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.

The last issue of 2011 highlighted serious concerns for global health, and the Treatment Access news in this issue continues this theme, with an indication that funding uncertainties will continue throughout the year.

This includes further changes at the Global Fund and responses to the suspension of Round 11 grantsan outcome-that became likely when donor pledges last year failed to match even the minimum working budget.

Fortunately these sobering events are balanced by more positive news.

The  FDA recently approved new indications and formulations of three important antiretrovirals. Tenofovir is now available as an oral powder and lower dose pills for an indication in children of two years and older. Raltegravir is available in a 100 mg scored chewable tablet and a 25 mg chewable tablet for children older than 2 and weighing greater than 20 kg. Finally, an oral suspension of darunavir was approved with two bands of dosing recommendations (age 3 to 6 years; and, older than 6 years) that, as with adult dosing include separate recommendation for naïve and experienced patients.

Our conference coverage in this issue comes from a meeting on HIV and women’s health, and from a biannual workshop on HIV persistence and cure research.

The report from Richard Jefferys both summarises the latest state-of-the-art in this field and comments on the complexity of interpreting these early data.  The excitement is that the slow momentum from numerous research groups carries our ultimate hope to for a future that may offer alternatives to our current life-long reliance on ARVs.

Finally, and closer to home, BHIVA have published both new monitoring guidelines and the draft for the 2012 UK treatment guidelines. As this is the first update since 2008, with only a few weeks to comment it is important that the writing committee receive feedback promptly if this to be considered for the final document.

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.

Workshop report and commentary

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

The lead in dose of 200 mg once daily (using the original formulation) is still required, with the same caution not to increase to the 400 mg daily dose if the patient shows rash at the end of these 14 days.

The daily price of nevirapine PR has been price matched to the price of the 200 mg formulation.

Reference:

Boehringer press release: Viramune (nevirapine) prolonged-release once-daily formulation receives approval in the EU. (Septemebr 2011).

http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2011/21_september_2011nevirapine.html

The recommended oral dose of 200 mg etravirine is one tablet taken twice daily following a meal. The previous formulation required 2 x 100 mg twice-daily.

These tablets are dispersible in a glass of water. This option may be important given the new pill is slightly larger than the 100 mg formulation (22 mm vs 19 mm long).

The monthly list price for the 200 mg formulation is matched to the current daily price for the 100 mg formulation at £301.27.

Source: Janssen PR: Janssen launches 200mg etravirine (Intelence) for anti-retroviral treatment-experienced adults with HIV-1. (17 January 2012).

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

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

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

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/

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

In writing to the Bill and Melinda Gates Foundation, the group were advocating against the proposed financial support for continued research into the use of the nucleoside analogue d4T (stavudine), even at the proposed lower 20 mg dose. [2]

Stavudine has long been discontinued in Western countries due to an unacceptably high risk of serious side effects in comparison to alternative drugs in the same class.

The letter argues strongly against this research and was concerned that previous meetings with representatives from the Foundation had not been formally answered. It argues for a focus on increasing access to safer cost-saving alternatives to d4T, not on seeking a comeback for a drug virtually abandoned in rich countries.

The objections, summarised from the letter, include:

d4T’s significantly worse side effects are well documented

In 2004, d4T was removed from the list of preferred first-line antiretroviral drugs recommended by the US Department of Health and Human Services (DHHS). [3]

Starting in 2006, the WHO recommended that countries start moving away from d4T, and in 2009 recommended that the drug be phased out in first-line antiretroviral treatment (ART) programmes. [4]

In 2011, the European Medicines Agency (EMA) revised the indication for d4T, noting, “…that the use of the medicine should be severely restricted in both adults and children… Prescribers are reminded of the severe side effects seen with Zerit [d4T] and should only use the medicine when other appropriate treatments are not available. Patients being treated with Zerit should be assessed frequently and switched to appropriate alternatives as soon as possible.” [5]

Evidence of d4T’s toxicity in an operational setting has been reported from studies in Lesotho [6] and South Africa. [7]

There is no prospect that d4T 20 mg is a better option than tenofovir and retains significant toxicity even at lower doses. Results from over 10,000 patients randomised to receive 40 (30) mg or 20 (15) mg in early access (1992-94), reported rates of 15% vs 21% in the lower vs higher dose arms. [8]

The cost of these side effects will significantly reduce price savings

MSF report higher inpatient care and essential drug costs were higher for people on d4T than those on tenofovir. In Lesotho, the tenofovir-containing regimen generated higher life years and QALYs than AZT or d4T-based treatment. [9] As the costs of tenofovir and especially efavirenz drop, the cost benefit to patients and to health systems will become clearer. Since the study was completed, the global best price of efavirenz – which partly drives tenofovir costs – has almost halved ($97 ppy in 2009 to $52 today).

d4T’s long-term toxicity will not be studied

The proposed 20 mg d4T dose might be acceptable in a short-term 48- or even 96-week virologic endpoint study (although Bristol-Myers Squibb studied and rejected 20 mg BID). But, because mitrochondrial toxicity is both dose and time dependent, many of d4T’s most serious side effects (such as peripheral neuropathy and lipoatrophy) would not necessarily emerge until after such a study was completed. This study does not include monitoring of surrogate markers for mitochondrial toxicity, so it cannot shed light on the incidence of this serious adverse event.

This trial will not therefore be able to answer the primary policy question which drives it – whether long-term 20 mg d4T BID is as good as tenofovir QD in first-line ART regimens for use in public health programmes in resource-limited settings.

Implications for HBV coinfection

A tenofovir-based regimen is recommended for HIV/hepatitis B (HBV) coinfection, because d4T has no activity against HBV and resistance to lamivudine is inevitable. While HIV/HBV co-infection is an exclusion criterion for this trial, it may encourage persistent use of a suboptimal regimen for HIV/HBV co-infected people. Giving a d4T/lamivudine-based regimen to HIV/HBV co-infected people will create lamivudine resistant HBV in this population (90% at four years). [10, 11]

Potential savings may be out-dated when the study ends

The rationale for this trial is to lower treatment costs but the price of alternatives, notably tenofovir, has come down dramatically in the last several years, and is expected to decrease further as demand increases. According to MSF’s annual ARV pricing report, tenofovir is now cheaper than AZT, with the price of single-drug tenofovir having decreased by 52% from 2008 to 2011, and the price of the triple fixed-dose combination of tenofovir, lamivudine and efavirenz having decreased by 53% to US$173 per person per year over that same time period. [12]

The proposed study will not have 96-week results before 2014, and will need perhaps five-year field effectiveness trial to determine longer-term tolerability.

The anticipated cost savings associated with d4T could easily be overtaken by expected further price reductions for tenofovir. Currently a one-pill-once-a-day regimen containing efavirenz and tenofovir costs roughly half of what d4T-based combinations cost when they was first introduced a decade ago.

Potentially greater savings could be achieved if the tenofovir prodrugs in development with both Gilead and Chimerix are approved. A recent announcement by Gilead of an agreement with Tibotec to develop an FDC of darunavir, emtricitabine, GS 7340 and cobicistat with “less than one tenth of the amount of the 300 mg of tenofovir disoproxil fumarate contained in Viread and Truvada” suggests that this is feasible. [13] Low milligram dosing (and therefore low potential cost) is also used for the integrase inhibitor dolutegravir (50 mg once daily).

The letter was signed by activists from Médecins Sans Frontières , HIV i-Base , Treatment Action Group (USA), Treatment Action Campaign (South Africa), Health GAP (USA) and the European AIDS Treatment Group.

The letter can be read in full on the TAG website:

http://www.treatmentactiongroup.org/hiv/2011/lowdose-stavudine-trial

comment

In the short time since the letter was distributed two further publications has supported caution into further use of d4T. Vichet Phan and colleagues published data on rates of severe d4T-associated toxicity in a cohort of patients in Cambodia, with 7% of people having neuropathy within the first years and a cumulative incidence of lipoatrophy of 56% by 3 years and 72% by 6 years. [14]

Further concerns from people directly affected by continued use of d4T, the Malawi Network of People Living with HIV/AIDS (MANET+) held a press briefing concerned by the slow pace for phasing out current use of this drug in Malawi. Despite the funding crisis the Malawi government has a priority for this to be completed by June 2012. [15]

It is unclear why the Gates Foundation considers this study to be a priority and it seems an aberration in an otherwise carefully considered strategy for supporting research into the optimisation of ART for resource limited settings . This includes the ENCORE 1 study of low dose efavirenz, the reformulation of tenofovir to increase its bioavailability (working with CHAI) and the development of innovative potentially long acting formulations.

