on the SIV reservoir could not be demonstrated.

The complicated sequence of treatments and outcomes in the three macaques that have controlled viral load off ART can be roughly summarised as follows:

• Macaque P252: ART, ART+auranofin, iART+auranofin, iART+SAHA, iART+auranofin, treatment interruption, viral load control to limit of detection, viral load rebound, Mega-ART, treatment interruption, viral load control, viral load rebound, viral load control, viral load rebound, Mega-ART, viral load control, viral load rebound, Mega-ART+BSO, viral load control (100+ days)
• Macaque P157: ART, iART, Mega-ART+auranofin+BSO, treatment interruption, viral load rebound, viral load control (~60 days), viral load blip, viral load control (~50+ days)
• Macaque P177: ART, iART, Mega-ART, Mega-ART+auranofin, treatment interruption, viral load rebound, Mega-ART, treatment interruption, viral load rebound, viral load control, viral load rebound, viral load control (~50+ days)

The data appear encouraging but there are some potential caveats:

• The model of SIVmac251 infection treated with combination ART (the drugs used in the study included tenofovir, emtricabine, raltegravir, ritonavir-boosted darunavir and maraviroc) is not well characterised, at least in terms of the published literature
• There were very few control animals, and the results are not from a single study but rather from multiple experiments, sometimes involving the same macaques being rolled over from prior experiments
• As can be seen from the sequence of events in the three controlling macaques, the treatments were complex and there was variability between animals in terms of exactly when different interventions were administered

As Savarino stresses in his video interview with Alain Lafeuillade, human trials are now required to ascertain if the macaque results can be translated to HIV.

Paul Luciw presented results of an experiment in which macaques infected with SHIV-RT had prostratin and valproic acid added to long-term ART (efavirenz, emtricitabine and tenofovir) prior to an interruption. Luciw showed evidence of reduced viral RNA and DNA in tissues but when treatment was interrupted there was no significant difference in viral load rebound compared to macaques treated with ART alone. Daria Hazuda from Merck has included several of Luciw’s slides in her recent presentations on cure research so the main findings can be viewed online, however note that prostratin is only referenced as a ‘protein kinase C activator’ and valproic acid as an ‘HDAC inhibitor’. [8]

Luciw also mentioned that he repeated the experiment adding raltegravir to the ART regimen and in that case there was no additional viral RNA and DNA reduction in tissues resulting from the anti-reservoir drugs, but he was running out of time and was unable to give any details; this finding is perhaps a reminder of how much uncertainty still surrounds macaque models for cure research.

Jerome Zack is trying to make drug-delivery nanoparticles out of weird cellular particles called ‘vaults’ made of three proteins and a bit of RNA. [9] Zack presented some preliminary evidence that they can be engineered to deliver potential latency activators prostratin and bryostatin, Zack is also working with Paul Wender at Stanford to develop better analogues of these drugs to use. The goal is to come up with some lead vault-delivered anti-latency compounds to test in the BLT humanised mouse model.

Shifting topics to the virological aspects of HIV persistence, Sarah Palmer from the Karolinska Institute reported results of an intensive evaluation of viral genetics pre-ART and on long-term ART (up to >12 yearrs) in 12 people (seven treated at acute infection, five during chronic infection) to look for evidence of viral evolution that would be indicative of ongoing replication. No evidence suggestive of HIV replication was found in various CD4 subsets and other cell types in blood, lymph tissue, bone marrow and gut. Palmer noted that no hematopoetic progenitor cells (HPCs) containing HIV DNA could be found; occasional positive signals from HPC samples turned out to be due to low-level contamination with CD4 cells. This finding was recently echoed in a paper from Bob Siliciano’s group at Johns Hopkins. [10]

Palmer drew attention to one case where a large amount of HIV DNA containing a huge deletion encompassing all of the protease gene was discovered. Since HIV can’t replicate without protease, this demonstrates that the division of CD4 T cells carrying integrated, non-functional proviral HIV DNA can contribute to what may appear to be an HIV reservoir by some measures (but really isn’t because the virus is defective). Mario Stevenson coined the term ‘junkyard DNA’ for these non-functional proviruses, and it was quickly adopted at the workshop.

Tae-Wook Chun from the National Institute of Allergy and Infectious Diseases (NIAID) offered some data suggesting HDAC inhibitors may not be all they’re cracked up to be in terms of reversing HIV latency, in the hands of his lab they didn’t induce a significant amount of viral RNA from latently infected cells compared to prostratin (which is a potent activator generally considered too toxic for human use). Chun also said that the latently infected cells induced to produce viral RNA don’t seem to die (“we haven’t seen any evidence of cell death’), suggesting that induction using HDACs might have little effect in the absence of an immune response capable of killing the infected cell.

Day two

Day two of the persistence workshop featured the presentations from industry, with Romas Geleziunas from Gilead and Roger Sutmuller from Janssen/Tibotec talking back-to-back about the ongoing work at their companies.

Gilead is looking at both virus activators and immune modulators, with Romas Geleziunas seemingly already having taken on board what Tae-Wook Chun had suggested the previous day: reactivating latent infection may not be enough to kill a cell, hence immune mechanisms may need to be induced to deliver the coup de grace. Geleziunas described Gilead’s high throughput primary cell screening assay, which is a modified version of an assay developed by Vincente Planelles and Alberto Bosque. [11]

So far they’ve identified three HDAC inhibitors from the Gilead drug library, imaginatively named 001, 002 and 003. 001 is 10-fold more potent than SAHA but inhibits all classes of HDACs (which I think is a bit of a worry from a toxicity perspective) while 002 is of interest because while less potent it doesn’t score positive on the AMES test (the standard test for assessing mutagenic potential). 001 and 003 were both AMES positive. Rats tolerated 3 weeks of 002 in a preliminary safety study. Romas noted that HDAC inhibitors only activate a fraction of the virus expression seen with pan-activating CD4 T cell stimulation using CD3 and CD28 antibodies, raising the question of whether the HDAC inhibitors are only activating a proportion of the latently infected CD4 cells, or rather causing less virus expression per cell. This question remains to be resolved.

High throughput screening of a Gilead library and a commercially available drug library produced a 1% hit rate, identifying 89 compounds that could be grouped into 15 clusters based on their structures. One was a calcium pump inhibitor named thapsigargin, possibly after a character from Lord of the Rings. It was a ‘robust activator’ of latency in cells from 6 out of 6 donors. Romas didn’t say anything more about it and Wikipedia offers an explanation as to why: “It is a tumor promoter in mammalian cells”. Another was a “broad spectrum nonspecific tyrosine kinase inhibitor” called tyrphostin A which worked on cells from 3/6 donors. Since they hadn’t expected to find kinase inhibitors, they then tried screening a library of those and got a 20% hit rate. Evidence of activity at low concentrations and dose responses were seen. Next steps are to confirm activity with more selective kinase inhibitors and explore the signaling pathways that are causing these compounds to work.

Switching to the topic of bolstering immunity, Romas said Gilead is looking at a TLR7 agonist it has in development for hepatitis B. It’s been tested in chimps and woodchucks, where it has shown antiviral activity and dose-dependent induction of alpha interferon production and T cell and B cell activation. In woodchucks, it led to induction of antibodies against the hepatitis B surface protein. A small phase I human study has been safely conducted, also showing evidence of some T cell and B cell activation. Next step is to study the impact on HIV-infected cells and potentially test it in animal models in combination with HDAC inhibitors.

Meanwhile the overarching goals of Gilead’s program continue to be:

• More high throughput screening
• Uncover novel mechanisms (e.g. as may happen as a result of the identification of kinase inhibitors)
• Discover new chemical entities (NCEs).

Roger Sutmuller from Janssen/Tibotec then described his company’s efforts which have not been discussed publically before. He outlined the basic goal of discovering safe and effective compounds to reactivate latent HIV i.e. those that cause little or no cell activation and ideally have the potential to be combined. Unlike Gilead, Tibotec starts with a Jurkat cell line assay to identify compounds, after which they have a preplanned set of steps involving evaluation of:

• Toxicity/immune stimulation
• Virus reactivation in primary T cell assays
• Virus reactivation in latently infected cells from HIV+ individuals ex vivo
• Medicinal chemistry selection of lead compounds
• Testing in a humanised mouse model developed by Roberto Speck
• Testing of the pathways involved in drug activity eg using microarrays, HIV mutants with various signaling elements disabled, short-interfering RNAs etc.

Using the Jurkat cell line assay, 35,000 compounds have been screened to date, and the next step is to screen 480,000 compounds from a Johnson & Johnson ‘diversity library.’ Of those screened to date, 800 HDAC inhibitors have popped out (a 20% hit rate), 25 protein kinase C agonists (a family prostratin belongs to) and 600 unknowns that can be grouped into 11 different ‘chemotypes.’

Sutmuller went on to describe their in-house primary T cell assay, which involves fresh cells expanded in the lab and infected with an HIV encoding green fluorescent protein (GFP). Cells are rested to create latency and then drug activity is measured based on the extent to which the cells light up green. They’re using this assay to screen medium sized libraries; it can handle about 2,000 compounds per week. He showed some data from one compound ‘229,’ which induced virus at about half the level of pan-stimulator PMA, and worked even better in combination with SAHA. The next step is to study these and other compounds in Roberto Speck’s humanised mouse model, which involves 3TC and TDF given in food pellets and a long-acting version of TMC 278 that is delivered by weekly injection. They have seen good viral suppression and can recover latently infected CD4 cells using this system.

Among the other highlights from day two, Una O’Doherty from the University of Pennsylvania showed that CD8 T cells from elite controllers can kill what appear to be latently infected CD4 cells because they express the HIV Gag protein, just with much slower kinetics than seen with activated CD4 cells (and without causing spreading infection). O’Doherty suggested that perhaps this means latently infected CD4 cells aren’t as invisible to the immune system as has been thought, which provoked some controversy because—as she happily acknowledged—it is not yet known whether the same holds true for latently infected CD4 cells from individuals on ART.

In an effort to hone in on which elements of the Berlin patient’s treatment were necessary to achieving the apparent cure of HIV infection, the ever-curmudgeonly John Mellors (University of Pittsburgh) presented an analysis of ten people who had undergone myeloablative chemotherapy and autologous stem cell transplants for lymphoma. None of these individuals were cured of HIV infection, leading Mellors to conclude that in the case of Timothy Brown, the CCR5-negative transplant was important, possibly along with the graft-versus-host disease Brown experienced. In the Q&A afterwards, workshop attendee Mike McCune from UCSF suggested that total body irradiation (TBI) might also have played a role.

Santiago Moreno (Hospital Ramon Y Cajal, Madrid, Spain) presented some preliminary evidence that the CCR5 inhibitor maraviroc may activate a protein complex named NF-kappaB when the drug binds to the CCR5 receptor. Because NF-kappaB activation can stimulate latent HIV, Moreno suggested that maraviroc might have anti-reservoir activity, as was previously suggested by a small uncontrolled pilot study conducted by Moreno’s laboratory and reported at a symposium prior to the 2010 International AIDS Conference in Vienna. However, results from a randomised trial of ART intensification with maraviroc were debuted at the persistence workshop by Maria Puertas, and this study was unable to document any additional declines in HIV reservoirs associated with receipt of the drug (HIV DNA levels fell by ~8-fold in both arms).

In a session on acute HIV infection, Marty Markowitz from Aaron Diamond AIDS Research Center presented 96-week results from a 3-drug vs. 5-drug treatment study, showing essentially no significant differences in a variety of reservoir and immunological measures in blood and gut. There was a slight reduction in cell-associated HIV RNA levels at week 96 in the 5-drug group but Markowitz felt this was unlikely to be meaningful. Jintanat Ananworanich (HIV Netherlands Australia Thailand Research Collaboration) described a study involving treatment of people with very, very early HIV infection, in which 60 people have so far been enrolled, with an average time from screening to enrollment of just 3 days. This would not seem like much time for someone to process the news that they have become HIV infected and make a decision to enter a trial involving a multiple treatments and sampling from the peripheral blood, CNS and GI tract, but Ananworanich said “acceptance rates are quite high.” Individuals were in what in the following Fiebig stages of seroconversion:

• 34% stage I: within 5 days of infection
• 9% stage II: within 10 days of infection
• 48% stage III: within 13 days of infection
• 9% stage IV: within 19 days of infection

24-week results on a subset of participants indicated significantly smaller reservoirs in blood and gut of stage I vs. III or IV, with total and integrated HIV DNA being undetectable in a proportion of the earliest-treated individuals.

The very last presentations of day two involved the tag team of Timothy Schacker (University of Minnesota), Courtney Fletcher (University of Nebraska) and Mario Stevenson (University of Miami) outlining very preliminary results from their small study of viral replication in anatomical and cellular reservoirs. A total of 12 individuals are enrolled, ART naive at baseline but then treated (mostly with TDF, FTC and ritonavir boosted atazanavir) and analysed regularly up to six months. Not all individuals have data available yet, and the number of individuals from whom data were reported varied between the different presenters. Courtney Fletcher looked at drug levels in nine people, finding that some drugs (particularly atazanavir, FTC and efavirenz) may not reach adequate levels in lymph nodes and gut. Mario Stevenson then showed that in some study participants, 2-LTR circles increased in lymph tissue after starting ART, in one case along with a rise in proviral DNA. In one other individual, levels of both 2-LTR circles and proviral DNA went down. Stevenson stated: “this does not necessarily denote ongoing replication” but proposed an alternative model in which a population of long-lived cells can generate virions that infect one more cell and that’s it – just one cycle of replication, in other words. He stated this would not lead to viral evolution but could replenish the latent reservoir. In the Q&A, John Coffin from the NCI got up to the microphone and noted that since latency is a rare event in infected cells, and since Stevenson was saying these were single-cycle rounds of infection, the number of times latency would be created is not known, and may well not be often enough replenish the reservoir.

Timothy Shacker closed out the talks with a description of his efforts to correlate Fletcher’s and Stevenson’s results with measurements of viral RNA on the follicular dendritic cell (FDC) network in lymph tissue (using in situ hybridisation). Schacker created 3D graphs for several participants that included 2-LTR circle levels, DNA levels, levels of viral RNA on FDCs and, lastly, drug levels. There appeared to be correlations between the various measures, but how many people had evidence of ongoing HIV replication cycles was unclear. Schacker noted that there was a significant inverse correlation between levels of FTC diphosphate in lymph tissue and viral RNA on FDCs. Additional results from the expanded version of this study are needed in order to understand if this is a broadly applicable phenomenon, and whether poor tissue penetration of antiretrovirals represents an under-appreciated obstacle to curing HIV infection.

Day three: Margolis reaches a milestone, the crowd thins for functional cures

The major news on day three of the workshop was the presentation by David Margolis (University of North Carolina) of very preliminary results from the phase I/II study of the HDAC inhibitor vorinostat (SAHA). The trial has a complicated schema, largely due to the safety concerns of the FDA regarding the drug, which scores positive on the AMES mutagenic test (a red flag for regulators even though the significance is not fully understood).

The first step of the protocol involved screening potential participants to assess whether vorinostat could reactivate latent HIV from their CD4 T cells ex vivo. Thirteen individuals had ~4 billion lymphocytes extracted by leukopheresis, then sorted into discrete pools of 1 million purified resting CD4 cells each (ending up with 24-36 pools per participant). These pools were exposed to either vorinostat or no drug, and a mean level of HIV RNA per million cells (and a standard deviation) was calculated for each person (the assay used can measure down to 10 copies per million cells). Margolis noted that the statistical approach used to calculate the mean RNA levels is robust but complicated, and a paper explaining it is currently in press at an unnamed statistics journal.

Four of the thirteen people screened showed a statistically significant upregulation of HIV RNA expression in this analysis and were therefore recruited into the next step of the trial. A 200mg dose of vorinostat was given first for safety, followed by a 400mg dose to study pharmacokinetics and for analyses of histone acetylation and acetylation of the p21 gene (in other words, analyses of the effects of the drug on cellular genetic machinery and not HIV). The pharmacokinetic data mirrored that reported in cancer studies and cellular acetylation (both total and p21 gene) was maximal by 8 hours then trended down by 24 hours.

A final 400 mg dose of vorinostat was then administered with leukopheresis performed 4-6 hours afterward based on the pharmacokinetic data indicating this would be around the time of maximum activity. No grade 1 or greater toxicities were seen, and HIV RNA expression increased compared to baseline in all four individuals by a mean of 4.4-fold (range: 3-6.6 fold). HIV RNA in peripheral blood was also assessed using a single copy assay but no change was detected, perhaps not surprisingly given that this was a single dose study.

Margolis was obviously very encouraged by the data and stated that they had successfully “demonstrated induction of full length HIV RNA expression within a window of time after a single vorinostat exposure.” He concluded that obstacles to HIV RNA expression can overcome “at least in some cells.” But he stressed that many questions remain, including:

• Is there an equal effect to multiple doses or does it become attenuated?
• How much exposure is needed?
• Should drug be administered continuously or pulsed?
• Will toxicities emerge?
• What number of cells is needed to measure relatively rare reactivation events?
• Does RNA expression lead to virion production or clearance of cell?
• Are additional inducers needed?
• Are additional interventions needed to clear the latently cells that have been induced to express HIV RNA?

The final session of the meeting was on functional cures. Dishearteningly, the crowd of attendees thinned noticeably but the first presenter, Paula Cannon, was undeterred. “This is the first time people are going to be talking about functional cures,” she opened sunnily. “I know you’re all very obsessed with the reservoirs but we don’t really care about the reservoir – if there’s a little bit of virus left in the body, so what?” Having stuck fear into the hearts of any remaining reservoir obsessives, she then outlined what she meant, highlighting three key goals for those in pursuit of a functional cure:

• Reducing the pool of HIV target cells and thereby reducing the harmful immune activation and inflammation that is central to pathogenesis.
• Creating HIV-resistant HIV-specific CD4 T cells.
• Taking advantage of HIV as a selection agent to drive the expansion of resistant cells.

Cannon went on to review the Sangamo zinc finger nuclease (ZFN) approach to deleting CCR5, the work conducted by her laboratory to adapt it to modify hematopoietic stem cells (HSCs), and the efficacy demonstrated in a published experiment in which humanised mice were engrafted with the CCR5-deleted stem cells and challenged with HIV. Work is now underway to advance the approach into HIV positive people who need stem cell transplants as treatment for lymphoma, in collaboration with John Zaia and David DeGusto from City of Hope who have previous experience of studying gene-modified HSCs in this setting. Cannon explained that preparation for the trial has involved switching from relatively easy-to-use HSCs obtained from fetal cord blood to rather more uncooperative adult stem cells. These cells are called mobilised peripheral blood stem precursor cells (mPSCs) and sampling involves giving G-CSF for four days then conducting apheresis to extract white blood cells, followed by ex vivo purification of CD34+ cells. This procedure has now been performed on 13 donors, obtaining 42 billion white blood cells of which around 0.5% were CD34+ cells; Cannon estimates that around 1% of the CD34+ cells are ‘true’ stem cells. These mPSCs are now being used in mouse studies to address a number of issues prior to human testing.

One such experiment assessed whether pre-existing immunity to adenovirus might be problematic, because an adenovirus vector is used to deliver the zinc finger nuclease into the mPSCs. Mice were given a high titer of anti-adenovirus antibodies prior to delivery of the mPSCs and, encouragingly, no difference was seen in the extent of engraftment compared to controls given phosphate buffered saline (PBS).

Next steps include large scale tumorigenicity studies in ‘NOD scid gamma’ (NSG) mice and evaluation of modified mPSC under ‘maximising’ conditions to test the upper limit of on and off target effects (there is some evidence that ZFNs can disrupt genes other than the CCR5 target, particularly a similar region of the CCR2 gene). Mice given the maximised mPSCs will be kept for many months and extensively analysed for safety.

Following Paula Cannon, Carl June gave an update on the use of the same technology to modify CD4 T cells that are extracted from individuals with HIV using apheresis, expanded and modified in the laboratory, and reinfused into the same individual. Previous presentations of data from these phase I trials has generated considerable excitement, because the proportion of modified CD4 T cells persisting in the blood and gut of participants far exceeds the extremely modest levels obtained with prior gene therapies delivered using the same approach. Significant CD4 T cell count increases have also been documented out to nine months of follow up. Unusually, CD4:CD8 ratios have also significantly improved from an average of 0.5 at baseline to 1.5 at last analysis; this type of improvement is rarely observed as a result of ART, and may have implications in terms of improving long-term health because inverted CD4:CD8 ratios are a well-documented risk factor for illness in the HIV-uninfected elderly.

Most intriguing, however, is a trial involving a 12-week analytical treatment interruption (ATI). Data is now available from six individuals who have undergone the ATI and while all experienced a viral load rebound, levels began falling prior to the reinitiation of ART, which June noted was not the case in a prior gene therapy study involving an ATI (an evaluation of a candidate named VRX496).

One notable individual controlled viral load to below the level of detection (<50 copies/mL) before ART was restarted. This person turned out to be heterozygous for the delta32 CCR5 deletion, which means that the ZFNs could work more efficiently because only one CCR5 gene in each cell had to be disrupted in order for CCR5 expression to be completely abrogated (instead of two as is normally the case). Importantly, June found a significant correlation between the proportion of modified CD4 T cells and viral load control during the ATI. This suggests that an antiretroviral effect is achievable with the approach, and that the potency of the effect may be boosted if the proportion of modified cells can be increased.

In the Q&A period, June was asked if he had assessed whether gene-modified HIV-specific CD4 T cells may have contributed the viral load results; he replied that HIV-specific CD4 T cell responses have not yet been analyzed in the ATI trial.

The last two talks in the final workshop session addressed the development of methods that attempt to specifically target latent HIV and excise it from the DNA of infected cells (or damage the provirus in order to render it non-functional). On paper, at least, these approaches sound very appealing but it was clear that significant hurdles remain. Jan van Lunzen (University Medical Centre Hamburg-Eppendorf) discussed the modification of an enzyme called Cre recombinase to target HIV DNA. The modified version, dubbed Tre recombinase, has successfully excised proviral DNA from cells in vitro and work is now underway to study how it might be delivered. Next steps involve studies in humanised mice using a lentiviral vector to deliver the Tre recombinase to CD34+ stem cells; the vector is designed to be ’self-inactivating’ in cells that do not contain HIV DNA. As an aside, Jan van Lunzen also mentioned a patient of his who started ART during early infection, was treated for five years, then stopped six years ago, had a small viral load blip and has been undetectable ever since. HIV RNA cannot be found in blood, gut or CNS. According to van Lunzen, the individual has a “very strong HIV-specific CD4 response,” and he highlighted the case as being similar to Christine Rouzioux’s report of five individuals treated very early who have controlled viral load to undetectable levels off ART for an average of around five years. [12] These case reports may bode well for prospects for a functional cure, van Lunzen suggested.

Keith Jerome from the Fred Hutchinson Cancer Research Center recounted the efforts of his group to employ different enzymes, endonucleases, to target latent HIV. The idea in this case is to induce mutations in the HIV provirus in order to render it non-functional. Some success has been achieved in vitro but considerable challenges remain in terms of improving the efficiency of targeting and developing delivery methods that might be able to get the endonucleases to where they are needed. Jerome’s work is now being supported by a Martin Delaney Collaboratory grant from NIH.

The last word at the 2011 persistence workshop was given to Nobel laureate Françoise Barré-Sinoussi, who outlined the International AIDS Society’s development of a Global Scientific Strategy ‘Towards an HIV Cure’ and encouraged audience members to attend an IAS symposium on the subject that will take place in Washington DC immediately ahead of the 2012 International AIDS Conference. Barré-Sinoussi also stressed the importance of the work and the need to continue the momentum which has placed curing HIV infection back at the top of the research agenda.

The 6th International Workshop on HIV Persistence, Reservoirs & Eradication Strategies is scheduled for 2013 in Miami.

References

1. Reference Portal on HIV Reservoirs and Eradication Strategies website.
   http://www.hiv-reservoir.net/
2. Margolis D. HIV Persistence during Therapy 5th International Workshop. natap.org, 2011.
   http://www.natap.org/2011/HIV/122111_01.htm
3. Cohen J. Tissue says blood Is misleading, confusing HIV cure efforts. Science 23 December 2011: Vol. 334 no. 6063 p. 1614.
   http://www.sciencemag.org/content/334/6063/1614.summary
4. Clinical Trial. Tissue drug levels of HIV medications.
   http://clinicaltrials.gov/ct2/show/NCT01490346
5. Mario Stevenson Interview. (9 December 2011).
   http://www.youtube.com/watch?v=_fhb95p__9g
6. Andrea Savarino Interview on HIV Cure. (10 December 2011).
   http://www.youtube.com/watch?v=xIqdDU_OEFU
7. Lewis MG et al. Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension. AIDS. 25(11):1347-1356, July 17, 2011.
   http://journals.lww.com/aidsonline/toc/2011/07170
8. Hazuda D. Powerpoint can be downloaded at the bottom of this page, Luciw’s data is on slides 21-25):
   http://www.iasociety.org/Default.aspx?pageid=416#session5
9. TEDxUCLA – Leonard Rome – online video. (29 August 2011).
   http://tedxtalks.ted.com/video/TEDxUCLA-Leonard-Rome-Vaults-mo
10. HIV-1 DNA is detected in bone marrow populations containing CD4+ T cells but is not found in purified CD34+ hematopoietic progenitor cells in most patients on antiretroviral therapy. J Infect Dis. (2012). First published online: 24 January 2012.
    http://jid.oxfordjournals.org/content/early/2012/01/24/infdis.jir884.abstract
11. Bosque A et al. Studies of HIV-1 latency in an ex vivo model that uses primary central memory T cells. 2011 Jan;53(1):54-61. Epub 2010 Oct 21.
    http://www.ncbi.nlm.nih.gov/pubmed/20970502
12. Hocqueloux C et al. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. 19 June 2010 – Volume 24 – Issue 10 – p 1598-1601.
    http://journals.lww.com/aidsonline/Fulltext/2010/06190/Long_term_immunovirologic_control_following.27.aspx

Unfortunately abstracts are not yet available online, and although webcasts, podcasts and PowerPoint slides are available these require a login name and password (obtainable by email from the EACS secretariat).

The same login details can also be used to access training resources from a pre-meeting training for doctors and other resources. iPhone and iPad versions are accessible using the free Talks On The Go App.

http://www.europeanaidsclinicalsociety.org/

The following reports are included in this issue.

• Raltegravir achieves superiority over efavirenz after four years
• Higher plasma levels of tenofovir and darunavir but not efavirenz in older patients
• Ritonavir levels reduced with high fat meal (900 kcal)
• Transplacental transfer of raltegravir and delayed plasma clearance in preterm neonates

Four year results from a five year, double-blind, randomised, non-inferiority study comparing raltegravir to efavirenz (each with tenofovir plus FTC) in treatment-naïve patients were presented by Jurgen Rockstroh.

The study design, matched baseline characteristics and safety and efficacy results from earlier analyses have already been presented at earlier meetings. The new subgroup analyses (including baseline CD4 <200 copies/mm3, viral load >100,000 copies/mL, hepatitis and demographic responses) focused on virological efficacy with discontinuations related to viral failure included but discontinuations for other reasons excluded and using an observed failure approach.

From approximately 280 patients in each arm at baseline, 223 (79%) and 197 (70%) completed the 192 week analysis, in the raltegravir and efavirenz arms respectively. Discontinuations were all less frequent in the raltegravir arm: virological failure (n=5 vs 8); side effects (n=13 vs 26); and loss to follow-up (n=8 vs 17)

At 192 weeks, the primary analysis of viral suppression to <50 copies/mL (non-completer=failure) saw raltegravir achieve statistical superiority compared to efavirenz [76% vs 67% (difference = +9.0; 95%CI 1.6, 16.4, p < 0.001: with the lower limit for non-inferiority set at –12% and superiority being achieved when both confidence intervals became greater than 1.0].

CD4 increases were + 60 cells/mm3 higher in the raltegravir arm (95%CI 24, 95).

Overall clinical events (96% vs 98%, p = 0.16), discontinuations due to drug-related events (5% vs 8%, p = 0.173) and serious adverse events (18% in each arm, p = 0.91) were similar between the two study groups, raltegravir was associated with significantly fewer drug-related events (50% vs 80%, p < 0.001).

There were no statistically significant differences in response between groups by gender, age, race/ethnicity, viral load >100,000 c/mL, CD4 > 200 cells/mm3, hepatitis coinfection or HIV sub-type. Raltegravir showed a significantly stronger virological response in the <100,000 c/mL group (93% vs 81%; difference +12; 95% CI 3, 22). Interpretation of a difference in favour of raltegravir when baseline CD4 was 50-<200 cells/mm3 is complicated by a trend to favour efairenz when CD4 counts were <50 cells/mm3.

comment

These results support durability and safety of raltegravir. they also show that after week 192 raltegravir achieves superiority compared to efavirenz with the difference largely driven by efavirenz-related side effects.

The CD4 difference may also be important for patients with sub-optimal CD4 responses on other HAART combinations.

Reference:

Rockstroh JK et al. Long-term efficacy of raltegravir or efavirenz combined with TDF/FTC in treatment-naïve HIV-1-infected patients: week-192 subgroup analyses from STARTMRK. 13th EACS, 12–15 October 2011, Belgrade. Abstract PS 1/1.

Several studies looked at the association between older age and antiretroviral pharmacokinetics (PK).

Tenofovir

Muge Cevik from the Chelsea and Westminster Hospital London reported results from a PK study suggesting that tenofovir clearance is significantly reduced with increasing age and resulting in higher drug levels (AUC and Ctrough). [1]

This included steady-state plasma levels from 52 men and 2 women (12 of whom were on PI/r-based combinations). Median age was 54 years (range 40–81 years) with only two people younger than 50. Samples were drawn randomly and population pharmacokinetics applied to predict values.

Tenofovir median clearance (CL/F), AUC (24hr) and Ctrough (C24) were 110.0 L/r (27.4–248.3). 2.2 mg.hr/L (1.0–9.0), and 0.06 mg/L (0.01–0.3) respectively.

Increasing age was significantly associated with slower clearance (p=0.0012), higher AUC (p=0.0012) and higher Ctrough (p=0.0017). People older than 60 had significantly lower clearances (p=0.0447) and higher AUC (p=0.0457) than those younger than 60.

No PK differences were seen between PI and NNRTI based combinations (p=0.08).

Efavirenz and darunavir/ritonavir

A similar analysis was presented by Ahmed and colleagues from the same group at Chelsea and Westminster on the PK of efavirenz or darunavir/ritonavir used by older patients (median age was 54 years (range 27-77) and 56 years (28-76), respectively). [2]

In 70 men and 7 women taking efavirenz, no differences were seen in any PK parameter when comparisons were made between people older and younger than 50 (all p-values >0.05 for between age comparisons).

In 33 men and one woman taking darunavir/ritonavir (23 using once-daily) oral clearance was significantly lower in people over 50 years old (10.3 vs 13.0 L/h; p=0.027) with higher AUC (80.9 vs 61.6 mg.h/L; p=0.021) and Ctrough levels (1.9 vs 1.2 mg/L; p=0.008) than those younger than 50.

Once-daily vs twice-daily could not be assessed because of unequal age distribution between the two dosing regimens.

References:

1. Cevik M et al. Tenofovir (TFV) pharmacokinetics (PK) in HIV infected individuals over 40 years of age. 13th EACS, 12–15 October 2011, Belgrade. Abstract PS 6/1.
2. Ahmed A et al. Efavirenz and Darunavir Plasma Concentrations in HIV-infected Patients Aged 50 Years or over. 13th EACS, 12–15 October 2011, Belgrade. Abstract PE6.2/1.

Researchers at Makerere University, Kampala and the pharmocology group at Liverpool University reported a significant interaction between high fat meals and ritonavir as a booster in lopinavir/r (Kaletra).

Three meal conditions were studied in an open-label, three part, cross over study in 12 HIV positive people (6 men, 6 women) using lopinavir/r (2 x 400/100 mg tablets) as second-line therapy. Median (IQR) age and weight of patients was 48 (44 – 49) years and 62 (59-68) kgs.

Intensive PK sampling after a moderate (20 g fat) and high (36 g) fat meal (on Day 1 and 8 respectively) were compared to fasted state on Day 15.

Compared to the fasting, administration with a high fat meal resulted in 29% lower ritonavir AUC (geometric mean ratio 0.71; 90%CI 0.61-0.84) and 29% lower Cmax (GM 0.71; 90%CI 0.60-0.84) while C12 increased non-significantly by 12% (GM 1.12 (90%CI 0.94-1.33).

Reference:

Lamorde M et al. – Steady-state exposure of ritonavir is reduced by a high fat meal in Ugandan patients receiving lopinavir plus ritonavir co-formulated tablets. 13th EACS, 12–15 October 2011, Belgrade. Abstract PE6.6/1 (BPD1/1).

Preterm birth is common in infants born to HIV positive mothers and is associated with an increased risk of mother to child transmission. Oral drug absorption in infants is unpredictable due to the immaturity of the gastro intestinal tract at this age. Preloading the foetus with maternal nevirapine (NVP) is common in these cases.

Raltegravir (RAL) is pregnancy category C and data to guide its use in pregnancy are limited. However, it has been used to achieve a rapid reduction in viral load before delivery, for preloading the foetus where poor oral absorption is anticipated and in cases where there is resistance or intolerance to other antiretrovirals.

RAL is absorbed rapidly (with a T max of about three hours) it takes two days to reach steady state concentrations and has an elimination terminal half-life of 9 hours. It uses the UGT 1A1 metabolic pathway. About half of the oral dose is excreted unchanged in the stool and 30% in the urine (about a third of which is as unchanged RAL and the remainder as the metabolite). There is considerable inter patient variability in its metabolism.

In an oral presentation, Aseel Hegazi from St Georges University Hospital, London showed three maternal infant case studies in which pregnant mothers of preterm neonates received RAL as part of their prevention of mother to child transmission (PMTCT) regimens. [1] The investigators looked at transplacental transfer of the drug and plasma clearance in the infants.

The same group has previously described the use of RAL in PMTCT regimens in mothers of three term infants. In these cases they found good transplacental transfer with higher concentrations in the infants than the mothers approximately three hours after delivery. [2] They also reported persistence of neonatal concentrations at three days (although below the therapeutic range). They suggested that poor neonatal and foetal maturity of the UGT-dependent pathways could account for this. And that it is possible that increased activity of UGT1A1, associated with progesterone, observed in pregnant women contributed to the disparity.

In the three cases of RAL use in preterm delivery, paired blood samples were taken as close as possible to delivery and then post partum. Maternal and neonatal RAL plasma concentrations were measured using liquid chromatography and mass spectrometry. Table 1 summarises these cases.

Dr Hegazi concluded that therapeutic RAL plasma concentrations (> 15ng/mL) might be persistent for up to five days in preterm neonates. She noted that this is longer than that observed in term infants and is probably linked to immature UGT1A1 mediated gluronidation. She suggested that maternal RAL preloading might be a good alternative to NVP where oral absorption is unreliable (particularly with preterm infants) and maternal options are limited

comment

These case studies are interesting and this use of RAL could prove important. RAL used this way is likely to be mentioned in the next BHIVA guidelines (although data is very sparse so evidence will be weak).

IMPAACT 1097 is a washout (passive) PK and safety study designed to investigate this phenomenon in neontates. It is the first clinical trial of an investigational drug to look at neonatal PK. It is recruiting mothers already receiving RAL in pregnancy and the infants will be sampled at intervals up to 30 to 36 hours after dosing.

After a review of PK and safety data from this and IMPAACT1060 – which is investigating this drug in children in de-escalated age bands with those below two years, receiving a granule formulation, now being studied – the company is planning a study of infants born to HIV positive mothers from immediately after birth until their status has been confirmed.

References:

1. Hegazi A et al. Raltegravir in the prevention of mother to child transmission of HIV: effective transplacental transfer and delayed plasma clearance observed in preterm neonates. 13th EACS, 12–15 October 2011, Belgrade. Oral abstract PS 6/7.
2. Mckeown D A et al. High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive pregnant women AIDS. 24 September 2010. Volume 24. Issue 15. p 2416–2418.

Unfortunately the conference restricts public access to this research. Although abstracts available online (for a short time) the database to access abstracts is not very user friendly and the long URLs often change, making referencing problematic.

Also, few, if any studies are supported by webcasts or the option to view slides or full PDF posters.

The following studies are largely thanks to natap.org.

• Monitoring kidney function change with cobicistat
• Intracellular raltegravir concentrations better with twice-daily than once-daily dosing

Cobicistat is a pharmacokinetic (PK) booster currently in phase 3 studies that unlike ritonavir has no direct antiretroviral activity. This Gilead booster might facilitate a wider range of coformulated boosted medicines: with elvitegravir and Quad (boosted elvitegravir plus Truvada) and with products developed by other companies (darunavir and atazanavir).

An early caution is that cobicistat produces significant reductions in estimated glomerular filtration rate (eGFR). These do not indicate clinically significant changes but will pose a problem for interpretation of routine monitoring tests where clinical changes in eGFR are a concern.

If average actual GFR (aGFR) is used to monitor cobicistat, determined by iohexol clearance (a probe drug excreted almost exclusively by glomerular filtration), no changes are observed.

At ICAAC, Gilead researchers presented results from a placebo controlled study in 36 HIV negative participants with normal renal function (eGFR >80 mL/min) and 18 HV negative participants with mildly impaired renal function (eGFR 50-79 mL/min).

Participants with normal function were randomised (12 per group) to one of three groups: 150 mg cobicistat + placebo; 100 mg ritonavir + placebo; or double placebo for 7 days, with both eGFR and aGFR measured at baseline, day 7 and day 14 (following a 7 day washout). All participants with reduced renal function took cobicistat for seven days with similar monitoring.

Independent of baseline eGFR, volunteers taking cobicistat experienced significant average reductions in eGFR by day seven which resolved seven days after discontinuation, with but showed no significant changes in aGFR (see Table 1). Similar changes were seen using either Cockcroft-Gault or MDRD to calculate eGFR. Participants taking ritonavir or placebo showed no significant changes in either measure.

The researchers interpret these findings to show that true GFR is not affected by cobicistat which affects proximal tubular secretion of creatinine.

While these results are reassuring in terms of clinical impact of cobicistat it is unclear how patients using other medications that affect eGFR would be managed in order not to misinterpret a genuine impact on real GFR.

Source: Mascolini M. Kidney Function Change With Cobicistat Calculated in HIV-Negative Volunteers. NATAP.org
http://www.natap.org/2011/ICAAC/ICAAC_66.htm

Reference:

German P et al. Effect of cobicistat on glomerular filtration rate (GFR) in subjects with normal and impaired renal function. 51st ICAAC, 17-20 September 2011, Chicago. Abstract H2-804.

Intracellular concentrations of raltegravir stayed above the 95% effective concentration (EC95) in higher proportions of people taking this integrase inhibitor twice daily than in those taking it once daily, according to results of a 13-person study [1]. The average intracellular-to-plasma ratio was 0.37.

Raltegravir is licensed for adults at a dose of 400 mg twice daily with or without food. A randomised trial of twice- versus once-daily raltegravir for antiretroviral-naive people found that 318 of 382 (83%) in the once-daily group versus 343 of 386 (89%) in the twice-daily group had a viral load below 50 copies/mL after 48 weeks, a significant difference (-5.7%, 95% confidence interval -10.7 to -0.83, P = 0.044) [2]. The investigators concluded that “despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing.”

