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

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

At 160 pages we are going green this year and publishing this in the UK as web articles and PDF file, although a limited print run of a second edition will be produced by TAG in the US.

Sections include:

• Introduction and executive summary
  • Dedication
  • Acknowledgments
• The antiretroviral pipeline
• The paediatric antiretroviral pipeline
• HIV point of care diagnostics pipeline
• Patents and the pipeline: is access under threat?
• Preventive technologies, immune-based and gene therapies, and research toward a cure
• The hepatitis C treatment pipeline
• The tuberculosis diagnostics pipeline
• The tuberculosis treatment pipeline
• The tuberculosis vaccine pipeline

The report is dedicated to Dr Robert Carr and David Kato Kisule.

We conclude our reports form the BHIVA and CROI meetings this year and include exciting news on treatment access due to Gilead entering an agreement with the Medicines Patent Pool.

New recently approved drugs (in the USA) include the new NNRTI rilpivirine and a new triple drug fixed-dose combination of rilpivirine/tenofovir/FTC.

We also launched the i-Base/TAG 2011 pipeline report in Rome as a supplement to HTB that updates the pipeline development of all important drugs, diagnostics and treatment strategies for HIV, hepatitis and TB.

Introduction

The biannual IAS Conference on HIV Pathogenesis, Treatment and Prevention is more scientifically focused than the World AIDS Conference held in alternate years and is considerably smaller. This makes both attending and reporting more manageable and concentrated.

This year the conference was held in Rome. While plenary lectures were held in the concert halls designed by Renzo Piano (the architect designing the Shard Tower in London), smaller meetings were often in rooms with a capacity of only 50 people and the poster and exhibition halls were less than ideal, being held in the venues garages.

Even prior to the conference, the frenzy to gain media coverage filled email boxes with press releases that made it clear that the meeting would be dominated by prevention studies.

The leading prevention reports, first and most importantly, involved the reduction in transmission from use of HIV treatment for HIV-positive people. The risk is not reduced to zero, but it is getting close, especially when condoms remain the mainstay of prevention work. It means that if a condom breaks, slips off, or is not used at all, an HIV positive person who has had an undetectable viral load for over six months would find it difficult to transmit HIV.

The shift in medical consensus is dramatic. While the Swiss Statement three years ago was met with anger publically from many prominent doctors, in private most also recognised that viral load was the driving factor behind transmission risk. It was good to hear Pietro Vernazza who authored the Swiss paper ask Myron Cohen after presenting the results of HPTN 052 on whether Cohen’s new results had prompted a change of heart.

IAS in Rome included four oral presentations from the HPTN 052 study. Together they showed that HIV-positive people in high incidence resource limited settings (predominantly Africa, Asia and Latin America) who started treatment at a CD4 count of 350-550 reduced the risk of transmitting HIV to their HIV-negative primary partner by 96% compared to people waiting until their CD4 count was 250. This was a study that intensely integrated other prevention strategies – condom provision and counselling reduced transmission too, but treatment extended this significantly further.

The second way that treatment reduces transmission was supported by new studies reporting the benefits of PEP/PrEP strategies. These involved HIV negative people taking a daily pill of tenofovir/FTC, or tenofovir alone, which led to reductions in their risk of catching HIV.

As with previous meetings, the conference has an open-access searchable abstract database online.

http://www.ias2011.org

However, many oral presentations are not included as webcasts or PowerPoint slides.

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

http://pag.ias2011.org/

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

We have also included reports from the 3rd International Workshop on HIV Pediatrics immediately preceding IAS 2011. This small annual meeting is becoming quite established and although abstracts are often submitted to both meetings, in this one they may often get an oral presentation instead of just a poster. For those specialising in paediatrics this meeting is a welcome opportunity to present and discuss work in a dedicated forum. Abstracts and presentations are online. We have included references from both meetings in our paediatric reports.

http://regist2.virology-education.com/abstractbook/2011_8.pdf

http://regist2.virology-education.com/2011/3HIVped/15_July.html

Reports in this issue of HTB South include:

• Webcasts for major research at IAS
• Treatment is prevention: ARV treatment in HPTN-052 reduces transmission by at least 96%: single transmission in treatment arm occurred prior to viral suppression
• Daily oral tenofovir/FTC PrEP reduces heterosexual transmission by 63% in the TDF2 study
• Tenofovir/FTC vs tenofovir as daily oral PrEP: preliminary results from Partners PrEP
• Elvitegravir vs raltegravir: 48 week results in treatment-experienced patients
• Dolutegravir: 48 week results from phase II study in treatment-naïve patients
• Lersivirine: 48 week results compared to efavirenz in phase 2 treatment-naïve study
• SPARTAC trial: treatment in primary infection for 48 weeks shows small delay in disease progression
• Hearing loss not associated with HIV in MACS and WIHS cohorts
• Pharmacokinetics of darunavir and fosamprenavir in pregnancy
• Low birth weight and preterm delivery
• Hormonal contraception and HIV transmission risk
• No difference in AIDS-free survival in children starting ART with a CD4% between 15%–24% compared to deferring until less than 15% in the PREDICT trial
• Paediatric antiretroviral pipeline: update on etravirine and maraviroc
• More metabolic abnormalities in children receiving a PI compared to NNRTI in NEVEREST study
• Prematurity not associated with early mortality in infants on ART
• Free online resource for treatment decisions without access to genotype resistance tests

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

Firstly, treatment as prevention – most notably in a study called HPTN-052 and PrEP studies. The Treatment Is Prevention session include links to abstracts, slides and webcasts from the HPTN-052 study.

http://pag.ias2011.org/session.aspx?s=98

Secondly, research relating to reservoirs, eradication and the cure was established throughout the programme. This included overviews of the different ways that this could be approached and preliminary results for early potential targets. Unfortunately very few of the lectures in these sessions are webcast. However, the overview by Anthony Fauci, is online and worth watching to understand the new strengthening steer from the US that dominates global research.

Tony Fauci: 30 years of HIV/AIDS: a scientific journey and a look to the future

http://pag.ias2011.org/flash.aspx?pid=409

Towards an HIV cure: insight into residual viral replication, establishment of reservoirs and understanding mechanisms of persistence

http://pag.ias2011.org/session.aspx?s=70

Towards an HIV cure: new strategies for an old challenge

http://pag.ias2011.org/session.aspx?s=15

Controversies in HIV cure research satellite meeting

http://pag.ias2011.org/session.aspx?s=39

Thirdly, there were important studies about New drugs and diagnostics and new strategies with oral presentations on new integrase inhibitors (elvitegravir and dolutegravir) and NNRTIs (lersivirine), using of HSV drugs (acyclovir/valacyclovir) and currently approved meds (maraviroc/atazanavir). Plus, also in the late breaker session, an exciting new rapid antibody test for cryptococcal meningitis developed in the UK that can be used at the point of care. These were presented mainly in the following two sessions.

New drugs and strategies

http://pag.ias2011.org/session.aspx?s=55

Late breaker Track B

http://pag.ias2011.org/session.aspx?s=44

Simon Collins, HIV i-Base

Four of the six oral presentations in the ‘Treatment is prevention: the proof is here’ session reported on the results from HPTN 052. [1] This study had been unblinded four years earlier than planned due to a review by the data and safety monitoring board (DSMB), with all patients now being offered active treatment.

In summary, HIV-positive people on treatment had a 96% reduction in sexual transmission to their HIV-negative partners if they started ARVs with a CD4 count of 350-550 cells/mm3 compared to waiting until it dropped below 250 cells/mm3. As with all prevention studies, condoms, testing and intensive counselling was included throughout the study.

The main study results were presented by Myron Cohen from University of North Carolina. [2]

HPTN 052 screened over 10,000 couples in order to randomise 1763 HIV-positive people with CD4 counts 350-550 to either immediate or delayed HIV treatment (CD4 confirmed <250 or an AIDS-defining illness). Screening failure was mostly due to CD4 or other criteria in the positive partner, but 300 couples were already both HIV-positive. This was an international study predominantly recruiting in Africa (Botswana, Kenya, South Africa and Zimbabwe, n=954), Asia (India and Thailand, n=531) and Latin America (Brazil, n=276). Men and women were equally distributed as the positive partners. Median baseline CD4 count was 436 cells/mm3 (IQR 365-522) and viral load was approximately 25,000 copies/mL (IQR 6,000-80,000) respectively.

This was generally a low risk population with only 6-8% reporting recent unprotected sex and only 16% aged 18-25 years (~ 60% were 25-40 years and ~20% > 40 years).

The primary transmission endpoint was the prevention of virologically linked transmissions with a primary clinical endpoint of WHO Stage 4 events (including pulmonary TB, severe bacterial infections and death).

Transmission events (n=39) occurred significantly less frequently in the immediate (n=4) compared to the deferred (n=35) treatment arms, p<0.0001. Of these, only 28/39 were linked transmissions (within the couple) with 1 case in the immediate arm vs 27 cases in the deferred arm, p=0.001 (see below for details). Eleven transmissions were either unlinked or undetermined. This translated to incidence rates of linked transmission of 0.1 (95%CI 0.00-0.04) vs 1.7 (95%CI 1.1-2.5) per 100 person years respectively over a median follow-up of 1.7 years.

The single transmission in the immediate treatment arm was detected at the first follow-up visit. However viral diversification analysis estimated that transmission occurred prior to the positive partner initiating treatment (baseline 87,000 viral load) or certainly prior to viral suppression to <400 copies/mL which was recorded at day 28.

Other transmission risk factors were similar between arms, including rates of STIs (low at <5% in both index and partner at baseline and during the study), sexual activity (approximately 70%) and condom use (>90% by all throughout).

Viral suppression (<400 copies/mL) was maintained by >90% of participants in the immediate arm. There was a slow increase in this percentage over time in the deferred arm as people started treatment (from <10% over the first year, 20% by month 24 and increasing to 50% at month 45, though with much fewer patients). The median viral load closest to the time of transmission in the deferred arm was considerable at 80,000 copies/mL but had a wide range from 600 to 630,000 copies/mL.

In multivariate analysis, treatment was the strongest protective effect [HR=0.04, 95%CI 0.01-0.28] compared to condom use [HR=0.33; 95%CI 0.12-0.91]. Factors associated with increased transmission included baseline viral load [per log increment: HR 2.84, 95%CI 1.51-5.41] and baseline CD4 count [per 100 count increment: HR 1.24 95%CI 1.00-1.54].

The second presentation by Susan Eshelman from Johns Hopkins University School of Medicine focused on the analysis of linked transmission. [3] This included a helpful introduction to the three types of phylogenetic analyses used: phylogenetic analysis of HIV pol sequences using population sequencing, and statistical analysis of genetic distances from pol sequence pairs for the clearest cases (n=26), and phylogenetic analysis of env sequences obtained by deep sequencing for more complex cases (n=12). Together these provided a high level of reliability for indentifying whether the source of new infections was the HIV-positive partner or whether this was from another partner.

Transmissions in previous serodifferent couple studies have been from outside the main relationship in 25-50% cases.

The deep sequencing (‘ultradeep pyrosequencing’) supported linked two further cases and confirmed non-linkage for seven others (4 in the immediate and 3 in the deferred arm). Three cases remained unidentified (all in the deferred arm). Transmission linkage was not associated with index partner gender or CD4 count, geographical regions or time on study but this was strongly associated with study group and number of sexual partners in the three months prior to new seroconversions.

Results on the clinical outcomes for the HIV-positive participants in HPTN 052 were presented by Mina Hosseinipour from the UNC Project, Malawi. [4]

Results comparing the two groups were presented as ITT analyses and included the approximate 20% (184/877) people randomised to the deferred arm who started treatment during follow-up.

Over two years, median CD4 counts increased from 442 to 662 cells/mm3 in the immediate group compared to reducing from 428 to 390 cells/mm3 in the deferred arm. These differences are blunted as the deferred arm includes the response for the 20% people who started treatment. Viral suppression was achieved and maintained <400 copies/mL by >90% of the immediate arm. Less than 5% of patients on immediate treatment experienced virological failure during follow-up with most (60%) of these switching to a second-line combination.

The decision to start treatment in the deferred arm was driven by CD4 declines in 75% of cases. This occurred at a median count of 225 cells/mm3 (IQR 199–247), with 25% over people not starting until their CD4 count was less than 200. Treatment in both arms was predominantly AZT/3TC/efavirenz (70%) with ~10% using AZT/3TC/atazanavir, and ~10% using tenofovir/3TC/efavirenz. CD4 responses in the deferred arm were similar to absolute increase in the immediate treatment arm but remained significantly lower at all timepoints, reflecting the lower counts when starting treatment. Although there are fewer patients with longer duration of follow-up in the deferred arm, other studies have reported that baseline CD4 correlates with CD4 response after treatment.

The analysis by geographical region reported that about 80% of both the linked and unlinked transmission events occurred in African sites, likely a reflection of the higher background population prevalence rates in those countries, although the researchers highlighted higher rates of unprotected sex in the last week (by 9% vs 4% of African vs non-African) and higher sexual activity (>3 acts). However, baseline CD4 count, viral load and adjusted time to initiation, median adherence (99%) and treatment responses were similar between African and Asian sites.

Further details on clinical outcomes were presented by Beatriz Grinsztejn from the Oswaldo Cruz Foundation, Rio de Janeiro. [5]

Primary clinical events occurred at least once in 105 participants over 3304 person-years (PY) of follow-up; 40 in the immediate arm (2.4/100PY) and 65 in the delayed arm (4.0/100PY), hazard ratio (HR) 0.59, 95% CI: (0.40, 0.88), p=0.01. Seventeen people experienced more than one event. Time to event was significantly shorter in the deferred arm (HR 0.6, 95%CI 0.4, 0.9, p=0.01)

CD4 counts were significantly higher in the immediate arm vs deferred arms for all clinical endpoints (TB 518 vs 316; bacterial infection (mainly pneumonia) 551 vs 337 and death 476 vs 372 cells/mm3 respectively).

The between-arm difference was driven by extrapulmonary tuberculosis with 3 cases in the immediate versus 17 cases in deferred arms (p< 0.002). These were peripheral lymph nodes (2 vs 4), abdominal (0 vs 8), pleural (1 vs 3), skeletal (0 vs 1) and meningeal (0 vs 1). Isoniazid prophylaxis was only being used by 4% of patients in each arm at baseline.

Of the 23 deaths observed, there was no difference between arms: 10 in the immediate arm and 13 in the delayed arm [HR 0.77, 95% CI: (0.34, 1.76), NS p>0.5]. Causes of death were similar, but with 3 vs 3 suicides; 0 vs 2 accidents; and 3 vs 6 unknown).

Adverse events potentially related to ART were reported in 24% of subjects in the immediate arm and 5% in the delayed arm, but severe or life-threatening events occurred equally in 14% of each group and grade 4 lab events were also similar (in <1-2% of participants).

Since the DSMB recommendation in April 2011, all participants in the deferred arm have been offered HAART based on the strength of the study findings. This study continues to monitor all participants and results will add to clinical data from use of earlier vs later treatment in people with CD4 counts >350 cells/mm3.

comment

These results add to research that not only correlates viral load with risk of sexual transmission but specifically demonstrates a protective impact with treatment. The two cases of transmission in the early treatment arm (a second was discussed during the presentation) were both detected at the beginning of the study prior to the positive person reaching suppressed viraemia <400 copies/mL.

The fewer clinical endpoints from earlier treatment for the HIV-positive partners in this study are important but were driven by extrapulmonary TB. This clinical difference has significance for people in geographical regions where this study was run, but this aspect of the results was unexpected and has yet to be explained. A more generalisable benefit to people in Western countries is probably the reduced CD4 response in the deferred arm and this needs to be supported by longer follow-up. The ongoing START study will report on whether clinical benefits result from earlier treatment in Western countries.

It would be interesting to model the potential number of transmissions that have already been prevented over the last ten years from the seven million people globally on HAART. Given the financial constraints of access to treatment the additional impact on prevention should be included in future cost: benefit analysis.

The results from HPTN 052 clearly support offering an option for treatment to HIV-positive people who have HIV negative partners. This has been included in UK (BHIVA) guidelines for many years.

When access to treatment is limited with a waiting list using CD4 upper cut-offs to access treatment, those with the most severe medical should clearly be prioritised. However, the majority of the nine million people currently identified by UNAIDS and WHO analyses as requiring but not yet able to access treatment are likely to be undiagnosed. Broadening the CD4 criteria for access to treatment as prevention at higher CD4 counts is unlikely to directly deny access to treatment for more advanced patients.

It was unfortunate that a WHO guideline due to be launched at the IAS meeting, that included the recommendation for treatment people with CD4 counts higher than 350 and who have HIV-negative partners, based on the HPTN 052 study was withdrawn at the last minute. [6]

Although printed for a launch at the conference there is concern that while the scientific evidence is clear – and this should be the focus for clinical guidelines – practical issues on implementation have stalled their release perhaps under pressure from prominent WHO funders. It is difficult to understand how such a useful document that included broad community consultation and approval to the stage of print would have been retracted at such a late stage. WHO say this is due to a need to make “small modifications” and “to review their modeling data they used to inform investment structures”. The timeline for these changes are 2-3 months.

This plausibility for intervention from outside the extensive WHO guidelines writing and advisory panels is supported by an article in Science magazine that names the Gates Foundation specifically related to their interest in the latest PrEP results also being included. [7]

References

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

1. Treatment is prevention: the proof is here. Oral abstract session: Monday 4.30-6.00pm.
2. Cohen M et al. Antiretroviral treatment to prevent the sexual transmission of HIV-1: results from the HPTN 052 multinational randomized controlled trial. Oral abstract MOAX0102. Webcast
3. Eshleman S et al. Analysis of genetic linkage of HIV from couples enrolled in the HIV Prevention Trials Network (HPTN) 052 trial. Oral abstract MOAX0103.
4. Hosseinipour M et al. Immunologic and virologic disease progression and responses to ART across geographic regions: outcomes from HPTN 052 study. Oral abstract MOAX0104. Webcast
5. Grinsztejn B et al. Effects of early versus delayed initiation of antiretroviral therapy (ART) on HIV clinical outcomes: results from the HPTN 052 randomized clinical trial. Oral abstract MOAX0105. Webcast.
6. WHO. Couples HIV testing and counselling and antiretroviral therapy for treatment and prevention in serodiscordant couples: Recommendations for a public health approach. 2011. Final version approved but not yet released. (PDF file)
7. Cohen J. New prevention data leads WHO to delay guidelines for couples. Science Insider (25 July 2011).

Simon Collins, HIV i-Base

Results from the double-blind placebo-controlled TDF2 study presented in an oral presentation in Rome provided additional supportive data for the benefit of daily oral tenofovir/FTC (Truvada) to reduce sexual heterosexual transmission. [1]

While the iPrEX study first reported a strongly protective impact in high risk MSM, the lack of protection in the FemPrEP study earlier this year has still to be explained. [2, 3]

TDF2 randomised 1200 sexually active HIV-negative adults (age 18-49: approximately 90% were between 21-29 years) and followed them for a year. Over 90% of participants were single with only 3% having low educations (primary or less) with >70% having secondary and >20% having post-secondary education. HIV testing was monthly and as with all prevention studies, intensive counselling on safer sex and free condom distribution was provided throughout the study. An indication of the background risk in this population is that 16% of people failing screening (197/2533) were excluded due to already being HIV-positive and 20% due to not being sexually active.

A slightly higher percentage of people in the active vs placebo arm (34% vs 31%) did not complete the study due to loss to follow-up, withdrawal of consent, relocations or other reason. The study had a good gender balance with 45% women.

With 33 seroconversions, primary efficacy results reported a 63% reduced risk of transmission with Truvada based on 9 new infections in the active arm compared to 24 in placebo group (difference 62%: 95%CI 21.5 to 83.4, p=0.0133).

When restricting the analysis (post hoc?) to infections within 4 weeks of a study visit (ie where the monthly visit schedule was being followed and the participant was under a prescription period) the association became stronger. Out of 23 seroconversions, 4 occurred in the active arm and 19 in the placebo group with 78% protection efficacy (95% CI 41.2 to 93.6, p=0.0053).

Although it was emphasised that the study was underpowered to draw any conclusion by gender, in an ITT analysis (33 cases) the intervention appeared protective in men (p=0.026) but not women (p=0.107) and in the observed results (23 cases) the protection was seen on women (p=0.021) but not men (p=0.065). Whilst interesting to see if a gender effect can shed light on the results from FemPREP, this will need to come from larger study numbers.

Resistance developed in one person enrolled in the active arm whose acute HIV infection was undiagnosed with K65R, M184V and A62V conferring nucleoside cross resistance. The person has achieved viral suppression after starting treatment with AZT/3TC/lopinavir/ritonavir. One person in the placebo group had low-level K65R suggesting an infection with drug resistant HIV.

Side effects were commonly reported in both arms, usually mild, with nausea (19% vs 7%, p=0.0001) and vomiting (11% vs 7%, p=0.005) occurring more significantly in the active arm compared to the placebo arm, but resolving within the first month. There were no differences in laboratory abnormalities with one case of elevated creatinine in the active group that resolved when treatment was stopped.

References

1. Thigpen MC et al. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study. Oral abstract WELBC01. Webcast.
2. Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM. 23 November 2010 (10.1056/NEJMoa1011205). Free full access.
3. FHI statement on the FEM-PrEP HIV prevention study: FHI to initiate orderly closure of FEM-PrEP. (18 April 2011).

Simon Collins, HIV i-Base

The final presentation in the Treatment is Prevention session was a summary of the first results from the Partners PrEP study that randomised the HIV-negative partner in 4758 HIV serodifferent heterosexual couples to daily tenofovir (TDF) vs tenofovir/FTC (TVD) vs placebo in a 1:1:1 ratio. [1]

The results presented were based on a DSMB analysis a week before the conference that recommended unblinding the placebo arm and switching those participants to active drugs. This was based on significantly reduced risks of transmission in both the active arms and was 18 months earlier than the planned study endpoint.

This study was run in nine sites in Kenya and Uganda with all participants receiving intensive healthcare and adherence counselling including free condoms. The negative partners were seen monthly for counselling with HIV and pregnancy testing and the positive partners were monitored for their HIV care every three months.

Baseline demographics were similar across the three arms and included age (of the negative partner) 33 years (IQR 28-40), with the positive partner diagnosed a median of 0.4 years (IQR 0.1-2.0 years), CD4 count 490 cells/mm3 (IQR 370-660) and viral load 3.9 log copies/mL (3.2-4.5 logs).

Nearly all couples were married (98%) with duration of relationship a median of 7 years (IQR 3-14). The positive partner was a woman in 40% of couples. Approximately 20% of positive partners started treatment during the study for their own health.

Study retention was high with fewer than 5% discontinuations over 7337 person years of follow up (median 12 months). Adherence was also estimated high at 97% based on pill count using returned bottles (98% of bottles were returned).

Up to May 2011, there were 90 new infections, 12 of which were HIV-positive at randomisation (3 TDF, 3 TVD, 6 placebo). Of the 78 transmissions that occurred as events for the primary endpoint, 18, 14 and 47 occurred in the TDF, TVD and placebo arms respectively. The was an incidence of 0.74, 0.53 and 1.92 per 100 patient years that produced protection rates of 62% (95%CI 34-78%, p=0.0003) in the tenofovir and 73% (95%CI 49-85%, p<0.0001) in the tenofovir/FTC arms compared to placebo.