As Bad Science’s Ben Goldacre wrote: “Why is the Gates Foundation supporting this trial of a rubbish AIDS drug?”. [16]

References

1. Andrieux-Meyer I et al. Letter Opposing a Proposed Low-dose Stavudine Trial (14 December 2011).
   http://www.treatmentactiongroup.org/hiv/2011/lowdose-stavudine-trial
2. A randomised, double-blind study to demonstrate non-inferiority of stavudine (20 mg BID) compared with tenofovir (300 mg QD) co-administered with lamivudine and efavirenz in antiretroviral-naive patients over 96 weeks. If funded and approved, the trial is anticipated to start early 2012.
3. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 29 October 2004.
   http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL10292004002.pdf
4. WHO Rapid Advice: Antiretroviral therapy for HIV infection in adults and adolescents. November 2009, page 10.
   http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf
5. EMA 17 February 2011. EMA/127094/2011. EMEA/H/C/000110/R/79. Questions and answers on the review of Zerit (stavudine): Outcome of a renewal procedure.
   http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/human/000110/WC500102227.pdf
6. Adjusted hazard ratio: 5.43, 95% confidence interval: 3.31 to 8.91. Bygrave H et al. 2011. Implementing a tenofovir-based firstline regimen in rural Lesotho: clinical outcomes and toxicities after two years. J Acquir Immune Defic Syndr. 2011 Mar 1;56(3):e75-8.
   http://www.ncbi.nlm.nih.gov/pubmed/21164354
7. Menezes et al. A longitudinal study of stavudine-associated toxicities in a large cohort of South African HIV infected subjects. BMC Infectious Diseases 2011, 11:244 doi:10.1186/1471-2334-11-244
8. Anderson R et al. Design and implementation of the stavudine parallel track programme. Comparison of safety and efficacy of two doses of stavudine in a simple trial in the US parallel track programme. J Inf Dis. 1995; 171:118-22.
9. Jouquet et al. Cost and cost-effectiveness of switching from d4T or AZT to a TDF-based first-line regimen in a resource limited setting in rural Lesotho. JAIDS Publish Ahead of Print. DOI: 10.1097/QAI.
10. Communication Dr Mark Sonderup, Division of Hepatology, University of Cape Town.
11. Benhamou Y et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virusinfected patients. Hepatology. 1999;30:1302-1306.
12. Untangling the Web of Antiretroviral Price Reductions, 14th Edition. July 2011. Médecins Sans Frontières Campaign for Access to Essential Medicines
13. Gilead press release. Gilead Sciences finalises agreement with Tibotec Pharmaceuticals to develop and commercialise a single-tablet regimen of Prezista(R) with Emtriva(R), GS 7340 and Cobicistat. (15 November 2011).
14. Phan V et al. Incidence of Treatment-Limiting Toxicity with Stavudine-Based Antiretroviral Therapy in Cambodia: A Retrospective Cohort Study. PLoS ONE 7(1): e30647. doi:10.1371/journal.pone.0030647
    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0030647
15. Nkhoma P. Manet+ wants ARV d4T phased out. The Daily Times (Malawi). (30 January 2012)
    http://www.bnltimes.com/index.php/daily-times/headlines/national/4079-manet-wants-arv-d4t-phased-ou
16. Goldacre B. Why is the Gates Foundation supporting this trial of a rubbish AIDS drug?
    http://bengoldacre.posterous.com/why-is-the-gates-foundation-supporting-this-t

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.

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.

Delamanid

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.

Reference:

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

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

• Read this guide online
• Order a free printed copy
• Download PDF

HIV Testing and Risks of Sexual Transmission was produced in response to the growing number of testing and transmission questions that i-Base receives.

This resource brings together research into the impact of treatment on transmission and explains aspects of transmission that are often missed from resources that focus almost exclusively on condoms to explain risk.

This guide, written in non technical language, will hopefully be as useful for training as for general information.

The guide is also already online, together with further reading, appendices and references that are not included in the print edition.

Additional copies are free – please order in the usual way (online, by email or fax-back the back page of HTB).

We welcome feedback on this guide and this short online survey includes space for comment:

http://i-base.info/guides/testing/feedback

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.

Two case reports of unintended pregnancies suggest that etonogestrel implants should be used with caution in patients on efavirenz.

The first case had been receiving efavirenz, zidovudine and lamivudine since November 2002 and had an etonogestrel implant inserted in January 2004. Pregnancy was detected in April 2006 and conception dated to December 2005. The second case had an etonogestrel implant inserted in July 2005 and started efavirenz, tenofovir and emtricitabine in April 2007: in October 2007 she became pregnant following a condom rupture. In both cases, implants were removed at pregnancy diagnosis and were found to have been properly inserted.

The most probable mechanism explaining the contraceptive failure is low etonogestrel concentrations due to induction of cytochrome P450 by efavirenz. As it is not currently possible to predict the decrease of etonogestrel implant efficacy when an enzyme inducing drug is coadministered, an alternative method of contraception should be recommended.

Source: hiv-druginteractions.org (06 December 2011).

http://www.hiv-druginteractions.org/LatestArticlesContent.aspx?ID=568

Reference:

Leticee N et al. Contraceptive failure of etonogestrel implant in patients treated with antiretrovirals including efavirenz. Contraception, 2011, epub ahead of print

http://www.ncbi.nlm.nih.gov/pubmed/22036046

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 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

• Increasing the uptake of HIV testing among black African communities living in England
• Increasing the uptake of HIV testing among men who have sex with men

The free access support tools from NICE includes:

• Online educational module developed in conjunction with BMJ Learning to help healthcare professionals in primary care and non-HIV specialist settings improve their knowledge of key clinical areas in relation to HIV testing
• Audit support for general practice, secondary care and specialist services to assist with the audit process, thereby helping to ensure that practice is in line with the NICE recommendations. This consists of audit criteria and data collection tool(s) and can be edited or adapted for local use
• Self assessment tools for services or local partnerships to establish how close their current practice is to that recommended in the guidance and to help with prioritising implementation activity
• Costing report which provides an overview of both the potential costs and savings from putting the NICE guidance into practice
• Costing template helps individual NHS organisations and local health economies to quickly assess any impact that the NICE guidance may have on local budgets
• Slide set for primary and secondary care featuring key recommendations for clinical practice: developed to support professionals in general practice and secondary care who are not specialists in HIV testing or treatment
• Clinical indicator diseases table (reproduced with kind permission from the British HIV Association) to accompany the above slide set
• Slide set for commissioning of specialist sexual health services developed for those involved in the commissioning or strategic planning of sexual health services, it provides an overview of all recommendations from both pieces of guidance.

The NICE tools and guidance are online via the following guidance pages:

• http://guidance.nice.org.uk/PH33
• http://guidance.nice.org.uk/PH34

The London SCG Commissioning intentions have been published and are available at this link below.

http://www.londonspecialisedcommissioning.nhs.uk/?assetId=705&assetGroupId=704

London Adult HIV Needs Assessment

The London SCG has published the Executive Summary of the Adult HIV Needs Assessment, This shows that HIV is one of the fastest growing chronic conditions in London.

http://www.londonspecialisedcommissioning.nhs.uk/?assetId=707&assetGroupId=704

Ensuring access to HIV care and treatment in London

With over 30,000 HIV positive patients receiving care in London, developing a plan to secure continued access to the best available treatment is critical.

http://www.londonspecialisedcommissioning.nhs.uk/?assetId=709&assetGroupId=704

This is the second edition of a book by the US activist Nelson Vergel. It is a users guide to testosterone by an HIV positive man who has researched the subject over many years for his own care.

The non-technical sections include helpful tips about what not to do as well as the best approaches. This looks at how to assess potential testosterone deficiency, including what to measure (free vs total), when and how, and the impact of age on target ranges including fluctuation in levels throughout the day. The information is in the context of supplementary approaches being dependent on working with your doctor, not only to ensure that an appropriate dose and formulation are used (oral supplementation being the least useful), but that routine monitoring guides the safety of this approach.

Replacement therapy is discussed, usually recognising this as a lifelong treatment, as testosterone supplementation reduces the need and ability for the body to continue it own production. The risks from interrupting treatment and a period of testosterone depletion until the body adjusts include depression, weight loss, lack of motivation and reduced sex drive – often the symptoms that suggested treatment in the first place.

The guide also discusses side effects from testosterone and how to manage these, including the experimental use of Human Chorionic Gonadotropin (HCG) to maintain normal testicular function and reverse shrinkage. It discusses alternative treatment for low sex drive and erectile dysfunction including a review of data (or lack of it) for non-approved products. It also includes the importance of lifestyle modifications including diet and exercise, the importance of adherence and on finding a doctor that will monitor and prescribe treatment.

This is a users guide, written by an activist who has used many of the available approaches for over 16 years and he shares his experiences of different approaches. But the author professionally trained as a chemical engineer, and this informs his discussion on the chemistry behind a daunting range of formulations (including injections, topical creams, patches, implants, underarm products and sublingual and buccal preparations).

Although titled ‘a man’s guide’ the book includes information on testosterone use in women, including links for further reading, though for future editions this might be helpful if this was collated and compiled in a separate chapter.

Nelson is also co-author of Built to Survive, a similar guide to using anabolic steroids, nutrition and exercise to develop and maintain muscle mass for HIV positive men.

Nelson Vergel – Testosterone: a man’s guide: practical tips for boosting physical, mental and sexual vitality; 2nd edition, 2011.

IBSN: 978-0-9837739-1-7. £12.00, paperback; £6.41 Kindle.

The abstract book and the late breakers are available in PDF format. This site includes daily summaries of the workshop that will be followed in the next few weeks by more detailed reports.