The study of plasma and intracellular raltegravir concentrations involved 12 people taking 400 mg of raltegravir twice daily and 1 taking 800 mg once daily for more than 1 week [1]. People on the twice-daily dose who had a viral load below 50 copies were offered a switch to once-daily dosing for at least 3 days so the investigators could assess raltegravir after once-daily dosing. Six people agreed.

In the twice-daily group, the researchers collected 26 paired samples of plasma and peripheral blood mononuclear cells (PBMCs) 2, 4 or 6, and 12 hours after dosing. In the once-daily group they collected 12 paired samples over the 24-hour dosing interval. Among people taking raltegravir twice daily, 3 had a detectable viral load; 2 of these were considered blips, and one load of 2649 copies came during the first 6 weeks of treatment.

No one taking raltegravir twice daily had a plasma trough concentration below the EC95 (14 ng/mL). Three of 12 had an intracellular trough below the EC95, at 7, 11.1, and 13.3 ng/mL.

Two of 6 people taking raltegravir once daily had a plasma trough below the EC95, at 7 and 13.8 ng/mL. Three of these 6 had an intracellular trough below the EC95, at 1.56, 4.06, and 6.56 ng/mL.

The mean ratio of intracellular-to-plasma concentrations was 0.37 and did not change over time. The ratio was higher than reported previously, probably because cell-wash steps in older methods flushed out some intracellular drug.

The researchers proposed that the high plasma and intracellular troughs with twice-daily raltegravir “may contribute to the efficacy observed with this regimen.”

UK researchers just published results of a 24-person study comparing plasma and intracellular raltegravir concentrations with once- and twice-daily dosing, with or without darunavir/ritonavir [3]. Study participants were taking 400 mg of raltegravir twice daily for at least 21 days. They added 800/100 mg of darunavir/ritonavir once daily for 14 days. During that 14-day period, people were randomised to continue twice-daily raltegravir (group 1) or to switch to 800 mg once daily (group 2).

Geometric mean ratios (and 90% confidence intervals) of raltegravir area under the concentration-time curve without and with darunavir/ritonavir for group 1 were 0.90 (0.73 to 1.44) in plasma and 1.02 (0.81 to 1.67) in cells and for group 2 were 1.21 (1.03 to 1.77) in plasma and 1.27 (1.07 to 1.94) in cells. These researchers concluded that “no remarkable interactions between darunavir/ritonavir and raltegravir in plasma or cells were seen.”

References

1. Sandkovsky US, Swindells S, Robbins BL, Nelson SR, Acosta EP, Fletcher CV. Measurement Of plasma and intracellular concentrations of raltegravir in patients with HIV infection. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract A1-1738b.
2. Eron JJ Jr, Rockstroh JK, Reynes J, et al. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect Dis. 2011 Sep 19.
   http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(11)70196-7/fulltext
3. Jackson A, Watson V, Back D, et al. Plasma and intracellular pharmacokinetics of darunavir/ritonavir once daily and raltegravir once and twice daily in HIV-infected individuals. J Acquir Immune Defic Syndr. 2011 Sep 15. Epub ahead of print.
   http://www.ncbi.nlm.nih.gov/pubmed/21926632

An oral powder (40 mg per 1 gram of oral powder) formulation and 150 mg, 200 mg and 250 mg tablets were also approved to support dosing in paediatric patients.

The major changes to the product labeling include information on dosing plus efficacy and safety concerns based on clinical studies.

These include:

Dosing

• Recommended dose in paediatric patients 2 years of age and older is 8 mg of tenofovir DF per kilogram of body weight (up to a maximum of 300 mg) once daily administered as oral powder or tablets. Tables 1 and 2 of the product labeling contain dosing recommendations for tenofovir oral powder and tablets based on body weight. Weight should be monitored periodically and the tenofovir dose adjusted accordingly.
• Tenofovir oral powder should be measured only with the supplied dosing scoop. One level scoop delivers 1 g of powder, which contains 40 mg of tenofovir DF. Tenofovir oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g. applesauce, baby food, yogurt). The entire mixture should be ingested immediately to avoid a bitter taste. Do not administer tenofovir oral powder in a liquid as the powder may float on top of the liquid even after stirring. Further patient instructions on how to administer tenofovir oral powder with the supplied dosing scoop are provided in the FDA-approved patient labeling.
• Tenofovir is also available as tablets in 150, 200, 250 and 300 mg strengths for paediatric patients who weigh >/=17 kg and who are able to reliably swallow intact tablets. The dose is one tablet once daily taken orally, without regard to food.
• There are no data to recommend use of tenofovir tablets 150, 200 or 250 mg or tenofovir oral powder in patients with renal impairment.

Safety and Efficacy

The safety and efficacy data of tenofovir in paediatric patients is supported by data from two randomised trials (Studies 352 and 321). This involved only 184 treatment-experienced children (aged 2 to <18 years), only half of who received tenofovir and half received d4T or AZT. Tenofovir was later provided to these children.

Bone Mineral Density (BMD)

Bone effects were similar to those observed in adult subjects. Under normal circumstances BMD increases rapidly in paediatric patients. In Study 352 (2 to less than 12 years), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the tenofovir and the d4T or AZT treatment groups. Total body BMD gain was less in the tenofovir compared to the d4T or AZT treatment group. One tenofovir-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z-scores were -0.012 for lumbar spine and -0.338 for total body in the 64 subjects who were treated with tenofovir for 96 weeks. In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the tenofovir compared to the placebo treatment group. Six tenofovir treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were -0.341 for lumbar spine and -0.458 for total body in the 28 subjects who were treated with tenofovir for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected. Markers of bone turnover in tenofovir-treated paediatric subjects suggest increased bone turnover, consistent with the effects observed in adults.

Eighty-nine paediatric subjects received tenofovir in Study 352 (48 who were initially randomised to tenofovir and 41 who were initially randomised to continue stavudine or zidovudine and then received tenofovir in the extension phase) for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these four subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score.

For full details please refer to the new label:

http://www.accessdata.fda.gov/scripts/cder/drugsatfda

In addition a 100 mg scored chewable tablet and 25 mg chewable tablet was approved for use in paediatric patients.

Safety, efficacy and formulation data were from the IMPAACT P1066 Phase I/II study in 126 treatment experienced children (age 2 to 18 years) who received either the 400 mg film-coated tablet formulation (6 to 18 years of age) or the chewable tablet formulation (2 to less than 12 years of age). Raltegravir was administered with an optimised background regimen.

The Dosage and Administration section includes the following dosing recommendations and dosing recommendations for pediatrics. Main changes to the product label are also included below.

General Dosing Recommendation

• Raltegravir Film-Coated Tablets and Chewable Tablets can be administered with or without food
• Maximum dose of chewable tablets is 300 mg twice daily.
• Raltegravir Chewable Tablets may be chewed or swallowed whole.
• Raltegravir Film-Coated Tablets must be swallowed whole.
• Because the formulations are not bioequivalent, the chewable tablets should NOT be substituted for the 400 mg film-coated tablet.
• During coadministration of raltegravir 400 mg film-coated tablets with rifampin, the recommended dosage of raltegravir is 800 mg twice daily in adults. There are no data to guide co-administration of raltegravir with rifampin in patients below 18 years of age. All interaction studies were performed in adults

Paediatric Dosing

Dosing is recommended based on age and weight:

• 12 years of age and older:
  • One 400 mg film-coated tablet orally, twice daily
• 6 to less than 12 years of age:
  • If at least 25 kg in weight:
    • One 400 mg film-coated tablet orally, twice daily OR
    • Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1 – please refer to prescribing information for details.
  • If less than 25 kg in weight:
    • Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1 – Please refer to prescribing information for details.
• 2 to less than 6 years of age:
  • If at least 10 kg in weight:
    • Chewable tablets: weight based to maximum dose 300 mg, twice daily as specified in Table 1 – Please refer to prescribing information for details.

Warnings and Precautions

Raltegravir chewable tablets contain phenylalanine, a component of aspartame. Each 25 mg raltegravir chewable tablet contains approximately 0.05 mg phenylalanine. Each 100 mg raltegravir chewable tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.

Adverse Reactions

In the IMPAACT P1066, frequency, type and severity of drug related adverse reactions through week 24 were comparable to those observed in adults.

One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behavior and insomnia; one patient experienced a Grade 2 serious drug related allergic rash.

One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious.

The following information was added to Section 12.3 Pharmacokinetics:

• Under Absorption: Based on a formulation comparison study in healthy adult volunteers, the chewable tablet has higher oral bioavailability than the film-coated tablet
• Under Effect of Food on Oral Absorption: Administration of chewable tablet with high fat meal led to an average 6% decrease in AUC, 62% decrease in Cmax and 188% increase in C12hr compared to administration in the fasted state. Administration of the chewable tablet with a high fat meal does not affect raltegravir pharmacokinetics to a clinically meaningful degree and the chewable tablet can be administered without regard to food
• Special Populations: The doses recommended for HIV-infected children and adolescents 2 to 18 years of age resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily. A Table was added to the package insert to display the raltegravir steady state pharmacokinetic parameters in paediatric patients.

Clinical Studies

The median age of the 96 study participants in IMPAACT P106 receiving the recommended raltegravir dose was 13 (range 2 to 18) years, 51% female, 34% Caucasian, and 59% Black. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL, median CD4 cell count was 481 cells/mm3 (range: 0 – 2361) and median CD4% was 23.3% (range: 0 – 44). Overall, 8% had baseline plasma HIV-1 RNA >100,000 copies/mL and 59% had a CDC HIV clinical classification of category B or C. Most subjects had previously used at least one NNRTI (78%) or one PI (83%).

Ninety-three (97%) subjects completed 24 weeks of treatment (3 discontinued due to non-compliance). At Week 24, 54% achieved HIV RNA <50 copies/mL; 72% achieved HIV RNA <400 copies/mL or =1 log10 HIV RNA drop from baseline. The mean CD4 count (percent) increase from baseline to Week 24 was 119 cells/mm3 (3.8%).

Source: FDA HIV/AIDS Update (21 December 2011).

For full details please refer to the updated prescribing information:

http://dailymed.nlm.nih.gov/dailymed/about.cfm

Additionally, the product labeling was updated to provide dosing recommendations for paediatric patients ages 3 to less than 6 years of age and for adult and paediatric patients greater than 6 years of age who can not swallow darunavir tablets.

Treatment-naïve adults and treatment experienced adults with no darunavir resistance associated substitutions can take darunavir 8 ml once daily with 1.25 ml of ritonavir once daily with food. The 8 mL dose should be taken as two 4 mL administrations with the included oral dosing syringe.

For treatment-experienced adults with at least one darunavir resistance associated substitution the dose for oral suspension is 6 mL twice daily with 1.25 mL ritonavir twice daily with food.

For paediatric patients, dosing with oral suspension or tablets is based on weight. Please refer to full prescribing information for details. Do not use darunavir/ritonavir in paediatric patients below 3 years of age.

Section 6 Adverse Reactions (ADRs) was updated as follows:

• ADRs to darunavir/ritonavir (all grades, >/= 3%), excluding lab abnormalities, were diarrhea (19%), vomiting (14%), rash (10%).
• There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this study.

Section 14: Clinical Studies was updated to reflect the results from the paediatric trial as follows:

Study TMC114-C228

Treatment-experienced paediatric subjects between the ages of 3 and less than 6 years and weighing greater than or equal to 10 kg to less than 20 kg received darunavir oral suspension with ritonavir oral solution plus background therapy consisting of at least two active non-protease inhibitor antiretroviral drugs. Twenty-one subjects received at least one dose of darunavir/ritonavir.

The 21 subjects had a median age of 4.4 years (range 3 to less than 6 years), and were 48% male, 57% Black, 29%, Caucasian and 14% other. The mean baseline plasma HIV-1 was 4.34 log10 copies/mL, the median baseline CD4+ cell count was 927 x 106 cells/l (range: 209 to 2,429 x 106 cells/l) and the median baseline CD4+ percentage was 27.7% (range: 15.6% to 51.1%). Overall, 24% of subjects had a baseline plasma HIV-1 RNA greater than or equal to 100,000 copies/mL. All subjects had used greater than or equal to 2 nucleoside reverse transcriptase inhibitors (NRTIs), 62% of subjects had used greater than or equal to 1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and 76% had previously used at least one HIV protease inhibitor (PI).

Twenty subjects (95%) completed the 24 week period. One subject prematurely discontinued treatment due to vomiting assessed as related to ritonavir.

The proportion of subjects with HIV-1 RNA less than 50 copies/mL and less than 400 copies/mL was -57% and 81%, respectively. The mean change in CD4+ percentage from baseline was 4%. The mean change in CD4+ cell count from baseline was 109 x 106 cells/L.

Dose recommendations from the two studies were based on the following:

• Similar darunavir plasma exposures in children compared to adults, and
• Similar virologic response rates and safety profile in children compared to adults

Source: FDA HIV/AIDS Update (16 December 2011).

For full details please refer to the updated prescribing information:

http://dailymed.nlm.nih.gov/dailymed/about.cfm

If Sustiva is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of Sustiva to 800 mg once daily is recommended.

The recommendation to increase the dose of efavirenz to 800 mg in patients weighing 50 kg or more when efavirenz is co-administered with rifampin is based on empirical data from two drug-drug interaction trials (one trial in healthy volunteers and one trial in HIV-1 infected patients) and semi-mechanistic population pharmacokinetic modeling. The population pharmacokinetic model was constructed using data collected in the drug-drug interaction trials and single-and multiple dose pharmacokinetic data of efavirenz from other healthy volunteer trials.

The data from the drug-drug interaction trials showed that rifampin decreased the exposure of efavirenz 600 mg once daily. Further, the systemic exposure of efavirenz, when efavirenz 800 mg was coadministered with rifampin, was similar to the systemic exposure of efavirenz when efavirenz 600 mg once daily was given alone. The results from the population pharmacokinetic analysis were consistent with the empirical data.

Source: FDA HIV/AIDS Update (06 January 2012).

For full details please refer to the updated prescribing information:

http://dailymed.nlm.nih.gov/dailymed/about.cfm

In addition, section 5.3 Severe Skin Reactions now includes the following text about combinations that include darunavir/ritonavir plus raltegravir:

Rash occurred more commonly in treatment-experienced subjects receiving regimens containing darunavir/ritonavir + raltegravir compared to subjects receiving darunavir /ritonavir without raltegravir or raltegravir without darunavir /ritonavir. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

Source:

FDA HIV/AIDS Update – Prezista label update includes 192-week safety, resistance and efficacy data (21 October 2011).

New label and supporting information

Postmarketing reports have included cases of severe, potentially life-threatening, and fatal skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterised by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure.

Patients should be advised to immediately contact their healthcare provider if they develop rash. They should discontinue raltegravir (with medical supervision) and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema).

Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping raltegravir treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Cerebellar ataxia and drug rash with eosinophilia and systemic symptoms have been added as side effects.

Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be ordered and appropriate therapy will be initiated.

Source: FDA HIV/AIDS Update – Isentress (raltegravir) package insert updated, (02 November 2011).

An article published online ahead of print in JAIDS, November 2011, shows findings from a pharmacokinetic (PK) study to evaluate a lower dose of lopinavir/ritonavir (LPV/r) than that currently approved.

Reshmie A Ramautarsing and HIV-NAT colleagues from Thailand and the Netherlands performed a two-arm crossover study including 20 HIV-positive Thai patients. Participants receiving a PI-containing regimen (virlogically suppressed <50 copies/mL for at least 4 weeks at enrollment) were randomised receive branded or generic LPV/r dosed at 200/50mg twice daily, in addition to an NRTI backbone.

Due to a compulsory license, Abbott only markets the paediatric formulation (100/25 mg) of LPV/r in Thailand. The Indian generic company, Matrix, has developed a 200/50 mg tablet formulation of LPV/r, which is currently used at the standard dose (400/100 mg twice daily).

Following sampling for PK analysis at week 2, all participants crossed over from their initial study arm to the other. A second sampling was performed at week 4. Participants continued with their study regimen until week 12, when they resumed their pre-study regimen.

There were 10 participants in each arm with a median age, weight and CD4 count of 38.6 (IQR 34.4 – 47.5) years, 59.8 (52.9 – 62.0) kg and 578 (476 – 795) cells/mm3, respectively. The majority (n=17) received standard dose LPV/r and the remainder saquinavir containing regimens prior to the study. None were lost or discontinued their medication during follow up.

The investigators reported comparable bioequivalence for the generic and branded formulations, with point estimates and 90% CI of the geometric mean ratios of 1.00 (0.92-1.09), 1.01(0.90-1.07) and 0.87 (0.76-1.31) for the AUC0-12, Cmax and Ctrough respectively.

Overall 10/40 (25%) samples had subtherapeutic (<1.0 mg/L) plasma concentrations of LPV. These were detected in 8 patients: 2 had subtherapeutic levels measured with both branded and generic formulations, 4 with branded and 2 generic. The lowest concentration was 0.25 mg/L. The investigators noted that all participants reported >90% rates of adherence and 7/8 reported 100% at the time that subtherapeutic plasma concentrations were found.

A comparison of PK parameters for different doses and formulations of LPV/r, using historical data from the same research group, revealed decreased concentrations at lower doses. When compared to LPV/r soft gel capsule (SGC) 400/100 mg twice daily, a dose of LPV/r SGC 266/66 twice daily resulted in 44.1%, 36.0% and 49.1% decreases in LPV concentrations for AUC0-12, Cmax and Ctrough respectively. Using LPV/r generic tablets 200/50mg twice daily decreased the same parameters by 63.5%, 56.6% and 70.2% respectively.

At week 12 all participants remained virologically supressed <50 copies/mL.

The researchers noted that LPV plasma concentrations are dependent on the RTV dose to a greater extent than some other PIs and in this study they had reduced both the LPV and RTV dose, which may explain the subtherapeutic LPV concentrations. They wrote that other dose reduction studies suggest that 200 mg of LPV is sufficient if there is a sufficient boosting dose of RTV (100 mg).

The researchers also noted that this bio-equivalence analysis of LPV/r, although not using the approved 400/100 mg twice-daily dose, demonstrated that the generic and branded tablets result in comparable PK parameters. They wrote: “These data are particularly important for clinicians working in settings where the branded tablets are not available due to compulsory licensing or cost. The availability of safe and effective generic alternatives to branded second line treatment will play an important role in the scaling up of second line treatment in low- and middle-income countries.”

comment

That the generic and originator products are bioequivalent is important.

Previous PK trials have shown that the dose of ritonavir affects LPV levels. In the first dose-ranging trial by Abbott, the dose with the best efficacy and safety profile was 200/100 mg twice daily. If we had 50 mg ritonavir tablets (see below), we could get back to this dose and it may be worth doing more studies.

However, the WHO and Clinton Foundation are more interested in ATV/r and DRV/r, which showed better efficacy and safety profiles than LPV/r (in the CASTLE and ARTEMIS trials, respectively).

Reference:

Ramautarsing RA et al. Neither branded nor generic lopinavir/ritonavir produces adequate lopinavir concentrations at a reduced dose of 200/50mg BID. J Aquir Immune Defic Syndr. Publish ahead of print. DOI: 10.1097/QAI.0b013e3182ba736.

Although not appropriate for LPV (see previous article), a 50mg boosting dose of RTV may be sufficient for selected PIs, argue researchers from the University of Liverpool and Chelsea and Westminster in a letter to the editor published in the December 15 2011 edition of JAIDS.

Lower doses of RTV may be better tolerated, cheaper and easier to co-formulate with PIs than the current dose.

Andrew Hill and colleagues identified four crossover PK studies evaluating 50 vs 100mg of RTV. These included boosting once daily atazanavir (ATV), 300/50 vs 300/100mg and once daily darunavir (DRV) 800/50 vs 800/100mg. The other two studies indentified by the researchers were with saquinavir and amprenavir, which are less commonly used PIs and not preferred options, particularly in resource-limited settings.

These small PK studies – conducted with 13 and 18 participants for ATV and DRV respectively – showed bioequivalent AUC and Cmax concentrations of both drugs using the lower and higher RTV doses. But Cmin concentrations were slightly lower when boosted with the 50 mg dose of RTV. See Table 1: PK parameters of ATV and DRV boosted with 50 and 100mg of RTV.

Mean PKs of boosted PI (SD)

The researchers explained that the clinical significance of the lower Cmin levels was not known and this would need to be investigated in larger studies including efficacy endpoints. They added that small differences in RTV boosting doses might have different consequences in treatment naïve and experienced patients.

They noted that as RTV is only marketed as a 100 mg tablet, these studies were conducted using the liquid formulation. If a 50mg heat stable tablet of RTV could be manufactured or 50 mg coformulated with either PI, new bioequivalence trials would be needed to ensure the boosting effects were similar to those achieved with the liquid.

A 50mg RTV tablet would also be very useful for paediatric dosing, as the liquid is expensive, impractical (particularly for resource limited settings) and tastes dreadful.

They concluded that if lower doses of RTV are able to achieve bioequivalence there is a strong justification for the development of a 50mg tablet and/or coformulations of RTV with these PIs.

comment

Once again, the 50 mg RTV tablet really would be useful in paediatrics.

The generic companies should be able to make 50 mg tablets and get approval by showing that 2 x 50 mg tablets are bioequivalent to an Abbott 100 mg tablet.

Reference:

Hill A et al. Should we switch to a 50mg boosting dose of ritonavir for selected protease inhibitors? J Acquir Immune Defic Syndr. Volume 58. Number 5. December 15, 2011.
http://journals.lww.com/jaids/Citation/2011/12150/Should_We_Switch_to_a_50_mg_Boosting_Dose_of.18.aspx

The last two months have been a lively time for pharmaceutical industry announcements concerning Fixed Dose Combinations (FDCs) and new compounds in the HIV and hepatitis pipelines.

Integrase FDC Quad submitted to the FDA

At the end of October, Gilead submitted a new drug application (NDA) to the US regulatory agency (FDA) for its four-drug formulation of elvitegravir, cobicistat, tenofovir and FTC (Quad). This is based on 48-week data from two Phase 3 studies.

Three weeks later Quad was also filed with the European Medicines Agency (EMA).

If these applications are given a fast track review a decision will be made by both agencies within six months.

Reference: Gilead press release: Gilead Submits New Drug Application to U.S. FDA for Once-Daily, Single-Tablet ‘Quad’ HIV Regimen (27 October 2011).

Planned co-formulations of cobicistat with atazanavir, darunavir and darunavir/FTC/GS7340

On 26 October, Bristol-Myers Squibb (BMS) announced that it has entered an agreement to develop and market an FDC of its protease inhibitor atazanavir (Reyataz) with a pharmacokinetic booster cobicistat, currently in development with Gilead. [1]

Phase 2 and 3 studies of atazanavir using cobicistat boosting are ongoing in treatment-naïve patients.

Cobicistat has a similar inhibitory impact on cytochrome P450 3A (CYP3A) and similar side effect profile to ritonavir.

Earlier this year a similar agreement was reached between Gilead and Tibotect to produce an FDC of darunavir with cobicistat. [2]

The press release also referred a further collaborate to produce an FDC of darunavir plus FTC together with cobicistat plus the new tenofovir prodrug (GS7340).

Reference:

1. Press release: Bristol-Myers Squibb and Gilead Sciences announce licensing agreement for development and commercialisation of new Fixed Dose Combination pill for People Living with HIV. (26 October 2011).
2. Press release: Gilead Sciences announces agreement with tibotec Pharmaceuticals to develop and commercialise a new fixed-dose combination of cobicistat and darunavir (Prezista). (28 June 2011).

Gilead license integrase inhibitor compounds from Boehringer Ingelheim

Gilead acquired a license for exclusive worldwide rights for the research, development and commercialisation of its novel non-catalytic site integrase inhibitors (NCINIs) for HIV. This includes the lead compound BI 224436, which has been evaluated in a Phase 1a dose-escalation study to assess bioavailability and pharmacokinetics in healthy volunteers.

NCINIs inhibit HIV integrase by binding to a novel site, distinct from the catalytic site used by the current class of integrase inhibitors, and therefore may possess a differentiated resistance profile from raltegravir or elvitegravir.

Reference:
Press statement: Gilead and Boehringer Ingelheim Sign License Agreement for Novel HIV Non-Catalytic Integrase Inhibitors. (05 October 2011).

Gilead spends $11 billion to buy Pharmasset

Finally, on 21 November 2011, Gilead announced that it would acquire Pharmasset for the not insignificant cost of $11 billion from ‘cash on hand, bank debt and senior unsecured notes’.

Pharmasset currently has three clinical-stage product candidates for the treatment of chronic hepatitis C virus (HCV) advancing in trials in various populations.

• The lead product compound, PSI-7977, an unpartnered uracil nucleotide analogue, has recently been advanced into two Phase 3 studies in genotype 2 and 3 patients. Both studies use 12 weeks of treatment with PSI-7977 in combination with ribavirin. Comparitor arms include pegylated : ‘interferon/ribavirin in treatment-naïve patients, and placebo in interferon- intolerant/ineligible patients. A third Phase 3 study in genotype 1 patients will be initiated in the second half of 2012.
• PSI-938, an unpartnered guanosine nucleotide analogue, is being tested in a Phase 2b interferon-free trial as monotherapy and in combination with PSI-7977 in subjects with HCV of all viral genotypes.
• Mericitabine (RG7128), a cytidine nucleoside analogue, is partnered with Roche and is being evaluated in three Phase 2b trials. Roche is responsible for all aspects of the development of mericitabine.

Reference:
Press statement: ‘Gilead Sciences to acquire Parmasset Inc for $11 billion’. (21 November 2011).

Abbott to separate treatment from medicinal products in company split

Abbott, the research-based company responsible for developing lopinavir/ritonavir (Kaletra) and ritonavir (Norvir) which has a annual revenue close to $18 billion dollars announced that it plans to divide into two separate companies: one focused on research and treatment and the other on diversified medical products.

The press statement listed immunology, Multiple Sclerosis, chronic kidney disease, Hepatitis C, women’s health and oncology, but not HIV, as future research priorities.

Reference:
Press statement: ‘Abbott to Separate into Two Leading Companies in Diversified Medical Products and Research-Based Pharmaceuticals’. (19 October 2011).

The comprehensive 40-page document includes a detailed review of the most important routine monitoring. It is an essential reference for understanding the current recommended minimum standard of care.

These guidelines include suggestions for audited targets and cover each stage of the treatment pathway from initial diagnosis, through to naïve and experienced management, and includes the case of transferred care.

It is also important for highlighting simple and inexpensive aspects of care that are important but if overlooked have the potential to greatly impact on patient quality of life. These include full patient history, psychological assessment (including depression, anxiety and social support), sexual history (including sexual health), support for evaluating adherence, baseline evaluations (including physical examination, waist circumference, blood pressure and BMI). Mental health has a separate consideration.

Recommendations for CD4 and viral load monitoring are similar to earlier guidelines. In naïve patients, as long as CD4 count remains 100 cells higher than the threshold for starting treatment (currently this would be 450), CD4 monitoring should be every 4-6 months, and 3-4 monthly if it falls below this. CD4 count should still be monitored four weeks after starting therapy (with viral load). In people who maintain an undetectable viral load for more than one year and whose CD4 count is greater than 200, CD4 monitoring can be reduced to six-monthly.

Viral load should still be a factor when deciding to initiate HAART, needing at least two results for patients in chronic infection to establish a reliable set point, six monthly thereafter and repeated within one month prior to treatment. Short term efficacy needs to be confirmed by a drop of at least I log, four weeks after starting treatment, and further tests at 3 and 6 months. Undetectable (<40 or <50 copies/mL) should be achieved by 4-6 months. Subsequent monitoring should be 3-4 monthly, and six-monthly viral load can be considered in a strictly adherent patients on stable treatment. Viral rebound to >50 copies/mL needs to be conformed with a new sample.

The cut-off for switching treatment is only briefly mentioned but blips are described as transient increases to between 50 and 1000 copies/mL (subsequent test being < 50 copies/mL) and multiple blips a signal to review drug potency, adherence, tolerability, resistance and potential modifications to the combination.

Resistance testing is still strongly recommended for all newly diagnosed patients and again prior to starting treatment if reinfection is possible, or in patients without results from first diagnosis, at week four of treatment if viral suppression is less than 1 log copies/mL, in all patients with confirmed viraemia (while on the failing combination) recognising that specialised labs are able to work with samples where viral load is ‘just over’ 50 copies/mL.

The guidelines also address laboratory monitoring for renal, hepatic, cardiovascular, bone and biomarkers, other infections including sexual health and for specific patient groups (women, older patients, injecting drug users and late presenters.

References and links:

British HIV Association guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals 2011

BHIVA site link:

http://www.bhiva.org/Monitoring.aspx

HIV Medicine, January 2012 Volume 13, Issue 1 Pages 1-88.

http://onlinelibrary.wiley.com/doi/10.1111/hiv.2011.13.issue-1/issuetoc

The scope of this document includes guidance on the initiation of ART in those previously naïve to therapy, support of patients on treatment, management of patients experiencing virological failure and recommendations in specific patient populations where other factors need to be taken into consideration.

The Treatment Guidelines Writing Group is grateful for all comments, which will be reviewed before publication.

Comments can be made online at the same URL for the draft document:

http://www.bhiva.org/treatmentguidelinesconsultation.aspx

comment

These guidelines have been produced based using a new methodology and grading system compared to earlier documents, and are clearly the result of considerable additional work.

The evidence base is published in a separate 270 page appendix.

Of note, some of the recommendations in the current draft include differences between the BHIVA writing committee and current prescribing by the London consortium.

Readers have until 5 March to comment.

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of HIV-infected pregnant women.

The scope includes guidance on the use of ART therapy both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration such as co infection with other agents.

Comments can be made online at the same URL for the draft document:

http://www.bhiva.org/PregnancyGuidelinesConsultation.aspx

This revision to the guidelines is focused on What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient. Additions and key changes to the section are outlined below. More detailed discussion of the rationale for changes can be found in the updated section. Related tables have also been updated.

In addition to the changes highlighted above, the following tables are updated with information relevant to rilpivirine:

• Tables 14, 15b, and 16b – Drug interaction tables
• Appendix B, Table 2 – Drug characteristic table
• Appendix B, Table 7 – Dosing recommendation for patients with renal or hepatic insufficiency

The DHHS guidelines are online in PDF and html page formats. The PDF file helpful highlight all recent changes in yellow.
http://www.aidsinfo.nih.gov/guidelines/

FDC: Fixed Dose Combination

‘Tentative Approval’ means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, but because of existing patents and/or exclusivity rights, it cannot yet be marketed in the United States. Tentative approval does, however make the product eligible for consideration for purchase under the PEPFAR program for use outside the United States.

Fixed Dose Combinations are reviewed for PEPFAR under the FDA guidance titled ‘Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously approved Antiretrovirals for the Treatment of HIV’. This document was developed to clarify what regulatory requirements apply to such applications, what issues might be of concern, and how these issues should be addressed. The guidance is intended to encourage sponsors to submit applications for combination and co-packaged products, and to facilitate submission of such applications to FDA.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079742.pdf

Effective patent dates are listed in the agency’s publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the Orange Book:

http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm

An updated list of generic tentative approvals (now at 140) is available on the FDA website:

http://www.fda.gov/oia/pepfar.htm

Source: FDA list serve:

http://www.fda.gov/InternationalPrograms/FDABeyondOurBordersForeignOffices/AsiaandAfrica/ucm119231.htm

Some of the first indications that the economic debt crisis in Europe will contribute to 2012 being a disastrous year for global health came in articles from the corporate financial institution Bloomberg Businessweek (not known for it’s focus on HIV news) and the mainstream scientific journal Nature.

This year will not be business as usual for anyone, and those most dependent on international aid are most vulnerable.

The impact of the suspension of Round 11 of Global Fund grants, reported in both this and the previous issue of HTB is causing global concern. The Bloomberg article includes MSF data on 28,000 people in the Democratic Republic of the Congo who will not now be able to start treatment. This seems likely to be an underestimate. Similar reports and concerns – often with a greater human impact – are likely to apply to every country with limited access to HIV treatment.

For example, in a report on the implications of the funding crisis for Malawi, which currently has no funding past 2013, an estimated 200,000 people currently in need of treatment will not be able to access antiretrovirals.

Both reports focus on the impact that unfulfilled pledges from 2008 from leading European countries has had on the Global Fund. According to the Fund’s website, outstanding pledges include $168 million from Italy (from 2009) and $116 million from Spain (from 2010). Five countries – Italy, Spain, Greece, Iceland and Portugal – also made no pledges last year. Holland has cut the proportion of GDP allocated to development assistance from 0.8 to 0.7%. While the US increased funding by 1.6% to $7.6 billion and the UK and Germany (the second and third largest donors after the US) increased pledges by 14%, global donor commitments that had increased to $8.7 billion in 2008, flat-lined in 2009 and dropped by 10% in 2010. The budget available for treatment in the PEPFAR fell by 17% and was accompanied by a shift from adult care exclusively to a mother and child programme. In countries where funding programmes has made treatment is available – and over six million people now access ARVs – it remains largely based on archaic use of d4T (stavudine) despite alternatives such at tenofovir being cost effective. The funding uncertainty will clearly also undermine key WHO recommendations to switch away from use of d4T and earlier treatment using a CD4 threshold of 350 rather than 200 cells/mm3.

Access to treatment has always provided the incentive for people to come forward to test. Whether this was for AZT in 1987 or HAART in 1997 in Western countries or in any of the global access programmes rolled out since 2000. Without the hope of any intervention to improve a person’s individual health it has always been difficult to argue that learning you are HIV positive is going to improve your quality of life. Even with treatment, diagnosis is currently late for the majority of people, when defined as a CD4 count lower than the threshold recommended for starting treatment. But without it, HIV will be driven back underground, testing programmes will falter, and the progress from the last ten years will slowly be lost.

It is spectacularly short sighted for this to be occurring at exactly the time when effective treatment is not only cheaper than every before but also proven to be the most effective method of preventing further transmission.

References:

Bennett S. Financial crisis may kill in Congo as global health aid stalls. Bloomberg Buisnessweek. 17 January 2012

http://www.businessweek.com/news/2012-01-18/financial-crisis-may-kill-in-congo-as-global-health-aid-stalls.html

MSF press statement: DRC: Majority of people living with HIV denied treatment. (25 January 2012).

http://www.doctorswithoutborders.org/press/release.cfm?id=5742&cat=press-release

Farquhar D et al. Breaking promises to the poor: the donor retreat puts Malawi’s AIDS programme in peril (unpub).

Wadman M. Cutbacks threaten HIV gains. Nature; 480; 159-160. (08 December 2011).

http://www.nature.com/news/cutbacks-threaten-hiv-gains-1.9581

On 24 January 2012, Michel Kazatchkine announced that he will “step down” as Executive Director of the Global Fund by mid-March. He said that his planned resignation resulted from a decision by the Global Fund Board two months ago to appoint a General Manager who will supervise many Global Fund activities and who will report direct to the Board. GFO understands that this decision by the Board to transfer many of Dr Kazatchkine’s responsibilities to someone else arose from the Board’s concern that the Fund’s managerial leadership was not sufficiently effective.

“For the last ten years, the Global Fund has been my passion and my most important undertaking,” Prof. Kazatchkine said in a statement to staff. Simon Bland, Global Fund Board Chair, responded by saying, “Few individuals have played a more central role in the creation and evolution of the Global Fund than Michel.”

The Global Fund also announced today that the General Manager will be Gabriel Jaramillo, a prominent banker from Latin America who was one of the members of the High Level Panel that extensively evaluated the work of the Global Fund during 2011. Mr Jaramillo spent three days last week meeting senior staff at the Global Fund.

The Global Fund said that Mr Jaramillo will take up a 12-month appointment on 1 February. The Fund did not specify whether Mr Jaramillo will serve as Acting Executive Director once Dr Kazatchkine leaves, but it implied that he will when it said, in a Q&A document sent to Board delegation members, that Mr Jaramillo will “take over all of the management responsibilities of the Global Fund Secretariat.” A spokesman told GFO that the Global Fund will launch a search for a new Executive Director “in due time.”

Mr. Jaramillo, a native of Colombia and a citizen of Brazil, is a former Chairman and Chief Executive Officer of Sovereign Bank. Since he retired a year ago, he has served as a Special Advisor to the Office of the Special Envoy for Malaria of the Secretary General of the United Nations. Mr Bland said in a press release that Mr Jaramillo “is an outstanding choice, and exactly what we need at this time: an excellent manager and a proven financial leader who can direct change and improve performance in a large institution during a time of transition.”

Source: Global Fund Observer (GFO) Issue 174: 24 January 2012.

http://www.aidspan.org.gfo

http://www.theglobalfund.org/en/mediacenter/pressreleases/2012-01-24_The_Global_Fund_Executive_Director_to_step_down_in_March/

The Medicine Patent Pool, founded and financed by UNITAID, seeks to increase access to HIV medicines by negotiating with pharmaceutical companies for voluntary licenses for ARVs that are still covered by patents. The work of the Pool has received support from the World Health Organization, UNAIDS, the Global Fund to Fight HIV, TB, and Malaria, and the G8.

Licensing agreements have already been developed with Gilead Sciences and the US National Institutes of Health, with ongoing negotiations with Boehringer-Ingelheim, Bristol-Myers Squibb, F. Hoffman LaRoche, Sequoia Pharmaceuticals, and ViiV Healthcare (GSK/Pfizer).

Generic companies contribute a royalty to make lower cost versions of new HIV treatments for use in developing countries.

Source: Patent Pool press release. Johnson & Johnson says ‘no’ to joining the Medicines Patent Pool. (19 December 2011).

http://www.medicinespatentpool.org/NEWS-ROOM/News-from-the-Pool/JandJ-Says-No

This included support for four years for the Medicines Patent Pool to negotiate voluntary licenses from brand companies to generic manufacturers to facilitate affordable access to HIV/AIDS medicines in developing countries.

“Precisely because funding for AIDS is threatened by the economic crisis, we need to leverage all the tools at our disposal to ensure staunch commitment to increase treatment coverage,” said Philippe Douste-Blazy, Chairman of the UNITAID Executive Board. “Innovative mechanisms that can increase treatment availability and decrease prices, such as the Pool, are critical components of UNITAID’s strategy to address the funding gap… The Pool has achieved promising results in its first year and we urge all pharmaceutical companies to enter into licensing agreements to breach the gap of 15 million people who need treatment.”

The UNITAID Board committed US$62 million to continue supporting the scale-up of HIV/AIDS treatment for children in partnership with the Clinton Health Access Initiative. US$50 million was committed to the Global Fund to increase access to artemisinin-based combination therapy in the eight African countries that bear the largest malaria burden.

Source: UNITAID press release: UNITAID continues funding the Patent Pool and paediatric HIV medicines: Additional US$50 Million Allotted to Malaria. (14 December 2012).

http://www.unitaid.eu/en/component/content/article/3-press/380-additional-us-50-million-allotted-to-malaria

The exorbitant price of AIDS medicines, especially antiretrovirals, has been one of the main barriers to people with HIV accessing them, especially in developing countries. As activist organisations we have been at the forefront of many of the struggles to make medicines affordable.

A patent gives a pharmaceutical company the exclusive right to manufacture and market a medicine. The patent lasts for 20 years from the date of filing the patent application. Companies typically patent medicines that they develop, they buy patents from other companies or they enter into exclusive licensing arrangements with universities or small companies that have developed medicines but do not have the capacity to bring them to market.