The study reported of a similar response between the two active arms (p=0.18 for comparison, NS). However, protection was numerically greater with the dual therapy and the gender analysis reported wider confidence intervals for tenofovir monotherapy with lower levels that were lower.

For women, protection rates were 68% (29-85%) and 62% (19%-82%) in the TDF vs TVD arms; for men these were 55% (4-79%) vs 83% (49-94%). The plausibility for greater protection from dual therapy would be extended with either lower adherence or less-than-daily dosing, both of which might be key public health factors for considering use of PrEP outside of clinical trials.

Safety results were very similar between all three arms for serious events and lab abnormalities including creatinine increases (1%, mainly grade 1) and reduced phosphorus (9%, equal across arms). As with other PrEP studies, nausea and diarrhoea were significantly more common in the active arms, but generally only for the first month of treatment.

As with other PrEP research, results from the pharmacokinetic will be important to correlate drug levels with level of protection and partner viral load with risk of infection. Resistance results will also be analysed.

Reference

Baeten J et al. Antiretroviral Pre-Exposure Prophylaxis for HIV-1 prevention among heterosexual African men and women: the Partners PrEP Study. Oral abstract MOAX0106. Webcast.

Simon Collins, HIV i-Base

Elvitegravir is a once-daily integrase inhibitor being developed by Gilead. This was a double-blind, placebo-controlled study that randomised 702 treatment-experienced patients to compare elvitegravir (150 mg once-daily; reduced to 85 mg with atazanavir/r or lopinavir/r) to raltegravir (400 mg twice-daily), each with a background regimen of sensitive boosted-PI plus a third sensitive drug selected by phenotype (from NRTI, maraviroc, etravirine or T-20) and including the use of 3TC/FTC with the M184V mutation. The primary endpoint was proportion of patients with viral load <50 copies/mL at week 48 (TLOVR analysis, ITT), This was a non-inferiority study with the lower limit of the 95%CI set at –10%.

Baseline characteristics included mean age 45 years; 18% were women; mean CD4 count 260 cells/mm3 (45% cell <200), median viral load ~ 20,000 copies/mL (with 26% >100,000 copies/mL) and approximately 5% and 15% of patients were coinfected with HBV or HCV respectively. Approximately 63% patients had primary resistance to two or more classes (PI 33%, NRTI 72%, and NNRTI 61%), balanced between arms.

Choice of background PI was largely darunavir (58%), lopinavir/r (19%) or atazanavir (16%). The third drug was an NRTI in 80% of patients (tenofovir 59%, tenofovir/FTC 27%, abacavir 4%, 3TC 3%, other 7%) with 13% using etravirine and 6% using maraviroc.

At week 48 a similar virological response rate was reported in each arm: 59% vs 58% in the elvitegravir vs raltegravir arms respectively which was strongly significant for non-inferiority (difference 1.1%, 95%CI –6.0% to +8.2%; p= 0.001). Approximately 20% of patients in each arm were reported as discontinuing due to virological failure: due to viral rebound (11% vs 16%) or never suppressing (8% vs 5%) in the elvitegravir vs raltegravir arms respectively with 1% or patients in each arm failing due to a switch of background drugs. A summary of virological and safety results is included in Table 1.

However, discontinuations in a following slide were reported at 24% in each arm, mainly due to non-adherence, loss to follow-up or withdrawn consent and are detailed in Table 2, with virological failure reported in only 9 patients in each arm.

When looking at drug resistance in the patients with virological failure, this included 61 and 75 people in the elvitegravir and raltegravir arms respectively. In this dataset, failure with integrase-associated mutations was reported at a comparable number though with increased frequency (16/60; 27% vs 15/72; 21%) in the elvitegravir vs the raltegravir patients. Development of new PI- or NRTI-associated resistance was generally low and similar between the two groups.

Less than 5% of participants discontinued due to side effects. The only difference between arms in terms of adverse events was a higher rate of diarrhoea with elvitegravir (12% vs 7%), not associated with discontinuation. This was similar for laboratory abnormalities, with a slightly higher percentage of patients reporting grade 3/4 ALT/AST elevations with raltegravir (~1-2% vs 5%).

This study concluded that this demonstrated that once daily elvitegravir was non-inferior to twice-daily raltegravir in treatment-experienced HIV-positive patients.

comment

These are impressive results in treatment-experienced patients. The rate of 20% patients failing with integrase-associated mutations was considered low by the investigators given the low barrier to integrase mutations. This was partially explained by the low barrier to virological failure in the study design (<1 log by week 8).

Causes of the seven deaths were not apparently drug related. This included one intestinal perforation in the elvitegravir arm, and one lymphoma and two cardiovascular events in the raltegravir arm.

References

Molina J-F et al. Elvitegravir once-daily is non inferior to raltegravir twice-daily in treatment experienced patients: 48 week results from a phase 3 multicenter, randomized, double blind study. Oral late breaker abstract WELBB05. Webcast.

Simon Collins, HIV i-Base

Dolutegravir is an integrase inhibitor in development with ViiV/Shionogi that in earlier development was referred to as GSK-572. Results from the first monotherapy studies were presented only two years ago and the rapid development programme now includes phase III studies in naïve patients (using a 50 mg once-daily dose) with results already reported from phase II studies in experienced patients (using a higher 50 mg twice-daily dose).

Results from week 24 of a Phase IIb dose-ranging study treatment naïve study were presented in Glasgow last year with 90-96% of patients in the dolutegravir arms reducing viral load to <50 copies/mL compared to 78% patients in the efavirenz arm. These were updated to week 48 at in an oral presentation in Rome. The initial steep viral decline seen with integrase inhibitors as a class was probably a factor in choosing a primary endpoint at week 16 but this extended data is more crucial to understand sustainability. [1]

The study randomised 205 treatment-naïve patients 1:1:1:1 to 10 mg, 25 mg or 50 mg of dolutegravir or efavirenz 600mg once-daily, plus either investigator choice of either tenofovir/FTC (used by two-thirds of patients) or abacavir/3TC.

Baseline viral load was originally low (approximately 30,000 copies/mL) with only 26% participants >100,000 copies/mL. This would increase effectiveness for the a viral suppression (requiring less than a 3 log drop to achieve undetectable levels. Participants were largely male (86%) and white (80%), with mean CD4 count of 324 cells/mm3 (63% were <350). Median age was 32 (range 20-79 years).

By week 48, suppression in the dolutegravir arms had dropped slightly to 88-91% compared to 82% in the efavirenz arms. No between group analyses were presented but the confidence intervals for all groups broadly overlapped. Virologic non-response/rebound rates were low and similar between arms (8%, 6%, 4% vs 6% in the efavirenz arm) with the lower response in the efavirenz arm driven by discontinuations related to side effects (0, 2%, 0 vs 8% respectively). In the small percentage of patients failing with viral rebound 0/3 (none in the 50 mg arm) showed evidence of integrase-related mutations, though patients were proactively switched early due to this potential concern.

Virological results were also presented using a <2 copies/mL viral load test – the first time perhaps for an ongoing Phase II study. At the 50 mg dose approximate suppression to <2 copies at weeks 16, 24 and 48 was 48% 65% and 52% respectively compared to 35%, 45% and 58% in the efavirenz arm. These are small study numbers and neither confidence intervals nor statistical comparisons were provided but these are unlikely to show significant differences. It may be notable that the <2 copies/mL results for the lower doses of dolutegravir were not presented. Given the increased research focus on greater suppression at levels below < 50 copies/mL and the conflicting results from some of the intensification studies with raltegravir (broadly finding no impact in blood but perhaps in some tissue sites) this class potential is likely to inform future studies.

CD4 increases were similar by week 48 with +231 cells/mm3 in the combined dolutegravir vs +174 in the efavirenz arm vs EFV (p=0.076), reducing a difference that was significantly higher at week 24.

No new serious adverse events were reported out to week 48. The two discontinuations from the dolutegravir arms were due to dyspepsia (25 mg arm) and Burkitt’s lymphoma.

Grade 2-4 side effects were similar between arms, except for rash and CNS-related side effects occurring only in the efavirenz group. Nausea (11%), diarrhoea (8%) and headache (5%) were most frequently reported with dolutegravir compared to dizziness (18%), fatigue, insomnia and rash (8% each) with efavirenz. Grade 3/4 laboratory abnormalities occurred in 12% vs 14% of the combined dolutegravir vs efavirenz arm. Dolutegravir was associated with mean increases in creatinine (6.4-11.9 mmol/L) at week 1 that were stable to week 20 and decreased by week 48. In vitro data have shown that dolutegravir causes a benign inhibition of creatinine secretion. These were detailed in a separate poster presentation. [2]

Lipid changes were generally greater in the efavirenz arm but there were no differences either from baseline or between drugs in the TC/HDL ratio at week 48 (due to the impact of efavirenz in increasing HDL).

The pharmacokinetic summary slide showed an impact of dose on drug levels over 24 hours, but these had low inter-patient variability and at all doses remained above the IC90 (0.064 ug/mL) with Cmin levels [geometric mean (CV%)] of 0.30 (71), 0.54 (67) and 1.20 (62) and an inhibitory quotient of 4.7, 8.4 and 19-fold for the 10 mg, 25 mg and 50 mg doses respectively.

References

1. Van Lunzen J et al. Rapid, robust and sustained antiviral response with once-daily (QD) dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral-naïve adults: 48 week results from SPRING-1 (ING112276). Oral abstract TUAB0102. Webcast.
2. Min S et al. Safety profile of dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral (ART)-naïve and ART-experienced adults from phase 2b studies. IAS. 17-20 July 2011. Rome. Abstract TUPE238.

Simon Collins, HIV i-Base

Lersivirine is a once-daily NNRTI from ViiV that was originally developed by Pfizer and previously called UK-453061 and that is promising due to a resistance pathway at V108I that appears distinct from the K103N or Y181C pathways associated with first-generation non-nukes.

This double-blind, placebo-controlled study randomised 193 patients (1:1:1) to either 500 mg or 750 mg of lersivirine or to standard dose efavirenz, each with once-daily tenofovir/FTC. The primary endpoint was the percentage of patients with viral load reduced to <50 copies/mL at 48 weeks with follow up out to 96 weeks (by ITT missing = failure analysis).

Although enrollment criteria for the study included a CD4 count >200 cells/mm3, at baseline this ranged from 122 to 955 (median 310) suggesting that a few more advanced patients were included on an experimental combination than the European regulatory guidelines recommend for Phase II studies. Baseline viral loads ranged from 1,500 to 1,600,000 (mean: 50,000 copies/mL). Approximately 35% of patients had baseline viral load >100,000 copies/mL and this was reflected in pre-specified analysis of the results.

Other baseline characteristics included: mean age 36 years (range 21-62); 27% were women; race: 60% white, 30% black, 10% other. While the majority of people had sub-type B, ~30% of people were sub-type C which was reflected in ~ 30% enrolled in sites in South Africa.

At week 48, the percentage of patients with viral load <50 copies/mL was 79%, 79% and 86% in the 500 mg, 750 mg and efavirenz groups respectively. Although the study was not powered to detect a difference in efficacy between arms, the lersivirine arms suggested a poorer response compared to efavirenz (500 mg: –9% difference; 80%CI –18.1, 0.8 and 750 mg: –8% difference; 80%CI –17.0, 1.2).

Results stratified by baseline viral load (which was lower in the >100K group) or geographical region (which was lower for sites in South Africa) did not contradict this finding, see Table 1.

A mean CD4 count increased of approximately +190 cells/mm3 from baseline was similar between arms.

Virological failure occurred in 4, 5 and 3 patients in the 500 mg, 750 mg and efavirenz groups respectively, with people on lersivirine generally failing with M184V plus NNRTI mutations when resistance was isolated. The one person with identifiable mutations in the efavirenz arm failed with K103N alone.

Overall, the combined safety analysis reported a similar incidence of side effects in each group but fewer grade 3/4 events in the lersivirine groups (n= 2 and 3) compared to efavirenz (n=8) see Table 2. Laboratory abnormalities were infrequent and evenly distributed between arms. Lipids were broadly stable for lersivirine compared to increases in TC, LDL, HDL and TG for efavirenz, but this resulted in little difference between the LSV and EFV groups (+0.24 and -0.06 vs -0.3) in the change in the TC:HDL ratio used to evaluate cardiovascular risk.

However, the study concluded that both lersivirine doses showed similar efficacy to efavirenz over 48 weeks in treatment-naïve patients and had different side effect profiles compared with efavirenz.

* EU, Latin America, Australia, Canada

comment

There is still a role for new NNRTI with activity against nevirapine and efavirenz associated resistance with an improved safety profile to efavirenz.

The higher reports of nausea and headache appeared to be low grade but limited data was available on duration and severity of these events.

Reference

Pozniak A et al. Efficacy and safety of lersivirine (UK-453,061) vs. efavirenz in antiretroviral treatment-naïve HIV-1-infected patients: week 48 primary analysis results from an ongoing, multicentre, randomised, double-blind, phase IIb trial (study A5271015). Oral abstract TUAB0101. Webcast.

Polly Clayden, HIV i-Base

The main objective in the SPARTAC trial was to look at the impact on disease progression from two different short courses of antiretroviral treatment (ART) initiated during primary HIV infection compared to no immediate ART. Sarah Fidler from Imperial College London presented results from SPARTAC in an oral late breaker at IAS 2011.

In this study, adults with primary infection who were within 6 months of seroconversion were randomised to receive ART for 48 weeks, 12 weeks, or no therapy (standard of care, SOC). The primary endpoint was time from randomisation to either CD4 <350 cells/mm3 or initiation of continuous ART.

A sample size of 360 was calculated (using data from CASCADE) to provide 90% power to detect relative reduction in risk of time to primary endpoint of 50% – 25% in each of the ART arms – compared to SOC over four years of follow up.

A total of 366 participants were randomised from 35 sites in Australia, Brazil, Europe and Africa; 40% were from the UK and 35% South Africa. Of these, 60% were men (90% MSM) and 40% African women, with a median age overall of 31 years.

As would be expected, the median baseline CD4 was high at 543 cells/mm3 and viral load was 4.7 logs (~50,000 copies/mL). Participants were followed for a median of 4.2 years and 19% were lost to follow up. The majority (92%) of participants received lopinavir/r plus AZT and 3TC.

The investigators found no difference in time to primary endpoint in participants receiving 12 weeks of ART compared to SOC (HR 0.93: 95%CI 0.67-1.29, p=0.67). However, 48 weeks of ART conferred a statistically significant delay (HR 0.63: 95%CI 0.45-0.90, p=0.01). The median time to primary endpoint was 157, 184 and 222 weeks for the SOC, 12 week and 48 week arms respectively. Although, Dr Fidler noted that the 65 week (95%CI 17-114) delay in the 48-week arm was not significantly greater than the time spent on treatment.

A post-hoc analysis revealed two findings. There was a significantly more rapid rate of disease progression among participants identified within 12 weeks of acquiring infection in the SOC arm. Secondly, the delay to primary endpoint observed previously with 48 weeks of treatment compared to SOC was greater in participants who initiated ART initiated within 12 weeks of infection (HR 0.48: 95%CI 0.3-0.78). Overall, the investigators reported a non-significant trend to greater delay to primary endpoint the closer ART was initiated to the estimated time of seroconversion (p=0.09, NS).

There was a reduction in viral load of approximately half a log after interrupting ART in the 48-week arm compared to SOC, which was sustained until 60 weeks after stopping treatment. The mean CD4 count over the entire study period was 138 cells/mm3 higher in the 48-week arm than standard of care.

There were no significant differences between arms in AIDS, death or serious adverse events. In contrast to SMART there was no rebound in IL-6 and a drop in d-Dimer, compared to baseline, four weeks after stopping ART.

comment

By the time this study was completed the treatment landscape had changed considerably from when it was initially designed. So the big question now is “what would have happened with a continuous treatment arm?”.

As far as the implication for clinical practice is concerned, perhaps if someone is aware of their status and he or she wants to start treatment in primary infection there may be a slender argument to do so. But if they do start and are doing well, given the modest time off treatment until starting again, why stop?

Reference

Fidler S et al. The effect of short-course antiretroviral therapy in primary HIV infection: final results from an international randomised controlled trial; SPARTAC. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Oral abstract WELBX06.

Simon Collins, HIV i-Base

Hearing loss has been associated as a complication in HIV-positive people but it is unclear whether HIV is a direct factor or whether symptoms are more strongly correlated to risk factors reported in the general population. This will be increasingly important as the HIV population ages.

Researchers from Washington DC measured cochlear function in 334 men and 178 women from two of the earliest population cohorts established to look at differences between HIV-positive and HIV-negative patients (MACS and WIHS respectively), and related to this to social factors including noise exposure and HIV and treatment history.

The mean age was 54 years for the men (46% were HIV-positive), and 45 years for the women (77% were HIV-positive). People were excluded if they had hearing-impaired clinical symptoms or recent use of orotoxic medication. Approximately 20% of people in each of the HIV-positive and HIV negative groups self-reported exposure to occupational noise.

Cochlear function was measured by distortion product otoacoustic emission (DPOAE) testing which is a non-invasive procedure using two separate tones to stimulate the cochlea. Each ear was measured twice, with a third test if results were inconsistent and the number of non-responses added as an outcome variable (0-4).

In multivariate analyses, a 10-year increase in age [OR 2.78; 95%CI 2.07, 3.73], being male [OR 5.60; 95%CI 2.98, 10.49], and being non-black [OR 2.75; 95%CI 1.57, 4.83] were significantly associated with a higher number of non-responses (all p<0.001), but not HIV status [OR 1.20; 95%CI 0.7, 2.02; p =0.52 NS]. However, neither occupational or non-occupational noise exposure was associated with reduced function (p=0.33 and p=0.93, respectively).

Age, race, and gender remained significant risk factors for increasing non-responses in the HIV-positive model. However, none of the HIV-related factors including use of monotherapy, combination therapy, HAART use, 100-cell increase in peak CD8, HIV viral load, and 100-cell increase in nadir CD4 count came near approaching statistical significance (with p-values ranging from 0.2 to 0.7).

The researchers concluded that HIV status, combination therapy, nadir CD4 count, peak CD8 count, and HIV viral load did not significantly predict decreased cochlear function in this patient group.

Reference

Torre P et al. Cochlear function among Multicenter AIDS Cohort Study (MACS) and Women’s Interagency HIV Study (WIHS) participants. 16th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 17–20 July 2011, Rome. Poster abstract TUPE138. Poster. (PDF)

Polly Clayden, HIV i-Base

Physiological changes in pregnancy can affect drug disposition. Plasma concentrations of several PIs – including lopinavir, atazanavir and saquinavir – currently prescribed to HIV-positive pregnant women, are decreased during this period. Pharmacokinetcs (PK) for darunavir (DRV) and fosamprenavir (FPV) in pregnancy are not well characterised. Two posters presented at the paediatric workshop and IAS 2011 showed data from PK studies of these antiretrovirals in pregnant women. [1, 2]

Darunavir

Edmund Capparelli and colleagues from the IMPAACT P1026s study group presented PK and safety data of DRV dosed twice-daily (BID) and once-daily (QD) during the third trimester of pregnancy, at delivery and post partum. These data were shown at the paediatric workshop in Rome.

IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral PK in pregnancy. It comprises of two groups of women receiving ritonavir-boosted DRV either as 600/100mg BID, or 800/100 mg, QD, as part of an ART regimen during pregnancy and 6-12 weeks postpartum (PP).

All women had received at least two weeks of ART at the time of the evaluation. Intensive steady-state 12 or 24-hour PK profiles were performed during the 3rd trimester and PP. Cord blood and maternal samples were taken at delivery when possible. DRV concentrations were measured by HPLC (limit of detection 0.09 mcg/mL). The minimum exposure targets were DRV AUC0-12 or 24 of 43.6 or 56.5 mcg*hr/mL, for BID or QD, respectively. This represents >70% median for non-pregnant adults.
PK data were available for 31 women (19 BID, 12 QD). Two PP PK evaluations (1 BID and 1 QD) were excluded for non-adherence with no detectable DRV concentrations. Geometric mean 3rd trimester/PP ratios were 0.74 (90% CI 0.54-0.92) and 0.76 (90% CI 0.64-0.91) for AUC and 1.42 (90% CI 1.09-1.84) and 1.31 (90% CI1.10-1.55) for CL/Fs with BID and QD dosing respectively.

For the PK parameters presented below for 3rd trimester and PP the investigators indicated values with p<0.05 compared to PP with an asterisk (*). They found, AUC0-12 were median 50.7 (range 23.8-102)* mcg*hr/mL for 3rd trimester and 70.0 (range 40.3-175.5) mcg*hr/mL PP for women who received DRV/r 600/100mg BID. Of those with PK parameters available, 13/19 (68%) and 11/13 (85%) met the AUC-12 target. CL/F was 11.82 (range 7.58-26.4)* L/h and 8.57 (range 3.42-14.89) L/hr. C12h was 3.13 (range 0.78-8.85) mcg/mL and 2.81 (range 1.61-5.50) mcg/mL.

AUC0-24 were 67.7 (range 30.3-105.5) mcg*hr/mL and 87.9 (77.5- 150.2) mcg*hr/mL, for the women who received DRV/r 800/100mg QD. Of these 8/12 and 7/7 met the AUC0-24 target. CL/F was 11.82 (7.58-26.4) L/h and 9.10 (5.33-10.32) L/hr. C24h was 1.37 (0.15-3.49) mcg/mL and 2.59 (<0.09-3.96) mcg/mL.
A total of 20 paired samples of maternal delivery and cord blood were collected. Of these, 6 pairs had concentrations below the limit of detection. For the remainder (n=14) median cord blood DRV concentrations were 0.19 (<0.09-1.1) mcg/mL. Maternal delivery plasma DRV concentrations were 1.42 (<0.09-5.62) mcg/mL. The median ratio of cord blood/maternal delivery plasma concentrations was 0.24 (0.062-0.58) indicating limited transplacental transport of DRV.

The investigators concluded that lower troughs and AUC with QD compared to BID dosing combined with pregnancy lowering DRV exposure suggests BID dosing should be used in pregnancy and higher doses may be required.

Of note, not all women achieved viral suppression in both dosing groups (at delivery overall, 57% and 79% <50 and <400 copies/mL respectively), and there was at least one vertical transmission among 24 (77%) infants with data available at the time of this analysis.

Fosamprenavir

There are limited data describing safety and outcomes of FPV in pregnancy or plasma concentrations of FPV’s active metabolite, amprenavir (APV), during pregnancy, PP and in cord blood.

Michelle Cespides and colleagues from New York University School of Medicine showed findings from a phase I, open-label, single-centre study to evaluate APV PK following dosing of ritonavir boosted FPV 700/100mg BID in pregnant women. The investigators evaluated steady-state PK in the second and/or third trimesters and 4-12 weeks PP. Maternal plasma and cord blood samples were taken at the time of delivery. APV concentrations were measured by LC-MS/MS, and PK were determined using WinNonlin. This study was presented at IAS 2011.

The study evaluated 10 women receiving DRV/r based regimens. Cord blood samples were available from six deliveries. The median ratio of cord blood/maternal APV concentrations was 0.27, again, indicating limited transplacental transfer of this PI. Individual APV AUC was 22-34% lower, Cmax 9-41% lower and C12 27-28% lower in pregnancy than PP. See Table 1: Amprenanvir concentrations during pregnancy.