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

The article reviews the available evidence to demonstrate how a comprehensive response can reduce HIV infection rates in people who use drugs, by implementing coherent public health and law enforcement strategies. It is argued that cost-effective interventions such as needle and syringe exchange programs, increased access to treatment and the decriminalisation of people who use drugs, to name but a few, would benefit individuals, families and communities.

The documents can be downloaded from:
http://www.soros.org/initiatives/drugpolicy/articles_publications/publications/time-to-act-20100907

http://jac.oxfordjournals.org/content/early/2012/01/31/jac.dkr599.full

Are there reasons to be optimistic that a cure for HIV infection may be achieved? From our point of view the answer is ‘yes’, but this will not be achieved in the short term.

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

Download HTB January/February 2012e PDF file (600 Kb)

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.

• European guidelines (EACS) – 2011 update
• 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

The launch of 2011 guidelines from the European AIDS Clinician Society (EACS), extensively revised and updated, was probably one of the scientific highlights of the conference.

The three guidelines, previously printed separately, have now been collated together in a slightly larger format. This makes the print edition now more comprehensive and also easier to use and reference.

Based on essential bulleted lists, treatment algorithms, and reference tables the guidelines are an excellent format for rapidly reviewing the current best standard of care in four key areas of HIV management:

1. Assessment and monitoring at initial and subsequent visits
2. ARV treatment in adults
3. Prevention and management of non-infectious co-morbidities
4. Clinical management and treatment of hepatitis B and C in HIV-positive patients

Although additional resources have been produced to compliment the guidelines in many important areas of HIV management, these had no yet been posted online when we went to press.

The guidelines (version 6.1) can be downloaded free as a PDF file and print copies can be order on the EACS website:
http://www.europeanaidsclinicalsociety.org/

Print versions can be ordered from EACS:
info@eacsparis.org

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.

• Statin blocks negative impact of PIs on bone formation in vitro
• HIV linked to frailty in middle-aged IDUs, especially with poor HIV control

Ritonavir-boosted or unboosted atazanavir or lopinavir promoted stem cell changes that could lead to decreased bone formation, according to results of cell studies by Jacqueline Capeau and colleagues at Saint-Antoine Hospital in Paris. Exposing the cells to pravastatin blocked these protease inhibitor (PI)-induced changes. [1]

Bone density declines with HIV infection, and that decline can accelerate with antiretroviral therapy. Treatment with certain PIs or tenofovir heightened the risk of osteopenia and osteoporosis in longitudinal studies. SMART trial participants randomised to take antiretrovirals continuously had more bone loss than those randomised to CD4-based treatment interruptions. [2]

Indinavir and nelfinavir – two PIs rarely used today – resulted in poorly functioning osteoblasts, the cells responsible for new bone formation. Capeau and coworkers planned a series of cell studies to see if two currently prescribed antiretrovirals, lopinavir and atazanavir with or without ritonavir, affect cell properties that could promote bone loss in people with HIV.

The researchers used menenchymal bone marrow stem cells from young, healthy donors. They passaged these stem cells every 5 days to simulate ageing. For up to 40 days, they exposed the cells to doses of lopinavir, atazanavir, and ritonavir equivalent to maximum concentrations of those PIs typically attained in people taking them at prescribed doses.

Stem-cell numbers dropped sharply after 10 to 15 days of lopinavir (with or without ritonavir) and after 20 to 25 days of atazanavir (with or without ritonavir). The PIs had no effect on cell survival, a finding suggesting that decreased proliferative capacity accounted for these declines in stem cell number.

Assessing stem-cell senescence by measuring senescence-associated beta-galactosidase activity, the researchers found that both atazanavir and lopinavir significantly induced premature senescence. Increased reactive oxygen species (ROS) production in these cells suggested that oxidative stress may be responsible for cell ageing. Atazanavir and lopinavir also raised levels of superoxide dismutase, an antioxidant enzyme, in these cells. Both PIs increased expression of the cell-cycle inhibitors P16 and P21. Finally, the two PIs induced accumulation of prelamin A, a cell-ageing marker associated with cell senescence.

Mesenchymal stem cells normally differentiate into an even balance of osteoblasts and adipocytes (fat cells). With ageing, differentiation to adipocytes begins to outweigh differentiation to osteoblasts. Age-related bone loss is marked by increased bone marrow fat, which leads to decreased bone formation.

Stem cells pretreated with lopinavir or atazanavir lost their ability to differentiate into osteoblasts, a result Capeau suggested could mean these PIs irreversibly affect the menenchymal stem cell pool in bone marrow. Lopinavir-exposed stem cells also failed to differentiate into adipocytes, while atazanavir-exposed cells promoted increased differentiation into adipocytes. The investigators proposed that atazanavir could lower the number of osteoblasts in treated people by upsetting the balance between adipocytes and osteoblasts in bone marrow.

When Capeau and colleagues exposed stem cells to pravastatin and the study PIs, they found that this statin prevented PI-induced senescence, reduced oxidative stress, and restored the differentiation of stem cells to an even balance of osteoblasts and adipocytes.

The researchers concluded that their cell-study data “show that some PIs can alter osteoblast formation by a direct effect on osteoblast differentiation and also by inducing premature senescence of the bone marrow progenitors.”

References

1. Hernandez-Vallejo S et al. Some HIV protease inhibitors induce premature senescence and alter osteoblastic cell fate determination of human bone marrow mesenchymal stem cells. 2nd International Workshop on HIV and Aging. October 27-28, 2011. Baltimore, Maryland. Abstract: O_14.
2. Grund B et al for the INSIGHT SMART Body Composition Substudy Group. Continuous antiretroviral therapy decreases bone mineral density. AIDS. 2009;23:1519-1529.
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748675/?tool=pubmed.

Comparing HIV-positive and negative injection drug users (IDUs) in a large Baltimore cohort, researchers determined that HIV infection independently raised the risk of objectively defined frailty and prefrailty. Frailty and prefrailty risks were highest in people with a CD4 count below 350 and a detectable viral load. [1]

Frailty boosts chances of hospital admission, disability, and death in older people without HIV.

In the Multicenter AIDS Cohort Study of HIV-positive and negative gay men. HIV infection raised the odds of earlier frailty [2], and frailty before combination antiretroviral therapy begins independently predicted AIDS or death [3]. But the impact of HIV on frailty risk and clinical outcomes is still in an early phase of study.

In this analysis Johns Hopkins University researchers focused on 1206 current or former IDUs with or without HIV infection seen from 2005 through 2009 in a prospective observational cohort. All cohort members were at least 18 years old and made twice-yearly visits for follow-up. The Hopkins team defined frailty (by the Fried system) as meeting 3 or more of 5 criteria: weakness determined by grip strength, slowed walking speed, weight loss, low physical activity, and exhaustion. They defined prefrailty as one or two of these criteria.

Of the 1206 IDUs assessed, 345 (29%) had HIV infection. Median age stood at 48 years, and one third in both the HIV-positive and negative groups were women. Higher proportions in the HIV group were African American (95.7% versus 87.6%), had less than a high school education (65.2% versus 57.0%), and were hepatitis C positive (93.3% versus 81.0%) (P < 0.05 for all comparisons). Lower proportions of HIV-positive cohort members were recent injectors (36.2% versus 47.4%), actively used alcohol (48.3% versus 56.8%), abused prescription drugs (6.4% versus 12.9%), or had a spouse or common-law partner (4.7% versus 8.8%) (P < 0.05 for all).

HIV-positive people had a median CD4 count of 290, a median CD4 nadir of 138, and a median viral load of 3.1 log (about 1250 copies). Half (51%) were taking combination antiretrovirals, and 21.7% had an AIDS diagnosis.

Overall frailty prevalence stood at 8.3%, with rates of 10.7% in the HIV group and 7.3% in the HIV-negative group; 59% of cohort members met prefrailty criteria. Through 4652 person-visits, both frailty and prefrailty proved more common in older IDUs, women, those with less than a high school education, people without a spouse or partner, those who abused prescription drugs, and those with depressive symptoms. African-American cohort members had a lower risk of prefrailty. Adjusting for all these factors, the researchers determined that HIV infection raised the prefrailty risk 28% (adjusted odds ratio [AOR] 1.28, 95% confidence interval [CI] 1.06 to 1.53), while raising the frailty risk 75% (AOR 1.75, 95% CI 1.27 to 2.39).

Compared with HIV-negative IDUs, HIV-positive cohort members had a higher risk of prefrailty or frailty with worse HIV disease status, as noted by the AORs (and 95% CIs) in Table 1.

The Hopkins teams evaluated frailty as a predictor of new hospital admissions in all 1206 cohort members from July 2005 through December 2009. During that time there were 374 hospital admissions, and the admission rate was significantly greater in frail than in nonfrail people (P = 0.006).

Compared with nonfrail cohort members, prefrail people did not have an independently higher risk of hospital admission, but frail people had a 60% higher risk (adjusted hazard ratio [AHR] 1.59, 95% CI 1.10 to 2.30). Female gender made hospital admission 66% more likely, homelessness raised the odds by 42%, active alcohol use by 32%, hepatitis C by 90%, and prescription drug use by 56%. Compared with HIV-negative people, HIV-positive people with a CD4 count under 350 and a detectable viral load had a doubled risk of hospital admission (AHR 2.12, 95% CI 1.61 to 2.79).