The purpose of patents is to encourage research and development into new medicines. The problem is that patents ordinarily create monopoly conditions which allow companies to charge exorbitant prices. Over the last 15 years, some developing world governments and activists have battled pharmaceutical companies to reduce medicine prices. They have won many hard-fought concessions that have brought down the prices of life-saving drugs and allowed millions of people to go onto antiretroviral treatment. But new generation patented drugs that have fewer side effects, are easier to take or offer treatment alternatives to people resistant to current regimens, are mostly unaffordable. Yet they will soon be needed by millions of people. Furthermore, the struggles for lower medicine prices have to a large degree depended on country-specific laws and the capacity of activists in those countries to organise. Crucially, it is not sustainable to fight drug-by-drug, country-by-country for concessions from the pharmaceutical industry.

One of the initiatives that has resulted from these struggles is the Patent Pool. This is an initiative by activists and UNITAID [1] to negotiate concessions from the pharmaceutical companies on an international scale to license their products through the patent pool. Multiple generic producers will then be able to access these licenses, stimulating sufficient competition between generic producers to drive down prices. The pool also aims to spur the production of generic combinations of medicines, where patents on medicines are held by a number of different companies.

There is no guarantee the Patent Pool concept will work. It ultimately depends on pharmaceutical companies entering into voluntary agreements that dilute the monopolies that patents give them. Getting pharmaceutical companies to the negotiating table requires ongoing activist pressure and protests. It requires co-ordinated strategies to monitor prices and patents, pressure governments to use the powers they have under TRIPS [2] to license essential medicines and campaigns to expose profiteering from health.

The Patent Pool has not been without teething problems and this has led to questions and criticism from activists around the world. It needs to improve its consultation mechanisms. We are pleased that it has begun to do so by meeting with key HIV civil society organisations around the world and by putting together an expert advisory group that will recognise the expertise and experience that members of civil society may bring.

So far only one antiretroviral patent-holding company, Gilead has signed an agreement with the Patent Pool. Gilead has agreed that the Patent Pool can license some of its antiretrovirals to generic companies in over 100 countries. The drugs include tenofovir (TDF), cobicistat (COBI), elvitegravir (EVG), and the Quad, a fixed-dose combination of TDF-COBI-EVG-emtricitabine. Gilead has also committed to not enforcing its exclusive rights on emtricitabine (FTC). It will also not stop companies from making fixed-dose combinations involving these compounds. [3]

The Gilead agreement has shortcomings. For example, Brazil, Thailand, China, Botswana, Namibia and Ukraine, all countries with significant numbers of people with HIV, and many other middle-income countries are excluded from part or all the agreement. Botswana, Thailand and Namibia are included in the TDF license, but excluded from the COBI one. The current agreement also unnecessarily restricts the sub-licensees to Indian generic manufacturers only.

Nonetheless these licenses are the most far-reaching of the concessions obtained from pharmaceutical companies on AIDS drugs. Millions of people can benefit and we must keep up pressure to ensure that all people do. That is why we demand that Gilead re-open negotiations with the Patent Pool to extend the licenses to include all the above countries and others in all aspects of the agreement. Also, the excluded countries can still access products produced by licensed companies if they make use of their TRIPS flexibilities; we therefore call upon them to do so.

We also demand that other pharmaceutical companies join the Patent Pool and make their essential HIV medicines available for voluntary licensing. In particular, we call on ViiV, Merck, Johnson & Johnson and Abbott to conclude agreements with the pool so that the antiretrovirals dolutegravir (still in clinical trials), raltegravir, darunavir, etravirine, rilpivirine and lopinavir and ritonavir become more accessible.

If these companies join the Patent Pool, the prices of these drugs are likely to drop substantially. Hundreds of thousands, perhaps millions, more people with HIV will therefore have access to these life-saving medicines.

Today six million people are alive and receiving antiretrovirals. Nine million more are in need. In some countries however, access to treatment is reducing rather than increasing. The unaffordable price of medicines is one of the reasons for this. We maintain the view that patents should not be used to make essential medicines unaffordable and that governments should play a much greater role in research and development of medicines. Access to essential medicines cannot be left to the market and the private sector; these cannot meet people’s needs.

We call on activists globally to unite and once again build powerful campaigns against pharmaceutical company profiteering so that access to antiretrovirals as part of the human right to the highest attainable standard of health, can be universally realised.

Joint Statement by Treatment Action Campaign, Treatment Action Group, HIV i-Base, European AIDS Treatment Group and SECTION27, 16 November 2011.

Notes:

1. UNITAID is a WHO initiative. Its mission is “to contribute to scaling up access to treatment for HIV/AIDS, malaria and tuberculosis, primarily for people in low-income countries, by leveraging price reductions for quality diagnostics and medicines and accelerating the pace at which these are made available.”
2. The WTO’s Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) was negotiated in the 1986-94 Uruguay Round. While imposing intellectual property regimes on countries that did not previously have them, it does contain some flexibilities.
3. TDF is an important drug because it can be used for first-line antiretroviral treatment instead of an older drug called stavudine which has much worse side-effects. Cobicistat, which is not yet approved, is potentially important because there is currently only one other drug that serves a similar purpose, i.e. to boost other antiretrovirals. The Quad is a four-in-one once daily pill that is not yet approved, but is hopefully going to be an excellent first-line antiretroviral regimen. Elvitegravir is also being tested. It will likely be useful for people who are resistant to other antiretrovirals.

Organised by civil society activists at the World AIDS Campaign they state that the cancellation by the Global Fund of all new programming until 2014 will cost lives and cripple international efforts to deliver on health-related goals, and that it breaks promises made to some of the world’s most vulnerable people.

The Call to Action demands that the Global Fund hold an emergency donor conference and issue a new call for proposals before the International AIDS Conference in July 2012. The Call says, “This is 200 days from 1 January. 200 days to save the Global Fund.”

Further information:

http://www.worldaidscampaign.org/2011/12/global-fund-call-to-action/

Source: Global Fund Observer (GFO) Issue 169: 5 December 2011.

http://www.aidspan.org.gfo

At its meeting in December 2010, the Global Fund Board approved the launching of Round 11. At its meeting in May 2011, the Board discussed but did not change this decision.

Therefore, in August 2011, Round 11 was launched, and many CCMs devoted enormous amounts of work to preparing their proposals. Then last month, in November 2011, the Board cancelled Round 11.

Why was Round 11 launched and then cancelled? And what does the decision to cancel Round 11 tell us about the Global Fund’s financial condition?

In a nutshell, the answer is…

Unlike what some news reports have suggested, the Global Fund has billions of dollars in the bank, with billions more expected to arrive during the next two years. The problem is that most of that money is needed for the current and renewal phases of existing grants. In addition, the Fund has introduced a more cautious methodology for estimating how much funding it will receive in future. Primarily because of these two factors, the Global Fund now estimates that until 2014, it will have almost no money for new grants. Hence, the need to cancel Round 11. It is not accurate to say that Round 11 was cancelled because of decisions by donors since May to cancel, reduce or delay their pledges, because that is not happening.

In somewhat more detail, the answer is….

As Simon Bland, Global Fund Chair, said, recently, the Global Fund disbursed $8 billion during the three-year period 2008-2010, and the Fund forecasts that it will have enough money to be able to disburse $10 billion during 2011-2013. This is a 25% increase from one period to the next.

Unfortunately, however, the $10 billion that the Global Fund expects to be able to disburse in 2011-2013 is about $1 billion less than the Fund had forecast in May 2011. Almost all of the $10 billion will be needed to fund existing grants and the renewals of existing grants. Grants are normally approved for a two-year Phase 1 followed by a three-year Phase 2. The Global Fund’s policies require that priority be given to Phase 2 renewals of existing grants, over the funding of new grants.

In May 2011, when the Global Fund was forecasting that it would be able to disburse about $11 billion in 2011-2013, the Fund estimated that $1.55 billion of that would be available for Round 11 grants. By the time of the Board meeting in November, that estimate went down to minus $0.6 billion. That meant that not only was there no money for Round 11, but also the Global Fund was short of money to pay for grant renewals and probably also for some unsigned Round 10 grants.

The decisions that were made during the Board meeting – decisions that achieved savings by reducing the amount of money required for future grant renewals – increased the estimate of available money from minus $0.6 billion to plus $0.6 billion. However, this amount was not deemed to be enough to permit the launching of Round 11 before 2014. Rather, the money has to be used primarily for funding those Round 10 grants for which grant agreements have not yet been signed, and for funding transitional arrangements (i.e., essential services) for grants that will end soon.

Thus, new grants now cannot be approved until 2014, though the Fund may decide to invite applicants to start preparing proposals during 2013.

In the last few years, the Global Fund has had some serious problems with certain donors, particularly the following:

• Italy has not yet pledged any money for 2011-2013, and has not delivered any of the $347 million it pledged for 2009-2010.
• Spain has not yet pledged any money for 2011-2013, and has not delivered $116 million of the $250 million it pledged for 2010.
• Ireland has not yet pledged any money for 2011-2013, and has not delivered $35 million of the $46 million it pledged for 2010.
• Netherlands has not paid $37 million of the $119 million it pledged for 2010.

However, those problems were all known when the Board agreed in May 2011 to launch Round 11. They are not new. The main factors that last month caused the Global Fund to reduce its revenue projections from the May 2011 levels, and therefore to cancel Round 11, were as follows:

• Many donors make their pledges in Euros and other non-dollar currencies. Between May and November, those currencies, on average, weakened against the dollar, so the anticipated dollar value of those pledges decreased by about $100 million.
• Some of the $4.0 billion that the U.S. announced last year for 2011-2013 will not be received until 2014, because U.S. legislation specifies that not all of each year’s money can be handed over until the U.S. government can certify to Congress that a number of conditions have been met.
• There has been a reduction in estimated interest earnings from the Fund’s money in the bank.
• Most significant by far: The Global Fund has developed a new and more cautious forecasting methodology regarding future income from donors. (The Global Fund refers to this as producing “risk-adjusted” forecasts.) The new methodology was introduced because the negative economic situation and the challenging political environment create uncertainties that are difficult to reflect in a multi-year forecast. In its new risk-adjusted forecasts, the Global Fund no longer automatically assumes that all countries will give the exact amount they pledged or that the funds will arrive equally distributed across the years to which the pledge applied. For example, the amount announced by the U.S. for the fiscal years 2011-2013 ($4.0 billion) is subject to Congressional approval each year. The Global Fund hopes – but cannot be certain – that the U.S. Congress will approve the full amount each year.

It is important to point out that only one country has formally cancelled or reduced the pledge that it originally made for 2011-2013. This is Denmark, which reduced its pledge by approximately $10 million; this represents well under one percent of what would have been needed for Round 11.

At the Accra Board meeting, the Executive Director said that the problems which then led the Board to cancel Round 11 represented a “perfect storm” of factors. Some participants privately blamed the Secretariat for not taking the possibility of those factors into consideration when it launched Round 11. Others blamed the Board for accepting the Secretariat’s May projections.

Source: Global Fund Observer (GFO) Issue 170: 9 December 2011.

http://www.aidspan.org.gfo

The following reactions from key organisations to the Global Fund’s decision to do away with Round 11 were highlighted in a GFO article.

Health GAP

“The funding window that was cancelled today would have enabled scale-up of lifesaving treatment and prevention services for HIV, tuberculosis and malaria to millions of poor people in developing countries.

“What is particularly scandalous about this cancellation is that donors didn’t have to do it. The amounts of money we’re talking about are barely a rounding error in donor budgets.”

MSF

“There’s a shocking incongruence between both the new HIV science and political promises on one hand, and the funding reality that is now hitting the ground on the other. Donors are really pulling the rug out from under people living with HIV/AIDS at precisely the time when we need to move full steam ahead and get life-saving treatment to more people.”

ITPC

“The lack of political and financial commitment to the AIDS response is deeply worrisome. The millions of people living with and fighting against these deadly diseases will pay an enormous price. Rather than building on the new evidence that AIDS treatment saves lives and prevents new infections, and scaling up treatment programs to try to end this epidemic, donor governments are now implicitly supporting a policy of triage, determining who lives and who dies.”

“The shortfall in funding for the Global Fund is an insignificant amount in comparison to the bank bailouts made by the U.S. and European governments, or even the bonuses set aside for Goldman Sachs executives this year.”

International HIV/AIDS Alliance

“The news that the Global Fund Board had decided to cancel Round 11 has devastated civil society organisations across the Alliance global partnership. We should not be shy in saying this decision and the financial situation of the Global Fund at this moment is a disaster for Africa.”

“International solidarity, perhaps the most precious resource needed to reach the Millennium Development Goals, is in dangerously short supply. A few days ago at the Fund’s meeting, tensions were high among representatives of implementer countries: They were fighting to be granted the dubious recognition of being the poorest among the poor in order to guarantee their access to the few resources still left. During these discussions, we tend to forget that people have a right to live regardless of where they were born.”

Coalition of AIDS activist organisations in Southern Africa

“It is a disaster for Zimbabwe as a country. More than 86,000 people will be left without treatment and about 5,000 children will be affected. The situation in Swaziland, where approximately 26 percent of the population of 1.2 million live with HIV, is dire, with stockpiles of ARVs already dwindling”.

The Guardian

The Global Fund has been “staring at a financial black hole ever since its big replenishment meeting in New York a year ago failed to deliver the sums it hoped for. It wanted $20bn. It got $11.7bn. That was in spite of exhortations to donors to pledge money from the U.N. Secretary General, Ban Ki-moon, who warned that the stakes were high and that lives would be lost if pressure on the big killer diseases was not maintained.”

New Statesman

“it reveals just how precarious daily life has become for the global 99 per cent: those whose very health, as much as their job security, is pegged to the rise and fall of the money markets. The politics of austerity we are going through has not even begun to be properly costed. This is the real lesson of the Global Fund’s demise and it will require much more than simply getting wealthy donors back on board to address it.”

Source: Adapted from Global Fund Observer (GFO) Issue 169: 5 Dec. 2011.

http://www.aidspan.org.gfo

The decision to start ART in children is made with guidance based on age and CD4 percentage or count. Guideline recommendations are based on observed short-term risk of morbidity and mortality. ART can be delayed in children with CD4 values above the recommended thresholds for initiation to avoid toxicities, resistance and some of the practical considerations associated with giving ART to children.

Investigators from ICH and the PENTA group suggest that current guidance assumes such a delay in treatment initiation is without detrimental long-term consequences. In a paper published ahead of print in JID, 28 December they write that evidence suggests differences between children and adults in the level of T-cell repopulation due to children’s greater thymic activity. A number of paediatric studies show poorer recovery of CD4 count on ART is associated with older age and lower CD4 count at initiation. Using longitudinal data from the PENTA 5 study and non-linear mixed-effects models, the group investigated the relationships between age, CD4 count at start of treatment, and CD4 repopulation. As well as confirming the associations previously described, their findings illustrate the importance of the naïve subpopulation for this recovery and they explore the consequences for ART naïve children of different age groups and with different CD4 counts.

The PENTA 5 trial assessed different ARV regimens in perinatally infected, treatment-naïve children. Among the 127 children starting treatment, the median age at initiation was 5.3 (IQR 2.4 to 8.6) years; CD4 count was 620 (IQR 343 to 912) cells/mm3; z-score (indicating the rank of a recorded CD4 count within the expected distribution for HIV-negative children of the same age, born to HIV-positive mothers expressed in terms of the standard, normal distribution) was -2.3 (IQR -4.1 to -1.3) and follow-up was 5.7 (IQR 5.1 to 6.5) years.

In a multivariate model the investigators estimated the children’s pre-treatment z-score to be -0.41+ 0.07 (point estimate ±SE) lower for each year older at initiation and their long term z-score -0.5+ 0.03 lower for each year older at initiation, both p<0.001. In addition to these effects, there was a strong positive association (p<0.001) between pre-treatment and long-term z-score – that is, children with z-scores below (or above) average for their age before treatment still had below (or above)-average scores in the long term.

Naïve and memory CD4 counts were recorded in a substudy of 26 children. This analysis revealed T-cell reconstitution in these children appeared to arise mainly from the naïve compartment with a comparatively small increase memory cell count, although on a faster timescale. However this potential for recovery via the naïve pool is apparently progressively reduced with age and/or duration of infection. The model illustrated suggests that the threshold currently recommended for initiating treatment in younger children results in a higher count in the long term than that for older children. Therefore guidelines for older children may not be optimal for maintaining CD4 counts in adulthood.

Reference:

Lewis J et al. Age and CD4 count at initiation of antiretroviral therapy in HIV-infected children: effects on long-term T-cell reconstitution. JID. Published ahead of print 28 December 2011.

An article in the December 1 2011 edition of JAIDS describes efavirenz (EFV) exposure in African children in the ARROW trial, dosed according to the 2006 WHO weight bands, which are similar to the manufacturer’s recommendations (the current approved paediatric doses).

ARROW is an open label randomised trial comparing routine laboratory to clinical monitoring (a paediatric version of DART) in children in Uganda and Zimbabwe. It also compares different ART strategies. Quirine Fillekes and colleagues from the trial team conducted a pharmacokinetic (PK) sub study in Ugandan children aged 3-12 years. The children evaluated had received twice daily lamivudine plus abacavir (3TC+ABC) with once daily EFV and participated in a crossover study comparing twice to once daily 3TC+ABC.

EFV was dosed according to WHO 2006 weight bands. Doses were 200, 250, 300 and 350 mg for children weighing 10 to <15, 15 to <20, 20 to <25 and 25 to >30 kg respectively. The children received 200/50mg capsules or halved 600mg tablets.

At week 36 from initiating treatment (once daily EFV plus NRTIs), 12 hour PK sampling was performed, pre-dose and at 1, 2, 4, 6, 8 and 12 hours post dose. The children were switched to once daily NRTIs at 36 weeks. Intensive PK sampling was repeated at 40 weeks, including an extra PK sample at 24 hours post dose.

A total of 41 (24 girls and 17 boys) were enrolled in this sub study. Of these, 4 children increased weight bands between the first and second PK sampling but were included in the analyses and 2 were excluded due to implausible time concentration curves (believed to be labeling errors).

Eighteen of the children were age 3 to 6 years and 23 children were 7 to 12 years. The majority were moderately stunted and wasted. Five, 16, 17 and 3 children were in the 10 to <15, 15 to <20, 20 to <25 and 25 to >30 kg weight bands respectively, at the first PK sampling.

Doses in mg/kg were highest in the 15 to <20 kg (median 14.7 mg/kg) and lowest in the 20 to <25 kg (median 13.0 mg/kg) weight bands. The median dose received overall was 13.6mg/kg.

The geometric mean EFV plasma concentrations time curves obtained at the first and second samplings were similar. Six children at the first sampling and 7 children at the second had subtherapeutic (<1.0 mg/L) plasma concentrations at 8 hours and/or at 12 hours; 7/41 (17%) at either sampling. At the second sampling 15/39 (38%) of children had subtherapeutic levels at 24 hours. Ten (24%) children at the first sampling and 11 (28%) at the second had potentially toxic levels >4 mg/L at 8 hours and/or at 12 hours; 12/41 at either sampling.

Overall the EFV Cmax, Cmin and AUC0-24 were respectively 15%, 36% and 10% lower than those observed in adults receiving the 600mg tablet.

The authors observed wide intersubject but modest intrasubject variability across EFV PK parameters. There was no evidence of significant differences across the four weight bands for all PK parameters evaluated (suggesting no major effect of using divided tablets) however, with only 41 children in total the sub study was rather underpowered to show this.

They wrote that these data (and that of two previous studies) strongly suggest that children should receive EFV doses higher than the WHO 2006 recommendations or the manufacturers daily dose in the leaflet (50mg higher only for children weighing 14 to <15 kg and 30 to 32.5 kg).

More recent 2010 dosing guidelines have higher EFV doses than evaluated in this study for children weighing 14 to <20, 25 to <30 and 35 to <40 kg. The authors noted that these higher doses were not only selected in response to concerns about under doing but to remove the 50 mg tablets from dosing tables as these were being discontinued.

They expressed concern that although these data suggest that higher doses should lead to greater exposure and in turn better virological efficacy, the trade off is that more than one-third of children will be exposed to potentially toxic EFV levels.

Reference:

Fillekes Q et al. pediatric underdosing of efavirenz: a pharmacokinetic study in Uganda. J Acquir Immune Defic Syndr. Volume 58. Number 4. December 1, 2011.

Investigators from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord evaluated response to antiretroviral therapy (ART) and predictors of switching or interrupting treatment in children starting in infancy up to 5 years from treatment initiation. Findings from this study were reported in the 28 November 2011 edition of AIDS.

The study evaluated data from nine observational cohorts in 13 European countries. A total of 437 HIV-infected, ART naïve infants, less than 12 months of age, born between 1996 and 2008 were included.

The infants started ART at a median of 3.7 (IQR 2.1-5.8) months. About 40% were from UK/Ireland and 20% each from France and Italy. About half were black and half female. Just over a third had been exposed to maternal antiretrovirals in pregnancy and just under a third neonatal prophylaxis. One third were breast-fed.

The median duration of follow up after starting ART was 5.9 (IQR 2.3 – 7.6) years. During this time 20 children died and 32 were lost to follow up. The median CD4 percentage and viral load at treatment initiation of were 29% (IQR 17 – 39%) and 5.7(IQR 4.9 – 5.9) log10 copies/mL respectively.

The majority (76%) started ART before 6 months of age. Twenty four percent started on an NNRTI plus 2 NRTIs, the most common backbone being ddI/d4T from 1996 – 1999 and AZT/3TC from 2000 onwards. Four drug regimens, most frequently NNRTI plus 3NRTIs, were used more often in the later time period (18% compared to 3%) and in UK/Ireland. Boosted PIs were used only from 2001 onwards (34% 2004-2008). Nelfinavir use declined over calendar time.

Just over half (53%) the infants initiating ART in 1996 – 1999 had viral load <400 copies/mL by 12 months, this increased to 57% in 2000 – 2003 and 77% in 2004 – 2008, but the difference was not statistically significant, p=0.09. Infants aged 6 -12 months at ART initiation were more likely to be suppressed than those aged <3 months AOR 1.98 (95% CI 0.92 – 4.25), but again, this difference did not reach statistical significance, p=0.06.

Four-drug NNRTI regimens were associated with significantly better viral load suppression; AOR 3.00 (95% CI 1.24 – 7.23) compared to three drug NNRTI (reference) regimens, p<0.001. But boosted PI plus 2 NRTI regimens performed similarly to the reference regimen, AOR 1.39 (0.62 – 3.13). Higher baseline viral load was associated with less likelihood of virological suppression, AOR 0.67 per log10 copies/mL (95%CI 0.50 – 0.89), p=0.01.

For infants with data available, median baseline and 12 month CD4 count, CD4 percentage and CD4 z-score were 520 (IQR 271 – 1340) cells/mm3, 6% (-6 to 16%) and 0.92 (-0.14 to 2.34), respectively. Median CD4 z-score increase was 2.29 in infants receiving four-drug NNRTI regimens compared to 0.65 in those receiving three-drug NNRTI regimens and 0.91 for boosted PI regimens, p=0.04.

Eighteen percent of infants switched to second line treatment. The cumulative incidence of switching was 10.2% (95% CI 7.5 – 13.4) and 16.7% (13.0 – 20.7%) by 2 and 5 years respectively. Children starting treatment with a four drug NNRTI or boosted PI-based regimen were slower to switch; AHR 0.41 (95% CI 0.15 – 1.14) and AHR 0.26 (95% CI 0.06 – 1.19) respectively, p=0.03. Although the investigators noted data were sparse.

Twenty eight percent of children experienced at least one treatment interruption of more than 14 days, no factors predicted interruption.

Sixty five percent of children remained on treatment without interruption at last follow-up. Of these 36% had been treated for at least 5 years. The estimated probability of remaining on first-line ART without interruption was 79.3% (95% CI 75.1 – 83.1%) and 63.8% (95% CI 58.7 – 68.9%) by 2 and 5 years from starting ART respectively.

comment

That boosted PI-based regimens performed similarly to NNRTI-based is contradictory to findings from IMPAACT 1060 that showed 20% higher rates of failure at 24 weeks in children aged 2 months to 3 years receiving NNRTI-based regimens compared to PI-based (whether or not they had been NNRTI exposed through PMTCT). Although IMPAACT 1060 was an RCT and these are cohort data – the difference in length of follow up is considerable.

That four drug NNRTI-based regimens did well is notable and induction/maintenance strategies in young children remain under explored.

Reference:

European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord. Early antiretroviral in HIV-1 infected infants, 1996-2008; treatment response and duration of first-line regimens. AIDS: 25(18):2279-2287, 28 November 2011.

Two ongoing concerns for HIV positive people on ART are (1) whether long-term side effects shorten life-expectancy? and (2) is premature ageing related to either ART or HIV?

While both short and medium term outcomes have so far been very good, data for these questions requires following large numbers of patients over many years. Since it is impossible to have randomised control groups, the interpretation of cohort results also needs to consider numerous confounding variables.

The second question is a particular focus for current research. But a new analysis from the EuroSIDA cohort comes close to answering the first. In an article published in the 21 January 2012 edition of AIDS, there was no evidence in this huge cohort that the risk of death, all-cause or AIDS, increased with length of time on ART. [1]

EuroSIDA is one of the largest prospective observational ART cohorts. It includes nearly 17,000 patients from Europe, Israel and Argentina. This cohort’s researchers previously have published important papers showing the benefits of ART on life expectancy. The authors explain that this is the first study “to look into the association of non-AIDS deaths with duration of time spent on combination antiretroviral therapy (cART) and with a long-term perspective of exposure to treatment. The results are reassuring that so far prolonged use of cART does not appear to be leading to increased risk of death due to some previously identified cumulative effect or a drug effect whereby there is a long induction period before disease appears.”

Just over 12,000 patients were followed from baseline, defined as the time of starting ART or enrolment into EuroSIDA after 1996. Three quarters of the cohort is male. About 40% acquired HIV homosexually, 22% from IDU and 30% heterosexually. Interestingly, nearly 60% of the cohort are current or previous smokers and smoking status was unknown in more than 20%. At baseline about 21% were confirmed hepatitis C positive and about 53% were confirmed negative. About 10% had confirmed hypertension and just over 2% confirmed diabetes.

The researchers calculated incidence rates of death, AIDS-related and non-AIDS-related, per 1000 person-years of follow-up stratified by time of exposure to cART (< 2 years, 2 to 3.99 years; 4 to 5.99 years; 6 to 7.99 years and > 8 years).

During 70,613 person years of follow-up, a total of 1,297 patients died. AIDS caused 413 and non-AIDS diseases caused 884 deaths. Incidence rates per 1,000 years of follow-up were 18.3 overall (95% CI: 17.4-19.4), 5.85 for AIDS deaths (95% CI: 5.28-6.41) and 12.5 for non-AIDS deaths (95% CI: 11.7-13.3).

For the non-AIDS related deaths, 121 were due to infections, 182 due to liver-disease, 125 due to cancer, 122 due to cardiovascular disease, 90 due to violence (including suicide) and 91 due to other causes.

The main analysis compared mortality over the predefined periods on ART. The researchers used 2 to 3.99 years on ART as reference. In a multivariate analysis controlling for sex, ethnic origin, region of Europe, hepatitis B and C status, diabetes, hypertension, smoking, viral load, CD4 cell count, prior AIDS and age, they found the following incidence rate ratios of all-cause, AIDS-related and non-AIDS related deaths (see Table 1).

Longer time on ART was associated with a reduction in the risk of liver-related death, violent, and unknown deaths. But longer time on ART was also associated with an increase in mortality attributed to non-AIDS-related cancers. The researchers suggest this “may reflect ageing of the HIV population, as the effect was no longer present after adjustment for time updated age …”

comment

This article is reassuring for people who are recently diagnosed, who have access to modern ARVs and a medical history that is uncomplicated by coinfections or prior drug resistance. It is important that there is no signal of additional risk from treatment that is otherwise stable and effective.

The risk of premature ageing is the focus for research into immune activation and inflammation. It is also dependent on HIV negative controls to understand the impact of residual inflammation in people suppressed on HAART. In an editorial in Current Opinion Infect Diseases, Martin Fisher and Vanessa Cooper suggest caution over links between HIV or ART and ageing. They conclude, “Although undoubtedly there are higher rates of comorbidities in the HIV-positive population [...] Further research is needed to explore the mechanisms by which HIV/HAART may contribute to age-related diseases, the contribution of other important and potentially modifiable risk factors including smoking, alcohol and drug use, and the role of comorbid disease.” [2]

References:

1. Kowalska JD et al. for EuroSIDA. Long-term exposure to combination antiretroviral therapy and risk of death from specific causes: no evidence for any previously unidentified increased risk due to antiretroviral therapy. AIDS 26:315-323. (28 January 2012). Free full text online.
   http://journals.lww.com/aidsonline/Fulltext/2012/01280/Long_term_exposure_to_combination_antiretroviral.7.aspx
2. Fisher M and Cooper V. 2012. HIV and ageing: premature ageing or premature conclusions? Curr Opin Infect Dis 25:1-3. Free full text online.
   http://journals.lww.com/co-infectiousdiseases/Fulltext/2012/02000/HIV_and_ageing___premature_ageing_or_premature.2.aspx

Two experimental drugs for the treatment of MDR TB have completed phase II clinical trials. While neither is ready yet to be registered with a regulatory authority, bedaquiline (formerly TMC207, manufactured by Tibotec) is already better tested than most second-line TB drugs and has a good side-effect profile. The results of a Phase II trial of delamanid (formerly OPC-67683, manufactured by Otsuka Pharmaceuticals) are expected to be published soon.

Bedaquiline

HTB previously reported the development of bedaquiline and Phase II trial results [1,2]. Tibotec reported further results at a Critical Path to TB Drug Regimens meeting in Arlington in November. In this trial of 160 MDR TB patients, that compared an optimised background regimen plus either placebo or bedquiline, there was faster culture conversion in the bedaquiline arm by 24 weeks (p=0.003). This was the primary endpoint. In secondary analyses, median time to culture conversion was 12 weeks vs 18 weeks. And at 24 weeks 79% of bedaquiline patients vs 58% of placebo ones had converted to sputum-negative (p=0.008). Side effects were distributed evenly over the two groups. There were no serious study drug-related side effects nor were there clinically significant differences in laboratory results. QT prolongation was seen on the bedaquiline arm, but there were no adverse events associated with this nor were there any prolongations greater than 500 milliseconds. [3]

In an ongoing open-label study (C209) that is assessing safety, efficacy and tolerability over two years of bedaquiline in smear-positive MDR TB patients, there was an 80% response rate at 24 weeks. Resistance to more drugs was associated with poorer response rates (56% for XDR, 77% for pre-XDR and 87% for MDR; p=0.0006). Patients with no cavitations also responded better (p=0.0157), as did patients on three or more potentially active drugs (p=0.0376). The most frequent side effects were nausea (11%), arthralgia (12%) and hyperuricaemia (14%). About 2% of the patients stopped bedaquiline due to an adverse event.

Tibotec has planned a Phase III superiority study (C210) with 600 subjects. The primary endpoint is intended to be relapse free cure at 15 months and a final analysis will also be done at 21 months.

The company is also considering a paediatric trial of 60 children to examine PK and safety.

The company has a compassionate use/expanded access programme. In countries that have a mechanism to authorise pre-approval access of unregistered medicines, patients with pre-XDR or XDR TB at what the company describes as validated centres can obtain bedaquiline. In countries where this is not feasible, such as China, Russia and Lithuania, an expanded access trial is planned. But at the time of the Critical Path meeting when this was presented, fewer than 30 patients had accessed the drug via compassionate use or expanded access.

Delamanid

In a phase II trial (Trial 204), about 480 patients with MDR TB were divided into three arms, stratified by disease severity. All patients received optimised background regimens. The first group received placebo, the second delamanid 200mg/day and the third delamanid 400mg/day for eight weeks. Patients were followed for an additional four weeks for safety and to confirm sputum conversion. The trial took place at 15 sites in 9 countries. Those patients who successfully completed Trial 204 were eligible to enroll in a 26 week open label protocol. Those who participated in Trial 204 and received placebo therefore had 26 weeks exposure to delamanid and those who received delamanid in trial 204 had a total of 34 weeks exposure to delamanid. [4]

Otsuka is currently recruiting for a Phase 3 trial to test the safety and efficacy of delamanid 200mg daily. [5]

comment

These two drugs are the furthest along in the pipeline to treat drug-resistant TB. It is essential that they soon be tested together, so that if or when they are approved clinicians do not have to grapple with whether or not to add a single drug to failing regimens.

TB drug development is painfully slow. Consider that rilpivirine (TMC278), an antiretroviral of minor importance, was presumably discovered after bedaquiline (given that TMC278 signifies a chronologically later drug than TMC207). Yet the rilpivirine phase III trial started in 2008 and the FDA approved the drug last year. In contrast, bedaquiline is not expected to be registered in the very near future. This is not to single out Tibotec: indeed their TB development is the most advance. But this example shows the comparative lack of resources invested in getting TB drugs to market. Regulatory hurdles specific to TB worsen the situation. For example, some regulators want to see two-year relapse rates before granting approval.

Pre-regulatory approval expanded access should be a priority. Tibotec has committed to this but because of regulatory hurdles, lack of knowledge about the programme and perhaps lack of urgency from the company, we remain far from significant expanded access. It is unclear what commitment Otsuka has to expanded access.

Activists and patients must increase the pressure on Otsuka, Tibotec, health ministries and service providers to make these drugs available more widely for pre-approval access. More pressure must be put on the entire industry to develop more drugs, though as recent TAG/i-Base pipeline reports show, this is starting to improve.

References:

1. Geffen N. 2009. TMC207 reduces time to sputum conversion in phase II trial on patients with drug-resistant TB. HTB 10(7) July/August 2009.
   http://i-base.info/htb/4403
2. Clayden P. 2011. Faster conversion rates with TMC-207 versus placebo plus OBT for the treatment of MDR-TB. HTB 12(1-2) January/February 2011.
   http://i-base.info/htb/14441
3. Presentation by Tibotec to Global TB Community Advisory Board at CPTR 2011.
4. Otsuka. A Placebo-controlled, phase 2 Trial to Evaluate OPC 67683 in patients with pulmonary sputum culture-positive, multidrug-resistant tuberculosis (TB).
   http://www.clinicaltrials.gov/ct2/show/NCT00685360 5.
5. Otsuka. Safety and efficacy trial of delamanid for 6 months in patients with multidrug resistant tuberculosis.
   http://www.clinicaltrials.gov/ct2/show/NCT01424670

The event at the World Lung Conference in Lille that generated the most media was the ZAMSTAR study results, presented by Peter Godfrey-Faussett of the London School of Hygiene and Tropical Medicine. [1] [2]

Four interventions were randomly assigned to six communities each, from a pool of 24 communities. The randomisation was also balanced across two regions comprising the study – Zambia and the Western Cape in South Africa – and high versus low TST levels, drawn at baseline from a sample of children in grades one to three. There were just under a million people altogether in the communities. Each community had a minimum of 25,000 people and a TB notification rate of more than 400 per 100,000 per year.

The primary endpoint was prevalence of active TB in a randomised sample drawn from the population.

The four interventions were as follows:

• Clinic based TB and HIV interventions (clinic, or control arm), which included TB and HIV programme collaboration, testing TB clients for HIV and voluntary HIV counseling and testing for clients screened for TB.
• Enhanced case finding (ECF), which included using community- based interventions to improve awareness of TB and HIV, fast track sputum collection for smear microscopy at a nearby health centre, a schools education campaign and mobile sputum collection points with community advocacy using local youth drama groups. Guiding principles of this intervention were that every person should be able to give sputum within a 30 minute walk and sputum smear results would be available within 48 hours.
• Household interventions (HH) which included, households of people with active TB being visited for active case finding, IPT for asymptomatic HIV-positive people and children less than six years old in the household, access to HIV counseling and testing and discussion with households to try to reduce risk of HIV-negative people contracting HIV, as well as counseling and referral for care.
• All of the above.

The study was run from 2006 to 2009. The ECF intervention attracted TB cases. Overall, 4.6% of the communities in ECF sites gave a sputum sample through ECF and 24% of smear-positive cases (20,630 people, of whom 14,130 were in the Zambian sites and 6,500 in South Africa) were detected via ECF. Interestingly, the South African sites, despite dealing with a smaller number of sputa, had far less efficient turnaround times on microscopy and more missing samples. The costs ranged from $17,137 to $24,455 per ECF site per year, which is equivalent to $0.31 to $0.71 per person per year.

In the HH sites, just over 9,350 households were visited, containing nearly 37,000 people, about 6% of the population. About 27,000 people experienced all three of the study’s scheduled visits. The cost ranged from $24,126 to $34,661 per site per year, or $0.48-$0.8 per person per year. Nearly every household individual received HIV education and group counseling, 67% had HIV tests and 38% (7,029 people) were HIV-positive. Godfrey-Faussett noted that 4,000 people were accessing ART and he described IPT as challenging.

The sample sizes in the prevalence survey at the end of the study were designed on the assumptions that there was a TB prevalence of 1% in the control arm and that a reduction of 30% in arms two and three would be detected. This turned out to be optimistic. On the basis of these assumptions the sample size was 4000 adults per community in each of the 24 communities. Geographically based cluster sampling was used based on standard census enumeration areas. All households in randomly selected enumeration areas were visited. A total of 55,450 households were visited including 123,790 individuals. Of these 90,600 were present and consented to a questionnaire, respiratory sample, HIV test and blood sugar test. Of these, 64,430 had evaluable TB cultures, of which 884 were positive for active TB. Overall prevalence in the Zambian sites was 542/100,000 adults, ranging from 221 to 1,096. Overall prevalence in the South African sites was 2,319/100,000 adults, ranging from 1,489 to 3,054.

The primary outcome was that prevalence for communities with the HH intervention was 746/100,000 versus 883/100,000 in communities without HH. The adjusted risk ratio was 0.78 [95%CI: 0.61-1.00]. The presentation is not clear here but this result appears to be adjusted for age, sex, TST prevalence, HIV prevalence, socio- economic status, education, marital status and smoking. Prevalence for communities with ECF was 927/100,000 versus 711/100,000 without ECF. The adjusted risk ratio was 1.11 [95%CI: 0.87-1.42].

Some secondary endpoints were also presented in Lille. From the presentation it appears that a baseline TST study was done in kindergarten children and then repeated on the TST-negative children at the end of the study four years later, in order to calculate infection incidence. A new infection was defined as a change in induration from 0mm to 15mm. Incidence in the HH arms was 0.87 per 100 person years versus 1.71 for the non HH arms. The adjusted rate ratio was 0.45 but this was non-significant [95%CI: 0.20-1.05]. For ECF this was 1.41 versus 1.05 for non ECF communities, for an adjusted rate ratio of 1.36, also non-significant [95%CI: 0.59-3.14].

Interestingly, incidence in Zambia was 1.2 per 100 person years versus 4.5 per 100 person years in South Africa.

No statistically significant effects were found for any of the interventions on TB treatment outcomes for index cases, cumulative TB incidence or HIV prevalence or incidence.

comment

The ZAMSTAR study has produced many interesting results, not least the differences between TB incidence and systems in Zambia and South Africa. Many interesting papers should come out of it.

Unfortunately there was only one statistically significant
endpoint presented: a lower prevalence at the end of the study in communities, which had the household (HH) intervention. But even this effect was modest. With a longer time period, the effect might have been greater. Moreover, since no baseline prevalence survey was done we cannot be sure that the differences in prevalence did not exist at baseline, but perhaps this concern will be allayed when the study results are published in a journal.

The household intervention appears to be affordable and certainly not harmful, so it might be worth implementing on a larger scale.