The investigators noted that although APV C12 was 27-28% lower in pregnancy, HIV was well suppressed for all subjects at delivery. Maternal and cord blood concentrations were above mean protein binding-adjusted IC50 (0.146 ug/mL) for wild-type virus.

Safety and outcomes data showed that FPV was well tolerated in this small study with no hepatic, renal, or adverse events attributed to ART.

At delivery, all women had viral loads < 400 copies/mL and nine women had <50 copies/mL. All infants were HIV PCR negative.

comment

The recommendation from the first study that higher doses of DRV may be required is consistant with US recomendations with other PIs such as lopinavir and atazanavir.

BHIVA guidelines do not recommended a dose increase.

References

1. Capparelli E et al. Pharmacokinetics of Darunavir Once or Twice Daily During and After Pregnancy. 3rd International Workshop on HIV Pediatrics. 15-16 July, 2011. Rome, Italy. Poster abstract P_72.
2. Cespedes M et al. Pharmacokinetics, cord blood concentrations, and tolerability of boosted fosamprenavir (FPV) in pregnancy. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TUPE278.

Polly Clayden, HIV i-Base

Data describing the risk of low birth weight (LBW) and preterm delivery (PTD) associated with maternal HIV and antiretroviral exposure are conflicting and international consensus has not been reached. Two posters from the Antiretroviral Pregnancy Registry (APR) and the Perinatal HIV Research Unit (PHRU), Soweto, South Africa, presented at IAS 2011, showed findings from their analyses of LBW and PTD in their respective cohorts. [1, 2]

APR is a prospective exposure-driven birth registry to monitor for potential increased birth defects following ART exposure in pregnancy.

In this study, Karen Beckerman and colleagues analysed reports to the APR cohort from 1989-2010. They restricted outcomes to singleton live births without birth defects. After establishing overall LBW(<2500 g)/PTD(< 37 weeks) prevalence by type of ART (2 or more drug regimens with and without PI), the data were stratified for maternal age, race/ethnicity and CD4 count. Stratified analysis is based on the 2×2 chi-square test and Cochrane-Mantle-Haenzel.

The investigators found, among the 10082 live births with birth weight data available, 16% were < 2500 g. Of those with reported estimated gestational age, 12.8% were <37 weeks. There were significantly higher LBW/PTD women receiving PI-containing regimens vs regimens without PI (LBW RR=1.22, p<0.001; PTD RR=1.27, p<0.001). But after controlling for maternal age, race/ethnicity and CD4 count they found no significant increase in incidence of LBW/PTD associated with PI exposure among groups with lower pre-existing risk. See Table 1: Low birth weight, preterm delivery and PI exposure in APR.

The investigators concluded that among prospective reports to APR, increases in LBW/PTD were not associated with PI exposure in women with low background risk for these complications.

In a related study, Fatima Laher and colleagues from PHRU investigated risk factors for PTD in their cohort. They noted that prevalence for PTD is 17.5 in Southern Africa.

This study was a retrospective review of all HIV-positive pregnant women who received triple-combination ART between August 2004 and September 2010. Obstetric history, ART history, maternal CD4 count and viral load during pregnancy were recorded for all live births. Univariate analysis included variables associated with preterm delivery.

The investigators found, out of a total 223 pregnancies, 58 were electively terminated (26%), 19 were spontaneous miscarriages (8%), 16 did not yet have recorded outcomes (7%), and 4 were stillbirths (2%). There were 126 (57%) live births, and 62/126 (49%) were PTDs with median gestational age 34.7 weeks (IQR 33.0-35.7). Mothers of preterm and term infants were similar in age, median 31.7 and 30.9 years respectively. Virological suppression <50 copies/mL during pregnancy was similar in both groups, 84% and 80% respectively.

The majority of women, 111/126 (88%) initiated ART was before conception. Maternal CD4 count during pregnancy below 200 cells/mm3 [OR 1.2; 95%CI 0.5-2.8, p= 0.76], 350 cells/mm3 [OR 1.4; 95%CI 0.7-2.8, p= 0.37], or 500 cells/mm3 [OR 1.1; 95%CI 0.4-2.8, p=0.87], were not risk factors for PTD.

Final-trimester maternal use of EFV-based regimens [OR 2.5; 95%CI 0.9-6.9, p=0.09], or PI-based regimens [OR 1.4; 95%CI 0.6-3.0, p=0.4], were not predictive of PTD compared to NVP-based regimens.

The investigators concluded that preterm delivery is common among pregnant ART-recipients in Soweto. Maternal CD4 count and final-trimester ART type seem not to predict preterm delivery. They noted that their small sample size in this study is a limitation.

comment

The APR data are unsurprising as 85% of the pregnancies enrolled are from the US and the association with PTD and PIs is largely not observed in American cohorts. The Soweto data may reflect a high background PTD rate and, as the investigators note, a small sample size.

Recently published data from Botswana does show an increased risk of PTD in women reciving PIs in pregnancy. [3]

References

1. Beckerman K et al. Exposure to combination antiretroviral (cARV) regimens containing protease inhibitors (PI) during pregnancy and prevalence of low birth weight/preterm delivery (LBW/PTD) among women with low pre-existing risk for LBW/PTD: a stratified analysis of 10,082 p. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TULBPE018.
2. Laher F et al. Maternal CD4 and HAART type are not risk factors for preterm delivery amongst HIV-infected pregnant women receiving HAART in Soweto, South Africa. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TUPE319.
3. Powis KM et al. Increased risk of preterm delivery Among HIV-infected women randomised to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. Journal of Infectious Diseases. Volume204, Issue4. Pp. 506-514.

Polly Clayden, HIV i-Base

Some epidemiological and laboratory studies have suggested that hormonal contraception can increase HIV transmission risk in women. There has been little research into the risk of transmission from women to men. To date findings have been inconsistent and WHO has called for high quality studies to look at potential interactions between hormonal contraception and HIV transmission.

Investigators from The Partners in Prevention HSV/HIV Transmission Study compared HIV incidence among women using hormonal contraception to those who were not. This analysis evaluated both HIV acquisition among women and transmission from women to men. Renee Heffron presented findings from this study in an oral presentation at IAS 2011. [1]

This was a prospective cohort study of 3790 serodiscordant couples from seven countries in East and southern Africa. The couples were enrolled from two studies conducted between 2004 and 2010, a randomised trial of acyclovir to reduce HIV transmission (n=3321) and a prospective cohort study of immune correlates of HIV protection (n=469).

Study participants were 18 years of age or older, and at enrollment the HIV-positive partners were not eligible for ART according to national guidelines. HIV-negative partners were tested quarterly and HIV-positive partners had CD4 measurements every six months and plasma and genital viral load at enrollment and six months later. The investigators used standardised questionnaires to measure sexual behaviour and contraceptive use.

They compared rates of HIV acquisition in women and HIV transmission from women to men using multivariate Cox proportional hazards regression and marginal structural modeling. The analyses were limited to infections acquired from the study partner (evaluated by viral genetic sequencing).

The negative partners were women in about a third (n=1314) of the couples evaluated, and two thirds (n=2476) were men.

Among the negative women, 21.2% overall used hormonal contraception at least once during follow up, of which 16% used injectable contraception at least once and 6.7% oral contraception. The HIV acquisition rates were 6.61 and 3.78 per 100 person-years in women currently using and not using hormonal contraception [AHR 1.98; 95%CI 1.06-3.68. p=0.03]. For injectable contraception the incidence rate was 6.85 per 100 person-years [AHR 2.05; 95%CI 1.06-3.68, p=0.04] and for oral contraception it was 5.94 per 100 person-years, [AHR 1.8 95%CI 0.55-5.82, p=0.33].

Overall, 33.3% of HIV-positive partners of negative men used hormonal contraception, 26.8% injectable and 8.9% oral. In these couples, HIV transmission rates from women to men were 2.61 and 1.51 per 100 person-years in those whose partners used and did not use hormonal contraception [AHR 1.91, 95%CI 1.12-3.45, p=0.02]. For injectable contraception the incidence rate was 2.64 per 100 patient years [AHR 1.95; 95%CI 1.06-3.58, p=0.03]. The incidence also increased in the group using oral contraception, 2.50 per 100 patient years, but as with HIV acquisition in negative women this did not reach statistical significance in this subgroup [AHR 2.09; 95%CI 0.75-5.84, p=0.16].

Results from marginal structural model analyses were consistent with those shown from the Cox proportional hazards regression.

When the investigators looked at this a possible explanation, there were significantly higher genital viral load concentrations overall in women using hormonal contraception [OR 1.51; 95%CI 1.13-2.01, p=0.01]. For injectable contraception these were significantly higher [OR 1.67; 95%CI 1.21-2.31, p=0.02]. But not for oral contraception [OR 1.06; 95%CI 0.62-1.84, p=0.49].

Dr Heffron noted that this was the first study to demonstrate that hormonal contraception increased an HIV-positive woman’s risk of transmitting HIV to her partner.

She added that the benefits of effective hormonal contraception are unequivocal and must be balanced with the increase in risk of HIV infection. These possible risks should be discussed with women and couples alongside the importance of HIV prevention.

Strategies to improve access to and usage of lower dose and non-hormonal methods – IUDs, implants, patches or combination injectables are warranted – she concluded.

comment

These findings understandably caused quite a stir and urgently need more investigation. This was followed by the report from Partners in Prevention that pregnancy doubles the risk of transmission from HIV-positive women to her male partner (to be reviewed in the next issue of HTB). [2]

References

1. Heffron R et al. Hormonal contraceptive use and risk of HIV-1 transmission: a prospective cohort analysis. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Oral abstract WEAX0206. Webcast.
2. Mulago NR et al. Increased risk of HIV-1 transmission in pregnancy: a prospective study among African HIV-1 serodiscordant couples. Advance online edition of AIDS 25, doi: 10.1097/QAD.0b013e32834a9338, 2011.

Polly Clayden, HIV i-Base

Information to guide initiation of treatment in children older than one year of age is scarce.

Results from the PREDICT trial – presented as late breakers at both IAS 2011 and the preceding pediatric workshop – found that deferring ART until CD4 count fell below 15% or the occurrence of CDC category C events did not affect AIDS-free survival in children compared to starting ART at a CD4 count between 15% and 24%. [1]

PREDICT was conducted in 299 children from nine sites in Thailand and Cambodia between April 2006 and September 2008. Children were randomised to receive immediate ART or defer until their CD4 reached less than 15%. The children’s baseline characteristics are shown in table 1.

The primary endpoints were AIDS free survival at week 144 and neurodevelopmental outcome by Beery visual motor interrogation test.

Age, CD4%, HIV RNA, weight-for-age z-score and height-for-age z-score are mean values.

Retention was high in this study (96%). At week 144, 69 (46%) children had started ART with a mean CD4 at initiation of 13.8% (SD+2.8%). Of these, 17 children were <5 years and had a mean CD4 count of 591 cells/mm3 (SD+508) and 52 children were >5 years and had a mean CD4 count of 309 cells/mm3 (SD+141).

AIDS-free survival was 97.9% (95% CI, 93.7 -99.3) in the immediate arm and 98.7% (95%CI 94.7-99.7) in the deferred arm. The incidence of CDC C events or death per 1000 person-years was 7.6 (95%CI 2.5-23.6) in the immediate arm and 4.9 (95%CI 1.2-19.7) in the deferred arm.

The incidence of CDC category B events per 1000 person-years was broadly similar in both arms, 88 (95%CI 61-123) in the immediate arm compared to 110 (95%CI 80-147) in the deferred arm. But there were more episodes of herpes zoster (2 vs 13) and thrombocytopenia (1 vs 10) in the immediate and deferred arms respectively. There were only two episodes of TB, one in each arm.

Weight for age z-score was similar, deferred vs immediate -0.12 (95%CI -0.25 to 0.01), p=0.074. But children grew at a slower rate in the deferred arm, height for age z-score, deferred vs immediate -0.23 (95%CI -0.38 to 0.08), p=0.003.

And at 144 weeks of follow up there was no significant difference by Beery visual motor test between the two arms; Beery score deferred vs immediate, 84.7 vs 86.8, p=0.5.

The investigators noted that at approximately three years of follow up, the rate of progression to AIDS is extremely low in both the immediate and deferred arms. The finding reflects a slow disease progression among HIV-infected children who survive the first year of life without treatment.

comment

This study is important and a bit of a surprise to many as it appears to contradict both adult data and that for young infants. But the median age in the study reflects a population that have survived without treatment for the first few years and therefore selects a group of healthier children without rapid disease progression.

References

Puthanakit T et al. Randomised clinical trial of immediate versus deferred antiretroviral therapy initiation in children older than one year with moderate immunodeficiency: the PREDICT Study (NCT00234091). 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract LB 01.

Also presented at the 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TULBPE023.

Polly Clayden, HIV i-Base

Data were presented at the paediatric workshop and IAS 2011describing recent developments in the paediatric pipeline.

Etravirine

Thomas Kakuda from Tibotec showed pharmacokinetic (PK) data of the NNRTI etravirine (ETV) in treatment experienced children and adolescents aged 6 to <18 years. [1, 2]

These 24-week results are from PIANO (Pediatric trial with Intelence as an Active NNRTI Option). PIANO is an ongoing Phase II, open label trial looking at the safety, efficacy and PK of ETV 5.2mg/kg bid (maximum dose 200mg bid).

In this study, 101 children (6 to <12 years, n=41) and adolescents (12 to <18 years, n=60) received ETV plus background regimen of a boosted protease inhibitor plus nucleoside/nucleotide inhibitors with optional enfuvirtide and/or raltegravir for 48 weeks. The trial participants received 25mg and 100mg tablets of ETV.

Sparse samples for population PK were taken at weeks 4, 8, 12, 24 and 48. At week 24 two samples were collected, a trough and one at least an hour after ETV dose. ETV plasma concentrations were measured using a validated high performance liquid chromatography-mass spectrometry/mass spectrometry assay.

The investigators developed a paediatric population PK model based on previous adult modelling and supplemented with rich and sparsely sampled PK data from TMC125-C126 [HTB ref] and PIANO respectively. They used the model to determine ETV AUC12h and C0h for all participants enrolled in PIANO up to 24 weeks.

There were 476 plasma concentration time samples available from 101 participants completing 24 weeks. There was an overall mean (SD) AUC12h and C0h of 5236 (+4314) ng*h/mL and 347 (+342) ng/mL respectively. In children in the younger age group these values were 5764 (+4044) ng*h/mL and 381 (+321) ng/mL. In adolescents they were 4834 (+4483) ng*h/mL and 323 (+357) ng/mL respectively. Adult reference values from the DUET trial were 5506 (+4710) ng*h/mL and 393 (+391) ng/mL for AUC12 and C0h respectively.

The investigators observed slightly lower exposures in the adolescents compared to the adults despite the majority (93%) of adolescents receiving the adult ETV dose of 200mg bid.

A dose of 5.2 mg/kg ETV is expected to be recommended for this population.

A related poster authored by Gareth Tudor Williams and colleagues described safety and efficacy from the same study. [3] The incidence of serious adverse events (AEs, grade 3 or 4) was low. A total of eight participants discontinued the trail due to AEs, this occurred more frequently in the older (n=6) than younger (n=2) age group. The most common AEs were upper respiratory tract infection (n=27) and rash (n=23).

Approximately half (n=51) of participants achieved a viral load <50 copies/mL. Response rates were higher in children than adolescents, with 24/41 (59%) achieving an undetectable viral load compared to 28/60 (47%). Response was similar in participants in both age groups considered adherent (measured by pill count and questionnaire) compared to non-adherent, respectively 48% (<95% adherent) compared to 53% (>95% adherent).

Of 28 participants with available genotype results at the time of virological failure, 54% developed NNRTI resistance mutations, mainly Y181C, E138A and V901.

Maraviroc

Carlo Giaquinto and colleagues presented preliminary PK data for the CCR5 antagonist maraviroc (MVC) in children and adolescents aged 2 to <18 years. [4, 5]

Data are from Study A4001031 – an ongoing open-label, non-comparative, multi-centre study in two stages (1: dose finding; 2: safety/efficacy) in treatment-experienced children, infected with CCR5-tropic HIV-1, receiving MVC 40-450 mg BID with optimised background therapy (OBT).

MVC PK were determined at Week 2. Participants (n=31) were stratified into four age cohorts. They were dosed twice daily. The initial dosing was calculated according to body surface area (BSA) with adjustments to take into account interactions between MVC and OBT (adult-recommended doses with/without CYP3A4 inhibitors/inducers).

Doses were adjusted and PK reevaluated if average concentrations (Cavg) at week 2 were <100 ng/mL. Cavg was estimated from AUC (AUC12h) calculated from seven samples taken over 12 hours.

The investigators reported, out of 22 participants receiving MVC with a potent CYP3A4 inhibitor (protease inhibitor based regimens). Only one failed to meet the PK target with the initial dose (this was due to poor adherence). But all five participants who did not receive a protease inhibitor (two nevirapine based regimens; two raltegravir based regimens; one NRTI based regimen) needed at least twice the initial MVC dose.

At the time of enrolment into stage 2, one participant did not meet the target after two dose adjustments but responded well clinically so was therefore included in the PK analysis. See Table 1: Preliminary PK results for maraviroc in children and adolescents aged 2 to <18 years.

The authors concluded that these preliminary data show that BSA-based dosing of MVC with CYP3A4 inhibitors provides MVC exposures associated with near- maximal efficacy (Cavg>100 ng/mL) in all age groups studied. But they noted that additional PK analyses are required to evaluate appropriate dosing when MVC is administered without CYP3A4 inhibitors in children.

A second poster from the same group showed safety and efficacy from the same study. [6]

At the time of analysis 35 children had been randomised (n=2, n=12, n=6 and n=15 in cohorts 1 to 4 respectively) and had received at least one dose of MVC. The median duration of treatment was 396, 493, 435 and 211 days in cohorts 1 to 4 respectively. The investigators observed 101 non-serious AEs in 21 patients; they considered 17 of these in 8 patients to be treatment related. Of those with elevated liver function test results, none were of grade 3 or higher. There were 8 serious adverse events of which none were judged to be treatment related and all resolved. There were no deaths.

Viral load <50 copies was achieved by 17/24 (71%) and 11/17 (65%) of participants at weeks 24 and 48 respectively. Five participants had virological failure; in four, this was due to poor adherence. The fifth had emergence of dual-mixed virus and developed 3TC resistance.

Enrollment in this study is continuing and long-term data will be collected and analysed.

References

1. Kakuda TN et al. Population pharmacokinetics of etravirine in HIV-1 infected treatment experienced children and adolescents (6 to <18 years). 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract PP_1.(PDF)
2. Kakuda TN et al. Population pharmacokinetics of etravirine in HIV-1 infected treatment experienced children and adolescents (6 to <18 years). 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TULBPE026.
3. Tudor-Willaims G et al. Safety and efficacy of etravirine in HIV-1-infected, treatment-experienced children and adolescents (6-17 years): week 24 primary analysis of the phase II PIANO study. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract TULBPE027.
4. Vourvahis M et al. Maraviroc (MVC) pharmacokinetics (PK) in CCR5-tropic HIV-1-infected children aged 2 to < 18 years: preliminary results from study A4001031. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract PP_4. (PDF)
5. Vourvahis M et al. Maraviroc (MVC) pharmacokinetics (PK) in CCR5-tropic HIV-1-infected children aged 2-< 18 years: preliminary results from study A4001031. 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract MOPE232.
6. Giaquinto et al. Safety and efficacy of Maraviroc (MVC) in CCR5-tropic HIV-1 infected children aged 2 to <18 years. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Poster abstract P_51. Also presented at the 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract MOPE237.

Polly Clayden, HIV i-Base

NEVEREST was a study in which young children who were exposed to nevirapine as PMTCT and initiated on PI-based HAART were randomised to continue on this regimen or switch to a nevirapine based regimen (we report the final results from NEVEREST later in this issue of HTB).

NEVEREST investigators evaluated body composition and metabolic abnormalities in 156 children exiting the trial. The objectives were to compare lipid profiles, markers of inflammation and regional fat distribution in children receiving a PI-based regimen of LPV/r plus 3TC plus d4T to those switched to an NVP-based regimen. [1]

The children’s weight (kg) and height (cm) was measured and weight-for-age, height-for-age and BMI-for-age z-scores (WAZ, HAZ, BAZ) calculated. Fasting total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG), C-reactive protein (CRP), viral load, absolute CD4 and CD4 percentage were obtained. Circumferences and skinfolds were also measured; waist to hip ratio (MWC:MHC) and skinfold sum (SFS) were calculated. Upper arm and thigh fat estimates (UFE, UTFE) were calculated by Rolland Cachera. Analyses were intent to treat.

At the time of analyses, children were a mean age of 5.1 (range 3.6 – 6.9) years and approximately half were boys; 85 (42 boys) were randomised to the PI arm and 71 (40 boys) to the NNRTI arm. There were no differences between the two groups in sex, age, total time on ART, time since randomisation, WAZ, HAZ or BAZ or proportion with viral load <50 copies/mL. But children in the NNRTI group had a higher CD4 count, 1480 cells/mm3 compared to 1356 cells/mm3, p=0.049.

The investigators found differences in metabolic measurements. Mean TC was greater in the PI group, 171 (SD+39) mg/dL vs 161 (SD+31) mg/dL, p=0.05 as was the proportion of children with hypercholesterolemia (TC >200 mg/dL), 18.8% vs 8.5%, p=0.03. They also observed lower mean HDL levels, 51 (SD+14) mg/dL vs 59 (SD+16) mg/dL, p=0.006 and higher mean LDL levels, 100 (SD 34) mg/dL vs 88 (SD+27) mg/dL, p=0.018, in the PI group. The mean TG level was also greater in the PI group, 94 (SD+39) mg/dL vs 72 (SD+29) mg/dL, p<0.001 as was the proportion with hypertriglceridemia (TG >150 mg/dL), 12.9% vs 2.8%, p=0.038.

The children in the PI group had significantly greater amount of total body fat compared to those receiving an NNRTI, with a mean SFS of 43 (SD+11.1) mm vs 39 (SD+10.1) mm, p=0.029 and % body fat by BIA (Horlick Equation) of 0.17 (SD+0.7) vs 0.14 (SD+0.08), p=0.042.

The percentage of fat in the upper arm did not differ between groups but the percentage of fat in the upper thigh was greater in the PI group, p=0.021. Also the PI group had a smaller ratio of trunk fat relative to thigh fat, p=0.03.

The investigators wrote: “These unfavourable alterations in lipids and lipoproteins are of great concern with respect to potential increase in long term CVD risk and should be considered in treatment strategies, such as the reuse of NNRTIs for NNRTI-exposed infants”.

References

Shiau S et al. Body composition and metabolic abnormalities of perinatally HIV-infected children in South Africa on long-term ARV treatment. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Oral abstract O_2. Also presented at the 6th IAS Conference on HIV pathogenesis, treatment and prevention. 17-20 July 2011. Rome, Italy. Poster abstract 252.

Polly Clayden, HIV i-Base

Prematurity is a known risk for infant mortality. Other risks include maternal immunosuppression, delayed initiation of ART and low baseline CD4 percentage.

Investigators from the Perinatal HIV Research Unit (PHRU) in Soweto, South Africa showed findings at the 2011 paediatric workshop from a cohort study designed to investigate prematurity among children born in 2009 and initiated on ART before one year of age. The study was a database and record review.

The background characteristics of the infants at time ART initiation are shown in Table 1.