The Johns Hopkins investigators concluded that HIV infection boosts the risk of prefrailty and frailty in current and former IDUs. They proposed that “early identification of frail and prefrail IDUs may provide opportunities for arresting progression to adverse clinical states.”

References:

1. Piggott D et al. Frailty and incident hospitalization in a cohort of HIV-infected and uninfected injection drug users (IDUs). 2nd International Workshop on HIV and Aging. October 27-28, 2011. Baltimore, Maryland. Abstract O_06.
2. Desquilbet L et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J Gerontol A Biol Sci Med Sci. 2007;62:1279-1286.
3. Desquilbet L et al. A frailty-related phenotype before HAART initiation as an independent risk factor for AIDS or death after HAART among HIV-infected men. J Gerontol A Biol Sci Med Sci. 2011;66:1030-1038.

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

The full contents highlights the breadth of these reports. Even for a publication heavily focussed on HIV treatment and research, this does not exist in isolation.

So along with reports from the EACS, ICAAC and HIV and ageing meetings we include positive news that the Iranian doctors have been released, that the HPA is now recommending wider testing in the UK, and that Richard Jeffreys, who leads on our basics science reporting each issue has successfully stood up to a high profile AIDS denialist. These people still exist. The New York Court summary judgement is a breath of fresh air and important glimpse of sanity.

But in global terms, the announcement by the Global Fund that it has suspended the next round of funding due to donor countries refusing to honour earlier pledges is an unhappy reality that dominates all other news.

There are 200 days to make up this shortfall. Otherwise, the benefits from the last ten years of both treatment and prevention programmes are likely to be quickly reversed and that this will further disrupt healthcare in poor countries and lead to millions of lost lives.

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

Rilpvirine (tradename Edurant) has a European indication for use as part of a combination for treatment-naïve patients with viral load <100,000 copies/mL.

The 25mg tablet must be taken with food and in Phase 3 studies had a tight relationship between adherence and efficacy. Low milligram medications are often vulnerable to a lower pharmacological safety buffer above the minimum effective concentration (MEC) at the end of the dosing period.

The license for rilpivirine stresses that it needs to be taken at the same time each day.

Additionally, patients who have experienced virological failure while taking rilpivirine can develop NNRTI cross-class resistance including to nevirapine and efavirenz.

The list price for rilpivirine is £200.27 per month (for 30 tablets).

A more detailed summary of the data from Phase 3 studies was included in the August edition of HTB, with announcement of approval in the US.

The FDC formulation (tradename Eviplera in Europe and Complera in the US) based on a similar indication to rilpivirine.

The list price for Eviplera is £618.77 for 30 tablets.

References and links:

1. Patient information and Summary of Product Characteristics for Edurant will be published to the EMA website.
   http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124
2. FDA approve new NNRTI rilpivirine (Edurant) in the US. HTB August 2011.
   http://i-base.info/htb/15538

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).

Two doctors, who raised awareness for testing and treatment of HIV in Iran and who were the focus of a human rights campaign have now both been released. Doctor Arash Alaei and Doctor Kamiar Alaei were detained in June 2008 by Iranian authorities without cause and without charges or trial. [1]

The physicians, who are brothers, were held for over six months before being tried. On 31 December 2008, the brothers were tried as conspirators working with an “enemy government” to overthrow the government of Iran in a one-day, closed-door trial. They were also tried on unspecified other charges which neither they nor their lawyer were allowed to know. [1]

In the autumn of 2010, Kamiar Alaei was released from Evin Prison after serving two years of his three-year sentence. He moved to the US and worked for the release of his brother.

In August 2011, Arash Alaei was also released from Evin Prison after more than three years of a six year sentence. He rejoined his mother and other family members in Tehran and anticipates the resumption of his life-saving work, as well as reuniting with his brother, Kamiar, and sister in the US.

Physicians for Human Rights (PHR) is a campaigning organisation that raised the profile of Drs. Kamiar and Arash Alaei. We included this as a new item in October 2008 as their situation was also highlighted prominently at the IAS conference in Mexico City. [2]

Both doctors received the Jonathan Mann Award for Global Health and Human Rights in June 2011. [3]

A video of the brothers speaking about their detainment and release can be viewed online. [4]

References

1. Dr. Arash is Freed! PHR news feature. (29 August 2011).

http://physiciansforhumanrights.org/blog/dr-arash-is-freed.html

2. Free The Iranian HIV/AIDS Doctors! HTB October 2008.

http://i-base.info/htb/140

3. Alaeis Honored at Global Health Council Event. PHR news feature. (17 June 2011).

http://physiciansforhumanrights.org/blog/alaeis-honored-at-global-health-council-event.html

4. http://physiciansforhumanrights.org/library/multimedia/released-iranian-aids-doctors-share-story.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

This is based the reduced infectivity associated with effective treatment together with high levels of infection control that are demanded of medical professionals that has resulted in much of Europe along with Australia and America having removed the restriction.

The article goes on to say that “sources in the medical profession say that even in Britain, where the ban is still in place, hospitals and dental surgeries have long operated a “don’t ask, don’t tell” policy with regard to practitioners who have HIV. They argue the policy is now clearly discriminatory as it can no longer be justified on public health grounds – despite the emotive nature of HIV.”

Apparently the decision to launch the review comes after the Department of Health’s Expert working group on AIDS and the UK Advisory Panel for Healthcare Workers Infected with Blood-borne Viruses both concluded that the risks could not justify the ban. They are believed to have told the Chief Medical Officer that the likelihood of any infection was as low as one case every 2,400 years.

Source: The Independent online. 24 November 2011.

http://www.independent.co.uk/life-style/health-and-families/health-news/ban-on-hivpositive-doctors-and-dentists-set-to-be-overturned-6267110.html

Simon Collins, HIV i-Base

This moving documentary interviews five people who lived in San Francisco in the 1970s and who came through the HIV epidemic. It takes you slowly through their involvement and the impact of their experiences on their personal and professional lives.

The interviews are intercut with film, newspaper cuttings, newsreels and stills from hundreds of people who fought before HIV had a name and before there was treatment.

It is important and difficult to remember, that AIDS only happened this way once and involved creating a framework to understand an epidemic that was already widely established before it was discovered. By 1981, it was likely that at least 20% of gay men in San Francisco were already HIV-positive and by the time the first HIV test became available in 1985 this figure was likely to be higher than 50%.

In the 1970s, people moved to San Francisco to escape hatred and isolation of homophobia. As one of the five says “If you had a bus ticket, it had better be going to San Francisco” and “when you arrived you knew you were home”. To understand the film means feeling the optimism shared from finding life and friends and sexuality in a new age when pregnancy was preventable and sexual diseases were treatable.

Against a background, not just of political indifference, but active persecution and hatred, these narratives show the breadth of the human and social responses. Hundreds of examples make up the body of the film. Dancer and florist (Guy) who gave away flowers with gentle dignity to help people bury their friends and lovers. Or the sister of a patient who was unaware of how much she helped a nurse by saying “it makes me feel better knowing that you were with him (her brother) to treat him with respect and to treat his body with love”.

The medical reality of having to help people die rather than treat them back to health is shown by a nurse (Eileen) telling of how she had never before been in a room full of doctors who were sobbing because their patients had all died. “But we did the research because there was nothing else”.

The sole survivor from a study of a compound called surinin (Daniel), tells of how he discontinued the treatment early because it was impossible to tolerate, but also how his lover, a researcher working at a key HIV virology laboratory, had died from liver complications within three months of ending the study.

These histories are time and place specific. Gay men in San Francisco had one of the highest prevalence rates reported (soon after to be superseded by people with haemophilia dependent on blood products) at a time before treatment. It includes the community, social and political responses to fighting AIDS.

Light comes slowly “as people started hanging on” and then as effective treatment became a reality “they found a way through the storm”. This film is moving and it is sad, but it is not depressing. Each person has a gentle eloquence and takes you through their journey so you glimpse how this has lead to a greater understanding of life and a closer connection to people who in other circumstances many of them might never otherwise have known.

AIDS has happened thousands of times for every new country, region or town and in many different populations, each with their own story and against their own background. This film should encourage others to shows their histories. And millions of people have their own story of how HIV has and still does affect them personally, and who despite differences of background and experiences will be touched with each of these stories.

Taken together, the film will affirm and strengthen your own history with HIV. And for those coming to understand HIV for the first time it should give a historical perspective from a setting that is hard to imagine even if you were there. Its humanity should fire a response that recognises the importance of preventing infections in new generations and ensuring effective and affordable treatment for all becomes a global reality.

“We were here” was screened twice at the London Lesbian and Gay Film Festival earlier this year and has been touring festivals to much acclaim since. Six months later, it had its official UK launch, a couple of showings at the ICA in London and a benefit for the THT. If this film doesn’t come to a cinema near you, organise a group screening, or get the DVD, which was released on 5th December.

We Were Here, USA, 2011, 90 minutes.

Directed by David Weissman.

Released on DVD from 5th December on Peccadillo Pictures.

http://wewereherefilm.com/

http://peccapics.com/View/id,245

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/

The Global Fund Board has cancelled Round 11 in light of the Global Fund’s financial difficulties. This difficult decision was made at a stressful two-day Board meeting in Accra, Ghana, that ended yesterday evening, 22 November. The Board also announced new rules for grant renewals in an attempt to find savings that can be applied to funding new proposals.