References:

1. Godfrey-Faussett P. Do we need to go beyond the clinic to control TB? 42nd Union World Conference on Lung Health, Lille, France (2011)
   http://uwclh.conference2web.com/content/1060
2. Ayles HM et al. ZAMSTAR, The Zambia South Africa TB and HIV
   Reduction study: Design of a 2 × 2 factorial community randomized trial. Trials 2008, 9:63 doi:10.1186/1745-6215-9-63.
   http://www.trialsjournal.com/content/9/1/63

Simon Johnstone-Robertson and colleagues at Cape Town and Stellenbosch universities have published the results of a model that calculated a TB transmission probability of 90% per year for awaiting trial prisoners in a large South African prison. They found that by implementing the national cell occupancy recommendation, the transmission probability could be reduced by 30%. And by implementing international recommendations, transmission probability could come down by 50%. They also found that implementing any one of improved passive case finding, modest ventilation increases or decreased lock-up times according to national or international standards would have a minimal effect. But by implementing all of these measures together including reduced occupancy, transmission could be reduced by 50% if national guidelines were adhered to and by 94% if international guidelines were used. [1]

The authors explain that South Africa has the fourth highest global incarceration rate, with more than 165,000 prisoners in 237 prisons. There is rapid turnover of awaiting-trial prisoners with 79% being imprisoned for less than 12 months and the number of people passing through the system annually exceeding 368,000. There are at any time about 3,200 prisoners awaiting trial in Pollsmoor, the 3rd-largest facility with awaiting trial prisoners in the country. Awaiting trial prisoners are mostly kept in communal cells of 40 to 60 prisoners each.

The South African Constitution’s Bill of Rights says “Everyone who is detained, including every sentenced prisoner, has the right … to conditions of detention that are consistent with human dignity, including at least exercise and the provision, at state expense, of adequate accommodation, nutrition, reading material and medical treatment”. [2]

A 2011 court judgment showed how far the country is from attaining this right. From November 1999 to 27 September 2004 Dudley Lee was an awaiting trial prisoner in Pollsmoor prison complex in Cape Town, except for a four month period in 2000 during which he was out on bail. In June 2003, while he was in prison, he became ill and was diagnosed with pulmonary TB. He later sued the Minister of Correctional Services because the state’s conduct caused him to become ill with TB.

Conditions in Pollsmoor Prison

In his court action, Lee’s legal team claimed that:

• It was common for prisoners in the prison, including Lee, to be in close proximity to one another and to be housed in mass cells;
• A considerable proportion of prisoners were infected with active TB and that it was inevitable that some of the prisoners with TB would infect non-infected prisoners in close proximity to them;
• The Department of Correctional Services was aware of the presence of TB in the prison and the risk of non-infected prisoners becoming infected;
• The Department failed to adhere to prisoners’ requests for adequate treatment to prevent and/or treat and/or cure people;
• The Department could have eliminated or reduced the spread of TB by creating conditions in the prison which made it impossible or difficult for tuberculosis to be spread by separating prisoners sick with TB from healthy prisoners, regular and effective checkups of prisoners to see whether or not they were actively infected with tuberculosis, and by providing regular and effective treatment for the control and elimination of the disease;
• The defendant’s actions towards the plaintiff were unlawful because the Department violated the Constitution and the Correctional Services Act 8 of 1959 including sections that deal with respect and protection of physical integrity.

The court judgment describes overcrowded cells in which inmates typically spend 23 hours a day and an hour in an overcrowded recreational area. The environment is engulfed in tobacco smoke and fumes and coughing. There is a chronic shortage of nurses and staff and so the DOTS system that is supposed to be used is implemented inconsistently at best. TB data in the prison is poorly kept and inconsistent. For example, one doctor testified that treatment cases had to be recorded in a treatment register, which was held in quadruplicate. One copy was to be sent off to the Medical Officer of Health but documents, which were supposed to have been forwarded to the Medical Officer, were still in the register. Another example: A schedule of TB cases covering the period 1998 to 2009 had been prepared by the prison but other records in the prison showed the schedule was wrong. The total number of TB cases for 2001, according to the register, was 177 but the schedule recorded 69 cases with no cases provided at all for April to October.

South Africa has an extraordinarily high crime rate and there is not much public sympathy for prisoners. Dostoevsky’s comment that a “society should be judged not by how it treats its outstanding citizens but by how it treats its criminals,” is not a widely held view, in spite of Constitutional guarantees and legislation protecting prisoner rights. It is therefore notable that Mr Lee was acquitted and therefore arguments lacking empathy for criminals are irrelevant to his case. Moreover, as Johnstone-Robertson and colleagues point out, high TB transmission rates in prison contribute to a high TB burden in the general population.

The judge explained the effect of prison conditions on Mr Lee’s testimony, “Given that prisoners who were awaiting trial spent approximately 23 hours out of every 24 in their cells, there must clearly have been little to distinguish one day from another. Indeed, the plaintiff himself said that one day was much like the next. The plaintiff spent approximately four and a half years in prison awaiting trial and attended court on approximately 70 occasions during that time. In these circumstances it does not appear to me to be surprising that the plaintiff became confused at times.”

The judgment describes a justice system that is under-resourced, cruel and careless.

It is difficult for current or former state employees to testify against the state. The South African state, both during and post-apartheid has a record of ostracising health workers who stand up for patient rights. During the Tshabalala-Msimang era, some doctors were dismissed for providing antiretroviral treatment. So it is worth mentioning that the judge depended on testimony by doctors Paul Theron and Craven, who had been employed as part-time district surgeons at the prison, as well as a male nurse, Frans Muller, formerly employed at the prison. The judge described their testimony of the problems at the facility and their attempts to bring these problems to the attention of authorities as reliable. All three described their frustrated attempts to get the authorities to improve prison conditions.

On the other hand, experts who provide dubious testimony to defend indefensible state policies act without concern for the consequences of their actions. Therefore it is also worth noting the judge’s views of one such witness. Prof. Paul van Helden, who is described on the website of Stellenbosch University’s Division of Molecular Biology and Human Genetics, as the 4th highest ranked scientist in the world in the field of tuberculosis, gave astonishing testimony for the state. He argued that the plaintiff’s acquisition of TB was primarily a consequence of genetics and re-activation, not the prison environment. Dr Theron rebutted his testimony. The judge pointed out a salient problem with it:

“Prof Van Helden also appeared to fall into the trap of losing his objectivity. So, for example, he used statistical evidence which was obtained in lower socio-economic areas such as Ravensmead and Masiphumelele to justify his opinion that the plaintiff, who came from a middle class environment, had probably been infected with TB prior to coming into the prison, in circumstances where he himself had admitted that those statistics would not be applicable in middle and higher socio-economic areas. Indeed, Prof Van Helden went so far as to say that the plaintiff’s chances of having been infected with TB prior to entering prison were ‘exceptionally high’.”

The judge concluded, “There is no doubt that Prof Van Helden is an expert is his field, but he is not a medical doctor and has had no experience in the diagnosis and treatment of TB. His experience relates to research. On the whole, Prof Van Helden’s evidence was tainted with bias and misinformation. As a consequence, his evidence is, in my view, in many instances unreliable and inaccurate.”

The judge drew several conclusions, “On the totality of the evidence, I am accordingly satisfied that it is more probable than not that the plaintiff contracted TB as a result of his incarceration in the maximum security prison at Pollsmoor.”

She also found “that a reasonable person in the position of the defendant would have foreseen that the prevailing conditions in the maximum security prison at Pollsmoor would reasonably possibly spread TB amongst inmates and cause inmates, such as the plaintiff, who had not previously been ill with TB, to succumb to the disease.”

She further wrote, “… the crisp answer to the question as to whether the defendant took reasonable steps to guard against the spread of TB, or to curb its spread in the maximum security prison, is no. There is no evidence that the defendant … took any steps whatsoever to guard against the spread of TB in the maximum security prison”.

And she found that “a reasonable person in the defendant’s position would, in my view, have taken steps to guard against the spread of TB in the maximum security prison, because it is such a formidable disease which is easily spread. More particularly, a reasonable person would have ensured that sufficient numbers of nursing staff were employed to perform the various tasks involved in the control and prevention of TB in the said prison.”

The judge found the state’s actions unlawful. She found the Minister liable to the plaintiff for having become ill with TB and ordered the state to pay costs. The damages amount was scheduled for a separate hearing.

Technical aspects of the model

Johnstone-Robertson and colleagues used data presented in the court case to construct their model. The court record provided several inputs into the model including TB incidence rate (5.5/100 person prison years, derived from 177 cases in a prison population of 3,200), period of infectiousness (1 to 180 days), ventilation (one air change per hour in a cell of 195m3) and floor area per prisoner (1.42m2). Other input parameters were infectious particles produced (1 per hour, a conservative estimate) and respiratory volume (360 litres per hour). The model was also run using other ventilation values: 3 air changes per hour (minimum international recommended ventilation), 8 (intermediate ventilation); and 12 (optimal ventilation), as well as different cell dimensions and floor areas per prisoner (3.34m2, a Red Cross recommendation and 5.4m2, WHO recommendation). The floor space per prisoner parameter corresponds to cell occupancy levels of about 250% (situation in Pollsmoor), 100% (South African recommendation) and 50% (international recommendation).

The authors explain that the model’s main equation is the number of TB infections (C) occurring in a prison cell with susceptible prisoners (S). This was assumed to be a function of the number of infectious cases (I), their infectivity (q, quanta of infectious particles produced per hour), time of exposure (t, minutes), respiration rate (p, litres per hour), and germ-free ventilation (Q, litres per hour):

C = S ( 1-exp( -Iptq/Q ) )

This is known as the Wells-Riley equation.

The authors further explain that the prevalence (P) of infectious adults at any time is the annual smear-positive incidence rate (M, per cent) and the period of infectivity (D, days) as

P = M/[365/D].

The risk of contact with an infectious adult was modeled using a Poisson distribution.

The model is restricted to calculating the risk of infection, not the risk of active disease. Calculating the latter is extremely complex.

Interpret the transmission rate with caution. It is the annual risk of transmission, but Johnstone-Robertson and colleagues explain that 79% of prisoners awaiting trial are incarcerated for less than a year. Also the Wells-Riley model averages the effect of several complex variables. The model is useful for showing that awaiting trial prisoners are at high risk of acquiring infection, but the 90% estimate is an approximation without a confidence interval and should not be cited as the definitive calculation of risk.

The annual risk of TB transmission in the Western Cape in poor communities is also extremely high. One of the authors has pointed out to me that reaching adulthood in the province carries a similar risk of TB acquisition as being incarcerated as an awaiting trial prisoner in Pollsmoor for a year.

Recommendations

The horrendous conditions are not confined to just one prison. We only have detailed information on the situation in Pollsmoor because of this court case.

Johnstone-Robertson and his colleagues explain that there are many strategies to deal with the high transmission rate. They suggest that ventilator grills should not be closed at night. Communal cells can be cross-ventilated by using barred rather than solid doors and using corridor ventilator extraction systems. Carbon dioxide monitoring should be implemented. There should be active case finding and new fast TB diagnosis methods, such as the Gene Xpert presumably, should be introduced. They also say that TB notification data for South African prisons should not be considered secret or restricted information and that accurate data should be made available to the Judicial Inspectorate of Prisons to include in the annual report on the state of our prisons.

The problem, acknowledged by the authors, is that sensible recommendations for improving the situation have been made repeatedly by the Judicial Inspectorate. These can be found in the annual reports. [4] Dr Theron, Dr Craven and Mr Muller testified about the efforts they made to get the authorities to act. In 2000 the Department of Health set up a special task team to deal with TB. But its recommendations were either followed only temporarily, too little or not at all.

A further problem apparent from the case and several cases that the Treatment Action Campaign has been involved in is the sheer inefficiency of the court system, which creates a bottleneck that results in large numbers of awaiting trial prisoners. This is evidenced by the large number of trial hearings Lee attended and that, despite being acquitted, he spent the amount of time in prison reserved for serious crimes.

There is clearly a lack of political will to address TB in South African prisons. The steps to address TB have been identified but are not being implemented. Perhaps more cases of infected prisoners or former prisoners suing the state, such as this one, and protests are the only way to address this ongoing public health crisis.

References:

1. Johnstone-Robertson S, Lawn S, Welte A, Bekker LG, Wood R. Tuberculosis in a South African prison – a transmission modelling analysis. South African Medical Journal, Vol 101, No 11 (2011). http://www.samj.org.za/index.php/samj/article/view/5043
2. Constitution of the Republic of South Africa, No. 108 of 1996.
   http://www.info.gov.za/documents/constitution/1996/a108-96.pdf
3. Lee v Minister of Correctional Services (10416/04) [2011] ZAWCHC 13; 2011 (6) SA 564 (WCC); 2011 (2) SACR 603 (WCC) (1 February 2011.
   http://www.saflii.org/za/cases/ZAWCHC/2011/13.html
4. Judicial Inspectorate for Correctional Services annual reports.
   http://judicialinsp.pwv.gov.za/Annualreports/annualreport.asp

Thank you to Alex Welte for advice.

Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV respectively in Africa.

However, there is the potential for drug interactions with this combination as artemether and lumefantrine are substrates of CYP3A4 and nevirapine is both a substrate and inducer of CYP3A4.

This parallel-design pharmacokinetic study, obtained concentration-time profiles for lumefantrine, artemether, dihydroartemisinin and nevirapine in two groups of HIV-infected patients: ART-naïve and those stable on nevirapine-based therapy. Both groups (n=18 per group) received the recommended artemether-lumefantrine dose (80/480 mg). The primary outcome was day-7 lumefantrine concentrations, as these are associated with therapeutic response in malaria.

Nevirapine decreased artemether (p<0.0001) and dihydroartemisinin (p=0.01) AUC, but unexpectedly increased lumefantrine exposure. Median (range) day 7 lumefantrine concentrations were 622 ng/mL (185-2040) and 336 ng/mL (29-934) in the nevirapine and ART-naïve groups, respectively (p=0.0002). In the ART-naïve group, 6/18 subjects had day 7 lumefantrine concentrations below target (280 ng/ml) compared with 1/18 in the nevirapine group (Odds Ratio=8.5, 95%CI 0.9 to 80.02, p=0.061). Adverse events were similar between groups, with no difference in electrocardiographic QTcF and PR intervals.

The mechanism of inhibition of lumefantrine remains to be elucidated. Studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed.

Source: hiv-druginteractions.org (16 November 2011).

http://www.hiv-druginteractions.org/LatestArticlesContent.aspx?ID=564

Reference:

Kredo T et al. The interaction between artemether-lumefantrine and nevirapine-based antiretroviral therapy in HIV-1 infected patients. Antimicrob Agents Chemother, 2011, 55(12): 5616-5323.

http://www.ncbi.nlm.nih.gov/pubmed/21947399

The use of traditional/complementary/alternate medicines in HIV/AIDS patients who reside in Southern Africa is quite common. This review looks at the mechanisms of pharmacokinetic interactions and summarises the published clinical studies and case reports of antiretroviral-herbal interactions. In vitro screening studies of several African traditional medicinal plants and extracts are described and details given in a very useful table.

The review highlights the lack of clinical studies – despite a high incidence of HIV/AIDS in the African region, only one clinical study (efavirenz and Hypoxis hemerocallidea) has been conducted. More studies on African traditional medicines are warranted in order for more meaningful data to be generated and the true potential for such interactions to be determined.

Source: hiv-druginteractions.org (24 November 2011).

http://www.hiv-druginteractions.org/LatestArticlesContent.aspx?ID=567

Reference:

Müller AC, Kanfer I. Potential pharmacokinetic interactions between antiretrovirals and medicinal plants used as complementary and African traditional medicines. Biopharm Drug Dispos, 2011, 32(8): 458-470.

http://www.ncbi.nlm.nih.gov/pubmed/22024968

This study aimed to i) evaluate the safety and toxicity of rapamycin (sirolimus) in HIV-infected individuals with KS receiving antiretroviral therapy, ii) investigate rapamycin interactions with both PI-containing and NNRTI-containing regimens, and iii) assess clinical and biological endpoints.

Seven participants, 4 on ritonavir-boosted PIs (2 lopinavir, 2 atazanavir) and 3 on NNRTI-based regimens (2 efavirenz, 1 nevirapine), had rapamycin titrated to achieve trough concentrations of 5-10 ng/mL. Patients were monitored for safety and KS response. Despite pharmacokinetic interactions resulting in >200-fold differences in cumulative weekly rapamycin doses between participants on PI-containing and NNRTI-containing regimens, treatment was well tolerated. Maintenance rapamycin doses in the PI subjects were 0.1 mg and 0.2 mg twice weekly with lopinavir and 0.2 mg twice weekly and 0.3 mg three times weekly for atazanavir; doses in the NNRTI subjects were 2.3 mg and 6.7 mg daily for efavirenz and 2.8 mg daily for nevirapine. There were no significant changes in viral loads or cytokine levels; modest initial decreases in CD4 counts occurred in some patients. Three participants, all on PI-containing regimens and with higher rapamycin exposure, showed partial KS responses.

Rapamycin appears safe in HIV-positive individuals with KS and can, in some cases, induce tumour regression and affect its molecular targets. Significant pharmacokinetic interactions require careful titration to achieve target drug trough concentrations, but may be exploited to achieve therapeutic benefit.

Source: hiv-druginteractions.org (29 November 2011).

http://www.hiv-druginteractions.org/LatestArticlesContent.aspx?ID=566

Reference:

Krown SE et al. Rapamycin with antiretroviral therapy in AIDS-associated Kaposi sarcoma: an AIDS Malignancy Consortium Study. J Acquir Immune Defic Syndr, 2011, epub ahead of print.

http://www.ncbi.nlm.nih.gov/pubmed/22067664

On 17 November a large international Phase 2b study looking at interventions to reduce HIV sexual transmission announced that it will discontinue use of a 1% tenofovir vaginal gel and matched placebo gel due to the study’s data and safety monitoring board (DSMB) finding no difference in efficacy between these two groups. [1]

In the latest review the DSMB found a 6% HIV incidence rate among participants in both the tenofovir gel group and the placebo gel group. No other safety concerns (other than efficacy) have been reported with any of the studied interventions.

This is the second major change in the US NIH funded VOICE study (Vaginal and Oral Interventions to Control the Epidemic) in two months. In September, we reported in HTB that the use of daily oral tenofovir was discontinued for a similar lack of efficacy. [2]

The study originally enrolled more than 5,000 HIV-negative women at 15 clinical research sites in Uganda, South Africa and Zimbabwe. The study randomised women to one of five groups: daily oral tenofovir, daily oral Truvada, daily oral placebo tablet, daily tenofovir gel or daily placebo gel.

Only the daily oral Truvada and oral placebo arms will continue to be studied, with results expected in 2013.

References:

1. NHI press statement: NIH discontinues tenofovir vaginal gel in ‘VOICE’ HIV prevention study: product safe but no more effective than placebo. (25 November 2011).
   http://www.niaid.nih.gov/news/newsreleases/2011/Pages/VOICEdiscontinued.aspx
2. DSMB stops oral tenofovir monotherapy arm of VOICE PrEP study due to lack of difference compared to placebo. HIV Treatment Bulletin (HTB), October 2011.
   http://i-base.info/htb/15779

Further information:

Statement and Q&A from Microbicide Trials Network (MTN):
http://www.mtnstopshiv.org/node/3909

TAC notes that recommendations and practice have been divided between the promotion of exclusive breastfeeding (mainly in Kwazulu-Natal) and formula feeding (mainly in Western Cape and Guateng).

Following recent studies showing that the risk of transmitting HIV during breastfeeding can be reduced significantly with antiretroviral (ARV) treatment for the mother or prophylaxis for the infant, the South African government plans to implement a new infant feeding policy from April 1 2012. This policy recommends exclusive breast feeding for the first 6 months and then the introduction of complementary foods and continuing breastfeeding until the infant is 12 months old. This will be accompanied by the provision of ARV treatment for women so indicated and nevirapine prophylaxis for infants of HIV positive mothers not yet indicated for treatment in South Africa.

The TAC statement calls for the new policy to cater for women who are unable to exclusively breastfeed for various reasons. TAC also stresses the regional variation in risk from formula feeding in South Africa and the importance of responsible introduction of the new policy, with an emphasis on the provision of ARVs. They are concerned that the Department of Health intends to end formula milk provision by September 2012, which, they are concerned is far too abrupt.

They state that patient education and counselling and provision of ARVs at PMTCT sites are critical for the success of the policy. And, that there should not be a sudden withdrawal of formula milk.

For more information info@tac.org.za.

16 FEBRUARY 2012 | GENEVA – WHO has concluded, on the advice of its Guidelines Review Committee, that women living with HIV or at high risk of HIV can safely continue to use hormonal contraceptives to prevent pregnancy. The recommendation follows a thorough review of evidence about links between hormonal contraceptive use and HIV acquisition.

Current WHO recommendations in the Medical eligibility criteria for contraceptive use (2009 edition) therefore remain: there are no restrictions on the use of any hormonal contraceptive method for women living with HIV or at high risk of HIV. Couples seeking to prevent both unintended pregnancy and HIV should be strongly advised to use dual protection – condoms and another effective contraceptive method, such as hormonal contraceptives.

A study published in Lancet Infectious Diseases in October 2011 suggested that hormonal contraceptives, such as the pill or injectable contraceptives, may increase a woman’s risk of HIV infection. It also found that women living with HIV and using hormonal contraception may be more likely to transmit the virus to their partner than women who did not use hormonal contraception.

WHO convened a technical consultation from 31 January – 1 February 2012 to review findings from all recent epidemiological studies on the issue. The meeting brought together 75 experts from 18 countries to review existing WHO recommendations in the light of these findings.

The experts recommended that women living with HIV, or at high risk of HIV, continue to use hormonal contraceptives to prevent pregnancy, but emphasised the need to also use condoms to prevent HIV acquisition and transmission. They also stressed the need for further research on the issue and the importance of offering a wider choice of contraceptive options.

On 15 February 2012 WHO’s Guidelines Review Committee upheld the recommendations.

Source WHO press release:
http://www.who.int/mediacentre/news/notes/2012/contraceptives_20120216/ en/index.html

It is with great pleasure, and considerable relief that we report that the New York State Supreme Court Justice Louis B. York granted summary judgment in favor of Richard Jefferys in a defamation lawsuit brought by an AIDS denialist named Celia Farber. [1] Jefferys was represented in the case by Joseph Evall of Gibson, Dunn & Crutcher.

The suit against Jefferys arose out of a May 12, 2008, comment he submitted via the now-defunct website for “Whistleblower Week,” conference. [2]

Jefferys was responding to an announcement that one of the conference sponsors was planning invite the AIDS denialists Celia Farber and Peter Duesberg to testify before a “tribunal” (including several Congresspeople), in the guise of whistleblowers.

In his comment, Jefferys asserted that Farber and Duesberg “are not whistleblowers, they are simply liars who for many years have used fraud to argue for Duesberg’s long-discredited theory that drug use and malnutrition – not HIV – cause AIDS.”

Jefferys wrote that he could provide “many, many examples, including their altering of quotes from the scientific literature, false representations of published papers, etc.” He stated that including Farber and Duesberg in this event “will, regrettably, discredit and demean your efforts to support the very real issues of recrimination against legitimate whistleblowers.”

Justice York found Farber to be a “limited purpose public figure,” which means that a defamation case can only be sustained if the alleged defamatory comments were malicious and knowingly false. Also, since HIV is a matter of public concern and debate, Jefferys would have to be shown to have been grossly negligent regarding the factual accuracy of his statements.

Justice York decided that Jefferys comments reflected his sincere and informed opinions and therefore met neither of these criteria. Justice York’s full opinion, which is available on the New York Courts website [3], provides a potted history of the AIDS denialism controversy and Celia Farber’s role within that controversy. But this decision is not a judicial verdict on AIDS denialism. Instead, it is a strong defense of freedom of speech on contested questions of public policy.

NY Law School Professor Arthur Leonard wrote: “In effect, Farber was contending that defamation law can be used to stifle criticism of a controversial position on a matter of great public importance.”

This report is edited from Arthur S. Leonard’s excellent detailed legal analysis of this case. [1]

References:

1. New York Court Rejects Journalist’s Defamation Claim Against AIDS Activist. (12 November 2011).
   http://newyorklawschool.typepad.com/leonardlink/2011/11/new-york-court-rejects-journalists-defamation-claim-against-aids-activist.html
2. Whistleblower Week In Washington (May 12-16 2008)
   http://web.archive.org/web/20080517225306/http://www.w3conference.org/contact.htm
3. Justice York, Supreme Court, New York. (09 November 2011).
   http://decisions.courts.state.ny.us/fcas/fcas_docs/2011NOV/3001063992009001SCIV.pdf

Registration details, including for community and community press are included on the relevant websites.

19th Conference on Retroviruses and OIs (CROI)

5–8 March 2012, Seattle

http://retroconference.org

10th European HIV & Hepatitis Drug Resistance

28–30 March 2012, Barcelona, Spain

http://www.virology-education.com

13th Intl Workshop on Clinical Pharmacology of HIV Therapy

16–18 April 2012, Barcelona

http://www.virology-education.com

47th European Liver Conference (EASL)

16–18 April 2012, Barcelona

http://www.easl.eu

18th Annual BHIVA Conference

17–20 April 2012, Birmingham

http://www.bhiva.org

20th International HIV Drug Resistance Workshop

9–13 June 2012, venue tbc

http://www.informedhorizons.com/resistance2012/

14th International Workshop on Co-morbidities and Adverse Drug Reactions (Lipodystrophy Workshop)

19–21 July 2012, Washington

http://www.intmedpress.com/comorbidities/

7th International Workshop on HIV Transmission

19–20 July 2012, Washington

http://www.virology-education.com

4th International Workshop on HIV Paediatrics

20–21 July 2012, Washington

http://www.virology-education.com

Towards a Cure: IAS pre-conference symposium

20–21 July 2012, Washington

http://www.iasociety.org/Default.aspx?pageId=606

19th IAS World AIDS Conference

22–25 July 2012, Washington

http://www.aids2012.org

11th International Congress on Drug Therapy in HIV

11–15 November 2012, Glasgow

http://www.hiv11.com

We also include summaries of journal articles, focusing on pregnancy and paediatrics, a summary of the new drug resistant TB guidelines and report the stopping of the oral tenofovir arm of VOICE PrEP study.

May we take this opportunity to wish you a happy new year and happy reading.

The conference has an open-access searchable abstract database online.
http://www.ias2011.org/

The ‘Programme at a glance’ can be searched for key words but requires a free software upgrade Silverlight which is quick and easy to do. Then from this page you can search abstracts or presentations.
http://pag.ias2011.org/

Sessions with PowerPoint slides or webcasts have relevant icons next to them. As with previous years, the PowerPoint links on the left under the session time are not active, so to download PowerPoint files scroll down to the bottom of the session page.

Reports in this issue of HTB include:

• Cure research and viral reservoirs
• Orange Farm circumcision results dispel concerns about risk compensation
• Randomised trial of ART in TB patients with high CD4 counts

Unless stated otherwise, all references are the Programme and Abstracts of the 16th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 17–20 July 2011, Rome.

In addition to the prevention studies and the progress on pipeline drugs that made most headlines (see the previous issue of HTB), a third set of presentations through the meeting supported the IAS Conference Statement on the need for the cure. [1]

That ‘the Cure’ might again re seen as an achievable goal for research was resuscitated in keynote lectures from NIAID lead Anthony Fauci several years ago and several medical networks, including the IAS, already hold annual meetings to coordinate different approaches. US public funding now requires cure research as a key work stream for HIV treatment networks.

Whilst the scientific challenge of curing HIV has been the consitent focus for many committed researchers, the renewed level of funding is clearly driven by the financial challenge of providing lifelong global treatment. Even when the generic costs are reduced to less than $100 per person per year, current treatment programmes need to more than double and then be sustained for coverage to meet the existing need. Perhaps increasing the resources for cure research is therefore perhaps also the most ethical way to be able to withdraw from responsibility for funding global treatment.

However, these sessions in Rome were mostly held in the smaller rooms, filled to capacity. They were also frustratingly insular with few being available as webcasts or slides to download, including the plenary session by IAS President Elect, Françoise Barré-Sinoussi. [2]

Neither the IAS pre-conference workshop (New concepts in HIV Immunopathogenesis, Treatment and Vaccine Strategies) nor the rapid summary report from that workshop in the main IAS conference by Nicolas Chomont was webcast. However, slides are available from some of the workshop sessions and for the summary by Chomont. [3, 4]

A satellite meeting cosponsored by amfAR and IAS also was not webcast, although the slide presentations can be downloaded. [5] This meeting focused on whether:

• viral replication persists on HARRT;
• eradication research can progress in animal models or is dependent on human studies;
• eradication is most likely to come from targeting the viral reservoir or more recent approaches using gene therapy.

Several other presentations at the conferences looked at strategies to selectively reactivate the reservoir of latently infected resting CD4 cells, either at the pre- or post-integration step. This challenge is highlighted by the pool being estimated to be less than one in a million resting cells for someone on stable treatment with undetectable viral load.

Some researchers believe that success in this goal might eradicate HIV, though this is dependent on whether current treatment suppresses replication sufficiently to halt viral evolution. This might turn out to be possible, as it has been the conclusion from several intensification studies that have shown no further reduction on low level viraemia after increasing the potency of a three drug combination with a fourth drug, including an integrase inhibitor. [6] An oral presentation from Brunetta and colleagues reported no impact on CD4 reservoirs in gut-associated lymphoid tissue obtained from sigmoid colon biopsies at 48 weeks of follow up following intensification with raltegravir. [7]

A case reported by Chun and colleagues in an article in AIDS last year perhaps also supports this view. [8] This paper described one person – ‘the Toronto patient’ – who was enrolled and treated prior to seroconversion. Viral load was suppressed to <50 copies/mL on HAART for more than ten years, driving the pool of infected CD4 T cells down to less than one in 1.7 billion cells. Against advice, the person decided to stop treatment under research conditions. Viral rebound only occurred after 50 days with an increased to 1600 copies/mL followed by spontaneous suppression by day 95 back to undetectable. Subsequently, viral load steadily increased to approximately 8600 copies/mL on day 143 when treatment was restarted.

So one interpretation of this case could be to emphasise the difficulty of eradication – even with such an early, effective and sustained level of treatment. Another interpretation is that eradication might almost have been achieved. Perhaps another month, or year, or few years on treatment might have been sufficient to final exhaust the remaining pool on resting infected cells. This study is unlikely to be repeated.

Another more optimistic, but also unexplained, set of cases includes the 32 patients from the ANRS Visconti study reported at CROI this year. This group received antiretroviral therapy within ten weeks of seroconversion for a median of three years (1-7.5 years). Five of these people sustained virological control for a median of 6 years (range 4-10) after treatment discontinuation. [9] It is unclear why similar cohorts (Rosenberg, Walker et al.) have not had the same success.

However, over time, so long as treatment is maintained, the resting pool of infected cells might be able to be agitated to become active, most likely by using multiple approaches. This could reduce the time needed to eliminate this reservoir from decades down to years – with residual virus mopped up by antiretrovirals, allowing treatment to be stopped.

Importantly, research into activation of latently infected cells is already investigating a broad group of drugs that are already licensed. Studying HIV transcription at the molecular level is driving the understanding of differences between latent and productively infected CD4 cells including HDAC-1 and methylation sites in latent infection with the hope that these targets might switch cells away from latency.

A comprehensive review of potential molecules by Sharon Lewin and Christine Rouzioux in the 24 April edition of AIDS [10] was the basis of one of the presentations at the IAS cure workshop. [11]

These include histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panabinostat, entinostat, belinostat, givinostat and at least nine others), a methylation inhibitor (5-azacytidine), cytokines (IL-7 – Eramune group, IL-15) and an antialcoholic (disulfiram). Immune modulators with similar potential incude antibotics (minocycline), antirheumatics (auranofin), anti-PD-1 (MDX-1106) and protein kinase C modulators (bryostatins and others). Many of these compounds are already being studied in HIV-positive people.

An oral presentation by Claire Vandergeeten from the Vaccine and Gene Therapy Institute reported results from in vitro studies that suggest that IL-15 therapy may be used as a strategy to deplete the latent HIV reservoir while IL-7 maintains the reservoir both in vitro and in patients on stable HAART. [12]

This research is important and exciting. Many of these compounds have been studied for several years and for other studies are ongoing. A combination therapy approach is therefore likely to have a greater chance of success, for example, valproic acid or vorinostat plus prostratin. [13]

However, other researchers believe that an as yet unidentified sanctuary site would prevent the latent reservoir from being a slowly diminishing pool that theoretically might wear itself out, with or without stimulation to do so. This includes Steven Deeks at UCSF who co-chairs the IAS working group on cure research and was heads a recent $4 million grant from the US NIH to develop a strategy to eradicate HIV. [14]

This raises the importance of finding out whether any compartments are actively replenishing the viral reservoir, currently untouched by the maximal suppression measured by plasma viral load.

If this is the case, then any strategy to activate latently infected cells would not be successful. In November 2010, Yuki and colleagues reported that ongoing replication (measured by unspliced HIV RNA in CD4 T cells) is present in higher levels in gut sites (duodenum, terminal illeum, right colon and rectum) compared to that in PBMCs in patients on HAART with viral load suppressed to <40 copies/mL. [15]

The same group then showed that intensification with raltegravir in this group of patients produced a reduction in levels of unspliced RNA in the terminal ileum and a trend towards reduced T cell activation in other gut sites. [16]

For these researchers, looking for the impact of intensification studies in plasma viral load is searching in the wrong place. If tissue compartments are a source of ongoing viral replication, the spillover pool found in plasma may have limited relevance.  Other cellular sites distinct from CD4 T cells contributing to the latent cellular reservoir include macrophages, hematopoetic stem cells, naive T cells, astocytes, thymocytes and others.

Also, Maria Buzon and colleagues in Nature Medicine in 2010 reported increases in episomes following raltegravir intensification (shown by an increase in 2LTR in PMBCs) as evidence of de novo infection and reduced levels of activation. The extremely low level or replication is used to account for the non-development of resistance even over years. Also perhaps indicating that the chronic source for new virus drives a limited number of rounds of infection. [17]

Finally, in one of the few late breaker presentations with slides posted online, Hiroyu Hatano working with Deeks’ group at UCSF reported that viral persistence was consistently associated with markers of immune activation and dysfunction (including PD-1 expressing cells) rather than plasma viral load. These measures were particularly elevated in people on treatment with low CD4 counts despite treatment (less than 350 cells/mm3 compared to higher), suggesting that patients below this cut-off present a more difficult and sobering challenge to any approach to a cure.

More optimistically, Hatano noted that the preferential expression of PD-1 by latently infected cells supports targeting this molecule as a strategy for depleting HIV reservoirs. The AIDS Clinical Trials Group (ACTG) in the US is planning an exploratory trial of Merck’s experimental PD-1 inhibitor for this purpose. [18]

References:

Unless stated otherwise, all references are to the abstracts and conference programme of the 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 1720 July 2011, Rome.

1. The Rome Statement for an HIV Cure: Major HIV/AIDS Stakeholders Call for HIV Cure Research to be Accelerated. International AIDS Society, July 2011.
   http://www.iasociety.org/Default.aspx?pageId=583
2. Barré-Sinoussi F. Discussing past and future accomplishments of HIV research. Abstract MOSS0103.
   http://pag.ias2011.org/session.aspx?s=83
3. Towards an HIV Cure: Insight into Residual Viral Replication, Establishment of Reservoirs and Understanding Mechanisms of Persistence. Conference workshop WEWS03.
   http://pag.ias2011.org/session.aspx?s=70
4. Chomont N. New concept in HIV: HIV immunopathogenesis, treatment and vaccine strategies – report back from pre-conference. Symposium WESY01.
   http://pag.ias2011.org/session.aspx?s=15
5. Controversies in HIV Cure Research. Joint IAS and amfAR workshop MOSA02.
   http://pag.ias2011.org/session.aspx?s=39
6. McMahon D et al. Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy. Clin Infect Dis. 2010 March 15; 50(6): 912–919.
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897152/
7. Kovacs C et al. Effect of intensification of long-term highly active antiretroviral therapy (HAART) with raltegravir on proviral HIV-1 DNA in gut associated lymphoid tissue (GALT): a randomized, placebo controlled trial. 6th IAS, Rome 2001. Oral abstract MOAA0103.
   http://pag.ias2011.org/Abstracts.aspx?SID=53&AID=1432
8. Chun T-W et al. Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS: 27 November 2010 – Volume 24 – Issue 18 – p 2803–2808.
   http://journals.lww.com/aidsonline/Fulltext/2010/11270/Rebound_of_plasma_viremia_following_cessation_of.6.aspx
9. Saez-Cirion A et al. Long-term HIV-1 control after interruption of a treatment initiated at the time of primary infection is associated to low cell-associated HIV DNA levels: ANRS VISCONTI study. 18th CROI 2011, Abstract 515.
   http://www.retroconference.org/2011/Abstracts/41477.htm
10. Lewin SR, Rouzioux C. HIV cure and eradication: how will we get from the laboratory to effective clinical trials? AIDS: 24 April 2011 – Volume 25 – Issue 7 – p 885-897.
    http://journals.lww.com/aidsonline/pages/articleviewer.aspx?year=2011&issue=04240&article=00001&type=Abstract
11. Lewin S. Contribution of the immune system to HIV persistence. Workshop: Towards an HIV Cure: insight into residual viral replication, establishment of reservoirs and understanding mechanisms of persistence, July 2011, Rome.
12. Vandergeeten C et al. Differential impact of IL-7 and IL-15 on HIV reservoir persistence. 6th IAS, Rome 2011. Oral abstract MOAA0101.
    http://pag.ias2011.org/Abstracts.aspx?SID=53&AID=2604
13. Reuse S et al, Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection. PLoS ONE 4(6): e6093.
    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0006093
14. NIH supports new research strategy for finding a cure for HIV. (July 2011).
    http://www.ucsf.edu/news/2011/07/10201/nih-supports-new-research-strategy-finding-cure-hiv
15. Yukl SA et al. Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. Journal of Infectious Diseases. Published online 12 October. 2010;202:000-000. DOI: 10.1086/656722.
    http://jid.oxfordjournals.org/content/202/10/1553.full
16. Yukl SA et al. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS. 2010 Oct 23;24(16):2451-60.
    http://journals.lww.com/aidsonline/Abstract/2010/10230/Effect_of_raltegravir_containing_intensification.4.aspx
17. Buzón M et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nature Medicine 16, 460–465 (2010).
    http://www.nature.com/nm/journal/v16/n4/full/nm.2111.html
18. Hatano H et al. Cell-based measures of viral persistence are associated with immune activation and PD-1+-expressing CD4+ T cells. 6th IAS Conference, Rome 2011. Oral late breaker WELBA01.
    http://pag.ias2011.org/abstracts.aspx?aid=4801

Amidst the excitement about HPTN 052 at the Rome IAS meeting, the results of the ANRS Orange Farm circumcision programme received little publicity, despite stunning data.

Orange Farm was the site of the first of three randomised control trials that showed that circumcision reduces the risk of men contracting HIV in a predominantly heterosexual population. Following the trial, the researchers implemented a scaled up circumcision programme in Orange Farm. Bertran Auvert presented a late-breaker describing the results of this programme. [1]

There are several important findings from this study:

• Post-trial uptake was large. Orange Farm has now carried out approximately 25,000 circumcisions.
• No deaths or permanent injuries have occurred due to circumcision. There have been ten hospitalisations and in all these cases the adverse events were resolved.
• The benefit of circumcision on HIV incidence is durable.
• There was no evidence that incidence was affected by risk compensation.