The investigators reported no difference in mortality between preterm and term infants, respectively, 3% vs 4% (OR 1.9; 95%CI 0.5-6.7). Lost to follow up was 8% overall.

Univariate analysis revealed non-significant p-values for all variables ie preterm vs term, baseline CD4%, baseline viral load, breast vs formula feeding and maternal PMTCT. The investigators noted the small sample size and that the mortality rate was low in this study.

They concluded that although HIV-infected preterm infants have significantly lower CD4% than term infants, with early ART initiation they are not at increased risk of mortality.

Reference

Lazarus E et al. Prematurity is not a risk factor for early mortality in HIV-infected infants on antiretroviral therapy. 3rd International workshop on HIV paediatrics. 15-16 July 2011. Rome, Italy. Poster abstract P_18.

Simon Collins, HIV i-Base

Results from a new online resource developed to predict treatment outcomes for settings without access to genotypic resistance tests were presented in a poster at the conference. [1]

The system was developed by training computer models to predict virological response to therapy using data from approximately 15,000 treatment changes drawn from over 15 countries. The models use CD4, viral load, treatment history and the drugs in the new regimen in making their predictions and can generate predictions of response at selected time points out to 48 weeks for all available combinations or for a selected combination. The system includes the option to select drugs that are available in each country and to exclude drugs that are contraindicated.

The accuracy of the models was assessed with an independent test set of 800 cases. Two further test sets from Romania (n=39) and South Africa (n=56) were also reported together with subset of 57 cases from the 800 test set that had genotypes available.

The mean area under the curve and overall accuracy were 0.77 and 71% with the 800 test dataset (with similar results during cross validation). The comparable results were 0.68 and 67% for the Romanian and 0.69 and 68% for the South African test sets respectively. When the 57 case test set was used to compare the performance of the models with and without genotype information the results were 0.77 and 74% using the genotype, compared to 0.76 and 68% for the ‘no-genotype’ models.

The models are now available via the RDI’s online treatment selection tool HIV-TRePS. Importantly, the resource includes the option to include, with permission, anonymised information on treatment decisions and outcomes to be collected to help further development of the system. [2]

The resource has been developed by researchers at RDI who were involved in much of the original pioneering work into HIV drug resistance technology and more recently have been developing prediction tools to interpret genotype results using computer-developed neural networks.

Future reports on how this resource is used in practice will be important given the extremely restricted access to resistance testing in most resource-limited countries and that this is unlikely to change in the near future.

References

1. Larder BA et al. Predicting response to antiretroviral therapy without a genotype: a treatment tool for resource-limited settings. 16th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 17–20 July 2011, Rome. Poster MOPE146.
2. The resource can be accessed free online after one-time free registration.

http://www.hivrdi.org

Our final reports from this important conference are:

• Monitoring treatment in resource limited settings: results from PHPT-3 and Stratall ANRS12110/ESTER trials
• DART: high rates of viral suppression after five years and a single CD4 test with a threshold of 250 cells/mm3 could reduce unnecessary switching
• Lopinavir/r monotherapy used as second-line therapy in resource-limited settings
• Pharmacokinetics of different rifabutin dosing strategies with lopinavir/ritonavir-based ART
• Initiation of ART during breastfeeding can induce multidrug resistance in infants
• Treating children previously exposed to single dose nevirapine: update on IMPAACT P1060 and NEVEREST
• Lopinavir/ritonavir oral solution toxicity in neonates
• Paediatric antiretroviral pipeline: darunavir and raltegravir

Unless mentioned otherwise, all references are to the Programme and Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections, 28 February–2 March 2011, Boston.

http://www.retroconference.org/AbstractSearch/

Webcasts are available at the following link:

http://www.retroconference.org/2011/data/files/webcast_2011.htm

In resource-limited settings, optimal monitoring and switching criteria from first-line to second-line therapy is unclear. Results from two trials were shown as oral presentations that suggest that monitoring viral load is not essential for switch to second line. [1, 2]

Marc Lallemant showed data from PHPT-3, which was conducted in Thailand. This was a randomised double-blind (until first switch) non-inferiority trial. Participants were randomised to CD4 or viral load monitoring, which was conducted every three months.

Dr Lallemant explained that the trial was designed for a setting with only two lines of treatment and where second line is far more expensive than first line. The investigators wanted to test whether monitoring and switching people without viral load compromised their health or their future options.

PHPT-3 enrolled HIV-positive adults (CD4 count 50 to 250 cells/mm3, not hepatitis B or C co-infected), starting NNRTI-based HAART.

In the CD4 monitoring arm, patients switched to second-line protease inhibitor (PI) -based therapy when they had confirmed CD4 decline of 30% or more from peak, and in viral load monitoring they switched when they had confirmed viral load >400 copies/mL.

The primary endpoint was death, new AIDS-defining event or clinical failure – defined as CD4 <50 cells/mm3 – at 3 years. Secondary endpoints included proportions switching to second line, time to switch, resistance mutations at failure and future treatment options.

The trial enrolled 716 patients of which 60% were women. Their median CD4 count at baseline was 144 cells/mm3 (range 90 to 200 cells/mm3).

Regimens were 65% efavirenz-based regimen and 66% of participants received tenofovir/FTC. Other study drugs were nevirapine and AZT/3TC. At 3 years of follow up 93.3% of patients were evaluable. Ten percent stopped treatment for toxicity across both groups.

There were 58 clinical failures overall, 28 and 30 in the CD4 and viral load groups respectively. The respective rates of clinical failure per patient years were 2.3 vs 2.5 and of death 1.1 vs 1.4.

In multivariate analysis, anaemia, adjusted HR 2.7 (95% CI 1.5-4.8), p=0.001; CD4 <150 cells/mm3, AHR 2.3 (95% CI 1.2-4.2), p=0.009 and viral load >5 log, AHR 1.8 (95% CI 1.0-3.0), p=0.04, were predictive of clinical failure at 3 years.

The probability of switch to second-line (excluding toxicity/intolerance) was 5.2% (95% CI 3.2-8.4%) vs  7.5% (95% CI 5.0 -11.1%) in the CD4 and viral load groups respectively, p= 0.10.

The respective median times to switch were 11.7 months (95% CI 7.7-19.4) vs 24.7 (15.9-35.0), p=0.001. And the median duration of viraemia >400 copies/mL was 7.2 months (IQR 5.8 to 8.0) vs 15.8 months (8.5 to 20.4), p= 0.002. But the median CD4 counts were 426 cells/mm3 vs 420 cells/mm3, respectively.

Dr Lallemant noted that 15/31 patients in the CD4 monitoring arm who switched to second-line had viral load <50 copies/mL at the time of switching.

Viral load was <50 copies/mL in 99% of patients at 3 years follow-up and patients with CD4 monitoring did not have fewer future treatment options, with the exception of one patient with multiple thymidine analogue mutations (D67N/M41L/L210W/T215Y).

Dr Lallemant concluded that, after 3 years, the rate of clinical failure was very low and did not differ between the two strategies. Most mutations had been selected at the time of virological failure. The additional time spent on failing treatment in the CD4 arm did not result in reduced future treatment options.

He noted that the conclusions from PHPT-3 are similar to those from DART and HBAC in adults and PENPACT-1 in children. He added that the need for viral load monitoring may be less important than close and regular safety, tolerability, adherence, and immunological monitoring. He remarked that the nurse/patient team with expert assistance from doctors, biologists and patient networks “maximizes efficacy and durability.”

This was followed by a related presentation of data from the Stratall ANRS12110/ESTER trial.

Charles Kouanfack showed findings from a trial designed to compare clinical monitoring alone with laboratory and clinical monitoring. This trial was conducted in 9 rural district hospitals in Yaounde, Cameroon.

Dr Kouanfack explained, in Cameroon, the national programme followed WHO guidance for a public health approach based on decentralised, integrated HIV care delivery in facilities where laboratory monitoring is generally unavailable. He noted that the 2010 guidelines also state that using viral load monitoring to detect treatment failure and switch is recommended but has “low quality evidence”.

Stratall ANRS12110/ESTER was a randomised non-inferiority trial enrolling HAART-naïve, HIV-positive adults with a WHO stage 3-4 disease or stage 2 and total lymphocyte count <1200 cells/mm3, who were followed for 2 years. Management was by the health workers in charge of routine activities.

The primary endpoint was mean increase in CD4. The increase in the clinical monitoring arm was judged to be non-inferior to that in the laboratory monitoring arm if the difference was less than or equal to 25%.

Secondary endpoints included: viral suppression, death, new stage 3 or 4 events, resistance, loss to follow up, adherence, treatment changes and toxicity.

Participants were monitored clinically 3 monthly in both arms and those in the laboratory monitoring arm also had CD4 and viral load measured every 6 months.

Switching to second line was indicated by grade 3 or 4 events in the clinical monitoring arm and persistent viral load >5000 copies/mL in the laboratory monitoring arm.

Of a total of 493 patients, 256 were assigned to clinical and 237 to laboratory monitoring. Of these, 93% were followed and included in the analysis. Patients were similar at baseline with CD4 counts of 179 cells/mm3 and 182 cells/mm3 in the clinical and laboratory monitored arms respectively. Both arms had high baseline viral loads of 5.6 log₁₀ copies/mL. Overall 70% were women. About 65% started treatment with d4T + 3TC + NVP.

The trial failed to demonstrate non-inferiority of clinical monitoring:  the mean increase in the CD4 count was 175 cells/mm3 (95%CI 151-200) vs 206 cells/mm3 (95% CI 181-231) in the clinical and laboratory arms respectively. This gave a difference –31 (–63 to +2), the non-inferiority margin was –52 (–58 to –45). The analysis was last observation carried forward.

The analysis also revealed that 13 (6%) laboratory-monitored participants switched to second-line regimens because of treatment failure, compared to none of the clinically monitored participants, p<0.001. But, viral suppression (49 vs 52%), resistance (both 10%), mortality (18 vs 14%), disease progression (36 vs 29%), adherence (both 64%), loss to follow-up (9 vs 8%), and toxicity (19 vs 25%) were similar between the two groups.

Dr Kouanfack concluded that failure to demonstrate non-inferiority of immunological recovery and the need to switch to second line in this trial supports the WHO recommendation of laboratory monitoring of HAART where possible.

He also concluded that the difference between the two strategies suggest that clinical monitoring alone can be used for at least the first two years of treatment in order to expand scale up and to take into account financial and infrastructural constraints in resource limited settings.

References

1. Jourdain G et al. PHPT-3: A randomised clinical trial comparing CD4 vs viral load ART monitoring/switching strategies in Thailand. 18th CROI, 27 February–3 March 2011, Boston. Oral abstract 44.
2. Kouanfack C et al. HIV viral load, CD4 cell count, and clinical monitoring vs clinical monitoring alone for ART in rural hospitals in Cameroon: Stratall ANRS 12110/ESTHER trial, a randomised non-inferiority trial. 18th CROI, 27 February–3 March 2011, Boston. Oral abstract 45LB.

Both webcasts: Research on Delivery of Care in Developing Countries. Monday 28 February 11 am.

DART was a randomised trial comparing clinically driven monitoring (CDM) to laboratory (CD4, haematology, biochemistry) plus clinical monitoring (LCM) of 3316 HAART-naïve adults conducted in Uganda and Zimbabwe. People in both monitoring arms showed high and similar 5-year survival rate – 90% vs 87% in the LCM and CDM arms respectively – differing by a small percentage that only occurred after two years of follow up. This compared to an historical 5-year survival rate prior to HAART of only 8% in the Uganda cohort. [1]

First line HAART in this trial was AZT/3TC plus either TDF (74%), ABC (9%) or NVP (16%). Participants needing to switch to second line received LPV/r plus NRTI/s and/or NNRTI. Neither the CDM nor LCM group had real time viral load monitoring.

Ugandan patients who did not participate in one of two, nested second line RCTs had a viral load test when they left the trial and joined the national programme.

Further findings from the DART trial were presented at CROI 2011.

Cissy Kityo and colleagues showed high rates of virological suppression at 5 years after HAART initiation among the Ugandan participants alive and in follow up. [2]

Both monitoring groups switched to second line therapy following WHO stage 4 or multiple stage 3 events; the LCM group also switched at CD4 <100 cells/mm3.

A viral load measurement was available the end of the trial for the majority of eligible participants: 1207 (80%) and 187 (70%) respectively receiving first and second line at exit. The viral load sample was taken at a median of 5.2 years after initiation of HAART and 2.7 years after start of second line for those who had switched.

Of the participants who remained on first line, 81.9% (95%CI 78.5-84.9%) in LCM and 74.2% (95%CI 70.6-77.6%) in CDM had viral load <200 copies mL, p=0.001. In the LCM group 5.6% (95% CI, 3.9-7.8% had viral loads <10,000 copies, which was lower than the 10.4% (95%CI 8.1-13.1%) of participants in CDM.

Of those who switched, viral loads were similar across the two monitoring groups, p=0.6. Viral load <200 copies/mL was achieved in 88.8% (95%CI 83.3-92.9%) of participants receiving second line.

When the investigators examined the CD4 count nearest to the exit viral load measurement (taken at a maximum of 6 months apart), they found a negative association, r=0.4, as would be expected.

Of 283 (20%) participants with viral load >200 copies/mL, 29% in the LCM group and 42.2% in CDM had CD4 <200 cells/mm3.

The investigators noted that CD4 counts <100 cells/mm3 were rare in either arm; only 2 people in LCM and 7 in CDM.

A related study showed a single CD4 test with a threshold of >250 cells/mm3 could reduce inappropriate switching in clinically monitored patients. [3]

Charles Gilks and colleagues investigated the relationship between CD4 count at switch and the reason for doing so in all 675 (361 LCM and 314 CDM) DART participants switching to second line.

In the CDM arm, 206 (66%) switched due to WHO stage 4 events and 76 (24%)/32 (10%) participants single or multiple WHO stage 3 events, respectively. In LCM 265 (73%) participants switched because their CD4 count fell below 100 cells/mm3, 43 (12%) for other CD4 reasons, 37 (10%) due to WHO 4 events and 6 (23%)/10 (3%) single or multiple WHO stage 3 events.

In the LCM arm, clinical failure provoked switching in 7 (2%) of patients with CD4 >250 cells/mm3; 3 due to WHO stage 4 events, 1 single WHO stage 3 event and 3 for other CD4 reasons. This compared to 64 (20%) of participants who switched with CD4 > in the CDM arm, p=0.001. The investigators noted, however, that deaths within one year of switching were similar in CDM whether participants switched above or below 250 cells/mm3, 11/64 (17%) vs 33/250 (13%) respectively.

In the CDM group, switching due to a single WHO grade 3 event was significantly more frequent with a CD4 count of >250 cells/mm3 (27/76, 36%) compared to multiple WHO stage 3 events (4/32, 12%) or WHO stage 4 events (33/206, 16%), p=0.001.

Viral load measurements at switch were available for 108 and 113 participants in the LCM and CDM groups respectively.  Of these, 15 (14%) vs 32 (28%) respectively were <400 copies/mL, p=0.009.

In the CDM group, 25/31 (81%) with clinical failure and CD4 > 250 cells/mm3 had viral load <400 copies/mL vs 7/82 (9%) with CD4 <250 cells/mm3, p<0.001.

The investigators noted a trend to switching for single WHO stage 3 events compared to multiple WHO stage 3 or stage 4, but this was not significant, p=0.22.

They concluded that among clinically monitored patients, a single CD4 test with a threshold of 250 cells/mm3 could identify up to 80% with viral load <400 copies/mL who are unlikely to benefit from second line therapy. In DART, nearly 40% of participants who failed clinically with a single WHO stage 3 event had CD4 >250 cells/mm3. They wrote: “Targeting this group would be particularly likely to avoid premature, costly switching to second line.”

References

1. DART trial team. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial. The Lancet, Volume 375, Issue 9709. 9 January 2010.
2. Kityo C et al. High rates of virologic suppression among patients not receiving routine virologic monitoring after 5 years of first-line ART. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 677.
3. Gilks C et al. A single CD4 Test with threshold >250 cells/mm3 can markedly reduce switching to second-line ART in African patients managed without CD4 or viral monitoring. 18th CROI, 27 February–2 March 2011, Boston.  Poster abstract 676.

WHO guidelines recommend the use of boosted protease inhibitors second line in resource limited settings. Findings from strategies looking at using lopinavir/ritonavir (LPV/r) have been uncertain to date, both in limited and richer resourced settings.

Two posters at CROI 2011 presented data from studies evaluating LPV/r monotherapy, with showed further conflicting results.

ACTG 5230 evaluated lopinavir/ritonavir (LPV/r) monotherapy in a pilot study. It was a single arm multinational trial with sites in Malawi, Tanzania, South Africa, Thailand and India.

Participants had previously received first line NNRTI-containing regimens for at least six months and had detectable viral load 1,000–200,000 copies/mL. All participants received LPV/r monotherapy BID. The primary endpoint was remaining on monotherapy without virological failure at 24 weeks. This was defined as: failure to suppress viral load to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression.

People with virologic failure received intensification with emtricitabine (FTC) 200 mg/tenofovir (TDF) 300 mg.

There were 123 participants enrolled in this trial. About 60% were women and they were a median of 39 years of age, with a median CD4 of 164 cells/mm3 and viral load of 4.34 log₁₀ copies/mL (17% were >100,000 copies/mL).

Other baseline characteristics included: 93% with >1 year HAART, 98% with >1 NNRTI mutation and 95% with >1 NRTI mutation (87% M184V, 84% TAM, 11% K65R, 4% Q151M/L).

The majority, of participants completed 24 weeks of follow-up with the exception of one death at week 20 with a viral load of <400 copies/mL.

The investigators reported, at week 24, 107 (87%; 95% CI 80-92%) of participants remained on LPV/r monotherapy without virologic failure.

Of the remaining, 15 met the criteria for virologic failure and one added FTC/TDF before failure. Of 13 participants with data after intensification, 11 (85%) suppressed viral load to <400 copies/mL.

At virologic failure, 2/11 participants who were successfully sequenced had selected new resistance mutations (both had A71T and V82F). The overall mean CD4 count increase from baseline to week 24 was 107 cells/mm3. Overall 31 (25%) of participants experienced grade 3 or 4 toxicities. The most commonly reported grade 3 or 4 toxicities (9% of participants) were metabolic (mostly elevated lipids). Self reported adherence was high; at week 24, 83% of participants reported no missed doses.

The investigators concluded that LPV/r monotherapy showed promising preliminary activity as second-line HAART following failure of first-line NNRTI-containing regimens at 24 weeks. The lower bound of the 90% CI (81-92%) of the observed success rate (87%) was above 65%.

Torsak Bunupuradah and colleagues from the HIV STAR Study in Thailand looked at LPV/r monotherapy as second line but they also evaluated viral suppression to <50 copies/mL and included a comparison arm with triple therapy.

The STAR investigators enrolled 200 participants with viral load >1000 copies/mL on NNRTI-containing first line therapy. Participants were randomised to receive either LPV/r monotherapy ot LPV/r + TDF + 3TC.

Treatment failure was defined as viral load >400 copies/mL at >24 weeks. Participants meeting these criteria in the monotherapy arm received intensification with TDF + 3TC.

Participants in this study were about 60% men with a median age of 37 years, CD4 of 188 cells/mm3, and viral load of  4.1 log10 copies/mL.

Prior to switching, 92% of participants were receiving 3TC, 63% d4T, 23% AZT and 5% TDF. Nevirapine and efavirenz were received by 86% and 14% participants, respectively. Without significant differences between arms, 15% of participants had ≥3 TAMS, 82% had M184V/I, 6% had Q151M, and 7% had K65R.

By intent-to-treat analyses at 48 weeks, the proportion of patients with viral load <400 copies/mL the LPV/r monotherapy arm was 75% vs 86% in the TDF/3TC/LPV/r arm, p=0.53. But, only 61% of the LPV/r monotherapy arm vs 83% in TDF/3TC/LPV/r arm had a viral load <50 copies/mL, p<0.01.

Major PI mutations were detected in 1 of 2 LPV/r monotherapy and 0 of 3 TDF/3TC/LPV/r treated participants with genotype results following treatment failure. There was no significant difference in CD4 count increase between arms: 114 vs 137 cells/mm3 in the LPV/r monotherapy and TDF/3TC/LPV/r arms respectively. One death (unrelated to study drugs) was reported in each arm. Serious adverse events were reported in two patients in the LPV/r monotherapy arm and seven patients in the TDF/3TC/LPV/r arm.

The investigators concluded that LPV/r monotherapy should be used with caution as a second-line option, particularly in settings where close viral load monitoring is not available.

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The ongoing EARNEST Trial (NCT00988039) will answer the question whether or not lopinavir/r monotherapy is a sufficiently potent regimen compared to lopinavir/r combined with two NRTIs or raltegravir.

Results from this trial are expected in 2013.

References

1. Bartlett J et al. A pilot study of LPV/r monotherapy following virologic failure of first-line NNRTI-containing regimens in resource-limited settings: The Week-24 primary analysis of ACTG 5230. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 583.
2. Bunupuradah T et al. Second-line LPV/r monotherapy was inferior to TDF/3TC/LPV/r in patients who failed NNRTI regimen: HIV STAR Study. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 584.

Interactions between rifampicin and protease inhibitors makes treating patients coinfected with HIV and TB more complicated.

Rifabutin is an alternative rifamycin, which can be used in patients receiving a protease inhibitor. Recent findings suggest that the current recommended dose of lopinavir/r (LPV/r) is suboptimal. There are limited data regarding the newer formulation of LPV/r.

Investigators from University of Cape Town, International Union Against Tuberculosis and Lung Disease and WHO evaluated the pharmacokinetics (PK) of rifabutin in co -infected patients on a first line TB regimen before and after the initiation of LPV/r-based ART.

Suhashni Naiker and colleagues showed findings from this study in a poster at CROI 2011.

A group of 16 patients on stable rifabutin-containing TB regimens were initiated on LPV/r-containing HAART. At HAART initiation they were randomised to receive either: rifabutin 150 mg daily for 1 month followed by 150 mg 3 times weekly, or 3 times weekly doses followed by daily doses.

The investigators measured serial rifabutin and 25-O-desacetyl rifabutin concentrations during a dose interval after 4 weeks of rifabutin 300 mg daily, after 4 weeks of 150 mg rifabutin daily with LPV/r-based HAART, and after 4 weeks of rifabutin 150 mg 3 times a week with LPV/r-based ART.

At baseline the participants were a mean (SD) of 31.6 (5.5) years, 59.0 (9.4) kg, 160.1 (7.1) cm and 147 (43) CD4 cells/mm3. Ten were men. Two were not included in the analysis due to poor adherence.

The investigators reported median AUC0-24 and Cmax, for participants receiving 300 mg rifabutin daily, 150 mg rifabutin three times a week, and 150 mg rifabutin daily, respectively, of 3026 ng/mL.h and 297ng/mL, 2307 ng/mL.h and 168 ng/mL, and 5010 ng/mL.h and 311ng/mL.

They found that rifabutin was well tolerated at all dosing strategies. There was one case of uveitis that occurred before  LPV/r was initiated, and one grade 2 transaminitis and one grade 2 neutropenia were also reported.

They concluded that rifabutin 150 mg daily used with LPV/r produces Cmax concentrations within the recommended target range of 300 to 900 ng/mL.

Reference

Naiker S et al. Pharmacokinetic evaluation of different rifabutin dosing strategies in African TB patients on lopinavir/ritonavir-based ART. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 650.