The original decision to launch Round 11 in August 2011 was made at a Board meeting in December 2010. At its meeting in May 2011, the Board did not make any changes to its plans for Round 11, having been told by the Secretariat that sufficient funding (an estimated $1.6 billion) would be available for that round. But the estimate of funds available for Round 11 declined to $0.8 billion in September 2011, and then to a negative amount this month. The decline was caused primarily by some donors changing their minds regarding their so-called pledges, and other donors saying that they would delay payment of their pledges.

The Global Fund has long had a policy that the financing of Phase 2 renewals of existing grants has a higher priority than the financing of new grants. As a result, the Board concluded that almost all of the $8.2 billion in revenues that is now projected to arrive by the end of 2013 will be needed for renewals, leaving no money for Round 11.

The next replenishment period will be 2014-2016. Given that there is no money for Round 11, the next opportunity for countries to apply for new grants will be during the 2014-2016 period. They will be able to do so using a new funding model that is called for in the Fund’s new Strategy 2012-2016, also approved at this Board meeting.

Some countries have existing grants that will reach the end of Phase 2 well before 2014. Many of those countries have been hoping to be approved for Round 11 grants. Because that will not be possible now, the Board has agreed to put in place a Transitional Funding Mechanism that will provide for continuation of essential prevention, treatment and/or care services by current grantees. Details of this mechanism will likely be announced in the coming weeks.

However, even with the cancellation of Round 11, the Global Fund did not have enough money to pay for the Transitional Funding Mechanism, and for some Round 10 grants, unless further savings could be found. (The Fund stopped signing Round 10 grant agreements about a week ago because of its financial problems.)

The Board decided to find some of the required savings in the following ways:

The one-year Grace Period provision for changes in country income classification will be rescinded. (See explanation in GFO 80.)

The “counterpart financing” and “focus of proposal” requirements that already apply to new grants will also apply to Phase 2 renewals. (See description in GFO 146.)

Instead of Phase 2 financial commitments being made in two tranches (i.e., the first two years, and then the third year), they will be made one year at a time (“1+1+1″).

But even more money had to be freed up. The Board discussed two options for this. One was to say that all eligibility rules that apply to new proposals would also apply to Phase 2 renewals. The other was to say that countries are not eligible for Phase 2 renewal of their current grants if they are Group of 20 (G-20) upper-middle-income countries “with less than an extreme disease burden.” Following a difficult discussion, the Board chose the second option. This means, for example, that Argentina, Brazil, China, Mexico and Russian Federation will not be eligible for Phase 2 renewal. (South Africa is a G-20 country, but it has an “extreme” disease burden, so it will be allowed through.)

China is, by far, the country that will suffer most from this decision, because China had been expecting to be eligible for some $880 million in grant renewals.

Now that the above measures have been agreed, the Fund will temporarily be able to resume signing Round 10 grant agreements. However, because the signing of new grant agreements can only be done when the required funds have been received by the Global Fund from its donors, and because Phase 2 renewals take priority over new grants, it is always possible that the signing of Round 10 agreements will be put on hold again. It all depends on whether donors deliver their 2011 pledges during 2011, and whether at least some of them deliver their 2012 pledges earlier rather than later in 2012.

comment

There are 200 days to make up the current shortfall, driven by underpayment by US, Italy, Germany (paid since), Japan, Spain and EC.

The significance of capped funding cannot be overestimated. Years of progress with strategies to combat HIV – including testing and prevention programmes – have been and continue to be dependent on increasing access to effective treatment.

Source: GFO issue 167 – 23 November 2011.

http://www.aidspan.org

Documents from the Global Fund Board meeting and the related decisions are online.
http://www.theglobalfund.org/en/board/meetings/twentyfifth/

http://www.treatmentactiongroup.org/cure/2011-workshop-report

The meeting included a focus on the following issues:

• If HIV eradication is the goal, how can this be proved when the best currently available tests may still miss the tiny residual amount of the virus that can bring the infection roaring back to life when antiretroviral drugs are withdrawn?
• If treatment interruptions are necessary, how can they be conducted safely in research participants when prevailing data suggest that even relatively short treatment interruptions can be harmful for some?
• If immune control of the virus is the objective, what kinds of changes in the immune system and inflammatory markers will tell us we are on the right track? and
• If early trials require participants to take greater risks with little hope of gain, how can we ensure that studies are ethical and guarantee that those taking the risks are fully informed?

Optimal uses of antiretrovirals for prevention in HIV-1 serodiscordant heterosexual couples in South Africa: a modelling study. Hallet TB et al.

PLoS Medicine Volume 8 (11) November 2011.

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001123

Timothy Hallett and colleagues use a mathematical model to examine the long-term impact and cost-effectiveness of different pre-exposure prophylaxis (PrEP) strategies for HIV prevention in serodiscordant couples.

Cost-effectiveness of early versus standard antiretroviral therapy in HIV-infected adults in Haiti. Koenig SP et al.

PLoS Medicine Volume 8 (9) September 2011.

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001095

In a cost-effectiveness study, Bruce R Schackman and colleagues compares early versus standard antiretroviral treatment (ART) for HIV, based on randomised clinical trial data from Haiti, revealing that the new WHO guidelines for early ART initiation can be cost-effective in resource-poor settings.

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 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

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.

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.

The executive summary and full guidelines are both available to download in PDF format.

The report is part of the organisations’ HIV and Ageing Consensus Project, developed to assess how the presence of both HIV and common age-associated diseases, alter the optimal treatment of HIV as well as other co-morbidities. The purpose of the report, developed by a panel of experts with experience both in the fields of HIV and Geriatrics, is to provide best practice guidance for HIV practitioners and other health care providers who treat, diagnose and refer older patients with HIV disease.

References:

The HIV and Ageing Consensus Project: Recommended treatment strategies for clinicians managing older patients with HIV.

View the executive summary: (direct PDF download)
http://www.aahivm.org/Upload_Module/upload/HIV%20and%20Aging/AAHIVM%20Executive%20Summary%20FINAL%202.pdf

Full report and guidelines: (direct PDF download)
http://www.aahivm.org/Upload_Module/upload/HIV%20and%20Aging/Aging%20report%20working%20document%20FINAL.pdf

The December 1st issue of Clinical Infectious Diseases contains a raft of papers addressing the issue of HIV and ageing.

A report from the Swiss HIV Cohort Study documents that illnesses typically associated with ageing are now the most common causes of morbidity in their cohort, which contains an increasing proportion of individuals aged 50 or older. [1] In contrast, opportunistic infections make only a minor contribution in the current era of effective antiretroviral therapy (ART). An accompanying editorial by Mike Saag highlights the implications for providing appropriate multidisciplinary care to people with HIV as they age. [2]

While there are ongoing debates about whether HIV infection is linked to premature ageing – some studies have suggested the risk of ageing-associated diseases is increased among HIV-positive people compared to age-matched HIV-negative individuals, while other studies have disputed these findings – the Swiss HIV Cohort Study paper emphasises that whether or not they are occurring sooner, these morbidities are now the main concern in the long-term care of people with HIV. In discussing their findings, the authors note that the incidence of cancer, heart attacks and diabetes among members of their cohort aged 50-64 was higher than described in studies of somewhat comparable HIV-negative cohorts, but they also stress that “a comparison of our results with an age-matched HIV-uninfected population with similar comorbidity or behavior is difficult, because we had no suitable HIV-uninfected control group in our country.”

Giovanni Guaraldi and colleagues from the University of Modena and Reggio Emilia in Italy attempted to address this issue in their study, which compared the occurrence of non-infectious co-morbidities (NICMs) and polypathology (the presence of more than one NICM) among HIV-positive people on ART and a matched HIV-negative control group from the general population (from 2002 through 2009). [3]

The NICMs captured in the study included cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure. The results revealed that prevalence of NICMs and polypathology was higher in HIV-positive individuals across all age categories. The prevalence of polypathology among people with HIV aged 41-50 was similar to the prevalence among HIV-negative controls aged 51-60.

Interpretation of the findings is complicated by the fact that the data from HIV-positive individuals was all derived from a metabolic clinic at Modena. Part of this population is comprised of local people from main HIV clinic at Modena who are automatically referred to the metabolic clinic if they are on ART. However, the population also includes a large proportion of HIV-positive individuals who are referred to the Modena metabolic clinic from neighboring centers due to metabolic issues such as lipodystrophy, and this would appear to account for the unusually high prevalence of this condition among the study cohort (74%). To assess whether this over-representation of people with metabolic issues had biased their results, the study authors compared the incidence of NICMs and polypathology among the local referrals to those from the neighboring centers but—perhaps surprisingly, as Jacqueline Capeau notes in an accompanying editorial commentary—they found no difference. [4]

The authors conclude: “our findings suggest that an aggressive approach to the screening, diagnosis, and treatment of NICMs is warranted as part of routine healthcare for HIV-infected patients. Furthermore, our data suggest that onset of such screening should commence at a substantially earlier age for HIV-infected persons, compared with HIV-uninfected persons, possibly at least a decade in advance. Additional studies are needed to further evaluate the impact of convergent age-related NICMs on age-related functional status, frailty, and disability among ART-experienced HIV-infected persons and to provide insights into accelerated ageing processes that may be associated with chronic HIV infection.”