Orange Farm is a township of about 110,000 adults about 45kms from Johannesburg. Since January 2008, free voluntary medical male circumcision to all boys and men older than 15 has been offered by the ANRS-sponsored project. The intervention includes community mobilisation and outreach, counselling, condom distribution, STI treatment, HIV voluntary counselling and testing and ART if eligible.

A baseline cross-sectional survey was done in 2007. This was a random sample of just under 1,200 males aged 15 to 49 years. The response rate was 74%. Male circumcision status was determined by genital examination. A second cross-sectional survey was done in 2010. It was almost the same size and the response rate was 88%. This survey included a background and sexual behaviour questionaire. Again male circumcision status was determined by genital examination. Blood samples were tested for HIV, ARVs and for recent infection (within 6 months) using a population incidence detuned HIV test (Calypte EIA BED).

Uptake

Male circumcision prevalence changed from 15.6% (95%CI: 13.6%-17.8%) of 15-49 year-olds in 2007 to 49.4% (95%CI: 46.5%-52.3%) in 2010. Using this data, the researchers calculated uptake, which increased across all age groups in the 2008-2010 period. In 15-49 year-olds it was 40% (95%CI: 38.0% to 43.5%) and 49.1% in 20 to 24 year-olds (95%CI: 42.1% to 52.4%). This substantial increase led Auvert to comment, “We are changing the social norms.”

In a comparison of 590 circumcised versus 605 uncircumcised men, circumcised men were younger, more educated, less likely to be married and more often aware of their HIV status. No difference in sexual behaviour was detected. For example reported condom usage was consistent (adjusted OR: 0.84; 95%CI: 0.63-1.1; p=0.26).

HIV prevalence and incidence

Among 586 uncircumcised men in the survey, 117 were HIV-positive (20%; 95%CI: 16.7%-23.2%). Among circumcised men, 36 out of 582 men were HIV-positive (6.2%; 95%CI: 4.3%-8.2%). This is a 55% reduction (95%CI: 39% to 70%).

In the 15-34 age group, the BED assay indicated that incidence in uncircumcised men was 3.7 per 100 person-years (95%CI: 2.2-6.1) and 0.6 per 100 person-years in circumcised men (0.19-1.9). The adjusted relative risk was 0.24 (95%CI: 0-0.66). Interestingly, this is equivalent to a 76% reduction that is exactly what the as-treated effect of the Orange Farm randomised control trial was.

Because of problems with the BED assay, a modelling exercise was also done in which HIV incidence was calculated from HIV prevalence data to determine the effect of circumcision on incidence. In this separate analysis the reduction in incidence was 83% (95%CI: 64%-98%) in 15-34 year-olds, consistent with the BED-based estimate.

It was estimated that without male circumcision, HIV prevalence would have been 25.1% higher in 15-49 year-olds in Orange Farm (95%CI: 13.1%-39.1%) and HIV incidence would have been 57.9% higher (95%CI: 17.0%-131%).

comment

The key limitation to a study like this is that it is observational. But randomised controlled trials have already proven the efficacy of circumcision. This was the first prospective study to show the benefits of circumcision in a real-world operational setting.

A widely expressed concern about circumcision is that risk compensation would undo much of its benefit. The finding that the operational effect of circumcision matched the as-treated effect of the Orange Farm clinical trial addresses this concern. The lack of difference in reported condom usage also indicates that risk compensation is not a factor, but this must be discounted against the fact that survey participants give answers that they believe are consistent with societal expectations rather than what they actually do.

There should be no further objections to scaling up voluntary medical male circumcision in appropriately equipped facilities. The South African Department of Health has committed to scaling up circumcision and implementation is taking place in several provinces. PEPFAR and the Gates Foundation have both committed to funding circumcision programmes across sub-Saharan Africa. However South African guidelines have still not been published, albeit that a draft exists. These guidelines need to be finalised and published. An implementation plan also needs to be devised.

The Orange Farm researchers hope soon to be able to do an analysis of the effect of medical male circumcision on incidence in women.

Reference:

Auvert B. 2011. Effect of the Orange Farm (South Africa) male circumcision roll-out (ANRS-12126) on the spread of HIV. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 17-20 July 2011, Rome, Italy.
http://pag.ias2011.org/Abstracts.aspx?SID=43&AID=4792

Thank you to Bertran Auvert, Dino Rech and Dirk Taljaard for assisting my understanding of this study.

Declaration of interest: Nathan Geffen am a member of the Orange Farm circumcision scientific committee.

The benefits of initiating antiretroviral treatment (ART) in TB co-infected patients with CD4 counts below 350 cells/mm3 have been demonstrated in a number of recent studies. [1-2]

Now an open-label randomised controlled trial by Nanteza and colleagues has been published that looks at patients with higher CD4 counts. The trial, run in Uganda, compared 6 months of ART concurrent with TB treatment versus only TB treatment in patients with CD4 counts > 350 cells/mm3. The trial was small, but it provides some evidence that there is clinical benefit to placing patients with high CD4 counts on ART. [3]

From October 2004 through September 2008, 4,951 people were screened. Of these 250 patients co-infected with TB and HIV and with CD4 counts >350 cells/mm3 were enrolled. Of these 232 were randomised and 214 remained on the trial and eligible for analysis. The final control and intervention arms each had 107 patients. Patients in the intervention arm were given ART (abacavir, lamivudine and AZT) for six months. Participants were followed up for 24 months. The trial was designed and approved before several studies demonstrated that structured treatment interruptions are not a viable treatment option. The authors explained that the rationale of the study was that a punctuated course of antiretroviral therapy in patients with high CD4 cell counts would suppress viral replication during therapy for tuberculosis, block the effects of immune activation on T cells harboring HIV, slow the pace of HIV disease progression, and improve clinical outcomes.

The baseline characteristics of the patients were mostly well matched. There were slightly more men in the control arm (63% versus 52%). Nearly all patients had at least one TB symptom, especially cough. Median age was 31 years. Nearly 90% of patients were both smear and culture-positive. Interestingly 8% of patients were smear-positive and culture-negative, while only 3% were smear-negative and culture-positive. The intervention and control arms had similar median CD4 counts (between 500 and 550 cells/mm3) and median viral load (4.6 and 4.7 log10 copies/mL).

The primary endpoint was a composite of CD4 cell count <250 cells/mm3, clinical AIDS, or death. In the intervention arm, 17 people reached this endpoint versus 25 in the control arm (p=0.17). Most people reached the endpoint on the basis of CD4 count, 15 in the intervention arm and 18 in the control arm. They initiated lifelong ART. Although not statistically significant, there were consistently fewer endpoint events in the intervention arm throughout the trial. At 12 months of follow-up the difference between the arms reached significance (98% and 90%, respectively; p=0.02), but became non-significant by the end of the follow-up period.

There were two deaths in the ART arm and no clinical endpoints. There were three clinical endpoints and four deaths in the control arm. Despite the tiny numbers, this was significant (p=0.048).

In the intervention arm, 86% of participants achieved a viral load <400 copies/mL at three and six months. Viral load rebounded upon discontinuation of treatment to near baseline. The average viral load of the control group did not change significantly over the 24-month period.

There were 45 versus 28 adverse events in the control and intervention groups respectively. When considered individually, the risk of a grade 3 or 4 adverse event was 76% greater in the control arm than in the intervention arm (rate ratio, 1.76; 95% CI: 1.24–2.53). About half the adverse events took place during the six months treatment (ART or TB) stage of the study. Neutropenia was high and not significantly different in both arms (17 versus 25% in the intervention and control arms respectively). The authors therefore concluded that neutropenia is common in patients with tuberculosis, even when CD4 counts are >350 cells/mm3 and that treatment with concurrent antiretroviral therapy only partially mitigates the effect of HIV infection on bone marrow suppression. As would be expected in a trial of people with relatively high CD4 counts, no Immune Reconstitution Syndrome was detected.

No patients were culture-positive after six months of TB therapy. The average time to culture conversion was 37.5 days in the intervention group versus 29 in the control, but this was not significant (p=0.37).

The authors state that the trial provides limited further support for early initiation of treatment.

comment

Although small and despite the outdated and short treatment intervention, this study does provide limited support for initiating all HIV-positive patients with TB on ART, even at high CD4 counts.

The World Health Organisation (WHO) recommends that treatment be provided to all patients with TB irrespective of CD4 count. The South African government has recently announced that it will treat all patients with CD4 counts <350 cells/mm3. This study offers some evidence, albeit not compelling, that South Africa should go further and implement the WHO recommendation. It seems likely that South Africa’s new HIV and TB National Strategic Plan for 2012-2016 will provide for this.

Also interesting was that in this Ugandan setting 25% of the TB and HIV co-infected patients who screened for the trial had CD4 counts above 350 cells/mm3.

In Khayelitsha, Cape Town, nearly one in five HIV-positive patients presents with a CD4 count >500 cells/mm3 (communication with MSF). These statistics show that the question of determining the optimal starting point affects many people and is an important one.

We look forward to the results of the TEMPRANO and START trials that have been designed to answer this question.

References:

1. Abdool Karim SS et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010; 362:697–706.
   http://www.nejm.org/doi/full/10.1056/NEJMoa0905848
2. Blanc FX et al. Significant enhancement in survival with early (2 weeks) vs. late (8 weeks) of highly active antiretroviral treatment (HAART) in severely immunosuppressed HIV-infected adults with newly diagnosed tuberculosis. Vienna: International AIDS Society, 2010:284–5.
   http://pag.aids2010.org/Abstracts.aspx?AID=17091
3. Nanteza MW et al. 2011. A randomized trial of punctuated antiretroviral therapy in Ugandan HIV-seropositive adults with pulmonary tuberculosis and CD4+ T-cell counts >= 350 cells/uL. JID 2011:204 (15 September)
   http://jid.oxfordjournals.org/content/204/6/884.abstract

FDC: Fixed Dose Combination

Effective patent dates are listed in the agency’s publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the Orange Book:
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm

An updated list of generic tentative approvals is available on the FDA website:
http://www.fda.gov/oia/pepfar.htm

Source: FDA list serve:
http://www.fda.gov/InternationalPrograms/FDABeyondOurBordersForeignOffices/AsiaandAfrica/ucm119231.htm

Global Fund adopts restructuring recommendations and close to 50% funding shortfall for next round of grants

The Mma Bana trial compared antiretroviral regimens to prevent mother-to-child transmission in pregnancy, with highly efficacious results and some of the lowest reported in Africa [1]

The investigators performed a secondary analysis to look at the occurrence of preterm delivery (PTD) among women in the trial with CD4 counts >200 cells/mm3 randomised to receive either ABC+AZT+3TC or LPV/r+AZT+3TC initiated at 26 to 34 weeks gestation. We reported the results from this analysis – presented at CROI 2011 – earlier this year [2]

Kathleen Powis and colleagues published the complete results of the PTD analysis in the August 15 2011 edition of the Journal of Infectious Diseases with an accompanying commentary from Athena P Kourtis and Mary Glenn Fowler. [3, 4]

There were 263 and 267 women in the NRTI and PI groups respectively in this study. Baseline characteristics were similar in the two groups, the women were a median age of 26.4 years with CD4 counts of about 400 cells/mm3 and approximately 67% were between 26 and 28 weeks gestation at enrollment. Overall 88 (16.7%) women had spontaneous PTDs.

Gestational age was calculated using an algorithm that combined maternal reported last monthly period and ultrasound.

In a multivariate analysis, adjusted for self reported maternal income (p=0.02 for 3 df), the investigators found PI-based HAART was associated with a two-fold higher rate of PTD compared to triple NRTI-based HAART, 21.4% vs 11.8%, AOR 2.02 (95% CI 1.25-3.27), p=0.003.

The investigators proposed that less weight gain in pregnancy due to possible gastrointestinal side effects of the PI might explain the increased PTD risk. However, although the mean change in BMI on HAART was lower in the PI group (p<0.001) this was not significantly associated with PTD.

Of the 464 women who initiated HAART before 32 weeks gestation, 12 (2.6%) had very PTDs (<32 weeks gestation). Of these, 8 (3.3%) were in the PI group and 4 (1.8%) in the NRTI group, p=0.39. The investigators noted that, only 3 of 12 women who had very PTDs completed 30 days of HAART prior to delivery limiting the interpretation of these findings.

By 6 months of age, preterm infants were significantly more likely to have a least one severe or life threatening respiratory tract infection than term infants, 9.1% vs 2.0%, p=0.03. Preterm infants were more likely to be hospitalised than term infants, 22.7 vs 12.7%, p=0.02. Their mortality was also higher in the first 6 months, 6.8% vs 1.4%, OR 5.3 (95% CI 1.7-16.9), p=0.002, compared to term infants.

When the investigators looked at infant morbidity and mortality by maternal treatment arm the only difference they found was infants born to mothers randomised to the NRTI arm were more likely to experience meningitis, 1.9% vs 0%, p=0.03.

In their commentary, Kourtis and Fowler explain that this is the first randomised clinical trial to demonstrate a difference between rates of PTD according to antiretroviral regimen. Although observational studies and analyses have suggested a risk with PI use others have not found this association.

They note that the Mma Bana trial was not designed to look at PTD specifically so the sample size may not be sufficiently powered to do so. Assuming a background PTD rate of 20%, in the general population in Botswana, a much larger sample would be needed to detect an increase in the risk of PTD of the size that was observed in the PI group. They point out that one unexplained finding is the lower rate of PTD seen in the NRTI group whereas the rate in the PI group does not appear to differ from the background rate in Botswana.

Their commentary suggests that the study by Powis et al may, “raise more questions than it answers”, despite providing interesting data, obtained in a randomised fashion from a resource limited setting, in a field were more is needed.

They raise the issue of the timing of treatment (ie the relatively late initiation), noting a third of women who delivered prematurely had only received less than 30 days of HAART, which is too short a period for there to have been an association with immune reconstitution and the resulting cytokine shift, which is one proposed mechanism for PTD. The design of the study also limits the investigation of very PTDs, which result in the most severe infant outcomes.

The only other randomised trial that may offer some more information is Kesho Bora, which did not show elevated PTD rates among women receiving PIs compared to AZT and single dose NVP (started between 28 and 36 weeks except the NVP), respectively 13% vs 11%.

They caution against the possible interpretation of these data and write, “it is too early to rush into recommendations without validation from further studies and careful consideration of the question at hand”.

comment

Although not the primary study endpoint, these are the first RCT data showing an association between PI use in pregnancy and PTD. This is consistent with observational UK and European data, though not all from the US.

This association will be related to the PTD rate in the general population and other factors including timing of treatment.

References:

1. Shapiro R et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med 2010; 326:2282-94. http://www.nejm.org/doi/full/10.1056/NEJMoa0907736
2. Clayden P. Preterm delivery and HAART. HTB April 2011.
   http://i-base.info/htb/14823
3. Powis KM et al. Increased risk of preterm delivery among HIV-infected women randomised to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis 2011, 204: 506-13. http://www.ncbi.nlm.nih.gov/pubmed/21791651
4. Kourtis P and Fowler MG. Antiretroviral use during pregnancy and risk of preterm delivery: more questions than answers. J Infect Dis 2011, 204: 493-4. http://jid.oxfordjournals.org/content/204/4/493.full

A systematic review and meta-analysis by Nathan Ford and colleagues, to February 2010, showed no increase in overall birth defects with efavirenz (EFV) use in the first trimester of pregnancy compared to other antiretrovirals or the general population. [1,2] But, the authors were unable to come to a definitive conclusion concerning the risk of rare outcomes such as neural tube defects due to the limited number of reports.

The same authors recently updated the meta-analysis to July 2011 and these findings were published ahead of print as a research letter in AIDS. [3]

This update found 181 additional live births with first trimester efavirenz exposure.

Across 21 studies, included in the analysis, 39 defects were reported among live births to 1437 women. The pooled prevalence of birth defects was 2% (95% CI, 0.82-3.18%) and ranged from 0% to 22.6%. There was one neural tube defect (myelomeningocele), an incidence proportion of 0.07% (95% CI, 0.002-0.39%). Prevalence appeared to be higher in developed countries compared to developing ones, p=0.015.

An analysis of the 11 studies that reported birth defects among women receiving EFV-containing regimens (38 defects from 1289 live births) vs non-EFV regimens (316 defects from 8122 live births) gave a relative risk of 0.85 (95% CI, 0.61-1.20).

There was variable reporting of secondary outcomes across the studies: 8 reported spontaneous abortion (prevalence range 0% to 16.05%); 8 stillbirth (prevalence range 0% to 13.3%), 5 preterm delivery (prevalence range 9.1% to 18.2%) and 10 termination of pregnancy (prevalence range 0% to 33.7%). From the three studies that reported termination of pregnancy for EFV-exposed vs non-exposed pregnancies, the relative risk for termination of pregnancy with EFV exposure was 2.81 (95% CI, 0.94-8.36).

The authors wrote that this expanded review confirms the findings from their previous meta-analysis. The pooled prevalence of defects for first trimester EFV-exposed births of 2% is similar to that reported for first trimester non-EFV exposed births in the Antiretroviral Pregnancy Registry of 2.9% and in the general population of 6%. They note that the incidence of neural tube defects of 0.07% remains low.

They add that the main limitation of the review is the small sample size, with over 80% of the data coming from just four studies where prospective reporting of birth outcomes has been established. With data for only 181 found for the update in the 18 months since the original review, “Prospective surveillance systems particularly in developing countries are needed to improve data reporting and inform the assessment of rare birth defects”, they wrote.

comment

That there were data for, what would work out as, an average of ten efavirenz-exposed pregnancies reported per month since the previous analysis definitely highlights the authors conclusion.

If more countries go down the same path as Malawi and recommend universal efavirenz-based HAART (lifelong from initiation) for pregnant women, it is hoped that there will be good surveillance systems with these programmes to help to improve the numbers.

References:

1. Ford N et al. Safety of efavirenz in first trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. AIDS 2010; 24:1461-70. http://journals.lww.com/aidsonline/Fulltext/2010/06190/Safety_of_efavirenz_in_first_trimester_of.8.aspx
2. Clayden P. Pregnancy outcomes with efavirenz. HTB June 2010
   http://i-base.info/htb/10464
3. Ford N et al. Safety of efavirenz in first-trimester of pregnancy: an updated systematic review and meta-analysis. AIDS DOI:10.1097/QAD.0b013e32834cdb71

A study, first presented at CROI 2011, compared mother to child transmission rates for women receiving AZT (with or without single dose NVP) or HAART in pregnancy in the Botswana national programme. [1] We reported these data in the May issue of HTB. [2]

This prospective observational study conducted between February 2009 and April 2010, showed of 428 infants born to either 258 mothers receiving HAART or 170 mothers receiving AZT, those in the AZT group were significantly more likely to be HIV infected than those whose mothers received AZT, relative risk 13.9 (95% CI 1.8-108), p=0.001. There were nine transmissions in the AZT group and one in the HAART group.

Notably the women eligible for HAART had CD4 counts <250 cells/mm3 and those receiving AZT >250 cells/mm3.

Scott Dryden-Peterson and colleagues reported complete results in an online article published ahead of print in JAIDS. [3]

The overall findings are unchanged from those presented previously but the article includes some more details and discussion. The authors write: “Our findings do not support the equivalence of zidovudine and HAART for the prevention of MTCT.” In the study over half (5/9) infections in the AZT group occurred in women with CD4 counts <350 cells/mm3.

The authors observed difficulties with the delivery of single dose NVP in this cohort (women receiving <4 weeks of AZT were eligible) with only 5 (22.7%) women receiving this. Preterm delivery rather than delayed initiation was the main reason in this cohort for short duration of antenatal antiretrovirals, with nearly one-third of infants born preterm or of low birth weight.

They add that the findings from this study indicate that a strategy to provide HAART for all HIV-positive pregnant women, as is being piloted in Botswana, could almost eliminate infant HIV infection.

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Although better transmission results for women not indicated for treatment have been demonstrated in trials, programmers have often remarked that having a two-tiered approach to PMTCT is too complicated to implement.

References:

1. Dryden-Peterson S et al. Effectiveness of Maternal HAART vs ZDV to Prevent MTCT in a Programmatic Setting: Botswana. 18th CROI. Boston. February 2011. Poster abstract 740. http://www.retroconference.org/2011/Abstracts/42123.htm
2. Clayden P. HAART more effective than AZT monotherapy in the Botswana PMTCT programme. HTB May 2011.
   http://i-base.info/htb/14821
3. Dryden-Peterson S et al. Highly active antiretroviral therapy versus zidovudine for prevention of mother to child transmission in a programmic setting, Botswana. JAIDS. Publish ahead of print DOI: 10.1097/QAI.0b013e31822d4063.

Physiological and behaviour changes during pregnancy may increase risk of HIV transmission. Results from previous studies looking at HIV acquisition in women in pregnancy have been inconsistent. No study has looked at transmission from HIV-positive pregnant women to men directly.

Investigators from the Partners in Prevention HIV/HSV Transmission study – a randomised controlled trial of acyclovir suppressive HSV treatment for the prevention of HIV transmission in serodiscordant African couples – evaluated the relationship between pregnancy and risk of HIV acquisition in women and transmission from women to men. Nelly Mugo and colleagues reported findings from this study in an article published ahead of print in August 2011 AIDS.

There were 3321 couples included in the overall analysis, of these, in 1085 (32.7%) and 2236 (67.3%) couples, the man and the woman were the HIV-positive partner respectively. The median follow up was about 20 months. Pregnancy testing was quarterly.

At enrollment, 94 (8.7%) HIV-negative and none of the HIV-positive women were pregnant (pregnancy was an exclusion criterion for HIV-positive women). Subsequently, there were 226 and 503 pregnancies among the HIV-positive and HIV-negative women respectively, during the study period. This gave an incidence of 15.3 pregnancies per 100 person years, with 1480 person-years of follow up at risk of pregnancy for the HIV-negative women and 16.0 per 100 person-years with 3147 person-years of follow up at risk of pregnancy for the HIV-positive women. A proportion of women (27 from each group) had two pregnancies during follow up and one HIV-positive woman was pregnant three times.

Out of a total of 61 seroconversions among women, 17 (27.9%) were during pregnancy. The incidence of HIV during pregnancy was 7.35 per 100 person years compared to 3.01 per 100 person years during times when the women were not pregnant, HR 2.34 (95% CI 1.33-4.09), p=0.003. In multivariate analysis, this effect of pregnancy on HIV acquisition was weakened and did not reach statistical significance, AHR 1.71 (95% CI 0.93-3.12), p=0.08.

Of the 58 HIV transmissions to men, 12 (20.7%) were during pregnancy. The incidence of female to male HIV transmission was 3.46 per 100 person years during pregnancy compared to 1.58 per 100 person years, HR 2.31 (95% CI 1.22-4.39), p=0.01. This effect remained statistically significant in multivariate analysis, AHR 2.47 (95% CI 1.26-4.85), p=0.01. A subgroup analysis suggested the risk may increase in early and late pregnancy – AHR 2.64 (95% CI 1.02-6.84), p=0.05 and AHR 2.37 (95% CI 1.03-5.46) p=0.04 respectively – but the numbers in the subgroups were tiny (only 5 and 7)

The investigators also examined the use of antiretrovirals among women in pregnancy and the relationship to female to male transmission. Of the 503 pregnancies reported in HIV-positive women 216 (42.9%) resulted in live births, 143 (28.4%) in pregnancy losses, 14 (2.8%) had unknown outcomes and 128 (25.5%) were ongoing at study exit. The investigators noted that 119/143 (83.2%) of the pregnancy losses were before 20 weeks gestation, partly reflecting chemical pregnancies that were detected due to quarterly pregnancy testing in the study protocol.

Of the 216 pregnancies that ended in live births, 176 (81.5%) women received antiretrovirals but only 74 women received combination ART. The remainder received either short course or dual or single agent prophylaxis at the time of delivery. Of the 12 female to male transmissions during pregnancy, 9 (75%) women received antiretrovirals but this coincided with the time of transmission in only two couples. One woman was using short course AZT during labour and the second initiated ART in early pregnancy and her partner seroconverted shortly after. Adjustment for antiretroviral use in pregnancy did not alter the estimated risk of transmission, AHR 2.3 (95% CI 1.15-4.61), p=0.02.

The investigators wrote that this novel finding that pregnancy increases the risk of female to male HIV transmission has important public health implications and requires further studies to understand the possible biological mechanisms.

Reference:

Mugo N et al. Increased risk of HIV-1 transmission in pregnancy: a prospective study among African HIV-1 serodiscordant couples. AIDS published ahead of print August 2011.

In an article in the September 2011 edition of Antimicrobial Agents and Chemotherapy, Jennifer R King and colleagues from the P1058 protocol team reported pharmacokinetic (PK) data from children and adolescents treated with tenofovir (TDF) in combination with antiretrovirals with potential interactions.

PK results were shown for 47 participants aged 8 to 18 years, receiving a 300mg once daily TDF-based regimen. Participants received regimens that also contained an NTRI plus efavirenz (EFV) or darunavir/ritonavir (DRV/r) or atazanavir/ritonavir (ATV/r). The antiretrovirals and doses combined with TDF in are shown in Table 1.

Plasma samples were obtained pre-dose and over 24 hours. Statistical comparisons determined whether the 90% confidence intervals of the geometric mean (GM) AUC and Cmin for each antiretroviral were within 25% of those observed in previous studies demonstrating safety and efficacy. The AUC and Cmin target ranges and GMs (90% CI) are shown in Table 2.

BD: twice-daily; QD: once-daily.

Values mg*h/liter (AUC) and mg/liter (Cmin)

In the presence of EFV only the GM for TDF Cmin was very slightly above the target upper limit of the 90% CI. In contrast the GM (90% CI) for EFV Cmin was above the target upper limit. The investigators noted that EFV exposure was high overall in this analysis although the participants were dosed according to FDA recommendations; six participants with high exposure were receiving the EFV-based triple fixed dose combination (Atripla) which they suggest may alter drug absorption in this population. They recommend a crossover study comparing Atripla to the individual formulations in children and adolescents to answer this question.

The GMs (90% CI) for TDF AUC and Cmin were within the target ranges when it was given with DRV/r, however they were below the target ranges for DRV. The investigators wrote that these data suggest that higher than recommended doses of DRV may be necessary in paediatric patients in the presence of TDF, but the small sample size warrants a larger study to confirm these findings.

The GMs (90%CI) for TDF AUC and Cmin were only slightly higher in the presence of ATV/r, in contrast with that observed in healthy adults where these elevations are significant.

The investigators also observed that TDF PK did not differ between groups 1,2 and 3. This finding was unexpected as several PIs modestly alter TDF concentrations.

They concluded that none of the 90% CI AUC and Cmin values for the drugs tested were entirely outside the target range. So the recommended doses should provide exposure levels similar to that seen in adults. However they recommended that if individual patients experience adverse events or reduced clinical outcomes, while taking these agents in combination, monitoring exposure could be considered.

comment

Gilead has now filed with the FDA and EMA for an indication for tenofovir for the 2-12 year age group. In Europe tenofovir is not approved for adolescents aged 12-18 (although there is considerable off label use), so we may be faced with the curious situation of approval for the younger but not older age group of children and adolescents.

The WHO expert paediatric group, consider a fixed dose combination dispersible tablet of EFV/TDF/3TC, scored once on one side and twice on the other to make dividing easy, to be an essential missing formulation for treating children. Modelling suggests that dosing delivered with divided tablets could work with weight band tables.

WHO is producing a white paper on tenofovir use in children.

Reference:

King JR et al. Steady state pharmacokinetics of tenofovir-based regimens in HIV-infected paediatric patients. Antimicrob Agents Chemother 55: 4290-4.

An article in the July 31 2011 edition of AIDS describes atazanavir (ATV) pharmacokinetics (PKP in infants, children and adolescents given alone and boosted with ritonavir (ATV/r). Jennifer J Kiser and colleagues from the IMPAACT 1020A phase I/II study evaluated two formulations of ATV, capsules and a dispersible orange-vanilla flavoured powder across a range of age groups in treatment naïve and experienced participants from the United States and South Africa.

Participants were aged 91 days to 21 years and received unboosted or boosted (using ritonavir capsule or liquid formulations) ATV as part of a combination antiretroviral regimen. All participants underwent intensive 24-hour PK sampling on day 7; 195 enrolled and 172 had evaluable data.

All groups were started at a target dose of 310mg/m2. To establish an acceptable ATV or ATV/r dose for an age group, 10 participants had to meet PK and safety criteria as defined by the protocol.

For PK these were: ATV AUC AUC0-24hr of at least 30,000ng x h/mL and C24 of at least 60ng/mL in at least 80% of participants; no AUC0-24hr less than 15,000ng x h/mL and median AUC0-24hr of 60,000ng x h/m/L or less. And for safety: no life threatening toxicities; one or fewer participants with grade 3 or 4 toxicities (excluding bilirubin) linked to study treatment, and two or fewer participants with total bilirubin values greater than 5.1 times the upper limit of normal.

If these criteria were not met, the ATV starting dose was modified for the age group, either increased to 415, 520 then 620mg/m2 or decreased to 205mg/m2.

Nearly half (45%) of the participants were antiretroviral naïve at enrollment; 62% received ATV capsules and the remaining 38% ATV powder.

The investigators found unboosted ATV capsules met PK criteria at a dose of 520mg/m2 for participants >2 to 13 years of age and 620mg/m2 for those >13 to 21 years of age. Boosted ATV capsules met PK criteria at a dose of 205mg/m2 for those >2 to 21 years of age. Boosted ATV powder met PK criteria at a dose of 310mg/m2 for those >2 to 13 years of age.

Infants and young children aged 3 months to 2 years dosed with boosted ATV powder failed to meet PK criteria. There was a lot of intersubject variability in exposures this age group so that a dose escalation to 415mg/mL may have given ATV exposures in some young children greater than 90,000ng x h/mL.

The investigators wrote that additional studies are needed in this age group to determine if an appropriate ritonavir boosted dose can be identified.

Reference:

Kiser JJ et al. Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV infected infants, children and adolescents. AIDS 2011, 25:1489-96.

Crushing lopinavir/ritonavir (LPV/r; Kaletra) tablets is not recommended by the manufacturer as pre-clinical studies showed poor absorption with this method of administration compared to whole tablets with a single dose.

The liquid formulation of LPV/r is unpalatable and inconvenient so administrating crushed tablets could potentially overcome this barrier to the paediatric use of this PI.

As single dose pharmacokinetics (PK) do not predict steady state LPV concentrations (due to the complex interaction with ritonavair [RTV]), investigators from the Children’s National Medical Center (CMC) in Washington, DC, looked at LPV/r exposure in whole and crushed 200/50mg tablets in children. Results were published ahead of print in JAIDS.

Brookie M Best and colleagues conducted a prospective, open label, cross over PK study in 13 (6 boys, 7 girls) children and adolescents with a median age of 13 years (range 10-16) taking LPV/r tablets BID as part of their antiretroviral regimen with two NRTIs. The median LPV/r dose was 275/69mg/m2 (range 193/48-372/93mg/m2. Two participants were excluded from the analysis, one refused to take the crushed tablets, and the other had very low or undetectable levels of LPV with both methods of administration. Data are from 11 participants.

The median LPV AUC, after receiving crushed and whole tablets respectively were, 92 (IQR 79-103) mg*hr/L and 144 (IQR 101-202) mg*hr/L; crushed/whole GM 0.55 (90% CI0.45-0.69), p=0.003. The corresponding values for RTV were AUC 7(IQR 4.5 -11.1) mg*hr/L and 13.3 (IQR 9.6-17.9) mg*hr/L; GM 0.53 (90% CI 0.4-0.71), p=0.006.

Oral CL/F (L/hr/m2) was significantly increased with crushed tablets for both drugs, respectively 1.4 and 1.6 times for LPV and RTV. The maximum post dose concentrations (Cmax) were also reduced, (significantly for LPV, p=0.021) with crushed tablets.

The investigators wrote: “The reduced exposure with crushed Kaletra tablet dosing reinforces the need to discourage this practice.”

comment

This study was conducted prior to the introduction of the smaller tablet formulation (100/25 mg, LPV/RTV).

These data reinforce both the importance of following manufacturers instructions about dividing protease inhibitors and the need for an alternative formulation to the oral suspension. The sprinkle formulation, being developed by Cipla and studied in CHAPAS 2, is still eagerly awaited, particularly for the very young age group.

Reference:

Best BM et al. Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. JAIDS. Publish ahead of print. DOI: 10.1097/QAI.0b013e318232b057.
http://217.160.60.64/2/medicine/art/jaids.htm

The World Health Organisation (WHO) has updated its guidelines for drug-resistant TB. [1]

The guidelines were last published in 2008. [2]

The guidelines make eleven recommendations. All of them were supported by very low quality evidence.

1. Rapid drug susceptibility testing of isoniazid and rifampicin or rifampicin alone is recommended if there are resources to do it and if rifampicin resistance is not rare in the patient group. Currently the line probe assay and the GeneXpert are the only diagnostic tools to meet the WHO criteria for rapid diagnosis (two days or less).

2. Sputum smear microscopy and sputum smear culture, rather than sputum smear microscopy alone is recommended for the monitoring of patients with MDR TB during treatment.

This is a change from the 2008 guidelines that recommended monthly sputum smear microscopy and culture examination prior to culture conversion to negative and quarterly culture, with monthly smear examination after conversion.

Data pooled from 10 observational studies indicated that monthly sputum smear microscopy and culture performed best at identifying treatment failures early. This is conditional recommendation because of the resources required to implement it.

3. MDR TB patients should be treated with a flouroquinoline. This is a strong recommendation.

4. MDR TB patients should be treated with a late-generation flouroquinolone (levofloxacin, moxifloxacin, gatifloxacin and sparfloxacin) rather than an earlier-generation one. This is a conditional recommendation.

5. MDR TB patients should be treated with ethionamide or prothionamide. This is a strong recommendation.

6. In the treatment of MDR TB patients, four second-line drugs likely to be effective (including an injectable, kanamycin, amikacin or capreomycin) as well as pyrazinamide should be included in the intensive treatment phase. This is a conditional recommendation.

7. MDR TB patients should be treated with at least pyrazinamide, a fluoroquinolone, an injectable, ethionamide (or prothionamide) and cycloserine (or PAS if cycloserine cannot be used). This is a conditional recommendation.

Recommendations 3 to 7 were based on the results of three systematic reviews of observational data. Bias was likely substantial because some drugs may have been used for sicker patients. Nevertheless, this is the best available evidence.

Analysis showed that in the intensive phase a regimen with at least four drugs was likely to be effective. The analysis did not show any injectable to be superior to any other, so kanamycin is recommended because of its lower cost.

Fluoroquinolones were significantly associated with cure and this association was greater with later-generation ones. The recommendations gave higher weight to interventions that increased the risk of cure and reduced the risk of failure, relapse and death. Consequently fluoroquinolines were strongly recommended despite potential long-term serious adverse events. The recommendation for later-generation fluoroquinolines was conditional because of the unknown long-term side effects of these drugs. Ciprofloxacin may have some anti-TB activity but it should not be used.

For oral bacteriostatic drugs the association with cure was higher for ethionamide than cycloserine which was higher than PAS. PAS is only recommended if there is no other effective drug available to make up the four-drug regimen. No significant association between cure and any of the following was found: amoxicillin/clavulanate, azithromycin, clarithromycin, clofazimine, roxithromycin and thiocetazone.

There were too little data on linezolid and high-dose isoniazid. Pyrazinamide showed slight benefit in one analysis.

Patients with XDR TB were excluded from this analysis so these recommendations do not necessarily apply to them. Nevertheless, the WHO recommends that the same principles used to design MDR TB regimens should be used for XDR TB regimens.

The regimen composition recommendations differ only in small nuances from the 2008 guidelines. Ethambutol has been removed as an alternative to pyrazinamide in the new guidelines, albeit that the new guidelines acknowledge that the decrease in efficacy associated with ethambutol in their analysis could be due to confounding.

8. The intensive phase of treatment for MDR TB patients should be at least eight months. This is a conditional recommendation.
9. A total treatment duration of at least 20 months is recommended.

The evidence base for recommendations 9 and 10 is the same as recommendations 3 to 7 and subject to confounding and bias. There was an association between treatment success and the length of treatment and the length of the intensive phase.

The 2008 guidelines recommended at least six months intensive phase treatment and at least 18 months of total treatment.

10. ART is recommended for all HIV-positive patients with MDR TB irrespective of CD4 count, starting within eight weeks after TB treatment. This was a strong recommendation.

Ten studies, none of them randomised controlled trials, informed this recommendation. The quality of evidence varied from low to very low quality. The recommendation is based in part on evidence from studies for any patients with TB and HIV (ie majority non DR patients).

11. Patients with MDR TB should be treated using mainly ambulatory care rather than models of care based on hospitalisation. This is a conditional recommendation. The data for this recommendation came from published and unpublished studies in Estonia, Peru, Philippines and Russia, but none of these were randomised controlled trials. Nor did these studies allow direct comparisons of effects between models of care. The key considerations informing this recommendation was that the cost per disability adjusted life-year was generally lower in outpatient models and that these models appear to reduce exposure to infectious drug-resistant patients. However, the guidelines warn that ambulatory care can shift the burden of cost from the service provider to the patient (eg increased travel and food costs). Therefore implementation of ambulatory care models must be accompanied by provision of what the document calls “appropriate enablers”.

The guidelines state that important gaps in knowledge should be addressed in future research, particularly in the context of large-scale expansion of treatment for patients with drug-resistant TB. The document further calls for randomised controlled trials to determine the best combination of drugs and optimal treatment duration. Further research on (1) paediatric MDR TB treatment, (2) best regimens for patients with isoniazid resistance, (3) prophylaxis for contacts of MDR TB and (4) therapy for relief from adverse reactions due to second-line drugs is needed.

comment

A common theme throughout these guidelines is the lack of evidence to support the recommendations.

The development of new TB drugs like TMC207 and OPC-67683 needs to be completed. The phase IIB trial results of TMC207 suggest that it is already better tested than many second-line TB drugs and therefore should be available to patients.

MSF has pioneered outpatient MDR TB care in South Africa. It would strengthen recommendation 11 if they published more data on this.

References:

1. WHO. Guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.
   http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf
2. WHO. Guidelines for the programmatic management of drug-resistant tuberculosis, Emergency update 2008, WHO, Geneva, 2008.
   http://www.who.int/entity/tb/challenges/mdr/programmatic_guidelines_for_mdrtb/en/index.html

The 2011 edition of the World Health Organisation’s Guidelines for Intensified Tuberculosis Case-finding and Isoniazid Preventive Therapy for People Living with HIV in Resource-Constrained Settings has 12 recommendations. [1]

The fourth recommendation says that adults and adolescents living with HIV who have an unknown or positive tuberculin-skin-test (TST) status and who are unlikely to have active TB should receive at least 36 months of Isoniazid Preventative Therapy (IPT). Furthermore, IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women. The WHO says this is a strong recommendation with moderate quality of evidence to support it. The third recommendation is identical except that six months instead of 36 months of IPT is recommended and this is ranked as a strong recommendation with high quality of evidence.

The Guidelines for Tuberculosis Preventative Therapy Among HIV Infected Individuals in South Africa, published in 2010, are consistent with recommendation three. They further state, “Clinical trials have shown that the benefit of TB preventive therapy is greatest in HIV-infected persons with a positive tuberculin skin test. Where tuberculin tests are feasible and can be performed, IPT should only be offered to those who are TST positive. However, the practicalities and logistics of doing a tuberculin skin test are often an obstacle for provision of TB preventive therapy. Therefore the tuberculin skin test is no longer required to identify HIV infected people eligible for IPT.” [2]

This article deals solely with adults who are not pregnant, who are not health-workers with HIV and not in special high-risk settings such as mines or prisons. The removal of the necessity of the Mantoux test to determine TST status from IPT guidelines is concerning, as the data summarised here demonstrates.