In resource-limited settings some HIV-positive women initiate ART during breastfeeding. This exposes infected infants to the risk emergence of resistance to the antiretrovirals in their mothers’ regimen.

Investigators from the Post Exposure Prophylaxis of Infants (PEPI)-Malawi trial – in which infants were received up to 14 weeks of extended nevirapine (NVP) or extended NVP plus AZT – evaluated resistance in infants whose mothers began ART post-partum.

Interim data from this analysis was first presented as a poster at CROI. [1] Further findings were reported in a subsequent article in the April 24 2011 edition of AIDS. [2]

Infant plasma samples were collected at 14 weeks of age and tested using the ViroSeq HIV Genotyping System and LigAmp – a sensitive point mutation assay – to detect K103N (limit of detection 0.5%) and Y181C (limit of detection 1%). Later samples collected at 6 and 12 months of age were also analysed using LigAmp.

The investigators found that at 14 weeks 82/108 (75.9%) of infants evaluated had detectable NVP resistance using the Viroseq assay. The proportion of infants with K103N and/or Y181C detected by LigAmp was similar, 78/108 (72.2%), p=0.45. There were no significant differences between rates of resistance among infants receiving extended NVP or NVP plus AZT measured by either assay. Nor were: duration of prophylaxis received prior to infant diagnosis, maternal CD4 count, maternal single dose NVP use, or in utero infection, significantly associated with NVP resistance.

At 6 months, 38 out of 46 (82.6%) samples analysed still had K103N and/or Y181C. Again, results were similar across study arms, p=1.0. And at 12 months 19 out of 29 (66.5%) evaluable infants had these mutations in similar proportions across arms, p=0.43.

Although the data was not presented, the investigators noted that there was no significant difference in the percentage of the total viral population of either K103N or Y181C in infants in the two groups with these mutations at 6 and 12 months of age.

The investigators concluded that the frequent persistence of the K103N and Y181C mutations in infants after exposure to extended NVP prophylaxis, with or without AZT, may compromise the infants’ subsequent response to NNRTI-based treatment.

References

1. Fogel J et al. Initiation of ART in women after delivery can induce multi-class drug resistance in breastfeeding HIV-infected infants: PEPI-Malawi Trial. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 761.
2. Fogel J et al. Analysis of nevirapine (NVP) resistance in HIV-infected infants who receive extended NVP or NVP/zidovudine prophylaxis. AIDS 2011 25 911-917.24 April 2011.

Two oral presentations at CROI 2011 showed further findings from studies looking at treatment in children previously exposed or unexposed to maternal/infant single dose nevirapine (NVP) in prevention of mother to child transmission (PMTCT) programmes.

IMPAACT 1060

IMPAACT P1060 was a randomised trial to determine whether NVP- or lopinavir/ritonavir (LPV/r)-based treatment performed better in young children exposed and unexposed to single dose NVP. All children received AZT plus 3TC. The trial comprised of Cohort 1 (exposed children) and Cohort 2 (unexposed children). Data from Cohort 1 have previously been reported and this part of the study was stopped early after a scheduled Data Safety Monitoring Board (DSMB) review, as there was an unsurprising trend towards more failure in the children receiving NVP- compared to LPV/r-based treatment.

Peter Palumbo presented results from Cohort 2. This cohort enrolled children aged 2 to 36 months, who met WHO criteria for treatment and were unexposed to single dose NVP. Children were stratified by age < or ≥ 12 months. Children with TB were excluded from the trial.

The study had a composite primary endpoint of treatment failure, which comprised viral failure (<1 log10 decline from baseline to after 12 to 24 weeks or >400 copies/mL at week 24), or permanent discontinuation of NVP or LPV/r, including death by 24 weeks. Rates were calculated from Kaplan-Meier curves for each treatment group and age group.

Secondary endpoints included time to virological failure by 24 weeks, time to treatment failure throughout follow up and time to virological failure or death throughout follow up.

P1060 Cohort 2 was fully enrolled with 288 children by March 2010 and had 48-week planned follow-up to March 2011.  In October 2010, the DSMB recommended that the study was unblinded. All children had completed 24 weeks of follow up.

Dr Palumbo reported that the children’s median age at enrollment was 1.7 years (73% >12 months) and their median baseline viral load and CD4 percentage were 535,632 copies/mL and 15% respectively. The majority (79%) of children were subtype C.  The median follow-up was 72 weeks.

At week 24, 87 children had reached an endpoint; 60 in the NVP and 27 in the LPV/r arms. The overall difference in failure rate was 21.5% (95% CI, 11.2-31.8) in favour of LPV/r, p<0.001. This was similar in both age groups: 22.0% (<12 months) and 21.3% (>12 months).

There was also a significant difference in time to off study drug, over the full length of the trial, p<0.001. There were 10 vs 3 deaths in the NVP vs LPV/r arms during the entire follow-up

period (none judged related to study drugs), but this did not reach statistical significance, p=0.63.

There was a notable amendment during the course of the trial. In 2007 the recommended NVP dose in WHO guidelines increased from the FDA recommended dose of 7mg/kg to 160-200mg/m2 (max 200mg). Only 32 children were enrolled under the lower dose compared to 115 at the higher one but the investigators saw no effect associated with this change.

Dr Palumbo noted that the main reasons for off study were more virological failure, toxicity and death in the NVP arm.

As both the NEVEREST and P1060 Cohort 1 data had suggested poorer weight and CD4 improvement in children receiving LPV/r compared to NVP, the investigators also looked at this in Cohort 2. They did not find a statistically significant difference in CD4 improvement between the two arms but there was a difference in weight z-score favouring NVP at 24 and 48 weeks, respectively p=0.007 and p=0.009.

When the investigators looked at NVP resistance in samples from subsets of children at baseline and time of virological failure, they found 2.4% (5/206) with resistance at baseline compared to 56% (10/18) at time of virological failure.

These results were different to those in the sister study, OCTANE P1060, in which maternal data demonstrated non-inferiority of NVP- to LPV/r-based treatment, by the study definition, for NVP- unexposed women.

This highlighted the “unique and challenging situation of early paediatric HIV infection”, Dr Palumbo said, including very high baseline viral load and the unforgiving nature of NVP resistance. LPV/r is already recommended for NVP-exposed children and discussions are ongoing as to whether this recommendation should expand to all young children, possibly up to three years of age.

These data once again point to the importance of developing new first and second line options for use in this age group.

NEVEREST

Louise Kuhn presented data from NEVEREST, a study designed to evaluate a treatment switch strategy from LPV/r to NVP in NVP-exposed children.

In this study, 323 children aged 6 weeks to 2 years and eligible for treatment were initiated on LPV/r plus 3TC plus d4T. After achieving a viral load <400 copies/mL and maintaining it for > 3 months, children were randomised (n=195) to either remain on LPV/r (n=99) or switch to NVP (n=96). Time to any viral load >50 copies/mL or confirmed >1000 copies/mL was compared using Kaplan-Meier methods and log-rank tests.

Fifty-two week data post switch from this study has been reported previously. These data revealed a higher proportion of children suppressed to <50 copies/mL (the primary endpoint) in the NVP arm but also a higher proportion in that group with confirmed >1000 copies/mL.

Dr Kuhn showed longer term results from this study with follow up of 18-53 months.

There were three deaths in each group. At 36 months post randomisation, as with the earlier analysis, more children in the NVP group (40.5%) maintained viral load <50 copies/mL than those in the LPV/r group, p=0.01. Again, more in the NVP (23.9%) than in the LPV/r (11.1%) had confirmed >1000 copies/mL, p=0.01.

This difference persisted at 48 months, for <50 copies/mL and >1000 copies/mL, respectively p=0.02 and p=0.08.

At 6 months 59.1% of the failures in the NVP group had occurred vs 10% in the LPV/r group. By 12 months these proportions were 100% in the NVP group and 50% in the LPV/r group. Dr Kuhn noted that among children in the LPV/r group, 6% of failures occurred between 12 and 48 months.

Treatment failure >1000 copies/mL was associated with the presence of pre-treatment NVP mutations, p=0.02. There was no difference in response between children in the NVP and LPV/r groups in children who had no pre-treatment NVP resistance. Half the children with detectable NVP mutations failed when re-challenged with NVP.

Dr Kuhn concluded that viral load testing can identify all switch failures and that switching can be accomplished safely if viral load testing is available. Also that pre-treatment screening for resistance can be used to identify the children who could benefit from this strategy.

References

1. Palumbo P et al. NVP- vs LPV/r-based ART among HIV⁺ infants in resource-limited settings: the IMPAACT P1060 Trial. 18th CROI, 27 February–2 March 2011, Boston. Oral abstract 129LB.
2. Kuhn L et al. Long-term outcomes of switching children to NVP-based therapy after initial suppression with a PI based regimen. 18th CROI, 27 February–2 March 2011, Boston. Oral abstract 128.

Lopinavir/ritonavir (LPV/r, Kaletra) oral solution is approved by the FDA for infants 14 days of age and older. US guidelines do not recommend its use in preterm infants.

LPV/r oral solution has particular pharmacokinetic properties that make its use complicated in neonates. It contains high volumes of both ethanol (356.3 mg/mL, 42% volume solute/volume solution (v/v) and propylene glycol (152.7 mg/mL, 15.3% v/v).

Neonates have reduced alcohol dehydrogenase and CYP3A4 activity and immature renal function. Ethanol is 95% and propylene glycol is 55-75% metabolised in the liver by alcohol dehydrogenase. Ethanol inhibits the metabolism of propylene glycol by alcohol dehydrogenase leading to elevated concentrations. LPV is metabolised by CYP3A.

Reduced hepatic metabolism and renal clearance in neonates, particularly in preterm infants, can lead to accumulation of all three ingredients to toxic levels.

Acute ethanol toxicity is linked to central nervous system (CNS) and respiratory depression, and gastritis. Propylene glycol is also associated with CNS and respiratory depression, as well as renal failure and metabolic acidosis. LPV has been shown to cause PR and QT interval prolongation and AV block in adults with very high levels of the drug.

Cases of toxicity in neonates – particularly preterm – have been reported to the FDA Adverse Event Reporting System (AERS).

A poster authored by Debra Boxwell and colleagues from the FDA showed data from case studies from a search of the AERS database for all reports of toxicity in children 2 years of age or under following dosing with LPV/r oral solution.

The search revealed 10 unduplicated cases in neonates of whom 8 were preterm. Of the preterm infants, 3 were born at 28 weeks gestation, 1 at 30 weeks, 2 at 32 weeks and 2 at 34 weeks.

The documented adverse events included cardiac toxicity (bradycardia, complete AV block, bundle branch block, or cardiac failure; (n=7), acute renal failure (n=5), increased serum creatinine (n=1), elevated serum lactate level (n=2), hyperkalemia (n=4), respiratory failure (n=2), hypotonia (n=1), abnormal EEG (n=1), and CNS depression (n=1).

Outcomes included 1 death, 2 life threatening and 4 hospitalisations. Therapy was initiated on the day of birth in 7 neonates, day after birth in 1, day 34 in 1, and unknown in 1.

Onset the first adverse event occurred within 1 to 6 days (n = 8). Discontinuation of Kaletra (n=9) resulted in recovery within 1 day in 1, 2 days in 2, 3 days in 2, 6 days in 3, 20 days in 1 and was unknown in 1.

WHO set 25mg/kg as a maximum acceptable daily intake of propylene gel when it is used as a food additive. The European Medicines Agency (EMA) recommends that a 12.5mg/dL blood concentration of ethanol after a dose of any medication should not be exceeded. In IMPAACT P1030 – a PK sub-study in full-term infants 6 weeks of age – the mean steady state of LPV was 5.2+1.8ug/m2 twice daily. When the FDA investigators looked at neonatal exposure to the three ingredients in the cases for which data were available, the results were far in excess of these recommendations. See Table 1: Neonatal exposure to lopinavir, ethanol and propylene glycol.

The investigators concluded that the ten cases to the AERS suggest that neonates, especially those born preterm, who received LPV/r oral solution, were at increased risk of toxicities from drug accumulation. They added that the improvement of symptoms when the drug was stopped support this association.

There are limitations to the AERS however. Because reporting is voluntary, the quality of reporting is very variable. The database is subject to under reporting as well as reporting bias and both the numerator and the denominator are unknown for any event reviewed. Therefore the incidence or estimated risk cannot be calculated.

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This analysis provoked a FDA label change and the lopinavir/r oral solution is not recommended for neonates particularly preterm.

Reference

Boxwell D et al. Neonatal toxicity of Kaletra oral solution—LPV, ethanol or propylene glycol? 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 708.

Two posters at CROI 2011 presented pharmacokinetic (PK), efficacy and safety data of paediatric formulations of antiretroviral drugs. [1, 2]

Darunavir

ARIEL (TMC114-C228) is a 48-week, open-label, single-arm, phase II trial evaluating PK, safety and efficacy of darunavir/ritonavir (DRV/r) plus an optimised background regimen (OBR) in HIV-positive treatment-experienced children. Avy Violari and colleagues reported interim (24 week) data from ARIEL.

Children aged 3 to <6 years, weighing 10 to <20kg, with viral load >1000 copies/mL and <3 DRV resistance-associated mutations (RAM) at screening, received DRV. The formulation used in this study is a high concentrate oral suspension (100 mg/mL) – initially dosed at 20 mg/kg BID plus ritonavir (RTV) 2.6 to 3.2mg/kg BID with an OBR (>2 active NRTI) – over 48 weeks.

After a PK analysis at week 2, the DRV dose was amended to 25mg/kg BID children weighing 10 to 15kg and 375mg BID fixed for those weighing 15 to <20 kg (following Data Safety Monitoring Board recommendations).

A total of 27 patients – 55.6% male and mean age 4.6 years at screening – with DRV/r + an OBR. At baseline, the children’s median viral load was 4.51 log copies/mL, median CD4 count was 927 cells/mm3, and median CD4 percentage was 27.7% cells/mm3. The children had a median of 0 primary PI mutations at baseline and 4 PI RAM, 1 NRTI RAM, and 1 NNRTI RAM.

The majority of children, 23 (85.2%) experienced at least one adverse event (AE). One child discontinued treatment (due to grade 2 vomiting, believed to be associated with ritonavir). Most side effectss were grade 1-2. Grade 3-4 and serious side effects were reported in 18.5% and 11.1% of patients, respectively but none was considered treatment-related. Most commonly reported adverse events (occurring in over 10% of patients) were diarrhea, vomiting, pyrexia, nasopharyngitis, rhinitis, upper respiratory tract infection, hypokalemia, cough, acidosis, and alkalosis.

One child had a grade 3 laboratory abnormality – neutropenia – but this was present since baseline and not considered to be related to treatment.

There was a steady increase in response from week 2 to 24. By week 24, 55.6% of the children met the primary efficacy endpoint of viral load <50 copies/mL (ITT-TLOVR). The mean increase in CD4 at week 24 was 109 cells/mm3.

Two children had DRV RAMs at baseline but both were <50 cells/mL at week 24. Eleven children (40.7%) were considered virological failures. None of the six children with paired baseline/endpoint genotype samples developed PI or NRTI RAMS.

Raltegravir

P1066 is an open-label study of raltegravir (RAL) in treatment experienced HIV-positive children and adolescents. Sharon Nachman and colleagues reported PK, and week 12 and 24 efficacy and safety data for treatment-experienced children aged 2 to 5 years receiving the RAL chewable tablet formulation.

In this dose finding study, intensive PK was initially performed on 4 children and once PK targets were met, 8 more were enrolled. Inclusion criteria included viral load >1000 copies/mL, prior ART experience but naïve to integrase inhibitors. A RAL chewable tablet 6 mg/kg twice daily was added to the existing regimen, intensive PK samples were taken between days 5 and 12. Once the dose was selected, an additional 9 children were enrolled to assess longer-term safety and efficacy.

PK parameters were evaluated and a dose was selected using an AUC12h target (range 14 to 25uM*h) based on available PK data with a C12h target to exceed the protein-adjusted IC95 of RAL against wild type virus. The investigators compared PK parameters to existing data from 6 to 18 year old children and adolescents receiving the adult formulation and 6 to 11 year old children receiving RAL chewable tablet. Of the 12 children, 67% were female, they were a mean, age of 3 years old, viral load 4.14 log10 copies/mL, CD4%, 33% cells/mm3, CD4 count, 1505 cells/mm3, and weight, 14.3 kg. They received a mean RAL dose of 6.24 mg/kg (0.67).

The geometric mean AUC12 was 8.8hr*mg/L, 18uM*h; C12h 32ng/mL, 71nM; Cmax 4329ng/mL, 9.7uM; CL/F 10.5L/hr and %CV 77%.A 6mg/kg BID dose (maximum 300mg) was selected.

At week 24, by ITT analysis, 62% (95% CI, 53-92) of children (n=21) were <400 copies/mL and 52% (95% CI, 30-74) <50 copies/mL. CD4 gain from baseline was a median of 4.1% (95% CI 2.0-9.9) and 218 (95% CI 39-290) cells/mm3.

No child discontinued RAL due to AEs in this study. One child had grade 3 ALT (2 events), grade >3 AST and ungraded elevated GGT (5 events), considered possible treatment related. Three children had grade >3 neutropenia (7 events) but this was not judged to be treatment related. Other non-treatment related events were: grade 3 bronchopneumonia, grade 3 hydrogen ion concentration, ungraded lactic acidosis, decreased blood glucose, acute gastro enteritis and impetigo.

References

1. Violari A et al. ARIEL: 24-week safety and efficacy of DRV/r in treatment-experienced 3- to <6-year-old patients. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 713.

2. Nachman S et al. Interim results from IMPAACT P1066: RAL oral chewable tablet formulation for 2- to 5-year-olds. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 715.

The recommended dose of rilpivirine is one 25 mg tablet once daily taken orally with a meal.

The following points should be considered when initiating therapy with rilpivirine:

• More rilpivirine treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy
• The observed virologic failure rate in rilpivirine treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz
• More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz

Summary of clinical trial results

The approval of rilpivirine is based on Week 48 safety and efficacy analyses from two randomised, double blind, active controlled, phase 3 trials (TMC278-C209: ECHO and TMC278-C215: THRIVE) in treatment naïve subjects and Week 96 safety and efficacy analyses from a Phase 2b trial in treatment-naïve subjects.

The Week 48 efficacy outcome for the pooled data from TMC278-C209 and TIMC278-C215 are as follows.

Overall, the proportion of subjects with HIV RNA <50 copies/mL was 83% for rilpivirine based regimen compared to 80% for efavirenz based regimen. The predicted difference (95% CI) of response rates is 2.0 (-2.1; 6.1). The overall virologic failure rate was 13% for the rilpivirine compared to 9% for the efavirenz. The proportion of patients who discontinued study due to an adverse event or death was 2% for rilpivirine and 7% for efavirenz.

Response rate was also calculated by baseline plasma viral load. For subjects with baseline plasma viral load ≤100,000 copies/mL, >100,000 to ≤500,000 copies/mL and >500,000 copies/mL, the proportion of subjects with HIV RNA < 50 copies/mL was 89%, 78% and 65% for rilpivirine compared to 83%, 78% and 73% for efavirenz respectively.

The virologic failure rate by baseline plasma viral load is as follows. For subjects with baseline plasma viral load ≤100,000 copies/mL, the proportion of subjects with virologic failure was 5% for both rilpivirine and efavirenz. For subjects with baseline plasma viral load >100,000 to ≤ 00,000 copies/mL and >500,000 copies/mL, the proportion of subjects with virologic failure was 20% and 29% for rilpivirine compared to 11% and 17% for efavirenz, respectively.

In the pooled resistance analysis from the Phase 3 Studies C209 and C215, the emergence of resistance among subjects was greater in the rilpivirine arm compared to the efavirenz arm. In the combined studies, 41% (38/92) of the virologic failures in the rilpivirine arms had genotypic and phenotypic resistance to rilpivirine compared to 25% (15/60) of the virologic failures in the efavirenz arms who had genotypic and phenotypic resistance to efavirenz. Moreover, resistance to a background drug (emtricitabine, lamivudine, tenofovir, abacavir or zidovudine) emerged in 48% (44/92) of the virologic failures in the rilpivirine arms compared to 15% (9/60) in the efavirenz arms.

Emerging NNRTI substitutions in the rilpivirine virologic failures included V90I, K101E/P/T, E138K/G, V179I/L, Y181I/C, V189I, H221Y, F227C/L and M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6 – 621. The E138K substitution emerged most frequently on rilpivirine treatment commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and the tenofovir resistance-associated substitutions K65R or N emerged more frequently in rilpivirine virologic failures compared to efavirenz virologic failures.

Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and development of rilpivirine resistance. In the pooled analyses of the Phase 3 clinical trials, 38 rilpivirine virologic failure subjects had evidence of rilpivirine resistance. Of these subjects, 89% (n = 34) were resistant to etravirine and efavirenz, and 63% (n = 24) were resistant to nevirapine. In the efavirenz arm, none of the 15 efavirenz-resistant virologic failures were resistant to etravirine at failure. Subjects experiencing virologic failure on rilpivirine developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class than subjects who failed on efavirenz.

Contraindications and drug interactions

Rilpivirine is contraindicated with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs:

• The anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• The antimycobacterials rifabutin, rifampin, rifapentine
• Proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
• The glucocorticoid systemic dexamethasone (more than a single dose)
• St John’s wort

Warnings and precautions

The Warnings and Precautions for rilpivirine include fat redistribution, immune reconstitution syndrome and the following:

Drug Interactions: Caution should be given to prescribing rilpivirine with drugs that may reduce the exposure of rilpivirine.

In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Rilpivirine should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.

Depressive Disorder: The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with rilpivirine. During the Phase 3 trials (N = 1368), the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (n = 686) or efavirenz (n = 682) was 8% and 6%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among rilpivirine or efavirenz was 1% in each arm. Suicide attempt was reported in 2 subjects in the rilpivirine arm while suicide ideation was reported in 1 subject in the rilpivirine arm and in 3 subjects in the efavirenz arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to rilpivirine, and if so, to determine whether the risks of continued therapy outweigh the benefits.

Side effects

The most common adverse drug reactions to rilpivirine (incidence > 2%) of at least moderate to severe intensity (≥ Grade 2) were depression, insomnia, headache and rash. The most common adverse drug reactions leading to discontinuation were psychiatric disorders: 10 (1%) subjects in the rilpivirine arm and 15 (2%) subjects in the efavirenz arm. Rash led to discontinuation in 1 (0.1%) subject in the rilpivirine arm and 10 (1.5%) subjects in the efavirenz arm

Rilpivirine is a product of Tibotec Therapeutics.

Source: FDA list serve (20 May 2011).

Please refer to the full prescribing information for details.

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

Approval was based on bioequivilence to the individual drugs taken separately, together with the phase 3 registrational studies for rilpivirine (ECHO and THRIVE) – see FDA approve rilpivirine in the US.

References

US Food and Drug Administration approves Gilead sciences’ Complera, a new complete once-daily, single-tablet regimen for HIV-1 infection in treatment-naïve adults. Gilead press release. (10 August 2011).

http://www.gilead.com/pr_1595280

Prescribing information

http://www.gilead.com/pdf/complera_pi.pdf

Since the last issue of HTB, the US Food and Drug Administration (FDA) has granted tentative approval (or ** full approval) for the following new generic ARV products.