Source: TAG Basic Science web log. (1 November 2011).

References

1. Hasse B et al for the Swiss HIV Cohort Study. Morbidity and ageing in HIV-infected persons: the Swiss HIV Cohort Study. Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]
   http://cid.oxfordjournals.org/content/53/11/1130
2. Saag MS. Editorial commentary: HIV now firmly established in the Middle Ages. Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]
   http://cid.oxfordjournals.org/content/53/11/1140
3. Guaraldi G et al. Premature age-elated comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]
   http://cid.oxfordjournals.org/content/53/11/1120
4. Capeau J. Editorial commentary: Premature Aging and Premature Age-Related Comorbidities in HIV-Infected Patients: Facts and Hypotheses. Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]
   http://cid.oxfordjournals.org/content/53/11/1127

A population-based study carried out in Denmark to assess the risk of cataract surgery among HIV-positive individuals compared to large group of matched HIV-negative controls.

Risk was found to be greater among the HIV-positive population, with the highest risk among those with CD4 T cell counts below 200 (either on or off ART). Individuals on ART with CD4 T cell counts over 200 still showed a higher risk than both the general population and HIV-positive people with over 200 CD4 T cells who had not yet started ART; the authors note this could reflect a contribution of drug side effects or receipt of ART could be acting as a marker for having reached a stage of illness requiring treatment (which in turn is associated with an elevated cataract risk).

Supporting the latter possibility, no association with specific antiretroviral drugs was found. Although the researchers do not claim that their data represents evidence of accelerated ageing in the HIV-positive population, they acknowledge that such a phenomenon “cannot be excluded as a possible part of the explanation.”

Source: TAG Basic Science web log. (1 November 2011).

Reference:

Rasmussen LD et al. Risk of cataract surgery in HIV-infected individuals: a Danish nationwide population-based cohort study. Clin Infect Dis. 2011 Oct 13. [Epub ahead of print]
http://cid.oxfordjournals.org/content/53/11/1156

A study published in the July 1st edition of JAIDS by Michelle Yong from The Alfred Hospital, Melbourne, reported a significant association between CD4 count and risk of fractures that was independent of traditional risk factors including corticosteroid use.

The group performed a 1:2 matched case-control study in HIV positive patients attending a single hospital site between 1998 and 2009. Controls were matched on gender, age, and duration of HIV infection.

The overall fracture incidence rate was 0.53 per 100 person-years (95%CI: 0.43 to 0.65) and period prevalence of 3.34 per 100 patients (95% CI: 2.66 to 4.13). There were 73 low trauma fractures in 61 patients. Patients were predominantly male (89%) with a mean age of 49.8 years. Independent risk factors for fragility fracture were a CD4 cell count <200 cells/mm3 (OR 4.91: 95% CI 1.78 to 13.57, p = 0.002), corticosteroids (OR 8.96: 95% CI 1.55 to 51.88, p = 0.014) and anti-epileptic medications (OR: 8.88: 95% CI 1.75 to 44.97, p = 0.008).

No association was found between risk of fracture and HIV viral load (p = 0.18), use of antiretrovirals or class of antiretroviral medication. The majority patients with fracture (88%) had osteopenia or osteoporosis.

Reference:

Yong MK et al. Low CD4 count is associated with an increased risk of fragility fracture in HIV-infected patients. JAIDS, 1 July 2011 – Volume 57 – Issue 3 – pp 205-210
http://journals.lww.com/jaids/Fulltext/2011/07010/Low_CD4_Count_Is_Associated_With_an_Increased_Risk.5.aspx

Many studies have reported that regular exercise confers health benefits and that, conversely, a sedentary lifestyle is a major risk factor for morbidity and mortality (particularly from cardiovascular disease). In recent years, researchers have begun to look more specifically at the immunological effects of exercise. The scientist Richard Simpson, formerly at Napier University in Edinburgh and now based at the University of Houston in Texas, has pioneered the exploration of the intersection between exercise and immune senescence. [1, 2] This research is potentially relevant to HIV infection because, as reported in some prior blog posts), senescent immune cells – particularly CD8 T cells – accumulate over time and may persist despite antiretroviral therapy. [3]

Simpson’s recent work suggests that exercise mobilises senescent immune system cells from the tissues into the blood and increases their death by apoptosis; [4] if confirmed this may offer both a more practical approach to addressing senescence than the idea of physically removing cells, and could also explain some of the positive contributions of exercise to healthy ageing that have been described in the literature.

Exercise may also have a beneficial impact on inflammation, another problem common to both ageing and HIV infection. In Nature Reviews Immunology, Mike Gleeson and colleagues from Loughborough University in the UK review the mechanisms by which exercise may reduce inflammation, and highlight some of the questions that remain to be answered about which mechanisms are most important in producing beneficial health outcomes. [5]

Finally, in a paper in press at the Journal of the Association of Nurses in AIDS Care, Anella Yahiaoui and colleagues review the literature in an attempt to offer evidence-based exercise recommendations for older individuals with HIV. [6] They conclude that:

“Combined moderate to vigorous aerobic and resistance exercise for 20-40 minutes, 3 times per week, is safe and effective in older adults and has many benefits to decrease symptom burden, decrease disease progression, and increase quality of life.”

Additional specifics are included in the paper. The authors also recommend the basic ‘Exercise Tips for Older Americans’ offered on the website of the American Heart Association. [7]

comment

Of interest, a study at EACS in HIV positive patients with high cardiovascular risk, reported that an intensive and multidisciplinary intervention on lifestyle led to a significant improvement in lipid profile, quitting smoking and Framingham risk score. [8]

Source: TAG basic science blog (15 August 2011).

http://tagbasicscienceproject.typepad.com/

References:

1. Simpson RJ. Aging, persistent viral infections, and immunosenescence: can exercise “make space”?
   http://journals.lww.com/acsm-essr/Abstract/2011/01000/Aging,_Persistent_Viral_Infections,_and.6.aspx
2. Simpson RJ et al. Senescent phenotypes and telomere lengths of peripheral blood T-cells mobilized by acute exercise in humans. Exerc Immunol Rev. 2010;16:40-55.
   http://www.medizin.uni-tuebingen.de/transfusionsmedizin/institut/eir/content/2010/40/article.pdf (PDF)
3. http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/immunosenescence/
4. Spielmann G et al. Aerobic fitness is associated with lower proportions of senescent blood T-cells in man. Brain Behav Immun. 2011 Jul 19. [Epub ahead of print].
   http://www.sciencedirect.com/science/article/pii/S088915911100465X
5. Gleeson M et al. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol. 2011 Aug 5. doi: 10.1038/nri3041. [Epub ahead of print]
   http://www.nature.com/nri/journal/vaop/ncurrent/full/nri3041.html
6. Yahiaoui A et al. Development of evidence-based exercise recommendations for older HIV-infected patients. J Assoc Nurses AIDS Care. 2011 Jul 29. [Epub ahead of print]
   http://www.nursesinaidscarejournal.org/article/S1055-3290(11)00125-7/abstract
7. http://www.heart.org/HEARTORG/GettingHealthy/PhysicalActivity/GettingActive/Exercise-Tips-for-Older-Americans_UCM_308039_Article.jsp
8. Saumoy M et al. Efficacy of an Intensive and Multidisciplinary Intervention on Lifestyle in Cardiovascular Risk and Metabolic Variables in HIV-infected Patients: 96-week Results. 13th EACS, 12–15 October 2011, Belgrade. Abstract PE9.5/4.

Over the past couple of years, several new antibodies capable of neutralizing a broad array of HIV isolates have been discovered.

As mentioned in prior posts about these discoveries, one common feature of these antibodies is that the B cells that produce them have undergone an unusual degree of somatic hypermutation—a process in which the cell’s antibody-producing genetic code is progressively revised in order to increase the affinity of the antibody for its target. The genetic code that the B cell starts out with is called the germline sequence, and it is typically altered by around 5-15% to produce antibodies against common infections, whereas this figure ranges from 19-46% for the broadly neutralising antibodies against HIV that have been identified. Antibodies targeting the part of the HIV envelope that binds to the CD4 receptor, such as the recently discovered VRC01, are at the extreme end of this scale (showing sequence alterations of 40-46%).

In a recent article in Science Express, researchers from the Vaccine Research Center (VRC), the Center for HIV/AIDS Vaccine Immunology (CHAVI) and the International AIDS Vaccine Initiative (IAVI) published the latest results from their collaborative effort to better understand how these antibodies are generated. [1]

The work involves analyses of mind-boggling numbers of B cell genetic sequences, and identifies several new broadly neutralising antibodies from infected individuals that target HIV’s CD4 binding site. Of potential importance for vaccine design, the B cell sequences that give rise to the antibodies are not uncommon, and although a similarly extensive degree of somatic hypermutation is involved in their generation, it appears that the mutations do not have to be exactly the same to produce structurally similar antibodies.