Cochrane Review of IPT trials

A Cochrane Review of short-course chemotherapy trials (6 to 12 months) to prevent TB was published in 2010. [3]

Twelve trials met the strict criteria for inclusion in this meta-analysis. In all, 4811 participants were TST positive, 2030 were TST negative. Of these, 1,640 were known to be unable to mount an immune response to the Mantoux test (ie they were anergic). The TST status in 1737 participants was unknown. No differences were found in trials that compared effectiveness of different combinations of drugs, but all regimens significantly reduced the risk of TB as shown in Table 1.

Using INH alone reduced the incidence of confirmed, probable or possible TB by 32% (RR: 0.67 95%CI: 0.51-0.87, n=4136).

However, when analysed by TST status, the effect was only significant for TST positive participants as table 2 shows.

IPT showed no mortality benefit (RR: 0.95; 95%CI 0.85-1.06). When analysed by TST status, the benefit only just reached significance in TST positive participants (RR: 0.74; 95%CI 0.55-1.00) and there was no benefit to TST negative (RR: 1.02; 95%CI: 0.90-1.16) or TST status unknown participants (RR: 0.81; 95%CI: 0.52-1.27).

Botusa Trial

The Botusa trial has previously been reported in HTB South. [4]

Since then it has been published in the New England Journal of Medicine. The results of the trial, contrary to the way it has been reported, are not a resounding success for long-term IPT; on the contrary the trial raises difficult questions. [5]

In this double-blind randomised controlled trial in Botswana, 989 HIV-positive participants were randomised to receive six months of isoniazid and 1,006 were randomised to receive 36 months of isoniazid. All participants received open-label isoniazid for the first six months, after participants either took placebo or isoniazid for 30 months. Only 2% of participants were on ART at the start of the trial. At the end of the open-label phase, 821 participants continued in the placebo group and 834 in the isoniazid arm.

TB incidence between the two groups diverged at 200 days after the open-label phase, indicating not unexpectedly that the benefits of short-course IPT were transient.

The protocol defined definite, probable and possible TB as follows:

• Definite: one or more culture was positive M tuberculosis or if two or more sputum smears were positive for acid-fast bacilli
• Probable: one sputum smear or one biopsy specimen was positive for acid-fast bacilli
• Possible: if smears and cultures were negative or not done. A death defined as possibly related to tuberculosis was one that had clinical or verbal autopsy evidence consistent with tuberculosis as the proximate cause of death.

In an analysis of participants that actually remained on the study after the open-label phase ended, the only statistically significant result in favour of long-term IPT was the reduced incidence of definite, probable and possible TB, and here the confidence interval was wide (25 on placebo versus 12 on isoniazid; HR: 0.47; 95%CI: 0.24-0.94). No significant difference between the arms could be found when only definite and probable cases were counted (18 versus 10; HR: 0.55; 95%CI: 0.25-1.18). Nor was there significant difference if TB (definite, probable and possible) and deaths were combined (41 versus 37; HR 0.89: 95%CI: 0.57-1.39). However there were more deaths in the long-course arm, although this was not significant (16 versus 25; HR 1.54; 95%CI: 0.82-2.88).

When analysed by TST status, TST positive participants benefited from 36 months IPT. There were 11 cases versus only 1 case of definite, probable and possible TB (HR: 0.08; 95%CI 0.01-0.61). There were 10 cases versus only 1 case of definite and probable TB (HR:0.09; 95%CI 0.01-0.67). TB (definite, probable and possible) and all deaths were also significantly better (20 versus 4; HR: 0.17; 95%CI: 0.06-0.50). When just deaths were looked at, the 36 month arm did better though this was not significant (9 versus 3; HR: 0.28; 95%CI: 0.08-1.03).

However, the results for TST negative participants were surprising and worrying. There were no significant differences or even trends with respect to TB. But there were 21 deaths on the 36 month arm versus 7 on the short-course arm and this was significant (HR: 2.99; 95%CI: 1.27-7.04).

The reasons for this are unclear. Only one death, due to hepatic encephalopathy, appeared to be due to a known isoniazid side-effect. The adverse event rates between the arms were almost identical (1% versus 1.3%). Nevertheless, this was a double-blinded RCT and the significantly higher deaths in TST negative people in the 36 month arm should not be ignored.

comment

The findings of the Cochrane Review and the Botusa trial show that TST status is relevant. There is no evidence that TST negative people benefit from any form of IPT prophylaxis.

In the case of long-term prophylaxis, which is now recommended by WHO guidelines and likely where other guidelines are heading, TST negative people could be put at risk of harm unnecessarily.

Guideline writers appear to be focusing on reduced TB incidence demonstrated by IPT studies. But mortality is surely a more important measure from the perspective of patients than TB incidence.

Overall, the short-course IPT studies show no significant mortality benefit when TST status is not taken into account. And in the one major long-course IPT trial there is unequivocally no mortality benefit if TST status is not taken into account. The Mantoux test should therefore not be removed from guidelines.

There is a concern that implementing the Mantoux test is too burdensome for many health facilities. If that is the case, then we need to ask if such facilities should be implementing IPT, especially long-course IPT.

References:

1. WHO. 2011. Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings.
2. South African Department of Health. 2010. Guidelines for tuberculosis preventative therapy among HIV infected individuals in South Africa.
3. Akolo C et al. 2010. Treatment of latent tuberculosis infection in HIV infected persons.
   http://www2.cochrane.org/reviews/en/ab000171.html
4. Geffen N. Botswana IPT trial: Continuous isoniazid superior to 6 months short course. HTB South, April 2010.
5. Samandari T et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet 2011 May 7; 377(9777):1588-98.
   http://www.ncbi.nlm.nih.gov/pubmed/21492926

On 28 September 2001, the Microbicides Trial Network (MTN), announced that following an interim review by the Data and Safety Monitoring Board (DSMB), the study would be unable to show a reduction in transmissions in patients using daily oral teneofovir and that this arm of the study would be stopped.

Previous studies have reported a strongly protective effect in both high-risk MSM (iPrEX study) and heterosexual populations (Partners in Prevention and TDF2 studys) with a negative result reported in heterosexual women (FEM-PrEP study). The Caprisa 004 study found a 43% protective effect of daily tenofovir gel.

The phase 2b VOICE (Vaginal and Oral Interventions to Control the Epidemic) study has enrolled more than 5,000 HIV-negative women at 15 clinical research sites in Uganda, South Africa and Zimbabwe.

The study randomised women to one of five groups: daily oral tenofovir, daily oral Truvada, daily oral placebo tablet, daily tenofovir gel or daily placebo gel.

The remaining four arms will continue to be studied, with results expected in 2013.

Information on the numbers of HIV infections that have occurred in any of the study arms will not be available until this time. Without this analysis it is impossible to know explain the current study results.

References:

MTN press release. MTN statement on decision to discontinue use of oral tenofovir tablets in VOICE, a major HIV prevention study in women. (28 September 2011):
http://www.mtnstopshiv.org/node/3619

Questions and Answers about the modification of VOICE study:
http://www.mtnstopshiv.org/node/3622

Summary of other PrEP studies:

http://www.avac.org/ht/d/sp/i/326/pid/326.

This report covers the most recent and exciting developments in HIV, hepatitis and TB research.

The report was launched at the IAS conference in Rome but if you missed a print copy there, you will need to go online.

At 160 pages we are going green this year and publishing this in the UK as web articles and PDF file, although a limited print run of a second edition will be produced by TAG in the US.

Sections include:

• Introduction and executive summary
  • Dedication
  • Acknowledgments
• The antiretroviral pipeline
• The paediatric antiretroviral pipeline
• HIV point of care diagnostics pipeline
• Patents and the pipeline: is access under threat?
• Preventive technologies, immune-based and gene therapies, and research toward a cure
• The hepatitis C treatment pipeline
• The tuberculosis diagnostics pipeline
• The tuberculosis treatment pipeline
• The tuberculosis vaccine pipeline

The report is dedicated to Dr Robert Carr and David Kato Kisule.

We conclude our reports form the BHIVA and CROI meetings this year and include exciting news on treatment access due to Gilead entering an agreement with the Medicines Patent Pool.

New recently approved drugs (in the USA) include the new NNRTI rilpivirine and a new triple drug fixed-dose combination of rilpivirine/tenofovir/FTC.

We also launched the i-Base/TAG 2011 pipeline report in Rome as a supplement to HTB that updates the pipeline development of all important drugs, diagnostics and treatment strategies for HIV, hepatitis and TB.

Introduction

The biannual IAS Conference on HIV Pathogenesis, Treatment and Prevention is more scientifically focused than the World AIDS Conference held in alternate years and is considerably smaller. This makes both attending and reporting more manageable and concentrated.

This year the conference was held in Rome. While plenary lectures were held in the concert halls designed by Renzo Piano (the architect designing the Shard Tower in London), smaller meetings were often in rooms with a capacity of only 50 people and the poster and exhibition halls were less than ideal, being held in the venues garages.

Even prior to the conference, the frenzy to gain media coverage filled email boxes with press releases that made it clear that the meeting would be dominated by prevention studies.

The leading prevention reports, first and most importantly, involved the reduction in transmission from use of HIV treatment for HIV-positive people. The risk is not reduced to zero, but it is getting close, especially when condoms remain the mainstay of prevention work. It means that if a condom breaks, slips off, or is not used at all, an HIV positive person who has had an undetectable viral load for over six months would find it difficult to transmit HIV.

The shift in medical consensus is dramatic. While the Swiss Statement three years ago was met with anger publically from many prominent doctors, in private most also recognised that viral load was the driving factor behind transmission risk. It was good to hear Pietro Vernazza who authored the Swiss paper ask Myron Cohen after presenting the results of HPTN 052 on whether Cohen’s new results had prompted a change of heart.

IAS in Rome included four oral presentations from the HPTN 052 study. Together they showed that HIV-positive people in high incidence resource limited settings (predominantly Africa, Asia and Latin America) who started treatment at a CD4 count of 350-550 reduced the risk of transmitting HIV to their HIV-negative primary partner by 96% compared to people waiting until their CD4 count was 250. This was a study that intensely integrated other prevention strategies – condom provision and counselling reduced transmission too, but treatment extended this significantly further.

The second way that treatment reduces transmission was supported by new studies reporting the benefits of PEP/PrEP strategies. These involved HIV negative people taking a daily pill of tenofovir/FTC, or tenofovir alone, which led to reductions in their risk of catching HIV.

As with previous meetings, the conference has an open-access searchable abstract database online.

http://www.ias2011.org

However, many oral presentations are not included as webcasts or PowerPoint slides.

The ‘Programme at a glance’ can be searched for key words but requires a free software upgrade Silverlight which is quick and easy to do. Then from this page you can search abstracts or presentations.

http://pag.ias2011.org/

Sessions with PowerPoint slides or webcasts have relevant icons next to them. As with previous years, the PowerPoint links on the left under the session time are not active, so to download PowerPoint files scroll down to the bottom of the session page

We have also included reports from the 3rd International Workshop on HIV Pediatrics immediately preceding IAS 2011. This small annual meeting is becoming quite established and although abstracts are often submitted to both meetings, in this one they may often get an oral presentation instead of just a poster. For those specialising in paediatrics this meeting is a welcome opportunity to present and discuss work in a dedicated forum. Abstracts and presentations are online. We have included references from both meetings in our paediatric reports.

http://regist2.virology-education.com/abstractbook/2011_8.pdf

http://regist2.virology-education.com/2011/3HIVped/15_July.html

Reports in this issue of HTB South include:

• Webcasts for major research at IAS
• Treatment is prevention: ARV treatment in HPTN-052 reduces transmission by at least 96%: single transmission in treatment arm occurred prior to viral suppression
• Daily oral tenofovir/FTC PrEP reduces heterosexual transmission by 63% in the TDF2 study
• Tenofovir/FTC vs tenofovir as daily oral PrEP: preliminary results from Partners PrEP
• Elvitegravir vs raltegravir: 48 week results in treatment-experienced patients
• Dolutegravir: 48 week results from phase II study in treatment-naïve patients
• Lersivirine: 48 week results compared to efavirenz in phase 2 treatment-naïve study
• SPARTAC trial: treatment in primary infection for 48 weeks shows small delay in disease progression
• Hearing loss not associated with HIV in MACS and WIHS cohorts
• Pharmacokinetics of darunavir and fosamprenavir in pregnancy
• Low birth weight and preterm delivery
• Hormonal contraception and HIV transmission risk
• No difference in AIDS-free survival in children starting ART with a CD4% between 15%–24% compared to deferring until less than 15% in the PREDICT trial
• Paediatric antiretroviral pipeline: update on etravirine and maraviroc
• More metabolic abnormalities in children receiving a PI compared to NNRTI in NEVEREST study
• Prematurity not associated with early mortality in infants on ART
• Free online resource for treatment decisions without access to genotype resistance tests

Unless stated otherwise, all references are the Programme and Abstracts of the 16th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 17–20 July 2011, Rome.

Firstly, treatment as prevention – most notably in a study called HPTN-052 and PrEP studies. The Treatment Is Prevention session include links to abstracts, slides and webcasts from the HPTN-052 study.

http://pag.ias2011.org/session.aspx?s=98

Secondly, research relating to reservoirs, eradication and the cure was established throughout the programme. This included overviews of the different ways that this could be approached and preliminary results for early potential targets. Unfortunately very few of the lectures in these sessions are webcast. However, the overview by Anthony Fauci, is online and worth watching to understand the new strengthening steer from the US that dominates global research.

Tony Fauci: 30 years of HIV/AIDS: a scientific journey and a look to the future

http://pag.ias2011.org/flash.aspx?pid=409

Towards an HIV cure: insight into residual viral replication, establishment of reservoirs and understanding mechanisms of persistence

http://pag.ias2011.org/session.aspx?s=70

Towards an HIV cure: new strategies for an old challenge

http://pag.ias2011.org/session.aspx?s=15

Controversies in HIV cure research satellite meeting

http://pag.ias2011.org/session.aspx?s=39

Thirdly, there were important studies about New drugs and diagnostics and new strategies with oral presentations on new integrase inhibitors (elvitegravir and dolutegravir) and NNRTIs (lersivirine), using of HSV drugs (acyclovir/valacyclovir) and currently approved meds (maraviroc/atazanavir). Plus, also in the late breaker session, an exciting new rapid antibody test for cryptococcal meningitis developed in the UK that can be used at the point of care. These were presented mainly in the following two sessions.

New drugs and strategies

http://pag.ias2011.org/session.aspx?s=55

Late breaker Track B

http://pag.ias2011.org/session.aspx?s=44

Simon Collins, HIV i-Base

Four of the six oral presentations in the ‘Treatment is prevention: the proof is here’ session reported on the results from HPTN 052. [1] This study had been unblinded four years earlier than planned due to a review by the data and safety monitoring board (DSMB), with all patients now being offered active treatment.

In summary, HIV-positive people on treatment had a 96% reduction in sexual transmission to their HIV-negative partners if they started ARVs with a CD4 count of 350-550 cells/mm3 compared to waiting until it dropped below 250 cells/mm3. As with all prevention studies, condoms, testing and intensive counselling was included throughout the study.

The main study results were presented by Myron Cohen from University of North Carolina. [2]

HPTN 052 screened over 10,000 couples in order to randomise 1763 HIV-positive people with CD4 counts 350-550 to either immediate or delayed HIV treatment (CD4 confirmed <250 or an AIDS-defining illness). Screening failure was mostly due to CD4 or other criteria in the positive partner, but 300 couples were already both HIV-positive. This was an international study predominantly recruiting in Africa (Botswana, Kenya, South Africa and Zimbabwe, n=954), Asia (India and Thailand, n=531) and Latin America (Brazil, n=276). Men and women were equally distributed as the positive partners. Median baseline CD4 count was 436 cells/mm3 (IQR 365-522) and viral load was approximately 25,000 copies/mL (IQR 6,000-80,000) respectively.

This was generally a low risk population with only 6-8% reporting recent unprotected sex and only 16% aged 18-25 years (~ 60% were 25-40 years and ~20% > 40 years).

The primary transmission endpoint was the prevention of virologically linked transmissions with a primary clinical endpoint of WHO Stage 4 events (including pulmonary TB, severe bacterial infections and death).

Transmission events (n=39) occurred significantly less frequently in the immediate (n=4) compared to the deferred (n=35) treatment arms, p<0.0001. Of these, only 28/39 were linked transmissions (within the couple) with 1 case in the immediate arm vs 27 cases in the deferred arm, p=0.001 (see below for details). Eleven transmissions were either unlinked or undetermined. This translated to incidence rates of linked transmission of 0.1 (95%CI 0.00-0.04) vs 1.7 (95%CI 1.1-2.5) per 100 person years respectively over a median follow-up of 1.7 years.

The single transmission in the immediate treatment arm was detected at the first follow-up visit. However viral diversification analysis estimated that transmission occurred prior to the positive partner initiating treatment (baseline 87,000 viral load) or certainly prior to viral suppression to <400 copies/mL which was recorded at day 28.

Other transmission risk factors were similar between arms, including rates of STIs (low at <5% in both index and partner at baseline and during the study), sexual activity (approximately 70%) and condom use (>90% by all throughout).

Viral suppression (<400 copies/mL) was maintained by >90% of participants in the immediate arm. There was a slow increase in this percentage over time in the deferred arm as people started treatment (from <10% over the first year, 20% by month 24 and increasing to 50% at month 45, though with much fewer patients). The median viral load closest to the time of transmission in the deferred arm was considerable at 80,000 copies/mL but had a wide range from 600 to 630,000 copies/mL.

In multivariate analysis, treatment was the strongest protective effect [HR=0.04, 95%CI 0.01-0.28] compared to condom use [HR=0.33; 95%CI 0.12-0.91]. Factors associated with increased transmission included baseline viral load [per log increment: HR 2.84, 95%CI 1.51-5.41] and baseline CD4 count [per 100 count increment: HR 1.24 95%CI 1.00-1.54].

The second presentation by Susan Eshelman from Johns Hopkins University School of Medicine focused on the analysis of linked transmission. [3] This included a helpful introduction to the three types of phylogenetic analyses used: phylogenetic analysis of HIV pol sequences using population sequencing, and statistical analysis of genetic distances from pol sequence pairs for the clearest cases (n=26), and phylogenetic analysis of env sequences obtained by deep sequencing for more complex cases (n=12). Together these provided a high level of reliability for indentifying whether the source of new infections was the HIV-positive partner or whether this was from another partner.

Transmissions in previous serodifferent couple studies have been from outside the main relationship in 25-50% cases.

The deep sequencing (‘ultradeep pyrosequencing’) supported linked two further cases and confirmed non-linkage for seven others (4 in the immediate and 3 in the deferred arm). Three cases remained unidentified (all in the deferred arm). Transmission linkage was not associated with index partner gender or CD4 count, geographical regions or time on study but this was strongly associated with study group and number of sexual partners in the three months prior to new seroconversions.

Results on the clinical outcomes for the HIV-positive participants in HPTN 052 were presented by Mina Hosseinipour from the UNC Project, Malawi. [4]

Results comparing the two groups were presented as ITT analyses and included the approximate 20% (184/877) people randomised to the deferred arm who started treatment during follow-up.

Over two years, median CD4 counts increased from 442 to 662 cells/mm3 in the immediate group compared to reducing from 428 to 390 cells/mm3 in the deferred arm. These differences are blunted as the deferred arm includes the response for the 20% people who started treatment. Viral suppression was achieved and maintained <400 copies/mL by >90% of the immediate arm. Less than 5% of patients on immediate treatment experienced virological failure during follow-up with most (60%) of these switching to a second-line combination.

The decision to start treatment in the deferred arm was driven by CD4 declines in 75% of cases. This occurred at a median count of 225 cells/mm3 (IQR 199–247), with 25% over people not starting until their CD4 count was less than 200. Treatment in both arms was predominantly AZT/3TC/efavirenz (70%) with ~10% using AZT/3TC/atazanavir, and ~10% using tenofovir/3TC/efavirenz. CD4 responses in the deferred arm were similar to absolute increase in the immediate treatment arm but remained significantly lower at all timepoints, reflecting the lower counts when starting treatment. Although there are fewer patients with longer duration of follow-up in the deferred arm, other studies have reported that baseline CD4 correlates with CD4 response after treatment.

The analysis by geographical region reported that about 80% of both the linked and unlinked transmission events occurred in African sites, likely a reflection of the higher background population prevalence rates in those countries, although the researchers highlighted higher rates of unprotected sex in the last week (by 9% vs 4% of African vs non-African) and higher sexual activity (>3 acts). However, baseline CD4 count, viral load and adjusted time to initiation, median adherence (99%) and treatment responses were similar between African and Asian sites.

Further details on clinical outcomes were presented by Beatriz Grinsztejn from the Oswaldo Cruz Foundation, Rio de Janeiro. [5]

Primary clinical events occurred at least once in 105 participants over 3304 person-years (PY) of follow-up; 40 in the immediate arm (2.4/100PY) and 65 in the delayed arm (4.0/100PY), hazard ratio (HR) 0.59, 95% CI: (0.40, 0.88), p=0.01. Seventeen people experienced more than one event. Time to event was significantly shorter in the deferred arm (HR 0.6, 95%CI 0.4, 0.9, p=0.01)

CD4 counts were significantly higher in the immediate arm vs deferred arms for all clinical endpoints (TB 518 vs 316; bacterial infection (mainly pneumonia) 551 vs 337 and death 476 vs 372 cells/mm3 respectively).

The between-arm difference was driven by extrapulmonary tuberculosis with 3 cases in the immediate versus 17 cases in deferred arms (p< 0.002). These were peripheral lymph nodes (2 vs 4), abdominal (0 vs 8), pleural (1 vs 3), skeletal (0 vs 1) and meningeal (0 vs 1). Isoniazid prophylaxis was only being used by 4% of patients in each arm at baseline.

Of the 23 deaths observed, there was no difference between arms: 10 in the immediate arm and 13 in the delayed arm [HR 0.77, 95% CI: (0.34, 1.76), NS p>0.5]. Causes of death were similar, but with 3 vs 3 suicides; 0 vs 2 accidents; and 3 vs 6 unknown).

Adverse events potentially related to ART were reported in 24% of subjects in the immediate arm and 5% in the delayed arm, but severe or life-threatening events occurred equally in 14% of each group and grade 4 lab events were also similar (in <1-2% of participants).

Since the DSMB recommendation in April 2011, all participants in the deferred arm have been offered HAART based on the strength of the study findings. This study continues to monitor all participants and results will add to clinical data from use of earlier vs later treatment in people with CD4 counts >350 cells/mm3.

comment

These results add to research that not only correlates viral load with risk of sexual transmission but specifically demonstrates a protective impact with treatment. The two cases of transmission in the early treatment arm (a second was discussed during the presentation) were both detected at the beginning of the study prior to the positive person reaching suppressed viraemia <400 copies/mL.

The fewer clinical endpoints from earlier treatment for the HIV-positive partners in this study are important but were driven by extrapulmonary TB. This clinical difference has significance for people in geographical regions where this study was run, but this aspect of the results was unexpected and has yet to be explained. A more generalisable benefit to people in Western countries is probably the reduced CD4 response in the deferred arm and this needs to be supported by longer follow-up. The ongoing START study will report on whether clinical benefits result from earlier treatment in Western countries.

It would be interesting to model the potential number of transmissions that have already been prevented over the last ten years from the seven million people globally on HAART. Given the financial constraints of access to treatment the additional impact on prevention should be included in future cost: benefit analysis.

The results from HPTN 052 clearly support offering an option for treatment to HIV-positive people who have HIV negative partners. This has been included in UK (BHIVA) guidelines for many years.

When access to treatment is limited with a waiting list using CD4 upper cut-offs to access treatment, those with the most severe medical should clearly be prioritised. However, the majority of the nine million people currently identified by UNAIDS and WHO analyses as requiring but not yet able to access treatment are likely to be undiagnosed. Broadening the CD4 criteria for access to treatment as prevention at higher CD4 counts is unlikely to directly deny access to treatment for more advanced patients.

It was unfortunate that a WHO guideline due to be launched at the IAS meeting, that included the recommendation for treatment people with CD4 counts higher than 350 and who have HIV-negative partners, based on the HPTN 052 study was withdrawn at the last minute. [6]

Although printed for a launch at the conference there is concern that while the scientific evidence is clear – and this should be the focus for clinical guidelines – practical issues on implementation have stalled their release perhaps under pressure from prominent WHO funders. It is difficult to understand how such a useful document that included broad community consultation and approval to the stage of print would have been retracted at such a late stage. WHO say this is due to a need to make “small modifications” and “to review their modeling data they used to inform investment structures”. The timeline for these changes are 2-3 months.

This plausibility for intervention from outside the extensive WHO guidelines writing and advisory panels is supported by an article in Science magazine that names the Gates Foundation specifically related to their interest in the latest PrEP results also being included. [7]

References

Unless stated otherwise, all references are the Programme and Abstracts of the 16th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 17–20 July 2011, Rome.

1. Treatment is prevention: the proof is here. Oral abstract session: Monday 4.30-6.00pm.
2. Cohen M et al. Antiretroviral treatment to prevent the sexual transmission of HIV-1: results from the HPTN 052 multinational randomized controlled trial. Oral abstract MOAX0102. Webcast
3. Eshleman S et al. Analysis of genetic linkage of HIV from couples enrolled in the HIV Prevention Trials Network (HPTN) 052 trial. Oral abstract MOAX0103.
4. Hosseinipour M et al. Immunologic and virologic disease progression and responses to ART across geographic regions: outcomes from HPTN 052 study. Oral abstract MOAX0104. Webcast
5. Grinsztejn B et al. Effects of early versus delayed initiation of antiretroviral therapy (ART) on HIV clinical outcomes: results from the HPTN 052 randomized clinical trial. Oral abstract MOAX0105. Webcast.
6. WHO. Couples HIV testing and counselling and antiretroviral therapy for treatment and prevention in serodiscordant couples: Recommendations for a public health approach. 2011. Final version approved but not yet released. (PDF file)
7. Cohen J. New prevention data leads WHO to delay guidelines for couples. Science Insider (25 July 2011).

Simon Collins, HIV i-Base

Results from the double-blind placebo-controlled TDF2 study presented in an oral presentation in Rome provided additional supportive data for the benefit of daily oral tenofovir/FTC (Truvada) to reduce sexual heterosexual transmission. [1]

While the iPrEX study first reported a strongly protective impact in high risk MSM, the lack of protection in the FemPrEP study earlier this year has still to be explained. [2, 3]

TDF2 randomised 1200 sexually active HIV-negative adults (age 18-49: approximately 90% were between 21-29 years) and followed them for a year. Over 90% of participants were single with only 3% having low educations (primary or less) with >70% having secondary and >20% having post-secondary education. HIV testing was monthly and as with all prevention studies, intensive counselling on safer sex and free condom distribution was provided throughout the study. An indication of the background risk in this population is that 16% of people failing screening (197/2533) were excluded due to already being HIV-positive and 20% due to not being sexually active.

A slightly higher percentage of people in the active vs placebo arm (34% vs 31%) did not complete the study due to loss to follow-up, withdrawal of consent, relocations or other reason. The study had a good gender balance with 45% women.

With 33 seroconversions, primary efficacy results reported a 63% reduced risk of transmission with Truvada based on 9 new infections in the active arm compared to 24 in placebo group (difference 62%: 95%CI 21.5 to 83.4, p=0.0133).

When restricting the analysis (post hoc?) to infections within 4 weeks of a study visit (ie where the monthly visit schedule was being followed and the participant was under a prescription period) the association became stronger. Out of 23 seroconversions, 4 occurred in the active arm and 19 in the placebo group with 78% protection efficacy (95% CI 41.2 to 93.6, p=0.0053).

Although it was emphasised that the study was underpowered to draw any conclusion by gender, in an ITT analysis (33 cases) the intervention appeared protective in men (p=0.026) but not women (p=0.107) and in the observed results (23 cases) the protection was seen on women (p=0.021) but not men (p=0.065). Whilst interesting to see if a gender effect can shed light on the results from FemPREP, this will need to come from larger study numbers.

Resistance developed in one person enrolled in the active arm whose acute HIV infection was undiagnosed with K65R, M184V and A62V conferring nucleoside cross resistance. The person has achieved viral suppression after starting treatment with AZT/3TC/lopinavir/ritonavir. One person in the placebo group had low-level K65R suggesting an infection with drug resistant HIV.

Side effects were commonly reported in both arms, usually mild, with nausea (19% vs 7%, p=0.0001) and vomiting (11% vs 7%, p=0.005) occurring more significantly in the active arm compared to the placebo arm, but resolving within the first month. There were no differences in laboratory abnormalities with one case of elevated creatinine in the active group that resolved when treatment was stopped.

References

1. Thigpen MC et al. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study. Oral abstract WELBC01. Webcast.
2. Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM. 23 November 2010 (10.1056/NEJMoa1011205). Free full access.
3. FHI statement on the FEM-PrEP HIV prevention study: FHI to initiate orderly closure of FEM-PrEP. (18 April 2011).

Simon Collins, HIV i-Base

The final presentation in the Treatment is Prevention session was a summary of the first results from the Partners PrEP study that randomised the HIV-negative partner in 4758 HIV serodifferent heterosexual couples to daily tenofovir (TDF) vs tenofovir/FTC (TVD) vs placebo in a 1:1:1 ratio. [1]

The results presented were based on a DSMB analysis a week before the conference that recommended unblinding the placebo arm and switching those participants to active drugs. This was based on significantly reduced risks of transmission in both the active arms and was 18 months earlier than the planned study endpoint.

This study was run in nine sites in Kenya and Uganda with all participants receiving intensive healthcare and adherence counselling including free condoms. The negative partners were seen monthly for counselling with HIV and pregnancy testing and the positive partners were monitored for their HIV care every three months.

Baseline demographics were similar across the three arms and included age (of the negative partner) 33 years (IQR 28-40), with the positive partner diagnosed a median of 0.4 years (IQR 0.1-2.0 years), CD4 count 490 cells/mm3 (IQR 370-660) and viral load 3.9 log copies/mL (3.2-4.5 logs).

Nearly all couples were married (98%) with duration of relationship a median of 7 years (IQR 3-14). The positive partner was a woman in 40% of couples. Approximately 20% of positive partners started treatment during the study for their own health.

Study retention was high with fewer than 5% discontinuations over 7337 person years of follow up (median 12 months). Adherence was also estimated high at 97% based on pill count using returned bottles (98% of bottles were returned).

Up to May 2011, there were 90 new infections, 12 of which were HIV-positive at randomisation (3 TDF, 3 TVD, 6 placebo). Of the 78 transmissions that occurred as events for the primary endpoint, 18, 14 and 47 occurred in the TDF, TVD and placebo arms respectively. The was an incidence of 0.74, 0.53 and 1.92 per 100 patient years that produced protection rates of 62% (95%CI 34-78%, p=0.0003) in the tenofovir and 73% (95%CI 49-85%, p<0.0001) in the tenofovir/FTC arms compared to placebo.

The study reported of a similar response between the two active arms (p=0.18 for comparison, NS). However, protection was numerically greater with the dual therapy and the gender analysis reported wider confidence intervals for tenofovir monotherapy with lower levels that were lower.

For women, protection rates were 68% (29-85%) and 62% (19%-82%) in the TDF vs TVD arms; for men these were 55% (4-79%) vs 83% (49-94%). The plausibility for greater protection from dual therapy would be extended with either lower adherence or less-than-daily dosing, both of which might be key public health factors for considering use of PrEP outside of clinical trials.

Safety results were very similar between all three arms for serious events and lab abnormalities including creatinine increases (1%, mainly grade 1) and reduced phosphorus (9%, equal across arms). As with other PrEP studies, nausea and diarrhoea were significantly more common in the active arms, but generally only for the first month of treatment.

As with other PrEP research, results from the pharmacokinetic will be important to correlate drug levels with level of protection and partner viral load with risk of infection. Resistance results will also be analysed.

Reference

Baeten J et al. Antiretroviral Pre-Exposure Prophylaxis for HIV-1 prevention among heterosexual African men and women: the Partners PrEP Study. Oral abstract MOAX0106. Webcast.

Simon Collins, HIV i-Base

Elvitegravir is a once-daily integrase inhibitor being developed by Gilead. This was a double-blind, placebo-controlled study that randomised 702 treatment-experienced patients to compare elvitegravir (150 mg once-daily; reduced to 85 mg with atazanavir/r or lopinavir/r) to raltegravir (400 mg twice-daily), each with a background regimen of sensitive boosted-PI plus a third sensitive drug selected by phenotype (from NRTI, maraviroc, etravirine or T-20) and including the use of 3TC/FTC with the M184V mutation. The primary endpoint was proportion of patients with viral load <50 copies/mL at week 48 (TLOVR analysis, ITT), This was a non-inferiority study with the lower limit of the 95%CI set at –10%.

Baseline characteristics included mean age 45 years; 18% were women; mean CD4 count 260 cells/mm3 (45% cell <200), median viral load ~ 20,000 copies/mL (with 26% >100,000 copies/mL) and approximately 5% and 15% of patients were coinfected with HBV or HCV respectively. Approximately 63% patients had primary resistance to two or more classes (PI 33%, NRTI 72%, and NNRTI 61%), balanced between arms.

Choice of background PI was largely darunavir (58%), lopinavir/r (19%) or atazanavir (16%). The third drug was an NRTI in 80% of patients (tenofovir 59%, tenofovir/FTC 27%, abacavir 4%, 3TC 3%, other 7%) with 13% using etravirine and 6% using maraviroc.

At week 48 a similar virological response rate was reported in each arm: 59% vs 58% in the elvitegravir vs raltegravir arms respectively which was strongly significant for non-inferiority (difference 1.1%, 95%CI –6.0% to +8.2%; p= 0.001). Approximately 20% of patients in each arm were reported as discontinuing due to virological failure: due to viral rebound (11% vs 16%) or never suppressing (8% vs 5%) in the elvitegravir vs raltegravir arms respectively with 1% or patients in each arm failing due to a switch of background drugs. A summary of virological and safety results is included in Table 1.

However, discontinuations in a following slide were reported at 24% in each arm, mainly due to non-adherence, loss to follow-up or withdrawn consent and are detailed in Table 2, with virological failure reported in only 9 patients in each arm.

When looking at drug resistance in the patients with virological failure, this included 61 and 75 people in the elvitegravir and raltegravir arms respectively. In this dataset, failure with integrase-associated mutations was reported at a comparable number though with increased frequency (16/60; 27% vs 15/72; 21%) in the elvitegravir vs the raltegravir patients. Development of new PI- or NRTI-associated resistance was generally low and similar between the two groups.

Less than 5% of participants discontinued due to side effects. The only difference between arms in terms of adverse events was a higher rate of diarrhoea with elvitegravir (12% vs 7%), not associated with discontinuation. This was similar for laboratory abnormalities, with a slightly higher percentage of patients reporting grade 3/4 ALT/AST elevations with raltegravir (~1-2% vs 5%).

This study concluded that this demonstrated that once daily elvitegravir was non-inferior to twice-daily raltegravir in treatment-experienced HIV-positive patients.

comment

These are impressive results in treatment-experienced patients. The rate of 20% patients failing with integrase-associated mutations was considered low by the investigators given the low barrier to integrase mutations. This was partially explained by the low barrier to virological failure in the study design (<1 log by week 8).

Causes of the seven deaths were not apparently drug related. This included one intestinal perforation in the elvitegravir arm, and one lymphoma and two cardiovascular events in the raltegravir arm.

References

Molina J-F et al. Elvitegravir once-daily is non inferior to raltegravir twice-daily in treatment experienced patients: 48 week results from a phase 3 multicenter, randomized, double blind study. Oral late breaker abstract WELBB05. Webcast.

Simon Collins, HIV i-Base

Dolutegravir is an integrase inhibitor in development with ViiV/Shionogi that in earlier development was referred to as GSK-572. Results from the first monotherapy studies were presented only two years ago and the rapid development programme now includes phase III studies in naïve patients (using a 50 mg once-daily dose) with results already reported from phase II studies in experienced patients (using a higher 50 mg twice-daily dose).

Results from week 24 of a Phase IIb dose-ranging study treatment naïve study were presented in Glasgow last year with 90-96% of patients in the dolutegravir arms reducing viral load to <50 copies/mL compared to 78% patients in the efavirenz arm. These were updated to week 48 at in an oral presentation in Rome. The initial steep viral decline seen with integrase inhibitors as a class was probably a factor in choosing a primary endpoint at week 16 but this extended data is more crucial to understand sustainability. [1]

The study randomised 205 treatment-naïve patients 1:1:1:1 to 10 mg, 25 mg or 50 mg of dolutegravir or efavirenz 600mg once-daily, plus either investigator choice of either tenofovir/FTC (used by two-thirds of patients) or abacavir/3TC.

Baseline viral load was originally low (approximately 30,000 copies/mL) with only 26% participants >100,000 copies/mL. This would increase effectiveness for the a viral suppression (requiring less than a 3 log drop to achieve undetectable levels. Participants were largely male (86%) and white (80%), with mean CD4 count of 324 cells/mm3 (63% were <350). Median age was 32 (range 20-79 years).

By week 48, suppression in the dolutegravir arms had dropped slightly to 88-91% compared to 82% in the efavirenz arms. No between-group analyses were presented but the confidence intervals for all groups broadly overlapped. Virologic non-response/rebound rates were low and similar between arms (8%, 6%, 4% vs 6% in the efavirenz arm) with the lower response in the efavirenz arm driven by discontinuations related to side effects (0, 2%, 0 vs 8% respectively). In the small percentage of patients failing with viral rebound 0/3 (none in the 50 mg arm) showed evidence of integrase-related mutations, though patients were proactively switched early due to this potential concern.

Virological results were also presented using a <2 copies/mL viral load test – the first time perhaps for an ongoing Phase II study. At the 50 mg dose approximate suppression to <2 copies at weeks 16, 24 and 48 was 48% 65% and 52% respectively compared to 35%, 45% and 58% in the efavirenz arm. These are small study numbers and neither confidence intervals nor statistical comparisons were provided but these are unlikely to show significant differences. It may be notable that the <2 copies/mL results for the lower doses of dolutegravir were not presented. Given the increased research focus on greater suppression at levels below < 50 copies/mL and the conflicting results from some of the intensification studies with raltegravir (broadly finding no impact in blood but perhaps in some tissue sites) this class potential is likely to inform future studies.

CD4 increases were similar by week 48 with +231 cells/mm3 in the combined dolutegravir vs +174 in the efavirenz arm vs EFV (p=0.076), reducing a difference that was significantly higher at week 24.

No new serious adverse events were reported out to week 48. The two discontinuations from the dolutegravir arms were due to dyspepsia (25 mg arm) and Burkitt’s lymphoma.

Grade 2-4 side effects were similar between arms, except for rash and CNS-related side effects occurring only in the efavirenz group. Nausea (11%), diarrhoea (8%) and headache (5%) were most frequently reported with dolutegravir compared to dizziness (18%), fatigue, insomnia and rash (8% each) with efavirenz. Grade 3/4 laboratory abnormalities occurred in 12% vs 14% of the combined dolutegravir vs efavirenz arm. Dolutegravir was associated with mean increases in creatinine (6.4-11.9 mmol/L) at week 1 that were stable to week 20 and decreased by week 48. In vitro data have shown that dolutegravir causes a benign inhibition of creatinine secretion. These were detailed in a separate poster presentation. [2]

Lipid changes were generally greater in the efavirenz arm but there were no differences either from baseline or between drugs in the TC/HDL ratio at week 48 (due to the impact of efavirenz in increasing HDL).