** Full approval enables this generic to be sold in the US.

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

On 12 July, Gilead became the first commercial pharmaceutical company to sign up for the Medicines Patent Pool initiative to broaden generic manufacturing of antiretrovirals drugs for use in resource limited settings.

After many years in development, this programme was originally launched by UNITAID in November 2010 but now runs as an independent organisation. It aims to stimulate new drugs and formulations and increase access to HIV treatment by negotiating voluntary licenses on medicine patents.

The arrangement with Gilead includes tenofovir, FTC, the pharmacokinetic booster cobicistat and the integrase inhibitor elvitegravir. The agreement covers each drug individually and in appropriate combinations (as in the Gilead four-drug ‘Quad’ formulation). This is exciting as cobicistat, elvitegravir and the Quad are products still in clinical development. Importantly it provides some hope that integrase inhibitors will potentially be available in resource-limited countries.

The agreement provides Gilead with royalities calculated at 3-5% of generic sales, with royalties waived for any new paediatric formulations, and each license is granted for a limited number of countries: 111 for tenofovir and FTC, 102 of cobicistat and 99 for elvitegravir and Quad.

Médecins Sans Frontières in a press release following this news, while welcoming the news also highlighted limitations. [2]

MSF press release states that the agreement limits competition “by confining manufacturing to one country (India) and includes narrow supply options for APIs needed to make the drugs. Most critically, people living with HIV in certain middle-income countries are excluded. This contrasts sharply to the first Pool license granted by the US National Institutes of Health for all developing countries. If voluntary measures like the Patent Pool are unable to ensure people access to the medicines they need, countries that are left out will need to aggressively pursue non-voluntary paths such as compulsory licenses.”

The Patent Pool is negotiating with at least five other companies and have publically announced that talks with Boehringer-Ingelheim and Bristol-Myers Squibb have started. [3]

“Of all pharmaceutical companies with HIV medicines patents, only three are currently not in negotiation with the Pool. We call on Johnson & Johnson, Merck, and Abbott to follow the lead of their colleagues and enter into negotiations with us,” said Ellen ‘t Hoen, executive director of the Medicines Patent Pool.

The Pool received its first licence, related to darunavir, from the United States National Institutes of Health in September 2010.

References

1. Patent Pool press release. The Medicines Patent Pool announces first licensing agreement with a pharmaceutical company. (12 July 2011).
   http://www.medicinespatentpool.org/LICENSING/Current-Licences/Medicines-Patent-Pool-and-Gilead-Licence-Agreement
2. MSF press release. MSF reaction to Gilead’s announcement about AIDS drugs/patent pool. (12 July 2011).
   http://www.pharma-mag.com/News/tabid/63/EntryId/331/MSF-Reaction-to-Gileads-Announcement-about-AIDS-Drugs-Patent-Pool.aspx
3. Patent Pool press release. The Medicines Patent Pool announces negotiations with two additional pharmaceutical companies, landmark licensing deal. (18 July 2011).
   http://www.medicinespatentpool.org/NEWS-ROOM/Journalists/BI-BMS-Enter-Negotiations

Further information

Medicines Patent Pool

http://www.medicinespatentpool.org/

UNITAID

http://www.unitaid.eu/

Dolutegravir (S/GSK1349572) is an unboosted, once-daily, next-generation HIV integrase inhibitor. The effects of multivitamins (One-A-Day Maximum, single tablet), antacid (Maalox 20 mL single dose with or 2 hours after dolutegravir) and omeprazole (40 mg once daily for 5 days) on single doses of dolutegravir (50 mg) were studied in HIV-negative subjects.

Coadministration of the multivitamin modestly decreased dolutegravir AUC and Cmax by 33% and 35%, respectively.  Concurrent antacid co-administration reduced dolutegravir AUC and Cmax by 74% and 72%, respectively.  Staggered antacid dosing significantly diminished this interaction, with a reduction in dolutegravir AUC of 26% and Cmax of 18%. Omeprazole did not significantly affect dolutegravir exposure (no change in AUC, 9% decrease in Cmax).

Dolutegravir can be taken with proton pump inhibitors and multivitamins without dose adjustment but should be administered 2 hours before or 6 hours after antacids. The mechanism of the antacid interaction with dolutegravir is likely to result from chelation with metal cations in the antacid rather than an effect of pH and would be consistent with the omeprazole data.

Source: hiv-druginteractions.org (23 June 2011).

Ref: Patel P et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother, 2011, 66(7): 1567-1572.

http://www.ncbi.nlm.nih.gov/pubmed/21493648

Two cases have been reported recently of patients developing Cushing’s syndrome when treated with atazanavir/ritonavir and corticosteroids.

The first case describes a 75 year old man with a history of HIV for 27 years, hepatitis C, hypothyroidism, recurrent deep venous thrombosis, hypertension, and chronic kidney disease was admitted for treatment of worsening chronic diarrhea and bright red blood per rectum. [1]

His antiretroviral regimen was atazanavir/ritonavir (300/100 mg daily), lamivudine (150 mg daily) and nevirapine (300 mg twice daily). Other medications included atenolol, atropine/diphenoxylate, calcitriol, cholecalciferol, fondaparinux, levothyroxine, lisinopril, loperamide, ranitidine, testosterone patch, trazodone, and vardenafil.  Colonoscopy showed lymphocytic colitis at multiple biopsy sites and oral budesonide (3 mg 3 times a day) was started.

The patient’s diarrhea improved, but he was admitted 12 days later with 10.4 kg weight gain, severe leg and facial swelling, and uncontrolled hypertension.  Physical examination was notable for blood pressure 177/102 mm Hg, cushingoid facies, and 2+ pedal and pretibial edema to the knees.  As the colitis had improved dramatically with budesonide therapy, the plan was to continue it for a full 6-week treatment course, if possible. Amlodipine, hydralazine, and furosemide were added to control the hypertension and edema, but budesonide was discontinued after 3 weeks because of persistent severe edema that was refractory to furosemide.

The patient developed edema, weight gain, uncontrolled hypertension, cushingoid facies, hypokalemia, and metabolic alkalosis shortly  after initiation of budenoside, with resolution of all symptoms  soon after it was stopped.  Congestive heart failure, liver disease, and nephrotic syndrome were ruled out as causes of the edema, which supported the diagnosis of iatrogenic Cushing’s syndrome. Although budesonide concentrations were not measured, the very low serum cortisol level (0.8 µg/dL) in a clinical setting of hypercortisolism provides strong indirect evidence that levels of an exogenous corticosteroid (ie, budesonide) were high.

Budesonide is inactivated through extensive first-pass metabolism by hepatic CYP3A4. The P-glycoprotein (PGP) export pump also limits budesonide serum concentrations by promoting the gastrointestinal excretion of CYP3A4 substrates. By inhibiting CYP3A4 and PGP, protease inhibitors such as ritonavir and atazanavir limit both the first-pass metabolism and gastrointestinal excretion of CYP3A4 substrates and result in increased serum concentrations of steroids.

The second case was of Cushing’s syndrome and adrenal axis suppression in a patient treated with ritonavir and corticosteroid eye drops. [2]

A 51-year-old woman with HIV presented with weight gain and a 1-month history of right hip pain.  Her ART included tenofovir (300 mg once daily), emtricitabine (200 mg once daily), and atazanavir/ritonavir (300/100 mg once daily). Because of previous bilateral cytomegalovirus retinitis, complicated by immune recovery uveitis with severe, chronic, cystoid macular oedema, she was also using dexamethasone 0.1% eye drops six times daily, and betamethasone 0.1% eye ointment at night, in both eyes.

On examination, she was noted to have central adiposity and enlargement of the dorsocervical fat, but no peripheral lipoatrophy. An MRI scan of the hip showed avascular necrosis. A tetracosactide (Synacthen) stimulation test showed marked suppression of the pituitary-adrenal axis, with a baseline cortisol of less than 25 nmol/L rising to only 37 nmol/l 30 min after administration of tetracosactide 250mg (normal response at 30 min, >570 nmol/L). Adrenocorticotropic hormone (ACTH) was undetectable.

The presence of adrenal axis suppression with low ACTH, in the context of Cushingoid features and avascular necrosis of the hip, suggested ongoing exposure to high systemic levels of exogenous corticosteroids. Ritonavir and atazanavir were substituted with efavirenz (600 mg once daily), while continuing the steroid eye drops. Oral hydrocortisone 15 mg daily was added to avoid precipitating crisis due to adrenal insufficiency. Over the following year, the patient’s weight declined, with marked improvement in her adrenal function. Analysis of stored serum samples revealed elevated levels of dexamethasone

at presentation (1.4-1.7 nmol/L) which fell dramatically after discontinuation of protease inhibitor therapy (undetectable to 0.181 nmol/L).

Although prior courses of oral and intravenous corticosteroids may have contributed to adrenal axis suppression, the close temporal correlation between discontinuation of ritonavir, reversal of weight gain and recovery of adrenal function, combined with detectable levels of dexamethasone in the blood, strongly suggests that co-administration of ritonavir was responsible for the accumulation of excessive systemic levels of topical ocular corticosteroids, resulting in adrenal axis suppression and Cushing’s syndrome.

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

References

1. Frankel JK. Cushing’s syndrome due to antiretroviral-budesonide interaction. Ann Pharmacother, 2011, 45(6): 823-824. http://www.ncbi.nlm.nih.gov/pubmed/21558486
2. Molloy A et al. Cushing’s syndrome and adrenal axis suppression in a patient treated with ritonavir and corticosteroid eye drops. AIDS, 2011, 25(10): 1337-1338.http://www.ncbi.nlm.nih.gov/pubmed/21659797

Coadministration of rifampicin dramatically reduces plasma lopinavir (LPV) concentrations. In healthy volunteers, doubling the dose of lopinavir-ritonavir (LPV/r) capsules overcame this interaction, but a subsequent study of double doses of the tablets was stopped early owing to hepatotoxicity. However, healthy-volunteer study findings may not apply to HIV-positive adults.

This study evaluated the steady-state pharmacokinetics of LPV in HIV-infected adults stable on LPV/r tablets (400/100 mg twice daily) who were given rifampicin (600 mg daily), and the dose of the LPV/r gradually increased over a period of two weeks (first to 600/150 twice daily and then to 800/200 mg twice daily). Twenty-one subjects started the study, but two were withdrawn due to grade 3/4 transaminitis.

The median [IQR) pre-dose LPV concentrations were 8.1 (6.2 to 9.8) mg/L at baseline, 1.7 (0.3 to 3.0) mg/L after 7 days of rifampicin, 5.9 (2.1 to 9.9) mg/L with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/L with double-dose LPV/r. There were no significant differences in the LPV AUC, Cmax, pre-dose concentrations, 12-hour concentration, or half-life between the baseline and double-dose LPV/r time points.

Doubling the dose of the tablet formulation of LPV/r overcame induction by rifampicin, with less hepatotoxicity occurring in this cohort of HIV-infected participants than reported in healthy-volunteer studies.  The cohort consisted of HIV-infected patients who were virologically suppress with high CD4 counts – the risk of hepatotoxicity may be different in HIV-infected individuals with TB and/or with different CD4 counts.

Source: hiv-druginteractions.org (28 June 2011).

Ref: Decloedt EH et al. Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavir-ritonavir tablets. Antimicrob Agents Chemother,  2011, 55(7): 3195-3200.

http://www.ncbi.nlm.nih.gov/pubmed/21537021

Initiation of Antiretroviral Treatment Protects Uninfected Sexual Partners from HIV Infection (HPTN Study 052): 96% reduction in HIV transmission, according to study conducted by HIV Prevention Trials Network

Men and women infected with HIV reduced the risk of transmitting the virus to their sexual partners through initiation of oral antiretroviral therapy (ART), according to findings from a large multinational clinical study conducted by the HIV Prevention Trials Network (HPTN), a global partnership dedicated to reducing the transmission of HIV through cutting-edge biomedical, behavioral, and structural interventions.

The study, known as HPTN 052, was designed to evaluate whether immediate versus delayed use of ART by HIV-infected individuals would reduce transmission of HIV to their HIV-uninfected partners and potentially benefit the HIV-infected individual as well. Findings from the study were reviewed by an independent Data and Safety Monitoring Board (DSMB).The DSMB recommended that the results be released as soon as possible and that the findings be shared with study participants and investigators. The DSMB concluded that initiation of ART by HIV-infected individuals substantially protected their HIV- uninfected sexual partners from acquiring HIV infection, with a 96 percent reduction in risk of HIV transmission. HPTN 052 is the first randomised clinical trial to show that treating an HIV-infected individual with ART can reduce the risk of sexual transmission of HIV to an uninfected partner.

HPTN 052 began in April 2005 and enrolled 1,763 HIV-serodiscordant couples (couples that have one member who is HIV-infected and the other who is HIV-uninfected), the vast majority of which (97 percent) were heterosexual. The study was conducted at 13 sites across Africa, Asia and the Americas. The HIV-infected person was required to have a CD4 cell count between 350-550 per cubic millimeter (cells/mm3) at enrollment, and therefore did not require HIV treatment for his or her own health. Couples were randomized to one of two groups. In one group, the HIV-infected person immediately began taking ART (immediate ART group). In the other group, the HIV-infected person began ART when his or her CD4 cell count fell below 250 cells/mm3 or if he/she developed an AIDS-related illness (the delayed ART group).

Throughout the study, both groups received HIV-related care that included counseling on safe sex practices, free condoms, treatment for sexually transmitted infections, regular HIV testing, and frequent evaluation and treatment for any complications related to HIV infection. Each group received the same amount of care and counseling. Any HIV-uninfected person who became HIV-infected during the course of the study was referred to local services for appropriate medical care and treatment.

In its review, the DSMB found a total of 39 cases of HIV infection among the previously uninfected partners. Of those, 28 were linked through genetic analysis to the HIV-infected partner as the source of infection. Seven infections were not linked to the HIV-infected partner, and four infections are still undergoing analysis. Of the 28 linked infections, 27 infections occurred among the 877 couples in which the HIV-infected partner did not begin antiretroviral therapy immediately. Only one case of HIV infection occurred among those couples where the HIV-infected partner began immediate antiretroviral therapy. This finding was statistically significant and means that earlier initiation of antiretrovirals led to a 96 percent reduction in HIV transmission to the HIV-uninfected partner. The infections were confirmed by genetic analysis of viruses from both partners.

Additionally, 17 cases of extrapulmonary tuberculosis occurred in the HIV-infected partners in the deferred treatment arm compared with three cases in the immediate treatment arm, a statistically significant difference. There were also 23 deaths during the study. Ten occurred in the immediate treatment group and 13 in the deferred treatment group, a difference that did not reach statistical significance.

The press release noted that the ongoing international clinical study called Strategic Timing of Antiretroviral Therapy (START) also funded by NIAID is examining the optimal time for asymptomatic HIV-infected individuals to begin antiretrovirals.

http://www.niaid.nih.gov/news/newsreleases/2011/Pages/START.aspx

Source: NIAID Press release. (12 May 2011)

For additional information about the HPTN 052 study, see the Questions and Answers information on the NIAID website.

http://www.niaid.nih.gov/news/QA/Pages/HPTN052qa.aspx

http://www.youtube.com/watch?v=RK6aswNV08E&feature=channel_video_title

Other material including over 35 other presentations from this workshop are available at:

http://www.cfenet.ubc.ca/node/5536/

To download the word-file you have to scroll to the bottom of this page:

http://www.esar-society.eu/index.cfm/t/Tropism_Guidelines/vid/5436FB5B-B04D-6E04-05EDE1DDA908FBF7

Webcasts from this meeting include the interventions by women activists.

• Tatyana Afanasiady from the Ukranian Network of People Living with HIV at the opening session. Speaking as an openly HIV positive woman and drug user.

http://www.unmultimedia.org/tv/webcast/2011/06/23682.html (English and Russian)

• Siphiwe Hlope, Alessandra Nilo, Adrienne Germain, a powerful young woman speaker from Zimbabwe, Lisette Trinidad from Peru, and several other strong statements from women in the Women Panel meeting.

http://www.unmultimedia.org/tv/webcast/2011/06/panel-4-women-girls-and-hiv-english.html

• Anandi regional coordinator for Asia and the Pacific for the International Community of women living with HIV.

http://www.unmultimedia.org/tv/webcast/2011/06/side-event-aids-health-and-sustainable-development-who-owns-the-aids-response-high-level-meeting-on-aids-original-language.html

• Silvia Petretti, speaking at the closing plenary on why people with HIV and key populations need to be at the centre of the fight against the HIV epidemic.

http://www.unmultimedia.org/tv/webcast/2011/06/global-network-of-people-living-with-hiv-2011-high-level-meeting-on-aids-95th-plenary-meeting.html

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

51st ICAAC

17–20 September 2011, Chicago

http://www.icaac.org/

13th European AIDS Conference (EACS)

12–15 October 2011, Serbia

http://www.europeanaidsclinicalsociety.org

2nd International Workshop on HIV & Ageing

October 2011, Baltimore, USA

http://www.virology-education.com

4th Annual BHIVA Conference for the Management of HIV / Hepatitis Co-infection

16 November 2011, London

http://www.bhiva.org

BHIVA Autumn Conference including CHIVA Parallel Sessions

17–18 November 2011, London

http://www.bhiva.org

19th Conference on Retroviruses and OIs (CROI)

5–8 March 2012, Seattle

http://retroconference.org

18th Annual BHIVA Conference

17–20 April 2012, Birmingham

http://www.bhiva.org

We include reports from the 18th Conference on Retroviruses and Opportunistic Infections (CROI). This annual meeting showcases some of the most important new developments in HIV research each year.

In this issue we report successful early findings with immune -based treatment; better news with oral PrEP and topical gels and some important studies in focusing on pregnancy.

We also include some new drug approvals and label and guidance changes.

It is interesting to note that even a richly resourced setting like that provided for by the London Consortium in the UK, managing the HIV budget within the NHS has led to a recommendation that new patients start with abacavir instead of tenofovir.

Nearer to home, we include MSF data from Lesotho showing tenofovir to be associated with fewer side-effect related switches compared to AZT or d4T in first-line treatment. These data will also help to allay a concern that renal toxicity rates from tenofovir might be unmanageably high in an African setting.

And in contrast to the more optimistic prevention studies reported at CROI, the FEM-PrEP study (conducted at sites in Africa) was stopped by the trials Independent Data Monitoring Committee (IDMC) due to an interim analysis that showed no difference between rates of new HIV infections in the active tenofovir/FTC (Truvada) group compared to the people using placebo. Which is disappointing news.

Our next issue of HTB South will be also be rich with conference reports, including from the 5th Southern African AIDS Conference in Durban, where you might have received this one.

Happy reading!

We have plenty to report in this and subsequent issues of HTB, leading with the broad number of papers focusing on new drugs and biomedical interventions to reduce the risk of transmission.

http://www.retroconference.org

Reports in this issue include:

• Immune-based treatment increases HIV-resistant CD4 cells in phase 1 study
• Antiretroviral prevention: oral PrEP, gels and treatment studies
• Further efficacy analyses from the iPrEx study
• Topical gels as PEP and PrEP: animal and human studies
• Maternal risk following short course HAART
• Pre-term delivery and HAART
• HAART more effective than AZT monotherapy in the Botswana PMTCT programme
• Lopinavir/r monotherapy for PMTCT
• No evidence of increased risk of MTCT with sequential pregnancies in UK and Ireland
• Recently infected women at the time of delivery have a higher rate of in-utero transmission in PEPI-Malawi
• Reduced CCL22 concentrations in cervicovaginal secretions from pregnant women
• When to start ART in patients co-infected with TB: results from two trials presented at CROI

One of the first oral presentations of the conference reported results from an immune-based treatment from Sangamo Biosciences called SB-728 presented by Jay Lalezari from Quest Clinical Research in San Francisco. [1]

The intervention in people who were successfully treated with HAART but whose CD4 count remained between 200 and 500 cells/mm3 led to increases in CD4 cell counts of approximately 200 cells/mm3 that were sustained for a year.

This was a small open label phase 1 study in six people. The procedure involved blood apheresis to extract CD4 cells (mean ~43 billion), genetic modification to induce resistance to HIV infection, expansion and then reinfusion several months later with a single dose infusion of either 10 or 20 billion cells. Zinc finger nuclease (ZFN)-mediated gene editing technology was used to disrupt the naturally occuring CCR5 coreceptor. ZFNs are small peptides used to introduce a double-stranded break in DNA, that when repaired adds a five base-pair insertion including two stop codes in approximately 25% of treated hematopoietic stem cells.

In this study, the modification process affected a mean 26% of cells (14 to 36%) prior to reinfusion. The percentage of CCR5 disruption in the peripheral blood 14 days after reinfusion in five participants was 6, 3, 1, 2, and 2% and this persisted for the duration of follow up. CD4 counts increased in all participants (+35 to +1038 cells/mm3 at day 14). Mean follow up was 24 weeks and 4 weeks, in the low and high dose groups, respectively, with mean CD4 increases in these five people of 208, 86, 233, 911 and 210 cells/mm3. Although increased CD4 counts could be related to increased cellular transport, rectal tissue biopsies indicated that reinfused cells reached other tissue compartments. Infusion of both doses was safe and well tolerated with mild flu-like cytokine release-related side-effects immediately following the infusion, and garlic body odour related to one of the compounds used in the freezing process.

These results suggest that ZFN-modified gene disruption of CCR5 provides a feasible approach to generate a reservoir of HIV-resistant cells. Three new patients will receive 30 billion cells as a third cohort, two of whom have already received treatment.

A second presentation reported research into developing a similar disruption to CXCR4 virus that was able to shift tropism in a humanised mouse study suggesting that genetic manipulation may be able to be designed for people at all stages of HIV disease. [2]

The research was also the focus of two presentations in a symposium on the last day of the conference called Obstacles to a Cure. [3]

Paula Cannon from University of Southern California Los Angeles reported on early research in ZFN-treated autologous hematopoietic stem cells (HSC) to generate HIV resistant cells as a functional cure in mice.

Using an immune-depleted (NSG) mouse model allowed the researchers to transplant human cells grafted at day one and then analyse human cells after 2-3 months. At this time, 65% of the mouse bone cells are human origin, 80% of thymus cells, and 20-30% bone cells. The humanised mice were then infected with HIV and their viral infection was monitored over several months. While control mice showed expected CD4 declines, ZFN-treated mice maintained immune equilibrium. These differences were more striking when looking at tissue samples with severe cell depletion in bone marrow, thymus, spleen and gut mucosa in control mice (receiving untreated HSC) compared to ZFN-treated mice, who showed similar response to HIV uninfected and untreated control mice.

CCR5 expression in spleen and gut cells were only detected in the control HSC mice and not in the ZFN-HSC animals. Intriguingly, viral load curves were similar between the treated and untreated infected animals for the first six weeks, rising to >100,000 copies/mL. They remained at this level in the untreated mice but dropped to undetectable levels in both blood and tissues of the treated mice. Similar response were observed with other R5-tropic but not X4-tropic strains of HIV.

The group is now looking at additional gene deletions for CCR5 including developing responses resistant to X4 infection.

Scale up of this technology is starting with HIV-positive people diagnosed with AIDS-related lymphoma, including EBV-related lymphoma. Treatment included removing and treating HSC prior to chemotherapy and reinfusing after chemotherapy. Endpoints include immunologic and virological endpoints. This complements the SB-728 treated CD4 cells in phase 1 studies reported below.