The researchers are hopeful that these data can be used as a map for guiding the development of broadly neutralising antibodies using vaccines. [2]

Source: TAG basic science blog (12 August 2011).

http://tagbasicscienceproject.typepad.com/

References:

1. Wu X et al. Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science (11 August 2011). DOI: 10.1126/science.1207532.
   http://www.sciencemag.org/content/early/2011/08/10/science.1207532
2. NIAID Press Release: NIH-Led Team Maps Route for Eliciting HIV Neutralizing Antibodies.
   http://www.niaid.nih.gov/news/newsreleases/2011/Pages/HIVAntibodyEvolution.aspx

A small study of auranofin, a gold-based drug developed to treat rheumatoid arthritis, suggests it may be able to reduce the reservoir of SIV-infected CD4 T cells in macaques on antiretroviral therapy (ART). The paper appears in the 17 July issue of the journal AIDS [1], and previously generated some excitable media coverage when it appeared online-ahead-of-print in April (the researchers issued a press release at the time entitled ‘Gold-based Drug May Pave the Way to a Cure for AIDS’ [2]).

The mechanism of action of auranofin is not fully understood, but it has been shown to inhibit proliferation of CD4 T cells and thus may prevent the expansion of latently infected cells and/or shift these cells from a long-lived to short-lived phenotype. The authors note that there is one published case report on the use of auranofin in an individual with HIV, and it did not show an adverse effect on overall CD4 T cell numbers. [3]

A key issue in interpreting this or any other cure-related research study in rhesus macaques is that there is no consensus regarding the most appropriate way to try and model combination antiretroviral treatment of HIV infection in humans, because not all HIV drugs work against SIV. The researchers in this instance used a new approach that they first described last year, in which macaques are infected with SIVmac251 and treated with the combination of tenofovir+emtricitabine (Truvada) and raltegravir (Isentress). [4]

However, in this initial description of the model, follow-up was for 52 days and viral replication and persistence were only analysed in blood samples, not tissues, making the extent and durability of SIV suppression unclear.

The uncertainty regarding the animal model is thrown into sharp relief by the initial results of the new experiment in which auranofin was added to ART in six macaques: SIV DNA levels declined to undetectable levels after four weeks but rebounded by eight weeks. It is uncertain whether this reflects a transient effect of auranofin or some limitation of the ART combination to fully suppress SIVmac251.

In the second part of the study, the same six macaques had ART intensified by the addition of ritonavir-boosted Prezista (darunavir). Two control macaques on the same ART combination without auranofin were also added to the experiment at this juncture. After around two months of follow-up, the researchers report a trend toward declining SIV DNA levels in the auranofin group but not the controls; however the very small number of controls makes this data hard to interpret. An attempt was then made to see if the compound SAHA could stimulate production of virus in the auranofin-treated macaques. SAHA is a histone deacetylase (HDAC) inhibitor that can induce replication of latent HIV. SIV viral load did not increase after SAHA administration in the auranofin-treated macaques, but it’s not clear from the paper if SAHA was given to the two control macaques. Instead the researchers cite two “historical” control macaques treated with ART that showed viral load rebound after SAHA treatment.

Finally, ART was stopped in 5 out of 6 of the auranofin-treated macaques (one animal was spirited away to participate in another study) and both of the real-time controls. There was, on average, a slight delay in SIV viral load rebound in the auranofin group compared to the real-time two controls that just about achieved statistical significance. Set point viral loads were also lower than those documented prior to ART in the same animals, but the statistical significance of this finding was borderline and appeared to be driven by results in one macaque. There was absolutely no evidence that auranofin had led to a cure of SIV infection in any of the treated macaques, as all showed viral load rebounds.

In sum, these experiments may have identified a compound deserving of further evaluation in the context of efforts to deplete the latent HIV reservoir. However, the data are by no means clear-cut due to the use of a new macaque model of ART that is not well characterised, the small numbers of animals involved, and the use of historical controls (issues that likely reflect limitations on funding and access to macaques). Hopefully the publication of the data will help the researchers obtain the support necessary to conduct a larger and more rigorous evaluation of the reservoir-depleting potential of auranofin.

Additional background on the use of the drug in rheumatoid arthritis, along with an excellent potted history of the use of gold in medicine, can be found in a review published in 1997 in the British Journal of Rheumatology (free to access online). [5]

Source: TAG basic science blog (26 Jul 2011).

http://tagbasicscienceproject.typepad.com/

References

1. 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: 17 July 2011 – Volume 25 – Issue 11 – p 1347–1356.
   http://journals.lww.com/aidsonline/Abstract/2011/07170/Gold_drug_auranofin_restricts_the_viral_reservoir.1.aspx
2. Press release. Gold-based Drug May Pave the Way to a Cure for AIDS.
   http://www.hiv-reservoir.net/index.php/Latest-News-on-HIV-Reservoirs-Eradication/gold-based-drug-to-hit-hiv-reservoirs.html
3. http://www.ncbi.nlm.nih.gov/pubmed/8895167
4. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853490/?tool=pubmed
5. British Journal of Rheumatology, 1997.
   http://rheumatology.oxfordjournals.org/content/36/5/560.full.pdf (PDF)

Several recent papers offer insights into the role of the immune response in shaping the genetic make-up of HIV. In a well-publicised, open access paper by Vincent Dahirela, Karthik Shekhara and colleagues, a complex statistical approach called random matrix theory is used to analyse published HIV sequences and look for groups of sites that evolve collectively. [1]

The method allows the researchers to uncover a region of the Gag protein they dub “sector 3″ that is far more constrained in its ability to mutate than surrounding areas. Additional analyses reveal this constraint is likely due to an important role in the formation of the viral capsid. In collaboration with Bruce Walker’s group at the Ragon Institute, the researchers show that HIV-specific CD8 T cell responses in elite controllers preferentially target sector 3 of Gag, consistent with prior studies indicating that immune responses in these individuals work partly by compromising viral fitness. The findings suggest that vaccines should attempt to induce T cells against this potentially vulnerable region of HIV. The researchers also recommend using their technique to search for other “multidimensionally constrained” parts of viral proteins.

In a paper published in Blood, Tao Dong and colleagues describe the impact of CD8 T cell responses on HIV diversity in a population of Chinese individuals who were infected with genetically homogenous viruses as a result of plasma donation. [2]

Because of the similarity of the infecting viruses, the cohort offers a unique window into how individual variability in the parts of HIV targeted by CD8 T cells shapes viral evolution, by selecting variants able to escape recognition. Based on analyses of four HIV proteins—Gag, Reverse Transciptase, Integrase and Nef—the researchers find evidence that 24-56% of variable sites were subject to selection by CD8 T cell responses (over approximately 10-12 years since the time of infection). The results offer strong and unusually direct evidence for the key role of virus-specific immune responses in driving HIV diversity.

In a separate paper by the same authors, involving individuals from the same cohort possessing the beneficial HLA B51 immune response gene, CD8 T cell responses targeting specific epitopes from HIV Gag and Pol proteins are investigated in detail. [3]

The researchers show that mutations in these epitopes that abrogate CD8 T cell recognition are associated with higher viral loads and lower CD4 counts, whereas individuals in whom the epitopes are unmutated had higher CD4 T cell counts and lower viral loads. The findings add to the evidence that the beneficial effect of certain HLA genes in HIV infection is mediated by CD8 T cell responses targeting vulnerable parts of the virus.

Lastly, Ingrid Schellens and colleagues compare two groups of HIV-positive individuals who seroconverted in 1985 and 2005/6, respectively, to investigate whether CD8 T cell responses are altering the make-up of circulating HIV over time. [4]

The researchers report that certain HIV epitopes have become significantly less common, and these are epitopes known to be targeted by people with HLA-B alleles associated with slower HIV disease progression (such as HLA B27, B51 and B57). The implication is that HIV is adapting at the population level to avoid the most effective CD8 T cell responses, so HLA alleles that have been shown to be “protective” against disease progression in the past may not always show this association. As a possible example, the authors note that individuals with HLA B57 who seroconverted in 1985 had significantly lower viral loads than individuals lacking this allele, but this was not the case among the 2005/6 cohort.

Source: TAG basic science blog (05 Jul 2011).

http://tagbasicscienceproject.typepad.com/

References:

1. Dahirel V et al. Coordinate linkage of HIV evolution reveals regions of immunological vulnerability. Proc Natl Acad Sci U S A. 2011 Jun 20. [Epub ahead of print]
   http://www.pnas.org/content/early/2011/06/15/1105315108.long
2. Dong T et al. Extensive HLA-driven viral diversity following a narrow-source HIV-1 outbreak in rural China. Blood. 2011 May 11. [Epub ahead of print]
   http://bloodjournal.hematologylibrary.org/content/early/2011/05/10/blood-2010-06-291963.abstract
3. Zhang Y et al. Multilayered Defense in HLA-B51-Associated HIV Viral Control. J Immunol. 2011 Jun 13. [Epub ahead of print]
   http://www.jimmunol.org/content/early/2011/06/13/jimmunol.1100316.abstract
4. Schellens IM et al. Loss of HIV-1 derived CTL epitopes restricted by protective HLA-B alleles during the HIV-1 epidemic. AIDS. 2011 Jun 15. [Epub ahead of print]
   http://journals.lww.com/aidsonline/Abstract/publishahead/Loss_of_HIV_1_derived_CTL_epitopes_restricted_by.99152.aspx0

A number of studies have documented that the body’s machinery for producing new immune system cells is impaired by HIV infection. In a new paper in the journal Blood, Delphine Sauce and colleagues delve into the issue further by analyzing circulating CD34+ hematopoietic progenitor cells (HPC) in over one hundred HIV positive individuals at various stages of disease, compared to both age-matched and elderly (75-96 years old) uninfected controls. [1]

The research reveals significant correlations between the number of HPC and multiple types of immune cells including CD4 T cells, CD8 T cells, B cells, natural killer cells and neutrophils (the strongest correlation being between circulating HPC and CD4 T cells). The number of HPC is found to decline over the course of HIV disease progression such that middle-aged HIV-positive individuals with CD4 T cell counts less than 200 had similar levels of circulating HPCs to the elderly uninfected controls.