The pharmacokinetic summary slide showed an impact of dose on drug levels over 24 hours, but these had low inter-patient variability and at all doses remained above the IC90 (0.064 ug/mL) with Cmin levels [geometric mean (CV%)] of 0.30 (71), 0.54 (67) and 1.20 (62) and an inhibitory quotient of 4.7, 8.4 and 19-fold for the 10 mg, 25 mg and 50 mg doses respectively.

References

1. Van Lunzen J et al. Rapid, robust and sustained antiviral response with once-daily (QD) dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral-naïve adults: 48 week results from SPRING-1 (ING112276). Oral abstract TUAB0102. Webcast.
2. Min S et al. Safety profile of dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral (ART)-naïve and ART-experienced adults from phase 2b studies. IAS. 17-20 July 2011. Rome. Abstract TUPE238.

Simon Collins, HIV i-Base

Lersivirine is a once-daily NNRTI from ViiV that was originally developed by Pfizer and previously called UK-453061 and that is promising due to a resistance pathway at V108I that appears distinct from the K103N or Y181C pathways associated with first-generation non-nukes.

This double-blind, placebo-controlled study randomised 193 patients (1:1:1) to either 500 mg or 750 mg of lersivirine or to standard dose efavirenz, each with once-daily tenofovir/FTC. The primary endpoint was the percentage of patients with viral load reduced to <50 copies/mL at 48 weeks with follow up out to 96 weeks (by ITT missing = failure analysis).

Although enrollment criteria for the study included a CD4 count >200 cells/mm3, at baseline this ranged from 122 to 955 (median 310) suggesting that a few more advanced patients were included on an experimental combination than the European regulatory guidelines recommend for Phase II studies. Baseline viral loads ranged from 1,500 to 1,600,000 (mean: 50,000 copies/mL). Approximately 35% of patients had baseline viral load >100,000 copies/mL and this was reflected in pre-specified analysis of the results.

Other baseline characteristics included: mean age 36 years (range 21-62); 27% were women; race: 60% white, 30% black, 10% other. While the majority of people had sub-type B, ~30% of people were sub-type C which was reflected in ~ 30% enrolled in sites in South Africa.

At week 48, the percentage of patients with viral load <50 copies/mL was 79%, 79% and 86% in the 500 mg, 750 mg and efavirenz groups respectively. Although the study was not powered to detect a difference in efficacy between arms, the lersivirine arms suggested a poorer response compared to efavirenz (500 mg: –9% difference; 80%CI –18.1, 0.8 and 750 mg: –8% difference; 80%CI –17.0, 1.2).

Results stratified by baseline viral load (which was lower in the >100K group) or geographical region (which was lower for sites in South Africa) did not contradict this finding, see Table 1.

A mean CD4 count increased of approximately +190 cells/mm3 from baseline was similar between arms.

Virological failure occurred in 4, 5 and 3 patients in the 500 mg, 750 mg and efavirenz groups respectively, with people on lersivirine generally failing with M184V plus NNRTI mutations when resistance was isolated. The one person with identifiable mutations in the efavirenz arm failed with K103N alone.

Overall, the combined safety analysis reported a similar incidence of side effects in each group but fewer grade 3/4 events in the lersivirine groups (n= 2 and 3) compared to efavirenz (n=8) see Table 2. Laboratory abnormalities were infrequent and evenly distributed between arms. Lipids were broadly stable for lersivirine compared to increases in TC, LDL, HDL and TG for efavirenz, but this resulted in little difference between the LSV and EFV groups (+0.24 and -0.06 vs -0.3) in the change in the TC:HDL ratio used to evaluate cardiovascular risk.

However, the study concluded that both lersivirine doses showed similar efficacy to efavirenz over 48 weeks in treatment-naïve patients and had different side effect profiles compared with efavirenz.

* EU, Latin America, Australia, Canada

comment

There is still a role for new NNRTI with activity against nevirapine and efavirenz associated resistance with an improved safety profile to efavirenz.

The higher reports of nausea and headache appeared to be low grade but limited data was available on duration and severity of these events.

Reference

Pozniak A et al. Efficacy and safety of lersivirine (UK-453,061) vs. efavirenz in antiretroviral treatment-naïve HIV-1-infected patients: week 48 primary analysis results from an ongoing, multicentre, randomised, double-blind, phase IIb trial (study A5271015). Oral abstract TUAB0101. Webcast.

Polly Clayden, HIV i-Base

The main objective in the SPARTAC trial was to look at the impact on disease progression from two different short courses of antiretroviral treatment (ART) initiated during primary HIV infection compared to no immediate ART. Sarah Fidler from Imperial College London presented results from SPARTAC in an oral late breaker at IAS 2011.

In this study, adults with primary infection who were within 6 months of seroconversion were randomised to receive ART for 48 weeks, 12 weeks, or no therapy (standard of care, SOC). The primary endpoint was time from randomisation to either CD4 <350 cells/mm3 or initiation of continuous ART.

A sample size of 360 was calculated (using data from CASCADE) to provide 90% power to detect relative reduction in risk of time to primary endpoint of 50% – 25% in each of the ART arms – compared to SOC over four years of follow up.

A total of 366 participants were randomised from 35 sites in Australia, Brazil, Europe and Africa; 40% were from the UK and 35% South Africa. Of these, 60% were men (90% MSM) and 40% African women, with a median age overall of 31 years.

As would be expected, the median baseline CD4 was high at 543 cells/mm3 and viral load was 4.7 logs (~50,000 copies/mL). Participants were followed for a median of 4.2 years and 19% were lost to follow up. The majority (92%) of participants received lopinavir/r plus AZT and 3TC.

The investigators found no difference in time to primary endpoint in participants receiving 12 weeks of ART compared to SOC (HR 0.93: 95%CI 0.67-1.29, p=0.67). However, 48 weeks of ART conferred a statistically significant delay (HR 0.63: 95%CI 0.45-0.90, p=0.01). The median time to primary endpoint was 157, 184 and 222 weeks for the SOC, 12 week and 48 week arms respectively. Although, Dr Fidler noted that the 65 week (95%CI 17-114) delay in the 48-week arm was not significantly greater than the time spent on treatment.

A post-hoc analysis revealed two findings. There was a significantly more rapid rate of disease progression among participants identified within 12 weeks of acquiring infection in the SOC arm. Secondly, the delay to primary endpoint observed previously with 48 weeks of treatment compared to SOC was greater in participants who initiated ART initiated within 12 weeks of infection (HR 0.48: 95%CI 0.3-0.78). Overall, the investigators reported a non-significant trend to greater delay to primary endpoint the closer ART was initiated to the estimated time of seroconversion (p=0.09, NS).

There was a reduction in viral load of approximately half a log after interrupting ART in the 48-week arm compared to SOC, which was sustained until 60 weeks after stopping treatment. The mean CD4 count over the entire study period was 138 cells/mm3 higher in the 48-week arm than standard of care.

There were no significant differences between arms in AIDS, death or serious adverse events. In contrast to SMART there was no rebound in IL-6 and a drop in d-Dimer, compared to baseline, four weeks after stopping ART.

comment

By the time this study was completed the treatment landscape had changed considerably from when it was initially designed. So the big question now is “what would have happened with a continuous treatment arm?”.

As far as the implication for clinical practice is concerned, perhaps if someone is aware of their status and he or she wants to start treatment in primary infection there may be a slender argument to do so. But if they do start and are doing well, given the modest time off treatment until starting again, why stop?

Reference

Fidler S et al. The effect of short-course antiretroviral therapy in primary HIV infection: final results from an international randomised controlled trial; SPARTAC. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Oral abstract WELBX06.

Simon Collins, HIV i-Base

Hearing loss has been associated as a complication in HIV-positive people but it is unclear whether HIV is a direct factor or whether symptoms are more strongly correlated to risk factors reported in the general population. This will be increasingly important as the HIV population ages.

Researchers from Washington DC measured cochlear function in 334 men and 178 women from two of the earliest population cohorts established to look at differences between HIV-positive and HIV-negative patients (MACS and WIHS respectively), and related to this to social factors including noise exposure and HIV and treatment history.

The mean age was 54 years for the men (46% were HIV-positive), and 45 years for the women (77% were HIV-positive). People were excluded if they had hearing-impaired clinical symptoms or recent use of orotoxic medication. Approximately 20% of people in each of the HIV-positive and HIV negative groups self-reported exposure to occupational noise.

Cochlear function was measured by distortion product otoacoustic emission (DPOAE) testing which is a non-invasive procedure using two separate tones to stimulate the cochlea. Each ear was measured twice, with a third test if results were inconsistent and the number of non-responses added as an outcome variable (0-4).

In multivariate analyses, a 10-year increase in age [OR 2.78; 95%CI 2.07, 3.73], being male [OR 5.60; 95%CI 2.98, 10.49], and being non-black [OR 2.75; 95%CI 1.57, 4.83] were significantly associated with a higher number of non-responses (all p<0.001), but not HIV status [OR 1.20; 95%CI 0.7, 2.02; p =0.52 NS]. However, neither occupational or non-occupational noise exposure was associated with reduced function (p=0.33 and p=0.93, respectively).

Age, race, and gender remained significant risk factors for increasing non-responses in the HIV-positive model. However, none of the HIV-related factors including use of monotherapy, combination therapy, HAART use, 100-cell increase in peak CD8, HIV viral load, and 100-cell increase in nadir CD4 count came near approaching statistical significance (with p-values ranging from 0.2 to 0.7).

The researchers concluded that HIV status, combination therapy, nadir CD4 count, peak CD8 count, and HIV viral load did not significantly predict decreased cochlear function in this patient group.

Reference

Torre P et al. Cochlear function among Multicenter AIDS Cohort Study (MACS) and Women’s Interagency HIV Study (WIHS) participants. 16th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 17–20 July 2011, Rome. Poster abstract TUPE138. Poster. (PDF)

Polly Clayden, HIV i-Base

Physiological changes in pregnancy can affect drug disposition. Plasma concentrations of several PIs – including lopinavir, atazanavir and saquinavir – currently prescribed to HIV-positive pregnant women, are decreased during this period. Pharmacokinetcs (PK) for darunavir (DRV) and fosamprenavir (FPV) in pregnancy are not well characterised. Two posters presented at the paediatric workshop and IAS 2011 showed data from PK studies of these antiretrovirals in pregnant women. [1, 2]

Darunavir

Edmund Capparelli and colleagues from the IMPAACT P1026s study group presented PK and safety data of DRV dosed twice-daily (BID) and once-daily (QD) during the third trimester of pregnancy, at delivery and post partum. These data were shown at the paediatric workshop in Rome.

IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral PK in pregnancy. It comprises of two groups of women receiving ritonavir-boosted DRV either as 600/100mg BID, or 800/100 mg, QD, as part of an ART regimen during pregnancy and 6-12 weeks postpartum (PP).

All women had received at least two weeks of ART at the time of the evaluation. Intensive steady-state 12 or 24-hour PK profiles were performed during the 3rd trimester and PP. Cord blood and maternal samples were taken at delivery when possible. DRV concentrations were measured by HPLC (limit of detection 0.09 mcg/mL). The minimum exposure targets were DRV AUC0-12 or 24 of 43.6 or 56.5 mcg*hr/mL, for BID or QD, respectively. This represents >70% median for non-pregnant adults.
PK data were available for 31 women (19 BID, 12 QD). Two PP PK evaluations (1 BID and 1 QD) were excluded for non-adherence with no detectable DRV concentrations. Geometric mean 3rd trimester/PP ratios were 0.74 (90% CI 0.54-0.92) and 0.76 (90% CI 0.64-0.91) for AUC and 1.42 (90% CI 1.09-1.84) and 1.31 (90% CI1.10-1.55) for CL/Fs with BID and QD dosing respectively.

For the PK parameters presented below for 3rd trimester and PP the investigators indicated values with p<0.05 compared to PP with an asterisk (*). They found, AUC0-12 were median 50.7 (range 23.8-102)* mcg*hr/mL for 3rd trimester and 70.0 (range 40.3-175.5) mcg*hr/mL PP for women who received DRV/r 600/100mg BID. Of those with PK parameters available, 13/19 (68%) and 11/13 (85%) met the AUC-12 target. CL/F was 11.82 (range 7.58-26.4)* L/h and 8.57 (range 3.42-14.89) L/hr. C12h was 3.13 (range 0.78-8.85) mcg/mL and 2.81 (range 1.61-5.50) mcg/mL.

AUC0-24 were 67.7 (range 30.3-105.5) mcg*hr/mL and 87.9 (77.5- 150.2) mcg*hr/mL, for the women who received DRV/r 800/100mg QD. Of these 8/12 and 7/7 met the AUC0-24 target. CL/F was 11.82 (7.58-26.4) L/h and 9.10 (5.33-10.32) L/hr. C24h was 1.37 (0.15-3.49) mcg/mL and 2.59 (<0.09-3.96) mcg/mL.
A total of 20 paired samples of maternal delivery and cord blood were collected. Of these, 6 pairs had concentrations below the limit of detection. For the remainder (n=14) median cord blood DRV concentrations were 0.19 (<0.09-1.1) mcg/mL. Maternal delivery plasma DRV concentrations were 1.42 (<0.09-5.62) mcg/mL. The median ratio of cord blood/maternal delivery plasma concentrations was 0.24 (0.062-0.58) indicating limited transplacental transport of DRV.

The investigators concluded that lower troughs and AUC with QD compared to BID dosing combined with pregnancy lowering DRV exposure suggests BID dosing should be used in pregnancy and higher doses may be required.

Of note, not all women achieved viral suppression in both dosing groups (at delivery overall, 57% and 79% <50 and <400 copies/mL respectively), and there was at least one vertical transmission among 24 (77%) infants with data available at the time of this analysis.

Fosamprenavir

There are limited data describing safety and outcomes of FPV in pregnancy or plasma concentrations of FPV’s active metabolite, amprenavir (APV), during pregnancy, PP and in cord blood.

Michelle Cespides and colleagues from New York University School of Medicine showed findings from a phase I, open-label, single-centre study to evaluate APV PK following dosing of ritonavir boosted FPV 700/100mg BID in pregnant women. The investigators evaluated steady-state PK in the second and/or third trimesters and 4-12 weeks PP. Maternal plasma and cord blood samples were taken at the time of delivery. APV concentrations were measured by LC-MS/MS, and PK were determined using WinNonlin. This study was presented at IAS 2011.

The study evaluated 10 women receiving DRV/r based regimens. Cord blood samples were available from six deliveries. The median ratio of cord blood/maternal APV concentrations was 0.27, again, indicating limited transplacental transfer of this PI. Individual APV AUC was 22-34% lower, Cmax 9-41% lower and C12 27-28% lower in pregnancy than PP. See Table 1: Amprenanvir concentrations during pregnancy.

The investigators noted that although APV C12 was 27-28% lower in pregnancy, HIV was well suppressed for all subjects at delivery. Maternal and cord blood concentrations were above mean protein binding-adjusted IC50 (0.146 ug/mL) for wild-type virus.

Safety and outcomes data showed that FPV was well tolerated in this small study with no hepatic, renal, or adverse events attributed to ART.

At delivery, all women had viral loads < 400 copies/mL and nine women had <50 copies/mL. All infants were HIV PCR negative.

comment

The recommendation from the first study that higher doses of DRV may be required is consistant with US recomendations with other PIs such as lopinavir and atazanavir.

BHIVA guidelines do not recommended a dose increase.

References

1. Capparelli E et al. Pharmacokinetics of Darunavir Once or Twice Daily During and After Pregnancy. 3rd International Workshop on HIV Pediatrics. 15-16 July, 2011. Rome, Italy. Poster abstract P_72.
2. Cespedes M et al. Pharmacokinetics, cord blood concentrations, and tolerability of boosted fosamprenavir (FPV) in pregnancy. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TUPE278.

Polly Clayden, HIV i-Base

Data describing the risk of low birth weight (LBW) and preterm delivery (PTD) associated with maternal HIV and antiretroviral exposure are conflicting and international consensus has not been reached. Two posters from the Antiretroviral Pregnancy Registry (APR) and the Perinatal HIV Research Unit (PHRU), Soweto, South Africa, presented at IAS 2011, showed findings from their analyses of LBW and PTD in their respective cohorts. [1, 2]

APR is a prospective exposure-driven birth registry to monitor for potential increased birth defects following ART exposure in pregnancy.

In this study, Karen Beckerman and colleagues analysed reports to the APR cohort from 1989-2010. They restricted outcomes to singleton live births without birth defects. After establishing overall LBW(<2500 g)/PTD(< 37 weeks) prevalence by type of ART (2 or more drug regimens with and without PI), the data were stratified for maternal age, race/ethnicity and CD4 count. Stratified analysis is based on the 2×2 chi-square test and Cochrane-Mantle-Haenzel.

The investigators found, among the 10082 live births with birth weight data available, 16% were < 2500 g. Of those with reported estimated gestational age, 12.8% were <37 weeks. There were significantly higher LBW/PTD women receiving PI-containing regimens vs regimens without PI (LBW RR=1.22, p<0.001; PTD RR=1.27, p<0.001). But after controlling for maternal age, race/ethnicity and CD4 count they found no significant increase in incidence of LBW/PTD associated with PI exposure among groups with lower pre-existing risk. See Table 1: Low birth weight, preterm delivery and PI exposure in APR.

The investigators concluded that among prospective reports to APR, increases in LBW/PTD were not associated with PI exposure in women with low background risk for these complications.

In a related study, Fatima Laher and colleagues from PHRU investigated risk factors for PTD in their cohort. They noted that prevalence for PTD is 17.5 in Southern Africa.

This study was a retrospective review of all HIV-positive pregnant women who received triple-combination ART between August 2004 and September 2010. Obstetric history, ART history, maternal CD4 count and viral load during pregnancy were recorded for all live births. Univariate analysis included variables associated with preterm delivery.

The investigators found, out of a total 223 pregnancies, 58 were electively terminated (26%), 19 were spontaneous miscarriages (8%), 16 did not yet have recorded outcomes (7%), and 4 were stillbirths (2%). There were 126 (57%) live births, and 62/126 (49%) were PTDs with median gestational age 34.7 weeks (IQR 33.0-35.7). Mothers of preterm and term infants were similar in age, median 31.7 and 30.9 years respectively. Virological suppression <50 copies/mL during pregnancy was similar in both groups, 84% and 80% respectively.

The majority of women, 111/126 (88%) initiated ART was before conception. Maternal CD4 count during pregnancy below 200 cells/mm3 [OR 1.2; 95%CI 0.5-2.8, p= 0.76], 350 cells/mm3 [OR 1.4; 95%CI 0.7-2.8, p= 0.37], or 500 cells/mm3 [OR 1.1; 95%CI 0.4-2.8, p=0.87], were not risk factors for PTD.

Final-trimester maternal use of EFV-based regimens [OR 2.5; 95%CI 0.9-6.9, p=0.09], or PI-based regimens [OR 1.4; 95%CI 0.6-3.0, p=0.4], were not predictive of PTD compared to NVP-based regimens.

The investigators concluded that preterm delivery is common among pregnant ART-recipients in Soweto. Maternal CD4 count and final-trimester ART type seem not to predict preterm delivery. They noted that their small sample size in this study is a limitation.

comment

The APR data are unsurprising as 85% of the pregnancies enrolled are from the US and the association with PTD and PIs is largely not observed in American cohorts. The Soweto data may reflect a high background PTD rate and, as the investigators note, a small sample size.

Recently published data from Botswana does show an increased risk of PTD in women reciving PIs in pregnancy. [3]

References

1. Beckerman K et al. Exposure to combination antiretroviral (cARV) regimens containing protease inhibitors (PI) during pregnancy and prevalence of low birth weight/preterm delivery (LBW/PTD) among women with low pre-existing risk for LBW/PTD: a stratified analysis of 10,082 p. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TULBPE018.
2. Laher F et al. Maternal CD4 and HAART type are not risk factors for preterm delivery amongst HIV-infected pregnant women receiving HAART in Soweto, South Africa. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TUPE319.
3. Powis KM et al. Increased risk of preterm delivery Among HIV-infected women randomised to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. Journal of Infectious Diseases. Volume204, Issue4. Pp. 506-514.

Polly Clayden, HIV i-Base

Some epidemiological and laboratory studies have suggested that hormonal contraception can increase HIV transmission risk in women. There has been little research into the risk of transmission from women to men. To date findings have been inconsistent and WHO has called for high quality studies to look at potential interactions between hormonal contraception and HIV transmission.

Investigators from The Partners in Prevention HSV/HIV Transmission Study compared HIV incidence among women using hormonal contraception to those who were not. This analysis evaluated both HIV acquisition among women and transmission from women to men. Renee Heffron presented findings from this study in an oral presentation at IAS 2011. [1]

This was a prospective cohort study of 3790 serodiscordant couples from seven countries in East and southern Africa. The couples were enrolled from two studies conducted between 2004 and 2010, a randomised trial of acyclovir to reduce HIV transmission (n=3321) and a prospective cohort study of immune correlates of HIV protection (n=469).

Study participants were 18 years of age or older, and at enrollment the HIV-positive partners were not eligible for ART according to national guidelines. HIV-negative partners were tested quarterly and HIV-positive partners had CD4 measurements every six months and plasma and genital viral load at enrollment and six months later. The investigators used standardised questionnaires to measure sexual behaviour and contraceptive use.

They compared rates of HIV acquisition in women and HIV transmission from women to men using multivariate Cox proportional hazards regression and marginal structural modeling. The analyses were limited to infections acquired from the study partner (evaluated by viral genetic sequencing).

The negative partners were women in about a third (n=1314) of the couples evaluated, and two thirds (n=2476) were men.

Among the negative women, 21.2% overall used hormonal contraception at least once during follow up, of which 16% used injectable contraception at least once and 6.7% oral contraception. The HIV acquisition rates were 6.61 and 3.78 per 100 person-years in women currently using and not using hormonal contraception [AHR 1.98; 95%CI 1.06-3.68. p=0.03]. For injectable contraception the incidence rate was 6.85 per 100 person-years [AHR 2.05; 95%CI 1.06-3.68, p=0.04] and for oral contraception it was 5.94 per 100 person-years, [AHR 1.8 95%CI 0.55-5.82, p=0.33].

Overall, 33.3% of HIV-positive partners of negative men used hormonal contraception, 26.8% injectable and 8.9% oral. In these couples, HIV transmission rates from women to men were 2.61 and 1.51 per 100 person-years in those whose partners used and did not use hormonal contraception [AHR 1.91, 95%CI 1.12-3.45, p=0.02]. For injectable contraception the incidence rate was 2.64 per 100 patient years [AHR 1.95; 95%CI 1.06-3.58, p=0.03]. The incidence also increased in the group using oral contraception, 2.50 per 100 patient years, but as with HIV acquisition in negative women this did not reach statistical significance in this subgroup [AHR 2.09; 95%CI 0.75-5.84, p=0.16].

Results from marginal structural model analyses were consistent with those shown from the Cox proportional hazards regression.

When the investigators looked at this a possible explanation, there were significantly higher genital viral load concentrations overall in women using hormonal contraception [OR 1.51; 95%CI 1.13-2.01, p=0.01]. For injectable contraception these were significantly higher [OR 1.67; 95%CI 1.21-2.31, p=0.02]. But not for oral contraception [OR 1.06; 95%CI 0.62-1.84, p=0.49].

Dr Heffron noted that this was the first study to demonstrate that hormonal contraception increased an HIV-positive woman’s risk of transmitting HIV to her partner.

She added that the benefits of effective hormonal contraception are unequivocal and must be balanced with the increase in risk of HIV infection. These possible risks should be discussed with women and couples alongside the importance of HIV prevention.

Strategies to improve access to and usage of lower dose and non-hormonal methods – IUDs, implants, patches or combination injectables are warranted – she concluded.

comment

These findings understandably caused quite a stir and urgently need more investigation. This was followed by the report from Partners in Prevention that pregnancy doubles the risk of transmission from HIV-positive women to her male partner (to be reviewed in the next issue of HTB). [2]

References

1. Heffron R et al. Hormonal contraceptive use and risk of HIV-1 transmission: a prospective cohort analysis. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Oral abstract WEAX0206. Webcast.
2. Mulago NR et al. Increased risk of HIV-1 transmission in pregnancy: a prospective study among African HIV-1 serodiscordant couples. Advance online edition of AIDS 25, doi: 10.1097/QAD.0b013e32834a9338, 2011.

Polly Clayden, HIV i-Base

Information to guide initiation of treatment in children older than one year of age is scarce.

Results from the PREDICT trial – presented as late breakers at both IAS 2011 and the preceding pediatric workshop – found that deferring ART until CD4 count fell below 15% or the occurrence of CDC category C events did not affect AIDS-free survival in children compared to starting ART at a CD4 count between 15% and 24%. [1]

PREDICT was conducted in 299 children from nine sites in Thailand and Cambodia between April 2006 and September 2008. Children were randomised to receive immediate ART or defer until their CD4 reached less than 15%. The children’s baseline characteristics are shown in table 1.

The primary endpoints were AIDS free survival at week 144 and neurodevelopmental outcome by Beery visual motor interrogation test.

Age, CD4%, HIV RNA, weight-for-age z-score and height-for-age z-score are mean values.

Retention was high in this study (96%). At week 144, 69 (46%) children had started ART with a mean CD4 at initiation of 13.8% (SD+2.8%). Of these, 17 children were <5 years and had a mean CD4 count of 591 cells/mm3 (SD+508) and 52 children were >5 years and had a mean CD4 count of 309 cells/mm3 (SD+141).

AIDS-free survival was 97.9% (95% CI, 93.7 -99.3) in the immediate arm and 98.7% (95%CI 94.7-99.7) in the deferred arm. The incidence of CDC C events or death per 1000 person-years was 7.6 (95%CI 2.5-23.6) in the immediate arm and 4.9 (95%CI 1.2-19.7) in the deferred arm.

The incidence of CDC category B events per 1000 person-years was broadly similar in both arms, 88 (95%CI 61-123) in the immediate arm compared to 110 (95%CI 80-147) in the deferred arm. But there were more episodes of herpes zoster (2 vs 13) and thrombocytopenia (1 vs 10) in the immediate and deferred arms respectively. There were only two episodes of TB, one in each arm.

Weight for age z-score was similar, deferred vs immediate -0.12 (95%CI -0.25 to 0.01), p=0.074. But children grew at a slower rate in the deferred arm, height for age z-score, deferred vs immediate -0.23 (95%CI -0.38 to 0.08), p=0.003.

And at 144 weeks of follow up there was no significant difference by Beery visual motor test between the two arms; Beery score deferred vs immediate, 84.7 vs 86.8, p=0.5.

The investigators noted that at approximately three years of follow up, the rate of progression to AIDS is extremely low in both the immediate and deferred arms. The finding reflects a slow disease progression among HIV-infected children who survive the first year of life without treatment.

comment

This study is important and a bit of a surprise to many as it appears to contradict both adult data and that for young infants. But the median age in the study reflects a population that have survived without treatment for the first few years and therefore selects a group of healthier children without rapid disease progression.

References

Puthanakit T et al. Randomised clinical trial of immediate versus deferred antiretroviral therapy initiation in children older than one year with moderate immunodeficiency: the PREDICT Study (NCT00234091). 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract LB 01.

Also presented at the 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TULBPE023.

Polly Clayden, HIV i-Base

Data were presented at the paediatric workshop and IAS 2011describing recent developments in the paediatric pipeline.

Etravirine

Thomas Kakuda from Tibotec showed pharmacokinetic (PK) data of the NNRTI etravirine (ETV) in treatment experienced children and adolescents aged 6 to <18 years. [1, 2]

These 24-week results are from PIANO (Pediatric trial with Intelence as an Active NNRTI Option). PIANO is an ongoing Phase II, open label trial looking at the safety, efficacy and PK of ETV 5.2mg/kg bid (maximum dose 200mg bid).

In this study, 101 children (6 to <12 years, n=41) and adolescents (12 to <18 years, n=60) received ETV plus background regimen of a boosted protease inhibitor plus nucleoside/nucleotide inhibitors with optional enfuvirtide and/or raltegravir for 48 weeks. The trial participants received 25mg and 100mg tablets of ETV.

Sparse samples for population PK were taken at weeks 4, 8, 12, 24 and 48. At week 24 two samples were collected, a trough and one at least an hour after ETV dose. ETV plasma concentrations were measured using a validated high performance liquid chromatography-mass spectrometry/mass spectrometry assay.

The investigators developed a paediatric population PK model based on previous adult modelling and supplemented with rich and sparsely sampled PK data from TMC125-C126 [HTB ref] and PIANO respectively. They used the model to determine ETV AUC12h and C0h for all participants enrolled in PIANO up to 24 weeks.

There were 476 plasma concentration time samples available from 101 participants completing 24 weeks. There was an overall mean (SD) AUC12h and C0h of 5236 (+4314) ng*h/mL and 347 (+342) ng/mL respectively. In children in the younger age group these values were 5764 (+4044) ng*h/mL and 381 (+321) ng/mL. In adolescents they were 4834 (+4483) ng*h/mL and 323 (+357) ng/mL respectively. Adult reference values from the DUET trial were 5506 (+4710) ng*h/mL and 393 (+391) ng/mL for AUC12 and C0h respectively.

The investigators observed slightly lower exposures in the adolescents compared to the adults despite the majority (93%) of adolescents receiving the adult ETV dose of 200mg bid.

A dose of 5.2 mg/kg ETV is expected to be recommended for this population.

A related poster authored by Gareth Tudor Williams and colleagues described safety and efficacy from the same study. [3] The incidence of serious adverse events (AEs, grade 3 or 4) was low. A total of eight participants discontinued the trail due to AEs, this occurred more frequently in the older (n=6) than younger (n=2) age group. The most common AEs were upper respiratory tract infection (n=27) and rash (n=23).

Approximately half (n=51) of participants achieved a viral load <50 copies/mL. Response rates were higher in children than adolescents, with 24/41 (59%) achieving an undetectable viral load compared to 28/60 (47%). Response was similar in participants in both age groups considered adherent (measured by pill count and questionnaire) compared to non-adherent, respectively 48% (<95% adherent) compared to 53% (>95% adherent).

Of 28 participants with available genotype results at the time of virological failure, 54% developed NNRTI resistance mutations, mainly Y181C, E138A and V901.

Maraviroc

Carlo Giaquinto and colleagues presented preliminary PK data for the CCR5 antagonist maraviroc (MVC) in children and adolescents aged 2 to <18 years. [4, 5]

Data are from Study A4001031 – an ongoing open-label, non-comparative, multi-centre study in two stages (1: dose finding; 2: safety/efficacy) in treatment-experienced children, infected with CCR5-tropic HIV-1, receiving MVC 40-450 mg BID with optimised background therapy (OBT).

MVC PK were determined at Week 2. Participants (n=31) were stratified into four age cohorts. They were dosed twice daily. The initial dosing was calculated according to body surface area (BSA) with adjustments to take into account interactions between MVC and OBT (adult-recommended doses with/without CYP3A4 inhibitors/inducers).

Doses were adjusted and PK reevaluated if average concentrations (Cavg) at week 2 were <100 ng/mL. Cavg was estimated from AUC (AUC12h) calculated from seven samples taken over 12 hours.

The investigators reported, out of 22 participants receiving MVC with a potent CYP3A4 inhibitor (protease inhibitor based regimens). Only one failed to meet the PK target with the initial dose (this was due to poor adherence). But all five participants who did not receive a protease inhibitor (two nevirapine based regimens; two raltegravir based regimens; one NRTI based regimen) needed at least twice the initial MVC dose.

At the time of enrolment into stage 2, one participant did not meet the target after two dose adjustments but responded well clinically so was therefore included in the PK analysis. See Table 1: Preliminary PK results for maraviroc in children and adolescents aged 2 to <18 years.

The authors concluded that these preliminary data show that BSA-based dosing of MVC with CYP3A4 inhibitors provides MVC exposures associated with near- maximal efficacy (Cavg>100 ng/mL) in all age groups studied. But they noted that additional PK analyses are required to evaluate appropriate dosing when MVC is administered without CYP3A4 inhibitors in children.

A second poster from the same group showed safety and efficacy from the same study. [6]

At the time of analysis 35 children had been randomised (n=2, n=12, n=6 and n=15 in cohorts 1 to 4 respectively) and had received at least one dose of MVC. The median duration of treatment was 396, 493, 435 and 211 days in cohorts 1 to 4 respectively. The investigators observed 101 non-serious AEs in 21 patients; they considered 17 of these in 8 patients to be treatment related. Of those with elevated liver function test results, none were of grade 3 or higher. There were 8 serious adverse events of which none were judged to be treatment related and all resolved. There were no deaths.

Viral load <50 copies was achieved by 17/24 (71%) and 11/17 (65%) of participants at weeks 24 and 48 respectively. Five participants had virological failure; in four, this was due to poor adherence. The fifth had emergence of dual-mixed virus and developed 3TC resistance.

Enrollment in this study is continuing and long-term data will be collected and analysed.

References

1. Kakuda TN et al. Population pharmacokinetics of etravirine in HIV-1 infected treatment experienced children and adolescents (6 to <18 years). 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract PP_1.(PDF)
2. Kakuda TN et al. Population pharmacokinetics of etravirine in HIV-1 infected treatment experienced children and adolescents (6 to <18 years). 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TULBPE026.
3. Tudor-Willaims G et al. Safety and efficacy of etravirine in HIV-1-infected, treatment-experienced children and adolescents (6-17 years): week 24 primary analysis of the phase II PIANO study. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TULBPE027.
4. Vourvahis M et al. Maraviroc (MVC) pharmacokinetics (PK) in CCR5-tropic HIV-1-infected children aged 2 to < 18 years: preliminary results from study A4001031. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract PP_4. (PDF)
5. Vourvahis M et al. Maraviroc (MVC) pharmacokinetics (PK) in CCR5-tropic HIV-1-infected children aged 2-< 18 years: preliminary results from study A4001031. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract MOPE232.
6. Giaquinto et al. Safety and efficacy of Maraviroc (MVC) in CCR5-tropic HIV-1 infected children aged 2 to <18 years. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Poster abstract P_51. Also presented at the 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract MOPE237.

Polly Clayden, HIV i-Base

NEVEREST was a study in which young children who were exposed to nevirapine as PMTCT and initiated on PI-based HAART were randomised to continue on this regimen or switch to a nevirapine based regimen (we report the final results from NEVEREST later in this issue of HTB).

NEVEREST investigators evaluated body composition and metabolic abnormalities in 156 children exiting the trial. The objectives were to compare lipid profiles, markers of inflammation and regional fat distribution in children receiving a PI-based regimen of LPV/r plus 3TC plus d4T to those switched to an NVP-based regimen. [1]

The children’s weight (kg) and height (cm) was measured and weight-for-age, height-for-age and BMI-for-age z-scores (WAZ, HAZ, BAZ) calculated. Fasting total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG), C-reactive protein (CRP), viral load, absolute CD4 and CD4 percentage were obtained. Circumferences and skinfolds were also measured; waist to hip ratio (MWC:MHC) and skinfold sum (SFS) were calculated. Upper arm and thigh fat estimates (UFE, UTFE) were calculated by Rolland Cachera. Analyses were intent to treat.

At the time of analyses, children were a mean age of 5.1 (range 3.6 – 6.9) years and approximately half were boys; 85 (42 boys) were randomised to the PI arm and 71 (40 boys) to the NNRTI arm. There were no differences between the two groups in sex, age, total time on ART, time since randomisation, WAZ, HAZ or BAZ or proportion with viral load <50 copies/mL. But children in the NNRTI group had a higher CD4 count, 1480 cells/mm3 compared to 1356 cells/mm3, p=0.049.

The investigators found differences in metabolic measurements. Mean TC was greater in the PI group, 171 (SD+39) mg/dL vs 161 (SD+31) mg/dL, p=0.05 as was the proportion of children with hypercholesterolemia (TC >200 mg/dL), 18.8% vs 8.5%, p=0.03. They also observed lower mean HDL levels, 51 (SD+14) mg/dL vs 59 (SD+16) mg/dL, p=0.006 and higher mean LDL levels, 100 (SD 34) mg/dL vs 88 (SD+27) mg/dL, p=0.018, in the PI group. The mean TG level was also greater in the PI group, 94 (SD+39) mg/dL vs 72 (SD+29) mg/dL, p<0.001 as was the proportion with hypertriglceridemia (TG >150 mg/dL), 12.9% vs 2.8%, p=0.038.

The children in the PI group had significantly greater amount of total body fat compared to those receiving an NNRTI, with a mean SFS of 43 (SD+11.1) mm vs 39 (SD+10.1) mm, p=0.029 and % body fat by BIA (Horlick Equation) of 0.17 (SD+0.7) vs 0.14 (SD+0.08), p=0.042.

The percentage of fat in the upper arm did not differ between groups but the percentage of fat in the upper thigh was greater in the PI group, p=0.021. Also the PI group had a smaller ratio of trunk fat relative to thigh fat, p=0.03.

The investigators wrote: “These unfavourable alterations in lipids and lipoproteins are of great concern with respect to potential increase in long term CVD risk and should be considered in treatment strategies, such as the reuse of NNRTIs for NNRTI-exposed infants”.

References

Shiau S et al. Body composition and metabolic abnormalities of perinatally HIV-infected children in South Africa on long-term ARV treatment. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract O_2. Also presented at the 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract 252.

Polly Clayden, HIV i-Base

Prematurity is a known risk for infant mortality. Other risks include maternal immunosuppression, delayed initiation of ART and low baseline CD4 percentage.

Investigators from the Perinatal HIV Research Unit (PHRU) in Soweto, South Africa showed findings at the 2011 paediatric workshop from a cohort study designed to investigate prematurity among children born in 2009 and initiated on ART before one year of age. The study was a database and record review.

The background characteristics of the infants at time ART initiation are shown in Table 1.

The investigators reported no difference in mortality between preterm and term infants, respectively, 3% vs 4% (OR 1.9; 95%CI 0.5-6.7). Lost to follow up was 8% overall.

Univariate analysis revealed non-significant p-values for all variables ie preterm vs term, baseline CD4%, baseline viral load, breast vs formula feeding and maternal PMTCT. The investigators noted the small sample size and that the mortality rate was low in this study.

They concluded that although HIV-infected preterm infants have significantly lower CD4% than term infants, with early ART initiation they are not at increased risk of mortality.

Reference

Lazarus E et al. Prematurity is not a risk factor for early mortality in HIV-infected infants on antiretroviral therapy. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Poster abstract P_18.

Simon Collins, HIV i-Base

Results from a new online resource developed to predict treatment outcomes for settings without access to genotypic resistance tests were presented in a poster at the conference. [1]

The system was developed by training computer models to predict virological response to therapy using data from approximately 15,000 treatment changes drawn from over 15 countries. The models use CD4, viral load, treatment history and the drugs in the new regimen in making their predictions and can generate predictions of response at selected time points out to 48 weeks for all available combinations or for a selected combination. The system includes the option to select drugs that are available in each country and to exclude drugs that are contraindicated.

The accuracy of the models was assessed with an independent test set of 800 cases. Two further test sets from Romania (n=39) and South Africa (n=56) were also reported together with subset of 57 cases from the 800 test set that had genotypes available.