Carl June and colleagues from University of Pennsylvania presented combined early in vivo results from the Lalezari study reported above and from patients enrolled in second phase 1 open label study being run by Pablo Tebas at University of Pennsilvania. This second study uses single dose infusions of between 5–10 billion cells in 12 people on stable antiretrovirals: 6 with CD4 >450 (6 enrolled, 4 infused, 2 on treatment interruptions, one with data from July 2009) and 6 with <500 cells/mm3 (4 enrolled, 2 infused). This study also includes an ‘optional’ treatment interruption one month after the infusion.

Of 14 people treated, 9 have safety data. No serious events have been reported over median of 232 days (range 99–754 post infusion); 58 events were reported (48 mild, 10 moderate); 33/58 were judged related to infusion (fever, fatigue) and resolved without complications within 48 hours. No evidence was seen of genotoxicty.

All patients have an early CD4 increase post infusion of 200–300 cells/mm3 by day 14, with three people have greater than 1000 cell increases, with most people dropping to, or stabilising to, an increase of around 200 from baseline after 3 months. The CD4:CD8 ratio normalised to >1.0 in most patients out to 90 days. However, in these small numbers there were a range of responses and not all patients responded as strongly.

All patients but one maintained a level of approximately 4% of modified cells that were maintained and stable out to 6 months. The patient with longest follow-up has maintained a stable level of modified cells for over 400 days and is evidence that memory cells with stable persistence can be modified (though there are no phenotypic data on these cells yet). In vivo expansion of the modified cells was seen in 8/9 patients (mean 3-fold increase 14-30 days post infusion, but 2 people having 20–40 fold increases) with stable increases persisting for the extent of follow-up. Trafficking to other cellar tissue was demonstrated from rectal biopsy samples showing increases gene disrupted cells at least on a comparable level to that seen in blood.

The two patients who took a 12-week treatment interruption at day 28 experienced viral rebound to around 5 logs which then dropped by 1–2 logs prior to restarting treatment but larger patients numbers are needed to evaluate any consistent pattern or treatment effect.

comment

Currently this research is exciting. Up to 10% of people who respond virologically may fail to generate a similar or sufficient immunological response to HAART, and delayed initiation of HAART correlates to reduced likelihood of normalising CD4 counts (commonly referred to as >500 cells/mm3). IL-2-associated CD4 increases either failed to produce functional immune benefits or these were offset by the toxicity associated with IL-2 treatment.

While the publicity from this study associated the research with the case of the stem cell transplantation from a CCR5-delta32-deleted donor to a patient who has since been able to discontinue antiretroviral drugs for over three years without experiencing viral rebound, it is important to realise that these are two very different approaches.

References:

Unless mentioned otherwise, all references are to the Programme and Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections, 28 February–2 March 2011, Boston.
http://www.retroconference.org/AbstractSearch/

Webcasts are available at the following link:
http://www.retroconference.org/2011/data/files/webcast_2011.htm

1. Lalezari J et al. Successful and persistent engraftment of ZFN-M-R5-D autologous CD4 T Cells (SB-728-T) in aviremic HIV-infected subjects on HAART. 18th CROI, 27 February–2 March 2011, Boston. Oral abstract 46.
   http://www.retroconference.org/2011/Abstracts/41074.htm
2. Wilen C et al. Creating an HIV-resistant immune system: using CXCR4 ZFN to edit the human genome. 18th CROI, 27 February–2 March 2011, Boston. Oral abstract 47.
   http://www.retroconference.org/2011/Abstracts/41853.htm
   Webcast Session 11, Monday 10 am-12 noon; Auditorium. HIV: Innovative Therapeutic Approaches, ART, and Drug Resistance. Access from Tuesday 28th.
   http://www.retroconference.org/2011/Sessions/011.htm
3. Session 47-Symposium Obstacles to a Cure Wednesday, 4-6 pm. Webcast available online.
4. Cannon P et al. CCR5 knock-out in hematopoietic stem cells. Oral abstract 164.
   http://www.retroconference.org/2011/Abstracts/42649.htm
5. Tebas P et al. Disruption of CCR5 in zinc finger nuclease-treated CD4 T cells: phase I trials. Oral abstract 165.
   http://www.retroconference.org/2011/Abstracts/42650.htm

One of the most important themes from the conference this year was the high profile given to research into medical interventions to reduce transmission.

Last year, when the iPrEx and Caprisa 004 studies showed proof of principal for oral and topical use of ARVs to reduce the risk of sexual transmission, the differences between actual and reported adherence complicated the interpretation of the potential benefits.

These and other aspects of this research were addressed in many of the studies presented at CROI. This included two separate oral sessions and a plenary talk all of which are available as webcasts. [1, 2, 3]

Despite the high potential benefit for oral PrEP to reduce infections, the idea of using an oral antiretroviral to prevent transmission seems to make some people angry, to the point of losing the science and becoming blind to the level of protection already seen.

The increasing incidence of sexual transmissions in every country directly challenges the efficacy of condoms, however effectively they can protect sexual health including from HIV.

The safety concerns include daily tenofovir having a small impact on bone mineral density, the clinical importance of which is currently unclear. This is less than the impact reported in HIV-positive people on treatment and may be mitigated by intermittent dosing. Although intermittent dosing (once or twice weekly) would reduce cost and improve adherence this will depend on drug levels in tissue rather than blood. The use of intermittent dosing is supported by sustained drug levels in blood achieved with this strategy. However, protection comes from drug levels in the vaginal, rectal or penile tissue where HIV exposure takes place.

The risk of drug resistance from continuing to use tenofovir/FTC by people who become infected was not seen in iPrEx, but resistance data from daily dosing is very preliminary and based on frequent monitoring.

No one in this field is suggesting that oral PrEP becomes the only prevention technology, or even that it is ready for widespread use. The data do support use in specific circumstances, in high-risk individuals who include it to increase their protection.

CROI included studies looking at these issues and our reports in this issue include:

• Further efficacy analyses from the iPrEx study
• Bone mineral density (BMD) changes in HIV-negative men using tenofovir
• Topical gels as PEP and PrEP in human and animal studies

References:

Unless mentioned otherwise, all references are to the Programme and Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections, 28 February–2 March 2011, Boston.
http://www.retroconference.org/AbstractSearch/

Webcasts are available at the following link:
http://www.retroconference.org/2011/data/files/webcast_2011.htm

1. Oral abstract session: HIV Prevention: HSV2, Topical and Oral PrEP, and Circumcision, Monday 28 February 10:00 AM.
2. Oral abstract session: Advances in PrEP, Tuesday 1 March, 10.00 AM.
3. Celum C. Plenary 3/2/2011 8:30 AM Drugs for Prevention–Topical and Systemic PrEP. Wednesday 2 March 8:30 AM.

Robert Grant from the Gladstone Institute of Virology and Immunology San Francisco presented follow-up results from the international iPrEx study. [1]

The initial analysis published in the NEJM in November 2010 reported a 44% reduction (36 vs 64 infections; 95%CI 15 to 63%; p=0.005) from use of daily oral tenofovir/FTC compared to placebo in 2499 young sexually active MSM at high risk of catching HIV. However, all infections in the active arm of the study were associated with undetectable (91%) or low (9%) drug levels in blood (compared to 51% of uninfected matched cases) indicating higher protection rates (~95%) with actual use. [2]

Results presented at CROI from an additional final four months of blinded randomised arms included 12 new infections in the active vs 19 in the placebo groups (p=0.002). During follow-up three months after drug/placebo discontinuation there were 4 new infections in the active arm and 2 in the placebo group (p=NS).

By all analyses, these final data retained similar significant protection rates to the initial published results. Protection was seen in all subgroups (by age, ethnicity, region, schooling, alcohol use, circumcision) but greater protection was seen in people reporting higher risks (i.e. unprotected anal intercourse, p=0.03).

Side effects were reported at similar rates in both arms and are summarised in Table 1. Differences in nausea and weight loss were seen in the first four weeks that subsequently resolved to placebo levels. No differences were seen in laboratory safety markers including phosphate, electrolytes, AST, ALT, amylase, glucose etc. While encouraging, these safety data need to be interpreted with consideration of the minimal adherence in each arm suggested by the PK sub-study.

Drug resistance was not detected in any of the cases of seroconversion that occurred during the study, but resistance to FTC was found in three people who were seronegative at baseline but later found to be recently infected by PCR viral load.

Self-reported risk reductions in behaviour changes in terms of partner reduction and increased condom use should perhaps be considered cautiously given the low correlation between reported and actual adherence.

However, the positive results reported from the study should increase the likelihood for actual adherence in the future. Of interest, despite this optimism, Dr Grant suggested that actual adherence should not be assumed, even knowing when protection is proven.

Participants in iPrEx study are being given the option to enroll in a follow-up study of open label. tenofovir/FTC.

Bone mineral density (BMD) changes in HIV-negative men using tenofovir/FTC PrEP

Two studies were presented looking at the impact on bone mineral density during PrEP. These are important both for the opportunity to evaluate the safety of PrEP but also to look at the previously observed side effects of tenofovir separate from an additional impact of both HIV and ageing.

Albert Liu from University of California, San Francisco presented baseline (n=200) and longitudinal (n=184) results from HIV-negative men followed from 2005-2007 in a randomised tenofovir vs placebo study run in San Francisco. [3]

Demographics and baseline characteristics included: median age 40 years (range 19-60); 77% white, 7% Latino or Hispanic, 5% African American, and 5% Asian or Pacific Islander. Approximately 20% were smokers, 40% with moderate/heavy alcohol use, 15% corticosteroid use and 60% used multivitamin, calcium of vitamin D supplements. At baseline a higher proportion of men were found to have low BMD (defined as z-score > –2.0) than would have been expected (~10%; 20 vs 4.8 cases; p<0.001).

DEXA scans performed at baseline, 9 or 12 months, and 24 months showed –1.1% net decrease in mean BMD in the tenofovir vs placebo group at the femoral neck (95%CI 0.4 to 1.9%, p = 0.004) and a –0.8% net decline at the total hip (95%CI 0.3 to 1.3%, p = 0.003). At the spine (L2 to L4) there was a trend towards a –0.7% difference (95%CI –0.1 to 1.5%, p = 0.11). These results were similar after adjustment for baseline BMD, BMI, race, age, and creatinine clearance.

Declines mainly occurred during the first 12 to 15 months of treatment and were generally small. More significant losses (>3% BDM) occurred more frequently in the tenofovir group for hip and femoral neck (both p=0.02) but this was no longer significant at any location when using a >5% cut off (p=1.0, 0.13 and 0.72; for hip, neck and spine respectively).

The ten reported fractures (six in the active and four in the placebo group; p=0.75) were all trauma-related and judged unrelated to study drug.

In a second study, Kathleen Mulligan from University of California, San Francisco presented hip and spine BMD results measured every 24 weeks in approximately 500 people enrolled in a substudy of iPrEx. [4]

Participant were enrolled from sites in Peru (n=221), Thailand (n=95), the US (n=71), South Africa (n=61) and Brazil (n=55) and resulted in broader ethnicity: 18% were Caucasian, 13% black, 20% Asian, 49% mixed race; 52% were Hispanic or Latino. This was a younger population: 48% were under 25 years old and therefore likely to still be experiencing bone mass growth.

Although >60% were active (weight bearing exercise), alcohol (80%) and tobacco (43%) use was common. Mean body mass index was 23.5 (SE 0.2) kg/m2. At baseline, total age and race adjusted z-score for the group which would be expected to be 1.0 was negatively shifted to the left. Low bone mineral density (z-score < –1.0/–2.0) was seen in 36%/12% people in the spine and 18%/2% in the hip, with no difference between the active and placebo groups. Unfortunately there are limited studies of bone disease in otherwise healthy young men to verify the normative data used in bone studies, however the same data are used when evaluating low BMD related to HIV, where similar or greater rates of low BMD are commonly reported.

During the study, bone mineral density tended to increase in the placebo arm and decrease in the FTC/TDF arm, resulting in modest (–0.7 to –1.0%) but statistically significant differences between the groups by week 24 (see Table 2). These are lower than the –2 to –4% seen in HIV-positive people starting tenofovir-containing HAART. Lower patient numbers at later timepoints will require later analyses.

While these are encouraging data, it was also pointed out that it would not be expected to see differences in young healthy men, although limited drug exposure due to low treatment adherence, will also have diluted any reductions caused by tenofovir.

Pharmacokinetic substudy: drug levels in iPrEx

The nested case-control pharmacokinetic substudy in iPrEx matched samples from 34 newly infected participants to 43 controls who remained HIV-negative. The group tested for tenofovir diphosphate and FTC-triphosphate (the active moieties of tenofovir and FTC) in blood plasma and stored PBMCs.

The results were important in demonstrating a strong correlation between presence of active drug and risk of infection/protection (present in 9% of cases vs 51% of controls, p<0.001). Importantly, this was able to show >95% concordance between paired plasma and PBMC samples.

In the presentation at CROI, Peter Anderson presented pharmacokinetic results that were independently associated with detectable drug levels. [5]

This included study site region (97% for US vs 50% for non-US participants, p<0.0001), age (73% in 25 year olds vs 44% in under 25 year olds, p<0.001) recent sexual activity (73% with recent high risk URAI vs 59% without UAI vs 35% no activity within 12 weeks, p=0,003).

The open-label phase of the iPrEx study will include real-time drug level and adherence analysis that will help increase the understanding of drug concentration associated with protection.

The drug level test used in these studies was sensitive enough to drug use within the previous two weeks if the person was already at study state levels, but this period would have been shorter for sporadic adherence.

The relationship between drug levels and degree of protection are a crucial aspect of how and whether PrEP will find a role in prevention strategies.

Intracellular drug levels following single doses of tenofovir/FTC were reported from seven HIV-negative volunteers (5 women, 2 men) in a poster from the same study group. [6]

Tenofovir-DP levels were as expected in plasma but reduced in PBMCs: they were only 15% of those expected at steady state dosing and were only 35% of the levels seen in primate studies. FTC-TP levels achieved 30% of those expected at steady state but were similar to single-dose primate studies.

The clinical results from iPrEx may not have required the optimum levels achieved at steady state from daily dosing but current analysis are unable to show this.

It would seem to be important to prioritise this aspect of protection in animal studies to further inform the likely protection in humans from weekly or twice-weekly dosing.

References:

Unless mentioned otherwise, all references are to the Programme and Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections, 28 February–2 March 2011, Boston.
http://www.retroconference.org/AbstractSearch/

Webcasts are available at the following link:
http://www.retroconference.org/2011/data/files/webcast_2011.htm

1. Grant R et al. Pre-exposure Chemoprophylaxis for Prevention of HIV among Trans-women and MSM: iPREx Study. Oral abstract 92.
   http://www.retroconference.org/2011/Abstracts/42567.htm
2. Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM. 23 November 2010 (10.1056/NEJMoa1011205). Free access:
   http://www.nejm.org/doi/full/10.1056/NEJMoa1011205
3. Liu A et al. BMD loss in HIV-negative men participating in a TDF PrEP clinical trial in San Francisco. Oral abstract 93.
   http://www.retroconference.org/2011/Abstracts/40208.htm
4. Mulligan K et al. Effects of FTC/TDF on bone mineral density in seronegative men from 4 continents: DEXA results of the global iPrEx study. Oral abstract 94LB.
   http://www.retroconference.org/2011/Abstracts/42550.htm
5. Anderson P et al. Interpreting Detection Rates of Intracellular FTC-TP and TFV-DP: The iPrEx Trial. Oral abstract 96LB.
   http://www.retroconference.org/2011/Abstracts/42612.htm
6. Anderson P et al. Single-dose pharmacokinetic profile of intracellular TFV-DP and FTC-TP in HIV-negative volunteers. Poster abstract 641,
   http://www.retroconference.org/2011/Abstracts/40077.htm

The conference included a similarly broad range of studies looking at antiretroviral-based microbicide gels.

Rectal use of tenofovir gel protections against ex vivo exposure

Peter Anton from the University of California presented late breaker results from a phase 1 study of rectal use of the tenofovir gel used in the Caprisa 004 study. [1]

HIV-negative participants (14 men and four women) received sequentially a single oral dose of tenofovir, single rectal dose of tenofovir gel or placebo, and seven days rectal dosing, also randomised, each separated by a two week wash out and sampling period. The study measured efficacy by ex vivo infectibility of in vivo exposed cells from rectal biopsies, and monitored plasma drug concentrations in multiple compartments and general product acceptability.

Primary endpoint was safety defined by grade >/= 2 events and secondary safety by a large panel tests relating to mucosal injury that were developed for an earlier HPTN 056 rectal microbicide study.

Most side effects were grade 1 and occurred during the seven-day rectal use, more frequently with the active gel (12 vs 2 people, p=0.001; 37 vs 6 events, p=0.002) were gastrointestinal (GI). However, two people reported five grade 3 GI events. The only differences seen between groups in the panel of mucosal indices were decrease in two cytokines (IL1-beta and TNF-alpha) only seen at 30 minutes post dosing after the seven-day exposure.

Neither gel was particularly liked (25% tenofovir, 50% placebo) but approximately 75% in each group said they would use it if it proved to be effective.

As expected, plasma dosing achieved significantly higher levels (approximately 2 logs higher) in plasma compared to tissue, with rectal dosing not accumulating tenofovir levels in plasma.

Importantly, active drug levels of tenofovir diphosphate, 30 minutes post dosing with single rectal dose were >100-fold higher in rectal tissue compared to oral dose, achieved in 80% of samples, and were five times higher following the 7 day dosing.

Rectal biopies taken 30 minutes post dose were infectible at baseline. Single oral dose showed no effect and single rectal dose showed a trend to an effect but after 7 day rectal dosing the tenofovir exposed cells showed significantly greater resistance to infection.

This allows the first analysis to show a strong positive correlation between tenofovir DP drug level following in vivo exposure and HIV inhibition (r2=0.33, p=0.0011).

While the study concluded that although the acceptability of the gel was lower, the gel was safe in terms of tissue exposure, and topical application achieved tissue concentrations of tenofovir diphosphate that demonstrated ex vivo protection from infection.

Oral tenofovir vs daily gel vs both

Craig Hendrix from Johns Hopkins University, Baltimore, and colleagues presented results from an open-label phase 2 study of daily oral tenofovir, daily gel and dual oral/gel in 144 sexually active HIV-negative women (aged 18-45) at four US and three African sites. This was a three-stage cross over study with each stage lasting six weeks separated by one week washout. [2]

The study looked at safety, adherence, acceptability and pharmacokinetics.

The gel resulted in levels of tenofovir diphosphate that were 100-fold higher in vaginal tissues compared to oral dosing, and dual dosing made no additional impact on tissue concentrations.

Although excellent adherence was reported (>90% all doses reported as taken; and >80% people taking >90% of doses) the drugs levels observed at any time point in the pharmacokinetic study showed that 35-65% of the people in all groups had drug levels below the 99% confidence interval from historical reference cohorts.

No differences in side effects overall were seen between the three regimens, though nausea, diarrhoea and headache were more common during the oral and dual stages (all <15%). Vaginal symptoms and reduced phosphates (general transient) were similar between stages. Nine cases of grade 3/4 hypophosphatemia occurred in 4 oral, 2 gel and 3 dual participants.

The presentation noted that although active concentration in the target site were good from the gel, and not increased by additional oral dosing, the optimum dose required for efficacy is not known and this is an important point.

Raltegravir as a topical gel in macaques

Charles Dobard and colleagues from the CDC Atlanta presented data from using a 1% raltegravir-based gel applied three hours after vaginal exposure in six macaques. [3]

The rationale for this approach is that it is easier to use an intervention after exposure than to accurately predict when protection would be needed for a pre-exposure dosing – whether this involves a 24 hour or 2 hour preexposure window. Integrase inhibitors are a potential target for PEP/PrEP because they block later stages of the viral replication cycle, allowing an activity window 8-10 hours post exposure compared to 2 hours associated with RT inhibitors.

The gel formulation developed by this group was a clear, odourless gel that was stable for several years at room temperature. The macaques received vaginal SIV challenges twice weekly for up to 20 exposures.

Four control animals all became infected (after 10–20 viral challenges). In contrast, 5/6 macaques using the active gel remained protected through 20 exposures (p<0.005). Although one infection occurred, resistance did not develop while the gel was continued, although this was only for a short period. Systemic viral load in this animal was similar to control data, although levels of vaginal shedding were significantly lower.

Oral tenofovir/FTC protects macaques rectally exposed to FTC-resistant virus

Protection against exposure to FTC-resistant virus was reported by Gerardo Garcia-Lerma, also from the CDC, from macaques using oral tenofovir/FTC and following rectal exposure. [4]

The rationale for this study is to determine whether tenofovir protects against the common M184V mutation as one of the more common resistant mutations reported in drug resistance surveillance studies.

Five macaques received oral tenofovir/FTC in human equivalent doses 3 days before and two hours after rectal exposure, which was administered weekly for up to 14 weeks. Five untreated animals were included as controls. None of the treated animals become infected compared to all five control animals (p=0.0008).

References:

Unless mentioned otherwise, all references are to the Programme and Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections, 28 February–2 March 2011, Boston.
http://www.retroconference.org/AbstractSearch/

Webcasts are available at the following link:
http://www.retroconference.org/2011/data/files/webcast_2011.htm

1. Anton P et al. RMP-02/MTN-006: a phase 1 placebo-controlled trial of rectally applied 1% vaginal TFV gel with comparison to oral TDF. Oral poster 34LB.
   http://www.retroconference.org/2011/Abstracts/42556.htm
2. Hendrix C et al. MTN-001: a phase 2 cross-over study of daily oral and vaginal TFV in healthy, sexually active women results in significantly different product acceptability and vaginal tissue drug concentrations. Oral poster 35LB
   http://www.retroconference.org/2011/Abstracts/42418.htm
3. Dobard C et al. High protection against vaginal infection in macaques by PEP with gel containing RAL. Oral abstract 30.
   http://www.retroconference.org/2011/Abstracts/41607.htm
4. Garcia-Lerma G et al. Complete protection against rectal transmission of an emtricitabine-resistant SHIV162p3-M184V mutant by intermittent prophylaxis with Truvada. Oral abstract 31.
   http://www.retroconference.org/2011/Abstracts/40022.htm

Roger Shapiro and colleagues from the Mma Bana Study, Botswana looked at maternal and infant outcomes among women receiving short course HAART for PMTCT during pregnancy and breastfeeding. [1]

In Mma Bana, pregnant women with CD4 counts >200 cells/mm3 (n=560) were randomised to receive regimens of either abacavir+AZT+3TC (arm A) or LPV/r+AZT+3TC (arm B) from week 26 to 34 gestation until the infants were weaned at 6 months post partum. [2] The study also included an observational arm (n=170) in which women indicated for HAART according to local guidelines received lifelong NVP+AZT+3TC. Participants were followed for 24 months post partum.

Randomised women re-started HAART with NVP+AZT+3TC when indicated for treatment (at a CD4 count of 200 cells/mm3 at the beginning and changed to 250 cells/mm3 during the course of the study). This occurred in 9% of randomised women and 25% overall (randomised and observational) continued HAART past 6 months for treatment.

At 24 months, there were 14 (1.9%) maternal deaths: 2 during pregnancy following HAART initiation (1 arm A, 0 arm B, 1 observational), 2 from delivery to 6 months postpartum (0 arm A, 0 arm B, 2 observational), and 10 from 6 to 24 months postpartum (5 arm A, 3 arm B, 2 observational).