Additional analyses show that markers of immune activation such as CD38 expression on CD8 T cells are inversely associated with HPCs; the higher the levels of immune activation, the lower the HPC counts. The researchers demonstrate that among elite controllers with declining CD4 T counts, HPC numbers and functional capacity are diminished despite persistently low viral load, consistent with the link between immune activation and CD4 T cell loss that has been reported in this population. HIV-positive individuals with poor CD4 T cell recovery despite antiretroviral therapy (ART) also show reduced HPC numbers and functional capacity compared to individuals with better immune reconstitution.

The study authors conclude that preservation of lymphocyte production capacity (lymphopoiesis) is important for preventing HIV disease progression and that strategies for enhancing lymphopoiesis should be evaluated in the setting of poor CD4 T cell recovery on ART. One approach that is currently under evaluation in a clinical trial for people on ART with CD4 T cell counts less than 250 is TXA127 (angiotensin 1-7), a drug formulation of a naturally occurring substance that may stimulate production of HPCs. [2]

Source: TAG basic science blog (28 Apr 2011).

http://tagbasicscienceproject.typepad.com/

References:

1. Sauce D et al. HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis. Blood, 24 March 2011. doi: 10.1182/blood-2011-01-331306.
   http://bloodjournal.hematologylibrary.org/content/early/2011/03/24/blood-2011-01-331306.abstract
2. http://clinicaltrials.gov/ct2/show/NCT00757250

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

The number of people living with HIV in the UK reached an estimated 91,500 in 2010, with a quarter of those unaware of their infection, according to Health Protection Agency (HPA) figures published just ahead of World AIDS Day on 1 December.

The report also showed how in 2010, one in five people visiting an STI clinic did not accept an HIV test. This comes as the HPA calls for universal testing for HIV, so that no one leaves an STI clinic without knowing their HIV status.

The HPA is concerned that over half of people diagnosed in 2010 came forward for testing after the point at which treatment for their infection should ideally have begun. Late diagnosis is associated with an increased risk of AIDS and death. Among the 680 people with HIV who died in 2010, two thirds were people who had been diagnosed late. The HPA report recommends that in areas where prevalence of HIV is high, there should be universal testing for the infection in all new GP registrants and patients admitted to hospital so as to reduce late diagnosis.

The HPA’s annual ‘HIV in the UK’ report found 6,660 people were newly diagnosed with HIV in the UK. The report confirmed that infections probably acquired within the UK almost doubled in the last decade from 1,950 in 2001 to 3,640 in 2010 and exceed those acquired abroad – 3,020. This rise is mostly due to infections acquired among men who have sex with men, who remain the group most at risk of HIV infection in the UK.

In 2010, over 3,000 gay men were diagnosed with HIV – the highest ever annual number. One in 20 gay men are now infected with HIV nationally with one in 12 in London.

Dr Valerie Delpech, consultant epidemiologist and head of HIV surveillance at the HPA, said: “HIV is an infection which can nowadays be treated and those diagnosed promptly can expect to experience similar life expectancy as an individual without the infection. However, we are very concerned that a large number of people in the UK are unaware of their HIV status and are diagnosed late.

“We want to see increased access to HIV testing routinely offered in clinical settings such as new registrants at GPs and hospital general admissions, in areas of the country where rates of HIV infection are high. We are also urging sexual health clinics to ensure that HIV testing is offered as part of a universal sexual health screen at every new attendance.

“Research by the HPA has shown that routine and universal testing is feasible to undertake and acceptable to patients. Increased testing and greater access will help reduce the number of people who are unaware of their HIV status and increase the chances of early diagnosis, when treatment is more successful.”

Dr Delpech added: “Thanks to the development of anti-retroviral treatments and universal access to world class health care through the NHS, HIV is a manageable illness for the vast majority of people affected in this country. But an HIV diagnosis means a lifetime of medication and the costs of providing specialist HIV treatment and care are substantial and accelerating, so avoiding the infection altogether is essential for controlling the epidemic in the UK.

“If you are having sex, using condoms with any new or concurrent partners is the best way to prevent HIV. We encourage all people to take up the offer of an HIV test in whatever health care setting.”

Reference:

HPA press statement: HPA urges ‘universal testing’ for HIV as it is revealed more than 21,00 people are unaware they have the infection. (29 November 2011).
http://www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1317131678707x

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

The new tablet is indicated in combination with other antiretroviral medications for the treatment of HIV-1 infection. EU approval for the use of one 400 mg tablet once daily for adults and adolescents – and for 50 mg and 100 mg strengths for once-daily treatment of children – is based on results from clinical trials confirming the significant therapeutic benefits of nevirapine when administered in a convenient once-a-day formulation.

This formulation still requires a lead-in dose of 200 mg once-daily with the original twice-daily formulation of nevirapine, with a caution not to increase the dose if rash is present at day 14.

Nevirapine-XR was approved by the Food and Drug Administration (FDA) in the US in March 2011.

Source: Boehringer Ingelheim press release. Viramune® (nevirapine) prolonged-release once-daily formulation for the treatment of HIV-1 infection receives approval in the EU. (21 September 2011).
http://www.boehringer-ingelheim.com/

The fixed dose combination will be called Eviplera in Europe.

It is notable that the indication is restricted to treatment of HIV-1 infection in antiretroviral-naive adults with a viral load less than 100,000 HIV-1 RNA copies/mL.

In the US, where the fixed dose combination is already approved and marketed as Complera, the indication indication only included a caution against using in patients with baseline viral load >100,000 copies/mL.

The CHMPs positive recommendation will be reviewed by the European Commission, which has the authority to approve medicinal products for use in the 27 countries of the European Union (EU). Gilead expects the European Commission to issue its decision on the marketing authorisation for the Eviplera single-tablet regimen later this year.

Source: Gilead press release. European CHMP adopts positive opinion for Eviplera, a once-daily single-tablet regimen for the treatment of HIV infection. (23 Septemebr 2011).
http://www.gilead.com/pr_1609500

The submission was based on a sub-analysis of the original registrational studies in treatment-experienced patients, MOTIVATE 1 & 2. The press release stated that “although ViiV Healthcare remains committed to studying the potential for once-daily dosing of maraviroc in treatment-experienced patients, we have concluded that additional data is necessary to establish the efficacy of once-daily dosing”.

Source: ViiV Helathcare press release. Regulatory Update – Celsentri/Selzentry (maraviroc). (20 September 2011).
http://www.viivhealthcare.com/media-room/press-releases/2011-09-20.aspx

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 high level panel established six months ago by the Board of the Global Fund after widespread media publicity about corruption among some grant implementers released its report on 19 September 2011.

The panel, led by former President Mogae of Botswana and former US Secretary of Health and Human Services Michael Leavitt, was given a broad remit to look into the Global Fund’s problems and what should be done about them. Much is riding on the report as several donors delayed making, or implementing, their funding commitments for 2011 and later until they the report was published and the Global Fund responded.

While identifying many areas for improvement, the Fund was recognised as a vital part of what makes health care function in many countries. Its failure would bring serious, dramatic and tragic consequences. Many of the recommendations related to changing the organisations role from providing an emergency response to sustainability with heightened public responsibility.

It is clearly important that the majority of recommendations, including major structural changes, were accepted by the Fund when the report was formally accepted the following week.

However, perhaps more significantly, the Global Fund looks likely to have significantly less funding for new grants in Round 11 – barely more than half – than the estimate published in May 2011. The Global Fund Observers reported that “the panel found this situation a cause for deep concern”.

At the Global Fund Board meeting on 26 September 2011, the Fund revealed that its forecast of $1.5 billion for Round 11 has been lowered to “not more than” $0.8 billion, and that even this amount might not be available until the fourth quarter of 2013.

The previous forecast was based on the assumption that all donors would honour their pledges, and that donors that traditionally do not make pledges would provide funding at a level similar to what they had provided before. However, the global economic insecurity and other factors have shown these assumptions appear to be overly optimistic.

This has already resulted in an extended deadline for applications to at least March 2012 and a statement that given the financial restraints it will “consider options for reallocation of existing commitments” in order “to prioritize high-impact interventions.”

The need to pressure donor countries to follow through and expand on their commitments has never been stronger or more important.

Source: Global Fund Observer. Issues 158 and 159
http://www.aidspan.org/

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.

comment

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.

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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.