The mean area under the curve and overall accuracy were 0.77 and 71% with the 800 test dataset (with similar results during cross validation). The comparable results were 0.68 and 67% for the Romanian and 0.69 and 68% for the South African test sets respectively. When the 57 case test set was used to compare the performance of the models with and without genotype information the results were 0.77 and 74% using the genotype, compared to 0.76 and 68% for the ‘no-genotype’ models.

The models are now available via the RDI’s online treatment selection tool HIV-TRePS. Importantly, the resource includes the option to include, with permission, anonymised information on treatment decisions and outcomes to be collected to help further development of the system. [2]

The resource has been developed by researchers at RDI who were involved in much of the original pioneering work into HIV drug resistance technology and more recently have been developing prediction tools to interpret genotype results using computer-developed neural networks.

Future reports on how this resource is used in practice will be important given the extremely restricted access to resistance testing in most resource-limited countries and that this is unlikely to change in the near future.

References

1. Larder BA et al. Predicting response to antiretroviral therapy without a genotype: a treatment tool for resource-limited settings. 16th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 17–20 July 2011, Rome. Poster MOPE146.
2. The resource can be accessed free online after one-time free registration.

http://www.hivrdi.org

Our final reports from this important conference are:

• Monitoring treatment in resource limited settings: results from PHPT-3 and Stratall ANRS12110/ESTER trials
• DART: high rates of viral suppression after five years and a single CD4 test with a threshold of 250 cells/mm3 could reduce unnecessary switching
• Lopinavir/r monotherapy used as second-line therapy in resource-limited settings
• Pharmacokinetics of different rifabutin dosing strategies with lopinavir/ritonavir-based ART
• Initiation of ART during breastfeeding can induce multidrug resistance in infants
• Treating children previously exposed to single dose nevirapine: update on IMPAACT P1060 and NEVEREST
• Lopinavir/ritonavir oral solution toxicity in neonates
• Paediatric antiretroviral pipeline: darunavir and raltegravir

Unless mentioned otherwise, all references are to the Programme and Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections, 28 February–2 March 2011, Boston.

http://www.retroconference.org/AbstractSearch/

Webcasts are available at the following link:

http://www.retroconference.org/2011/data/files/webcast_2011.htm

In resource-limited settings, optimal monitoring and switching criteria from first-line to second-line therapy is unclear. Results from two trials were shown as oral presentations that suggest that monitoring viral load is not essential for switch to second line. [1, 2]

Marc Lallemant showed data from PHPT-3, which was conducted in Thailand. This was a randomised double-blind (until first switch) non-inferiority trial. Participants were randomised to CD4 or viral load monitoring, which was conducted every three months.

Dr Lallemant explained that the trial was designed for a setting with only two lines of treatment and where second line is far more expensive than first line. The investigators wanted to test whether monitoring and switching people without viral load compromised their health or their future options.

PHPT-3 enrolled HIV-positive adults (CD4 count 50 to 250 cells/mm3, not hepatitis B or C co-infected), starting NNRTI-based HAART.

In the CD4 monitoring arm, patients switched to second-line protease inhibitor (PI) -based therapy when they had confirmed CD4 decline of 30% or more from peak, and in viral load monitoring they switched when they had confirmed viral load >400 copies/mL.

The primary endpoint was death, new AIDS-defining event or clinical failure – defined as CD4 <50 cells/mm3 – at 3 years. Secondary endpoints included proportions switching to second line, time to switch, resistance mutations at failure and future treatment options.

The trial enrolled 716 patients of which 60% were women. Their median CD4 count at baseline was 144 cells/mm3 (range 90 to 200 cells/mm3).

Regimens were 65% efavirenz-based regimen and 66% of participants received tenofovir/FTC. Other study drugs were nevirapine and AZT/3TC. At 3 years of follow up 93.3% of patients were evaluable. Ten percent stopped treatment for toxicity across both groups.

There were 58 clinical failures overall, 28 and 30 in the CD4 and viral load groups respectively. The respective rates of clinical failure per patient years were 2.3 vs 2.5 and of death 1.1 vs 1.4.

In multivariate analysis, anaemia, adjusted HR 2.7 (95% CI 1.5-4.8), p=0.001; CD4 <150 cells/mm3, AHR 2.3 (95% CI 1.2-4.2), p=0.009 and viral load >5 log, AHR 1.8 (95% CI 1.0-3.0), p=0.04, were predictive of clinical failure at 3 years.

The probability of switch to second-line (excluding toxicity/intolerance) was 5.2% (95% CI 3.2-8.4%) vs  7.5% (95% CI 5.0 -11.1%) in the CD4 and viral load groups respectively, p= 0.10.

The respective median times to switch were 11.7 months (95% CI 7.7-19.4) vs 24.7 (15.9-35.0), p=0.001. And the median duration of viraemia >400 copies/mL was 7.2 months (IQR 5.8 to 8.0) vs 15.8 months (8.5 to 20.4), p= 0.002. But the median CD4 counts were 426 cells/mm3 vs 420 cells/mm3, respectively.

Dr Lallemant noted that 15/31 patients in the CD4 monitoring arm who switched to second-line had viral load <50 copies/mL at the time of switching.

Viral load was <50 copies/mL in 99% of patients at 3 years follow-up and patients with CD4 monitoring did not have fewer future treatment options, with the exception of one patient with multiple thymidine analogue mutations (D67N/M41L/L210W/T215Y).

Dr Lallemant concluded that, after 3 years, the rate of clinical failure was very low and did not differ between the two strategies. Most mutations had been selected at the time of virological failure. The additional time spent on failing treatment in the CD4 arm did not result in reduced future treatment options.

He noted that the conclusions from PHPT-3 are similar to those from DART and HBAC in adults and PENPACT-1 in children. He added that the need for viral load monitoring may be less important than close and regular safety, tolerability, adherence, and immunological monitoring. He remarked that the nurse/patient team with expert assistance from doctors, biologists and patient networks “maximizes efficacy and durability.”

This was followed by a related presentation of data from the Stratall ANRS12110/ESTER trial.

Charles Kouanfack showed findings from a trial designed to compare clinical monitoring alone with laboratory and clinical monitoring. This trial was conducted in 9 rural district hospitals in Yaounde, Cameroon.

Dr Kouanfack explained, in Cameroon, the national programme followed WHO guidance for a public health approach based on decentralised, integrated HIV care delivery in facilities where laboratory monitoring is generally unavailable. He noted that the 2010 guidelines also state that using viral load monitoring to detect treatment failure and switch is recommended but has “low quality evidence”.

Stratall ANRS12110/ESTER was a randomised non-inferiority trial enrolling HAART-naïve, HIV-positive adults with a WHO stage 3-4 disease or stage 2 and total lymphocyte count <1200 cells/mm3, who were followed for 2 years. Management was by the health workers in charge of routine activities.

The primary endpoint was mean increase in CD4. The increase in the clinical monitoring arm was judged to be non-inferior to that in the laboratory monitoring arm if the difference was less than or equal to 25%.

Secondary endpoints included: viral suppression, death, new stage 3 or 4 events, resistance, loss to follow up, adherence, treatment changes and toxicity.

Participants were monitored clinically 3 monthly in both arms and those in the laboratory monitoring arm also had CD4 and viral load measured every 6 months.

Switching to second line was indicated by grade 3 or 4 events in the clinical monitoring arm and persistent viral load >5000 copies/mL in the laboratory monitoring arm.

Of a total of 493 patients, 256 were assigned to clinical and 237 to laboratory monitoring. Of these, 93% were followed and included in the analysis. Patients were similar at baseline with CD4 counts of 179 cells/mm3 and 182 cells/mm3 in the clinical and laboratory monitored arms respectively. Both arms had high baseline viral loads of 5.6 log₁₀ copies/mL. Overall 70% were women. About 65% started treatment with d4T + 3TC + NVP.

The trial failed to demonstrate non-inferiority of clinical monitoring:  the mean increase in the CD4 count was 175 cells/mm3 (95%CI 151-200) vs 206 cells/mm3 (95% CI 181-231) in the clinical and laboratory arms respectively. This gave a difference –31 (–63 to +2), the non-inferiority margin was –52 (–58 to –45). The analysis was last observation carried forward.

The analysis also revealed that 13 (6%) laboratory-monitored participants switched to second-line regimens because of treatment failure, compared to none of the clinically monitored participants, p<0.001. But, viral suppression (49 vs 52%), resistance (both 10%), mortality (18 vs 14%), disease progression (36 vs 29%), adherence (both 64%), loss to follow-up (9 vs 8%), and toxicity (19 vs 25%) were similar between the two groups.

Dr Kouanfack concluded that failure to demonstrate non-inferiority of immunological recovery and the need to switch to second line in this trial supports the WHO recommendation of laboratory monitoring of HAART where possible.

He also concluded that the difference between the two strategies suggest that clinical monitoring alone can be used for at least the first two years of treatment in order to expand scale up and to take into account financial and infrastructural constraints in resource limited settings.

References

1. Jourdain G et al. PHPT-3: A randomised clinical trial comparing CD4 vs viral load ART monitoring/switching strategies in Thailand. 18th CROI, 27 February–3 March 2011, Boston. Oral abstract 44.
2. Kouanfack C et al. HIV viral load, CD4 cell count, and clinical monitoring vs clinical monitoring alone for ART in rural hospitals in Cameroon: Stratall ANRS 12110/ESTHER trial, a randomised non-inferiority trial. 18th CROI, 27 February–3 March 2011, Boston. Oral abstract 45LB.

Both webcasts: Research on Delivery of Care in Developing Countries. Monday 28 February 11 am.

DART was a randomised trial comparing clinically driven monitoring (CDM) to laboratory (CD4, haematology, biochemistry) plus clinical monitoring (LCM) of 3316 HAART-naïve adults conducted in Uganda and Zimbabwe. People in both monitoring arms showed high and similar 5-year survival rate – 90% vs 87% in the LCM and CDM arms respectively – differing by a small percentage that only occurred after two years of follow up. This compared to an historical 5-year survival rate prior to HAART of only 8% in the Uganda cohort. [1]

First line HAART in this trial was AZT/3TC plus either TDF (74%), ABC (9%) or NVP (16%). Participants needing to switch to second line received LPV/r plus NRTI/s and/or NNRTI. Neither the CDM nor LCM group had real time viral load monitoring.

Ugandan patients who did not participate in one of two, nested second line RCTs had a viral load test when they left the trial and joined the national programme.

Further findings from the DART trial were presented at CROI 2011.

Cissy Kityo and colleagues showed high rates of virological suppression at 5 years after HAART initiation among the Ugandan participants alive and in follow up. [2]

Both monitoring groups switched to second line therapy following WHO stage 4 or multiple stage 3 events; the LCM group also switched at CD4 <100 cells/mm3.

A viral load measurement was available the end of the trial for the majority of eligible participants: 1207 (80%) and 187 (70%) respectively receiving first and second line at exit. The viral load sample was taken at a median of 5.2 years after initiation of HAART and 2.7 years after start of second line for those who had switched.

Of the participants who remained on first line, 81.9% (95%CI 78.5-84.9%) in LCM and 74.2% (95%CI 70.6-77.6%) in CDM had viral load <200 copies mL, p=0.001. In the LCM group 5.6% (95% CI, 3.9-7.8% had viral loads <10,000 copies, which was lower than the 10.4% (95%CI 8.1-13.1%) of participants in CDM.

Of those who switched, viral loads were similar across the two monitoring groups, p=0.6. Viral load <200 copies/mL was achieved in 88.8% (95%CI 83.3-92.9%) of participants receiving second line.

When the investigators examined the CD4 count nearest to the exit viral load measurement (taken at a maximum of 6 months apart), they found a negative association, r=0.4, as would be expected.

Of 283 (20%) participants with viral load >200 copies/mL, 29% in the LCM group and 42.2% in CDM had CD4 <200 cells/mm3.

The investigators noted that CD4 counts <100 cells/mm3 were rare in either arm; only 2 people in LCM and 7 in CDM.

A related study showed a single CD4 test with a threshold of >250 cells/mm3 could reduce inappropriate switching in clinically monitored patients. [3]

Charles Gilks and colleagues investigated the relationship between CD4 count at switch and the reason for doing so in all 675 (361 LCM and 314 CDM) DART participants switching to second line.

In the CDM arm, 206 (66%) switched due to WHO stage 4 events and 76 (24%)/32 (10%) participants single or multiple WHO stage 3 events, respectively. In LCM 265 (73%) participants switched because their CD4 count fell below 100 cells/mm3, 43 (12%) for other CD4 reasons, 37 (10%) due to WHO 4 events and 6 (23%)/10 (3%) single or multiple WHO stage 3 events.

In the LCM arm, clinical failure provoked switching in 7 (2%) of patients with CD4 >250 cells/mm3; 3 due to WHO stage 4 events, 1 single WHO stage 3 event and 3 for other CD4 reasons. This compared to 64 (20%) of participants who switched with CD4 > in the CDM arm, p=0.001. The investigators noted, however, that deaths within one year of switching were similar in CDM whether participants switched above or below 250 cells/mm3, 11/64 (17%) vs 33/250 (13%) respectively.

In the CDM group, switching due to a single WHO grade 3 event was significantly more frequent with a CD4 count of >250 cells/mm3 (27/76, 36%) compared to multiple WHO stage 3 events (4/32, 12%) or WHO stage 4 events (33/206, 16%), p=0.001.

Viral load measurements at switch were available for 108 and 113 participants in the LCM and CDM groups respectively.  Of these, 15 (14%) vs 32 (28%) respectively were <400 copies/mL, p=0.009.

In the CDM group, 25/31 (81%) with clinical failure and CD4 > 250 cells/mm3 had viral load <400 copies/mL vs 7/82 (9%) with CD4 <250 cells/mm3, p<0.001.

The investigators noted a trend to switching for single WHO stage 3 events compared to multiple WHO stage 3 or stage 4, but this was not significant, p=0.22.

They concluded that among clinically monitored patients, a single CD4 test with a threshold of 250 cells/mm3 could identify up to 80% with viral load <400 copies/mL who are unlikely to benefit from second line therapy. In DART, nearly 40% of participants who failed clinically with a single WHO stage 3 event had CD4 >250 cells/mm3. They wrote: “Targeting this group would be particularly likely to avoid premature, costly switching to second line.”

References

1. DART trial team. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial. The Lancet, Volume 375, Issue 9709. 9 January 2010.
2. Kityo C et al. High rates of virologic suppression among patients not receiving routine virologic monitoring after 5 years of first-line ART. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 677.
3. Gilks C et al. A single CD4 Test with threshold >250 cells/mm3 can markedly reduce switching to second-line ART in African patients managed without CD4 or viral monitoring. 18th CROI, 27 February–2 March 2011, Boston.  Poster abstract 676.

WHO guidelines recommend the use of boosted protease inhibitors second line in resource limited settings. Findings from strategies looking at using lopinavir/ritonavir (LPV/r) have been uncertain to date, both in limited and richer resourced settings.

Two posters at CROI 2011 presented data from studies evaluating LPV/r monotherapy, with showed further conflicting results.

ACTG 5230 evaluated lopinavir/ritonavir (LPV/r) monotherapy in a pilot study. It was a single arm multinational trial with sites in Malawi, Tanzania, South Africa, Thailand and India.

Participants had previously received first line NNRTI-containing regimens for at least six months and had detectable viral load 1,000–200,000 copies/mL. All participants received LPV/r monotherapy BID. The primary endpoint was remaining on monotherapy without virological failure at 24 weeks. This was defined as: failure to suppress viral load to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression.

People with virologic failure received intensification with emtricitabine (FTC) 200 mg/tenofovir (TDF) 300 mg.

There were 123 participants enrolled in this trial. About 60% were women and they were a median of 39 years of age, with a median CD4 of 164 cells/mm3 and viral load of 4.34 log₁₀ copies/mL (17% were >100,000 copies/mL).

Other baseline characteristics included: 93% with >1 year HAART, 98% with >1 NNRTI mutation and 95% with >1 NRTI mutation (87% M184V, 84% TAM, 11% K65R, 4% Q151M/L).

The majority, of participants completed 24 weeks of follow-up with the exception of one death at week 20 with a viral load of <400 copies/mL.

The investigators reported, at week 24, 107 (87%; 95% CI 80-92%) of participants remained on LPV/r monotherapy without virologic failure.

Of the remaining, 15 met the criteria for virologic failure and one added FTC/TDF before failure. Of 13 participants with data after intensification, 11 (85%) suppressed viral load to <400 copies/mL.

At virologic failure, 2/11 participants who were successfully sequenced had selected new resistance mutations (both had A71T and V82F). The overall mean CD4 count increase from baseline to week 24 was 107 cells/mm3. Overall 31 (25%) of participants experienced grade 3 or 4 toxicities. The most commonly reported grade 3 or 4 toxicities (9% of participants) were metabolic (mostly elevated lipids). Self reported adherence was high; at week 24, 83% of participants reported no missed doses.

The investigators concluded that LPV/r monotherapy showed promising preliminary activity as second-line HAART following failure of first-line NNRTI-containing regimens at 24 weeks. The lower bound of the 90% CI (81-92%) of the observed success rate (87%) was above 65%.

Torsak Bunupuradah and colleagues from the HIV STAR Study in Thailand looked at LPV/r monotherapy as second line but they also evaluated viral suppression to <50 copies/mL and included a comparison arm with triple therapy.

The STAR investigators enrolled 200 participants with viral load >1000 copies/mL on NNRTI-containing first line therapy. Participants were randomised to receive either LPV/r monotherapy ot LPV/r + TDF + 3TC.

Treatment failure was defined as viral load >400 copies/mL at >24 weeks. Participants meeting these criteria in the monotherapy arm received intensification with TDF + 3TC.

Participants in this study were about 60% men with a median age of 37 years, CD4 of 188 cells/mm3, and viral load of  4.1 log10 copies/mL.

Prior to switching, 92% of participants were receiving 3TC, 63% d4T, 23% AZT and 5% TDF. Nevirapine and efavirenz were received by 86% and 14% participants, respectively. Without significant differences between arms, 15% of participants had ≥3 TAMS, 82% had M184V/I, 6% had Q151M, and 7% had K65R.

By intent-to-treat analyses at 48 weeks, the proportion of patients with viral load <400 copies/mL the LPV/r monotherapy arm was 75% vs 86% in the TDF/3TC/LPV/r arm, p=0.53. But, only 61% of the LPV/r monotherapy arm vs 83% in TDF/3TC/LPV/r arm had a viral load <50 copies/mL, p<0.01.

Major PI mutations were detected in 1 of 2 LPV/r monotherapy and 0 of 3 TDF/3TC/LPV/r treated participants with genotype results following treatment failure. There was no significant difference in CD4 count increase between arms: 114 vs 137 cells/mm3 in the LPV/r monotherapy and TDF/3TC/LPV/r arms respectively. One death (unrelated to study drugs) was reported in each arm. Serious adverse events were reported in two patients in the LPV/r monotherapy arm and seven patients in the TDF/3TC/LPV/r arm.

The investigators concluded that LPV/r monotherapy should be used with caution as a second-line option, particularly in settings where close viral load monitoring is not available.

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The ongoing EARNEST Trial (NCT00988039) will answer the question whether or not lopinavir/r monotherapy is a sufficiently potent regimen compared to lopinavir/r combined with two NRTIs or raltegravir.

Results from this trial are expected in 2013.

References

1. Bartlett J et al. A pilot study of LPV/r monotherapy following virologic failure of first-line NNRTI-containing regimens in resource-limited settings: The Week-24 primary analysis of ACTG 5230. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 583.
2. Bunupuradah T et al. Second-line LPV/r monotherapy was inferior to TDF/3TC/LPV/r in patients who failed NNRTI regimen: HIV STAR Study. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 584.

Interactions between rifampicin and protease inhibitors makes treating patients coinfected with HIV and TB more complicated.

Rifabutin is an alternative rifamycin, which can be used in patients receiving a protease inhibitor. Recent findings suggest that the current recommended dose of lopinavir/r (LPV/r) is suboptimal. There are limited data regarding the newer formulation of LPV/r.

Investigators from University of Cape Town, International Union Against Tuberculosis and Lung Disease and WHO evaluated the pharmacokinetics (PK) of rifabutin in co -infected patients on a first line TB regimen before and after the initiation of LPV/r-based ART.

Suhashni Naiker and colleagues showed findings from this study in a poster at CROI 2011.

A group of 16 patients on stable rifabutin-containing TB regimens were initiated on LPV/r-containing HAART. At HAART initiation they were randomised to receive either: rifabutin 150 mg daily for 1 month followed by 150 mg 3 times weekly, or 3 times weekly doses followed by daily doses.

The investigators measured serial rifabutin and 25-O-desacetyl rifabutin concentrations during a dose interval after 4 weeks of rifabutin 300 mg daily, after 4 weeks of 150 mg rifabutin daily with LPV/r-based HAART, and after 4 weeks of rifabutin 150 mg 3 times a week with LPV/r-based ART.

At baseline the participants were a mean (SD) of 31.6 (5.5) years, 59.0 (9.4) kg, 160.1 (7.1) cm and 147 (43) CD4 cells/mm3. Ten were men. Two were not included in the analysis due to poor adherence.

The investigators reported median AUC0-24 and Cmax, for participants receiving 300 mg rifabutin daily, 150 mg rifabutin three times a week, and 150 mg rifabutin daily, respectively, of 3026 ng/mL.h and 297ng/mL, 2307 ng/mL.h and 168 ng/mL, and 5010 ng/mL.h and 311ng/mL.

They found that rifabutin was well tolerated at all dosing strategies. There was one case of uveitis that occurred before  LPV/r was initiated, and one grade 2 transaminitis and one grade 2 neutropenia were also reported.

They concluded that rifabutin 150 mg daily used with LPV/r produces Cmax concentrations within the recommended target range of 300 to 900 ng/mL.

Reference

Naiker S et al. Pharmacokinetic evaluation of different rifabutin dosing strategies in African TB patients on lopinavir/ritonavir-based ART. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 650.

In resource-limited settings some HIV-positive women initiate ART during breastfeeding. This exposes infected infants to the risk emergence of resistance to the antiretrovirals in their mothers’ regimen.

Investigators from the Post Exposure Prophylaxis of Infants (PEPI)-Malawi trial – in which infants were received up to 14 weeks of extended nevirapine (NVP) or extended NVP plus AZT – evaluated resistance in infants whose mothers began ART post-partum.

Interim data from this analysis was first presented as a poster at CROI. [1] Further findings were reported in a subsequent article in the April 24 2011 edition of AIDS. [2]

Infant plasma samples were collected at 14 weeks of age and tested using the ViroSeq HIV Genotyping System and LigAmp – a sensitive point mutation assay – to detect K103N (limit of detection 0.5%) and Y181C (limit of detection 1%). Later samples collected at 6 and 12 months of age were also analysed using LigAmp.

The investigators found that at 14 weeks 82/108 (75.9%) of infants evaluated had detectable NVP resistance using the Viroseq assay. The proportion of infants with K103N and/or Y181C detected by LigAmp was similar, 78/108 (72.2%), p=0.45. There were no significant differences between rates of resistance among infants receiving extended NVP or NVP plus AZT measured by either assay. Nor were: duration of prophylaxis received prior to infant diagnosis, maternal CD4 count, maternal single dose NVP use, or in utero infection, significantly associated with NVP resistance.

At 6 months, 38 out of 46 (82.6%) samples analysed still had K103N and/or Y181C. Again, results were similar across study arms, p=1.0. And at 12 months 19 out of 29 (66.5%) evaluable infants had these mutations in similar proportions across arms, p=0.43.

Although the data was not presented, the investigators noted that there was no significant difference in the percentage of the total viral population of either K103N or Y181C in infants in the two groups with these mutations at 6 and 12 months of age.

The investigators concluded that the frequent persistence of the K103N and Y181C mutations in infants after exposure to extended NVP prophylaxis, with or without AZT, may compromise the infants’ subsequent response to NNRTI-based treatment.

References

1. Fogel J et al. Initiation of ART in women after delivery can induce multi-class drug resistance in breastfeeding HIV-infected infants: PEPI-Malawi Trial. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 761.
2. Fogel J et al. Analysis of nevirapine (NVP) resistance in HIV-infected infants who receive extended NVP or NVP/zidovudine prophylaxis. AIDS 2011 25 911-917.24 April 2011.

Two oral presentations at CROI 2011 showed further findings from studies looking at treatment in children previously exposed or unexposed to maternal/infant single dose nevirapine (NVP) in prevention of mother to child transmission (PMTCT) programmes.

IMPAACT 1060

IMPAACT P1060 was a randomised trial to determine whether NVP- or lopinavir/ritonavir (LPV/r)-based treatment performed better in young children exposed and unexposed to single dose NVP. All children received AZT plus 3TC. The trial comprised of Cohort 1 (exposed children) and Cohort 2 (unexposed children). Data from Cohort 1 have previously been reported and this part of the study was stopped early after a scheduled Data Safety Monitoring Board (DSMB) review, as there was an unsurprising trend towards more failure in the children receiving NVP- compared to LPV/r-based treatment.

Peter Palumbo presented results from Cohort 2. This cohort enrolled children aged 2 to 36 months, who met WHO criteria for treatment and were unexposed to single dose NVP. Children were stratified by age < or ≥ 12 months. Children with TB were excluded from the trial.

The study had a composite primary endpoint of treatment failure, which comprised viral failure (<1 log10 decline from baseline to after 12 to 24 weeks or >400 copies/mL at week 24), or permanent discontinuation of NVP or LPV/r, including death by 24 weeks. Rates were calculated from Kaplan-Meier curves for each treatment group and age group.

Secondary endpoints included time to virological failure by 24 weeks, time to treatment failure throughout follow up and time to virological failure or death throughout follow up.

P1060 Cohort 2 was fully enrolled with 288 children by March 2010 and had 48-week planned follow-up to March 2011.  In October 2010, the DSMB recommended that the study was unblinded. All children had completed 24 weeks of follow up.

Dr Palumbo reported that the children’s median age at enrollment was 1.7 years (73% >12 months) and their median baseline viral load and CD4 percentage were 535,632 copies/mL and 15% respectively. The majority (79%) of children were subtype C.  The median follow-up was 72 weeks.

At week 24, 87 children had reached an endpoint; 60 in the NVP and 27 in the LPV/r arms. The overall difference in failure rate was 21.5% (95% CI, 11.2-31.8) in favour of LPV/r, p<0.001. This was similar in both age groups: 22.0% (<12 months) and 21.3% (>12 months).

There was also a significant difference in time to off study drug, over the full length of the trial, p<0.001. There were 10 vs 3 deaths in the NVP vs LPV/r arms during the entire follow-up

period (none judged related to study drugs), but this did not reach statistical significance, p=0.63.

There was a notable amendment during the course of the trial. In 2007 the recommended NVP dose in WHO guidelines increased from the FDA recommended dose of 7mg/kg to 160-200mg/m2 (max 200mg). Only 32 children were enrolled under the lower dose compared to 115 at the higher one but the investigators saw no effect associated with this change.

Dr Palumbo noted that the main reasons for off study were more virological failure, toxicity and death in the NVP arm.

As both the NEVEREST and P1060 Cohort 1 data had suggested poorer weight and CD4 improvement in children receiving LPV/r compared to NVP, the investigators also looked at this in Cohort 2. They did not find a statistically significant difference in CD4 improvement between the two arms but there was a difference in weight z-score favouring NVP at 24 and 48 weeks, respectively p=0.007 and p=0.009.

When the investigators looked at NVP resistance in samples from subsets of children at baseline and time of virological failure, they found 2.4% (5/206) with resistance at baseline compared to 56% (10/18) at time of virological failure.

These results were different to those in the sister study, OCTANE P1060, in which maternal data demonstrated non-inferiority of NVP- to LPV/r-based treatment, by the study definition, for NVP- unexposed women.

This highlighted the “unique and challenging situation of early paediatric HIV infection”, Dr Palumbo said, including very high baseline viral load and the unforgiving nature of NVP resistance. LPV/r is already recommended for NVP-exposed children and discussions are ongoing as to whether this recommendation should expand to all young children, possibly up to three years of age.

These data once again point to the importance of developing new first and second line options for use in this age group.

NEVEREST

Louise Kuhn presented data from NEVEREST, a study designed to evaluate a treatment switch strategy from LPV/r to NVP in NVP-exposed children.

In this study, 323 children aged 6 weeks to 2 years and eligible for treatment were initiated on LPV/r plus 3TC plus d4T. After achieving a viral load <400 copies/mL and maintaining it for > 3 months, children were randomised (n=195) to either remain on LPV/r (n=99) or switch to NVP (n=96). Time to any viral load >50 copies/mL or confirmed >1000 copies/mL was compared using Kaplan-Meier methods and log-rank tests.

Fifty-two week data post switch from this study has been reported previously. These data revealed a higher proportion of children suppressed to <50 copies/mL (the primary endpoint) in the NVP arm but also a higher proportion in that group with confirmed >1000 copies/mL.

Dr Kuhn showed longer term results from this study with follow up of 18-53 months.

There were three deaths in each group. At 36 months post randomisation, as with the earlier analysis, more children in the NVP group (40.5%) maintained viral load <50 copies/mL than those in the LPV/r group, p=0.01. Again, more in the NVP (23.9%) than in the LPV/r (11.1%) had confirmed >1000 copies/mL, p=0.01.

This difference persisted at 48 months, for <50 copies/mL and >1000 copies/mL, respectively p=0.02 and p=0.08.

At 6 months 59.1% of the failures in the NVP group had occurred vs 10% in the LPV/r group. By 12 months these proportions were 100% in the NVP group and 50% in the LPV/r group. Dr Kuhn noted that among children in the LPV/r group, 6% of failures occurred between 12 and 48 months.

Treatment failure >1000 copies/mL was associated with the presence of pre-treatment NVP mutations, p=0.02. There was no difference in response between children in the NVP and LPV/r groups in children who had no pre-treatment NVP resistance. Half the children with detectable NVP mutations failed when re-challenged with NVP.

Dr Kuhn concluded that viral load testing can identify all switch failures and that switching can be accomplished safely if viral load testing is available. Also that pre-treatment screening for resistance can be used to identify the children who could benefit from this strategy.

References

1. Palumbo P et al. NVP- vs LPV/r-based ART among HIV⁺ infants in resource-limited settings: the IMPAACT P1060 Trial. 18th CROI, 27 February–2 March 2011, Boston. Oral abstract 129LB.
2. Kuhn L et al. Long-term outcomes of switching children to NVP-based therapy after initial suppression with a PI based regimen. 18th CROI, 27 February–2 March 2011, Boston. Oral abstract 128.

Lopinavir/ritonavir (LPV/r, Kaletra) oral solution is approved by the FDA for infants 14 days of age and older. US guidelines do not recommend its use in preterm infants.

LPV/r oral solution has particular pharmacokinetic properties that make its use complicated in neonates. It contains high volumes of both ethanol (356.3 mg/mL, 42% volume solute/volume solution (v/v) and propylene glycol (152.7 mg/mL, 15.3% v/v).

Neonates have reduced alcohol dehydrogenase and CYP3A4 activity and immature renal function. Ethanol is 95% and propylene glycol is 55-75% metabolised in the liver by alcohol dehydrogenase. Ethanol inhibits the metabolism of propylene glycol by alcohol dehydrogenase leading to elevated concentrations. LPV is metabolised by CYP3A.

Reduced hepatic metabolism and renal clearance in neonates, particularly in preterm infants, can lead to accumulation of all three ingredients to toxic levels.

Acute ethanol toxicity is linked to central nervous system (CNS) and respiratory depression, and gastritis. Propylene glycol is also associated with CNS and respiratory depression, as well as renal failure and metabolic acidosis. LPV has been shown to cause PR and QT interval prolongation and AV block in adults with very high levels of the drug.

Cases of toxicity in neonates – particularly preterm – have been reported to the FDA Adverse Event Reporting System (AERS).

A poster authored by Debra Boxwell and colleagues from the FDA showed data from case studies from a search of the AERS database for all reports of toxicity in children 2 years of age or under following dosing with LPV/r oral solution.

The search revealed 10 unduplicated cases in neonates of whom 8 were preterm. Of the preterm infants, 3 were born at 28 weeks gestation, 1 at 30 weeks, 2 at 32 weeks and 2 at 34 weeks.

The documented adverse events included cardiac toxicity (bradycardia, complete AV block, bundle branch block, or cardiac failure; (n=7), acute renal failure (n=5), increased serum creatinine (n=1), elevated serum lactate level (n=2), hyperkalemia (n=4), respiratory failure (n=2), hypotonia (n=1), abnormal EEG (n=1), and CNS depression (n=1).

Outcomes included 1 death, 2 life threatening and 4 hospitalisations. Therapy was initiated on the day of birth in 7 neonates, day after birth in 1, day 34 in 1, and unknown in 1.

Onset the first adverse event occurred within 1 to 6 days (n = 8). Discontinuation of Kaletra (n=9) resulted in recovery within 1 day in 1, 2 days in 2, 3 days in 2, 6 days in 3, 20 days in 1 and was unknown in 1.

WHO set 25mg/kg as a maximum acceptable daily intake of propylene gel when it is used as a food additive. The European Medicines Agency (EMA) recommends that a 12.5mg/dL blood concentration of ethanol after a dose of any medication should not be exceeded. In IMPAACT P1030 – a PK sub-study in full-term infants 6 weeks of age – the mean steady state of LPV was 5.2+1.8ug/m2 twice daily. When the FDA investigators looked at neonatal exposure to the three ingredients in the cases for which data were available, the results were far in excess of these recommendations. See Table 1: Neonatal exposure to lopinavir, ethanol and propylene glycol.

The investigators concluded that the ten cases to the AERS suggest that neonates, especially those born preterm, who received LPV/r oral solution, were at increased risk of toxicities from drug accumulation. They added that the improvement of symptoms when the drug was stopped support this association.

There are limitations to the AERS however. Because reporting is voluntary, the quality of reporting is very variable. The database is subject to under reporting as well as reporting bias and both the numerator and the denominator are unknown for any event reviewed. Therefore the incidence or estimated risk cannot be calculated.

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This analysis provoked a FDA label change and the lopinavir/r oral solution is not recommended for neonates particularly preterm.

Reference

Boxwell D et al. Neonatal toxicity of Kaletra oral solution—LPV, ethanol or propylene glycol? 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 708.

Two posters at CROI 2011 presented pharmacokinetic (PK), efficacy and safety data of paediatric formulations of antiretroviral drugs. [1, 2]

Darunavir

ARIEL (TMC114-C228) is a 48-week, open-label, single-arm, phase II trial evaluating PK, safety and efficacy of darunavir/ritonavir (DRV/r) plus an optimised background regimen (OBR) in HIV-positive treatment-experienced children. Avy Violari and colleagues reported interim (24 week) data from ARIEL.

Children aged 3 to <6 years, weighing 10 to <20kg, with viral load >1000 copies/mL and <3 DRV resistance-associated mutations (RAM) at screening, received DRV. The formulation used in this study is a high concentrate oral suspension (100 mg/mL) – initially dosed at 20 mg/kg BID plus ritonavir (RTV) 2.6 to 3.2mg/kg BID with an OBR (>2 active NRTI) – over 48 weeks.

After a PK analysis at week 2, the DRV dose was amended to 25mg/kg BID children weighing 10 to 15kg and 375mg BID fixed for those weighing 15 to <20 kg (following Data Safety Monitoring Board recommendations).

A total of 27 patients – 55.6% male and mean age 4.6 years at screening – with DRV/r + an OBR. At baseline, the children’s median viral load was 4.51 log copies/mL, median CD4 count was 927 cells/mm3, and median CD4 percentage was 27.7% cells/mm3. The children had a median of 0 primary PI mutations at baseline and 4 PI RAM, 1 NRTI RAM, and 1 NNRTI RAM.

The majority of children, 23 (85.2%) experienced at least one adverse event (AE). One child discontinued treatment (due to grade 2 vomiting, believed to be associated with ritonavir). Most side effectss were grade 1-2. Grade 3-4 and serious side effects were reported in 18.5% and 11.1% of patients, respectively but none was considered treatment-related. Most commonly reported adverse events (occurring in over 10% of patients) were diarrhea, vomiting, pyrexia, nasopharyngitis, rhinitis, upper respiratory tract infection, hypokalemia, cough, acidosis, and alkalosis.

One child had a grade 3 laboratory abnormality – neutropenia – but this was present since baseline and not considered to be related to treatment.

There was a steady increase in response from week 2 to 24. By week 24, 55.6% of the children met the primary efficacy endpoint of viral load <50 copies/mL (ITT-TLOVR). The mean increase in CD4 at week 24 was 109 cells/mm3.

Two children had DRV RAMs at baseline but both were <50 cells/mL at week 24. Eleven children (40.7%) were considered virological failures. None of the six children with paired baseline/endpoint genotype samples developed PI or NRTI RAMS.

Raltegravir

P1066 is an open-label study of raltegravir (RAL) in treatment experienced HIV-positive children and adolescents. Sharon Nachman and colleagues reported PK, and week 12 and 24 efficacy and safety data for treatment-experienced children aged 2 to 5 years receiving the RAL chewable tablet formulation.

In this dose finding study, intensive PK was initially performed on 4 children and once PK targets were met, 8 more were enrolled. Inclusion criteria included viral load >1000 copies/mL, prior ART experience but naïve to integrase inhibitors. A RAL chewable tablet 6 mg/kg twice daily was added to the existing regimen, intensive PK samples were taken between days 5 and 12. Once the dose was selected, an additional 9 children were enrolled to assess longer-term safety and efficacy.

PK parameters were evaluated and a dose was selected using an AUC12h target (range 14 to 25uM*h) based on available PK data with a C12h target to exceed the protein-adjusted IC95 of RAL against wild type virus. The investigators compared PK parameters to existing data from 6 to 18 year old children and adolescents receiving the adult formulation and 6 to 11 year old children receiving RAL chewable tablet. Of the 12 children, 67% were female, they were a mean, age of 3 years old, viral load 4.14 log10 copies/mL, CD4%, 33% cells/mm3, CD4 count, 1505 cells/mm3, and weight, 14.3 kg. They received a mean RAL dose of 6.24 mg/kg (0.67).

The geometric mean AUC12 was 8.8hr*mg/L, 18uM*h; C12h 32ng/mL, 71nM; Cmax 4329ng/mL, 9.7uM; CL/F 10.5L/hr and %CV 77%.A 6mg/kg BID dose (maximum 300mg) was selected.

At week 24, by ITT analysis, 62% (95% CI, 53-92) of children (n=21) were <400 copies/mL and 52% (95% CI, 30-74) <50 copies/mL. CD4 gain from baseline was a median of 4.1% (95% CI 2.0-9.9) and 218 (95% CI 39-290) cells/mm3.

No child discontinued RAL due to AEs in this study. One child had grade 3 ALT (2 events), grade >3 AST and ungraded elevated GGT (5 events), considered possible treatment related. Three children had grade >3 neutropenia (7 events) but this was not judged to be treatment related. Other non-treatment related events were: grade 3 bronchopneumonia, grade 3 hydrogen ion concentration, ungraded lactic acidosis, decreased blood glucose, acute gastro enteritis and impetigo.

References

1. Violari A et al. ARIEL: 24-week safety and efficacy of DRV/r in treatment-experienced 3- to <6-year-old patients. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 713.

2. Nachman S et al. Interim results from IMPAACT P1066: RAL oral chewable tablet formulation for 2- to 5-year-olds. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 715.