There were deaths across all baseline CD4 strata among randomised women (4, 2, and 3 with baseline CD4 200 to 350, >350 to 500, and >500 cells/mm3, respectively). In this group, 8 of 9 deaths were from 6 to 24 months; and 5 of these women had not re-started HAART as treatment.

There was a mean CD4 increase from baseline to 24 months in all treatment arms (15% of randomised women re-started HAART): 68 cells/mm3, 98 cells/mm3, and 283 cells/mm3 in arms A, B and observational respectively. Among women with baseline CD4 >250 cells/mm3, there was a significantly higher CD4 increase in arm B vs A (86 vs 46 cells/mm3, p=0.04).

Data were available for 96% of 709 live-born infants at 24 months of follow up. The majority (97%) of infants were breastfed for a median of 5.8 months. Nine deaths occurred before breastfeeding was initiated (7 <3 days of age, 3 arm A, 2 arm B, 4 observational). There was an increase in infant mortality after weaning, only 5 (0.7%) deaths were during breastfeeding (0 arm A, 2 arm B, 3 observational), compared to 23 (3.2%) after weaning (10 arm A, 11 arm B, and 2 observational). Of these, •14 (2.0%) deaths occurred less than 3 months from weaning which accounted for 38% of all infant deaths in the study. The death rate during breastfeeding was 1.76/100 person-years compared to 5.71/100 person-years within 6 months post-weaning, p=0.02.

Eight children (1.1%) were HIV-infected at 24 months, which did not change from 6 months. HIV infection or death occurred in 6.1% of infants (6.4% arm A, 5.9% arm B, 5.8% observational)..

Causes of maternal and infant deaths are shown in Table 1.

The authors concluded that maternal HAART from pregnancy through 6 months of breastfeeding was associated with low overall maternal and infant mortality at 24 months. They noted that this study found similar maternal mortality/lower infant mortality than in Mashi, a previous Botswana non-HAART MTCT intervention study. Following their observation of a trend for increased maternal mortality after stopping HAART for PMTCT they suggest that 24-month mortality may be higher when stopping HAART in this situation than if it is continued.

Increased infant mortality among weaned infants has been seen previously and later weaning is now recommended by WHO but MTCT and mortality tradeoff are unstudied.

A related poster from the MTCT-Plus Initiative also looked at the impact of stopping HAART used during pregnancy for PMTCT on maternal HIV disease progression. [2] This study evaluated maternal CD4 count decline after MTCT prophylaxis.

MTCT-Plus was a multi-country HIV care programme for women, children, and families in eight African countries and Thailand.

ART-naive, HIV-positive pregnant women with CD4 count >400 cells/mm3 at enrollment were included in the analysis.

The majority of the women evaluated received single-dose nevirapine (sdNVP) or short-course ARV prophylaxis with AZT or AZT+3TC. HAART (AZT+3TC+NVP or nelfinavir) was initiated during pregnancy in programmes in Thailand and Kenya. All regimens were stopped shortly after delivery with a median duration of 10 weeks.

Of 1563 women, 172 (10.9%) initiated HAART, 689 (43.5%) sdNVP, 532 (33.6%) short-course ARV prophylaxis, and 190 (12%) women received no documented prophylaxis.

At baseline, women were a median of 27 (IQR 23-30) years of age with a median CD4 count of 469 (IQR 361-613) cells/mm3. The median follow up time was 26.1 (IQR 14.5-40.7) months. Overall, 11.6% of women with enrollment CD4 >250 cells/mm3 declined to <200 cells/mm3.

Among women who initiated prophylaxis with CD4 >400 cells/mm3, the cumulative probability to reach endpoint of CD4 count <350 cells/mm3 at 24 months was 28.0% (95% CI 24.6, 31.6), overall. The proportions by intervention were: 36.3% (95% CI: 27.4, 47.2), 21.5% (95% CI: 16.4, 27.9), and 27.8% (95% CI: 23.0, 33.2) in the HAART, AZT or AZT/3TC, and sd-NVP groups respectively.

Almost half (47.8% [95% CI 41.2-54.8%]) of the women with baseline CD4 counts of 400-499 cells/mm3 declined to <350 cells/mm3 during follow up, compared to 18.3% (95% CI, 14.9-22.3%) of those with higher baseline CD4 counts, p<0.001.

HAART was significantly associated with CD4 decline compared to short course AZT or AZT/3TC, AHR 2.2 (95% CI 1.5-3.3), p<0.0001. Of note, in this analysis, both undocumented intervention and s/d NVP were also associated but to a lesser extent than HAART, p=0.02 and p=0.001 for short course and s/d NVP respectively. The only other association observed was with age 25-35 years.

Of women receiving HAART, 60.3% (CI 43.5-77.5%) with baseline CD4 counts of 400-499 cells/mm3 declined to <350 cells/mm3 during follow up compared to 48.4% (95% CI 34.8 – 64.2) with baseline CD4 >500 cells/mm3.

The authors wrote their findings suggest that women exposed to HAART as MTCT prophylaxis were twice as likely to have CD4 decline below the threshold of treatment eligibility at 24 months after delivery, than women receiving other PMTCT interventions. They propose that women with baseline CD4 <500 cells/mm3 would benefit from lifelong treatment. They urge caution in interpreting their findings though, as women in this observational cohort received a relatively short duration of HAART during pregnancy only.

comment

As the Botswana investigators note, significantly increased infant mortality, as in their study, associated with early weaning has been reported elsewhere. Later weaning protected by maternal HAART or infant prophylaxis is now recommended by WHO, although the risk/benefit of breastfeeding beyond 6 months is a bit of an evidence free zone.

With respect to maternal health and mortality these reports raise important issues. Following the results of the Strategies for Management of Anti-Retroviral Therapy, or SMART study (and a smaller west African study Trivican) in 2006 – which showed that stopping HAART doubled the risk of morbidity and mortality compared to continuing – there was concern about the consequences for women receiving HAART in pregnancy and stopping. [3] This is a population where (at least in richer countries) giving short course HAART for PMTCT is standard of care.

At enrolment, SMART participants were receiving HAART (for a median of 6 years) and had a CD4 count of >350 cells/mm3. They were randomised to continue or stop and those that stopped re-start when they reached CD4 <250 cells/mm3. Although the duration of HAART received by a pregnant woman is shorter than the that received by the majority of people in SMART – in these studies about 10 weeks and 8 months in MTCT-Plus and Mma Bana respectively – the hazard ratio for OI or death from any cause in SMART was 1.6 for the subgroup that received HAART 0 to <3 years before stopping (albeit looking at small numbers).

However, data from WITS looking at progression after stopping showed, among pregnant women with CD4 >350 cells/mm3 starting HAART for PMTCT, changes in CD4 and viral load were similar at one year post partum whether women stopped or continued therapy after delivery. [4] None of the WITS women progressed to AIDS or death during the first year post partum.

Although the causes of death were not SMART events in the Botswana study and numbers are very small, these and MTCT-Plus results if shown in other studies may mean that it is not safe for women to stop HAART for PMTCT whatever their baseline CD4.

These presentations make the results of the PROMISE study important, as it will give randomised, data to definitively answer the question. If there really is a big difference between stopping and not stopping, then this part of PROMISE may be able to end early as there will be a DSMB monitoring during the course of the study there are stopping rules at each interim evaluation.

Also, in Mma Bana, 6 of 9 (67%) maternal deaths among those randomised occurred in the Arm A triple nucleoside group. Six of 8 (75%) mother-to-child transmissions were in Arm A and those infants were 3 times more likely to be infected than Arm B. Again, numbers are tiny, neither outcome was statistically significant and triple nucleosides are not standard of care, but there may be a difference by regimen between this strategy and PI or NNRTI based HAART. It is likely though that LPV/r-based regimens will remain the standard of care for women in this situation particularly as it is more available and cheaper in Africa and has more safety data.

References:

1. Shapiro R et al. Increased Maternal and Infant Mortality following Completion of HAART and Breastfeeding at 6 Months Postpartum in a Randomised PMTCT Trial: Botswana, the Mma Bana Study. 18th CROI. Boston. February 2011. Poster abstract 747.
   http://www.retroconference.org/2011/Abstracts/42502.htm
2. Ekouevi K et al. Maternal HIV Disease Progression after the Interruption of Triple ARV or Short-course ARV Prophylaxis to Prevent MTCT: MTCT-Plus. 18th CROI. Boston. February 2011. Poster abstract 753.
   http://www.retroconference.org/2011/Abstracts/41792.htm
3. Watts DH, et al. Treatment interruption after pregnancy: effects on disease progression and laboratory findings. Infect Dis Obstet Gynecol. 2009;2009:456717.
4. Danel C et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. The Lancet. 2006;367(9527):1981–1989

A poster discussion session at CROI 2011 looked at HAART during pregnancy and pre-term delivery. [1]

Discussant Claire Thorne, from the MRC Centre of Epidemiology for Child Health and the Institute of Child Health, began with a quick overview of the inconsistent findings on this “controversial topic” to date.

Pre-term delivery is defined as birth before 37 weeks of gestation. Recent WHO estimates suggest about one in ten infants are born prematurely. The rate varies across the world with the lowest in Europe and highest in Africa. Pre-term infants account for 75% of perinatal mortality and 85% of all pre-term births occur in Africa and Asia. Dr Thorne noted that why this happens is still not completely understood.

An association between HAART and pre-term delivery was first observed in Europe in 2000. Since then several (mainly European) studies have reported similar findings and other (mainly American) reports have not found an association. Dr Thorne stressed that issues of populations and methods are critical to the interpretation of these diverse findings.

While the benefits to mothers and PMTCT from HAART are unequivocable, pre-term infants have higher morbidity and mortality risks than those carried to full term. Approximately 80% of pre-term infants of women receiving HAART are born between 32 and 36 weeks, when these risks are relatively low at least in industrialised countries. However striking inequalities exist in the chance of survival of pre-term infants between these settings and those with more limited resources.

This session included cohort data from France, Spain and Botswana and from a randomised trial in Botswana.

Jeanne Sibiude showed findings from the National ANRS French Perinatal Cohort. [2] This study investigated trends in pre-term delivery between 1990 and 2009 among all singleton pregnancies included in the cohort (n=13957). Risk factors were identified in a subgroup of women (n=2631) for which more detailed data were collected between 2005 and 2009.

The investigators performed multivariate analyses adjusted for maternal age, intravenous drug use, BMI, smoking, assisted conception, HCV coinfection, timing of initiation of ART and baseline viral load

They observed a steady rise in pre-term delivery by time period reflecting changes in routine management: 9.2% in 1990 to 1993 (no ART during pregnancy) and 9.6% in 1994 to 1996, (AZT monotherapy for 90% of women), to 12.4% during 1997 to 1999 (double NRTI treatment for the majority and HAART for selected women), and 14.3% in 2005 to 2009 (HAART), p<0.01. This exceeded the background rate in France of 4.3% in 1995 and 5.9% in 2005.

Between 1990 and 2009 the risk of pre-term delivery overall was higher for HAART and double NRTI treatment than for AZT monotherapy, AOR 1.69 (95% CI 1.38- 2.07) and 1.24 (95% CI 0.96-1.6) respectively, p<0.001.

Among the subgroup of women initiating HAART during pregnancy in 2005-2009 pre-term delivery rates were similar between women already receiving HAART at conception and those initiating HAART in pregnancy, respectively 14.2% and 13.6%, p=0.6.

Pre-term delivery was also associated with maternal age, IV drug use, smoking, BMI, marital status and late access to care.

Most women received a RTV-boosted PI. There was a higher risk of pre-term delivery among women receiving a boosted, compared to a non-boosted PI (very few women received NNRTI-based regimen in this cohort), 14.4 vs 9.1%, AOR 2.03 (95% 1.06-3.89), p=0.03.

Women initiating HAART with a boosted PI during pregnancy were more likely to be hospitalised for any cause, particularly premature labour, metabolic or vascular disease and infections, compared to those receiving a non-boosted PI, p<0.001. The investigators suggested this might be due to “increased toxicity at the end of pregnancy”.

Maria Isabel González-Tomé presented data from the Spanish Cohort for the Study of HIV MTCT. [3] This was a prospective cohort study of 803 children in 7 Spanish hospitals. MTCT interventions were: none, AZT monotherapy, double NRTI, HAART with PI and HAART without PI. Risk factors were evaluated for pre-term delivery and low birth weight <2500 grams.

This study found 175 (21%) pre-term deliveries and 200 (25%) infants with low birth weight.

Older age, HCV coinfection, prenatal care and no antiretroviral treatment during pregnancy were associated with pre-term delivery in univariate analysis.

In multivariate analysis, only illegal drug use was associated with pre-term delivery, OR 2.9 (95% CI 2.2-4.0), p=0.0001 and CD4 >250 cells/mm3 was protective, OR 0.4 (95% CI 0.2-0.65), p=0.0001.

In this cohort, unlike the other presentations, HAART with or without PI was not significantly associated with pre-term delivery or low birth weight.

The first presentation from Botswana was by Natasha Parekh from the Harvard School of Public Health who showed data from 16,203 deliveries from October 2007 to March 2010. [4] Data were taken from obstetric records of women with live births at 26 weeks or longer gestational age across 6 hospitals. Out of 15,326 women in this cohort with HIV status recorded, 4,343 were HIV-positive.

The investigators evaluated rates of pre-term delivery, very pre-term delivery (<32 weeks) and very small for gestational age (<3rd percentile on Botswana-specific weight-for-age curves). They then looked at risk factors for very pre-term delivery and very small for gestational age among all women and HIV-positive women.

They found a prevalence very pre-term delivery of 4.3% and respective rate of neonatal death of 26%, OR 49 (95% CI 38-64) and a prevalence of very small for gestational age of 3.7% with a respective rate of neonatal death of 8%, OR 5.2 (95% 3.8-7.1).

In multivariate analysis, very preterm delivery was associated with history of poor obstetric outcome (including stillbirth, preterm delivery, or low birth weight), AOR 2.12 (95% CI 1.54-2.93), hypertension in pregnancy AOR (1.75, 95% CI 1.17-2.63), and maternal HIV infection AOR 1.65 (95% CI 1.26-2.17). Very small for gestational age was also associated with a history of poor obstetric outcome AOR 1.77 (95%CI 1.23-2.53), hypertension in pregnancy AOR 3.44, (95%CI 2.40-4.93), and maternal HIV infection AOR 1.90 (95%CI 1.41-2.55).

Initiating HAART before conception was associated with very small for gestational age, AOR 1.75, (95% CI 1.21-2.52), but not with very pre-term delivery, AOR 0.78, (95% CI 0.49-1.26). Among HIV-positive women. HAART initiation before conception was also associated with hypertension in pregnancy, AOR 1.34 (95% CI 1.00-1.77).

Kathleen Powis presented the only data from a randomised controlled trial in the second presentation from Botswana. [5]

This study analysed 530 women (267 receiving PI-based and 263 triple NRTI HAART) in the randomised treatment arms of Mma Bana who received a median of 11.3 weeks (IQR 8.3-12.9 weeks) of HAART in pregnancy.

The investigators found higher rates of pre-term delivery in the women receiving a PI compared to those receiving triple NRTI treatment, 21.4% vs 11.8%, p=0.003. This was regardless of duration of HAART in pregnancy.

In multivariate analysis, PI-based HAART in the third trimester of pregnancy was associated with a two-fold increase in pre-term delivery AOR 2.03 (95% CI 1.26-3.27).

The investigators noted a lower maternal weight gain in the women receiving PI-based treatment compared to triple NRTI but this had no association with the likelihood of pre-term delivery.

They found a 2-fold higher rate of hospitalisation (22.7 vs 12.7%, p=0.02) and 5-fold higher rate of mortality (6.8 vs 1.4%, p=0.002) in the first 6-months of life among infants born pre-term but they did not observe a difference by maternal treatment regimen.

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Much discussion following the presentations focused on the difficulties of accurately determining pre-term delivery, which has contributed to uncertainty, particularly with observational data. PI-based HAART does appear to show increased likelihood of pre-term delivery from the “controversial” data to date.

References:

All references from 18th Conference on Retroviruses and Opportunistic Infections, Boston, February 2011 unless otherwise indicated.

1. Themed discussion: HAART during pregnancy and pre-term delivery. Tuesday, 1pm.
   http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20445&&dp=player.jsp&e=13730&mediaType=podiumVideo
2. Sibiude J et al. Large increase in prematurity between 1990 and 2009 in HIV-infected women in the National ANRS French Perinatal Cohort: does ritonavir boost play a role? Poster abstract 743.
   http://www.retroconference.org/2011/Abstracts/41464.htm
3. González-Tomé MI et al. Risk factors of preterm delivery and low birth weight in a multicentre cohort of HIV-positive pregnant women. Poster abstract 744.
   http://www.retroconference.org/2011/Abstracts/41494.htm
4. Parekh N et al. Risk factors for very premature and very mall for gestational age infants in Botswana. Poster abstract 745.
   http://www.retroconference.org/2011/Abstracts/40146.htm
5. Kathleen Powis et al. Protease inhibitor-based ART was Associated with pre-term delivery, but not adverse infant outcomes, in a randomised MTCT prevention study in Botswana. Poster abstract 746.
   http://www.retroconference.org/2011/Abstracts/39994.htm

There are limited data from programmes in resource-limited settings describing the effectiveness of HAART compared to AZT monotherapy for PMTCT.

Scott Dryden-Peterson and colleagues from Botswana showed findings from a prospective, observational study of infants, born to HIV-positive mothers, enrolled on the maternity wards of one urban and one rural hospital between February 2009 and April 2010.

The investigators followed the infants from birth to 6 months and compared transmission rates between infants born to mothers receiving either HAART or an AZT based PMTCT strategy. Infants were tested for HIV (DNA PCR) at 1 month of age.

In Botswana, in accordance with national guidelines, the PMTCT programme provided HAART for women with CD4 <250 cells/mm3 and AZT monotherapy from 28 weeks gestation for women with CD4 >250 cells/mm3 (with single-dose NVP if <4 weeks AZT received). Infants were given single dose NVP+ one month AZT.

A total of 423 mothers agreed to participate and had received either HAART or AZT. Out of 428 infants, 258 were born to mothers receiving HAART and 170 to those receiving AZT (with or without single dose NVP).

Mothers receiving HAART had a longer duration of antiretrovirals prior to delivery, median 12 weeks (IQR 7.1-17.7) compared to median 10.4 weeks (IQR 7.8-12.1) for those receiving AZT, p=0.001.

The median CD4 count was lower for women receiving HAART compared to AZT, respectively 262 vs 430 cells/mm3, p<0.001.

There were no significant differences in infant prophylaxis, infant feeding or prematurity between the two groups.

Overall 10 infants (2.5%) were HIV-infected, 9/158 (5.7%) in the AZT group and 1/249 (0.4%) in the HAART group, p=0.001. When the investigators restricted the AZT group to mothers with CD4 >350 cells/mm3, as recommended in WHO guidelines, their findings were similar, p=0.007. They noted that half the infections occurred among mothers with >350 cells/mm3.

In multivariate analysis, the adjusted risk ratio for AZT compared to HAART was RR 15(95% CI 2.1-109), p=0.008.

The investigators acknowledged that they were unable to determine HIV status for 21 (4.9%) infants, including 9 who died prior to testing. Also, they were unable to determine efficacy in protection during breastfeeding as few women opted to do so in this programme.

However they wrote: “Strategies to provide HAART for all pregnant women, as currently underway in Botswana, could nearly eliminate MTCT.”

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PROMISE will also more definitively address the AZT vs HAART debate for women who do not presently require therapy for their own health. In the Kesho Bora study with randomised comparison of women with similar CD4 200-500 cells/mm3, the transmission rate in women who received AZT vs those who received HAART was not significantly different. [2]

However real life is not always like a trial and notably in this analysis women with lower CD4 counts receiving HAART had better transmission rates than healthier women with AZT. That PMTCT strategies are complicated from an operational point of view has been a big concern among implementers.

If the differences between the groups are as great as appear to be in the retrospective analysis in the Botswana report, again PROMISE will then end early as there will be interim DSMB reviews of the data.

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. de Vincenzi I et al. Triple-antiretroviral (ARV) prophylaxis during pregnancy and breastfeeding compared to short-ARV prophylaxis to prevent mother-to-child transmission of HIV-1 (MTCT): the Kesho Bora randomized controlled clinical trial in five sites in Burkina Faso, Kenya and South Africa. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Abstract LBPECO1.
   http://www.ias2009.org/pag/Abstracts.aspx?AID=3631

In an oral late breaker, Roland Tubiana presented findings from a French multisite PMTCT study – PRIMEVA (NCT00424814) – designed to evaluate the use of lopinavir/r (LPV/r) monotherapy in pregnancy for women not needing treatment for their own health.

This was an open label, phase II/III trial. Untreated women with CD4 >350 cells/mm3 and viral load <30,000 copies/mL were randomised 2:1 to receive either LPV/r monotherapy (n=69) or LPV/r + AZT + 3TC (n=36), from 26 weeks gestation until delivery.

The primary endpoint of the trial was >75% women with viral load <200 copies/mL at week 8 of treatment. Secondary endpoints included viral load at delivery and comparative analysis of safety outcomes during pregnancy and until 24 months in children.

The baseline characteristics were similar between arms; women had a median CD4 count of 525 cells/mm3 and viral load of 2952 copies/mL.

Intent-to-treat analysis of the monotherapy arm revealed a viral load <200 copies/mL at week 8 in 61/69 women (88.4%, 95% CI 78.4-94.9). This was similar to that observed in the control arm (94.4%, 95% CI 81.3-99.3) p=0.18.

The proportions of women with viral load <200 copies/mL at delivery was similar between the LPV/r and control arms, 91.3% (95% CI, 82.0-96.7) vs 97.2% (95% CI, 85.5-99.9), p=0.41. But when the investigators looked at viral load <50 copies/mL at the same time point, a greater proportion of women in the control arm achieved this, 79.7% (95% CI 63.3-88.4) vs 97.2% 985.5-99.9) in the LPV/r and control arms respectively, p=0.01.

Similar proportions of cesarean section delivery (49.5%) and pre-term delivery (10.5%) were observed in both arms. Changes of ART due to tolerability were significantly less frequent the monotherapy arm compared to control, respectively 1.4% vs 11.1%, p=0.046.

There was one case of transmission in the control and none in the monotherapy arm.

Evaluation of the infants is ongoing.

Reference:

Tubiana R et al. LPV/r monotherapy during pregnancy for PMTCT of HIV-1: The PRIMEVA/ANRS 135 randomised Trial, pregnancy outcomes. 18th CROI. Boston. February 2011. Oral abstract 125LB.
http://www.retroconference.org/2011/Abstracts/42568.htm

Many HIV-positive women in the UK and Ireland have more than one pregnancy after their diagnosis. In 2009 40% of pregnancies in this population were sequential. The majority of these women will have received mother to child transmission (MTCT) interventions in previous pregnancies.

Clare French and colleagues from the MRC Centre of Epidemiology for Child House and UCL Institute for Child Health looked at whether sequential pregnancies are associated with increased MTCT risk.

Pregnancies in diagnosed HIV-positive women in the UK and Ireland are reported to the National Study of HIV in Pregnancy and Childhood (NSHPC).

The investigators analysed NSHPC data on live singleton births from 2000 to 2010. They compared the risk of detectable maternal viral load at delivery and of MTCT in sequential pregnancies with the risk in first reported index pregnancies. This included those in women with only one pregnancy. They conducted multivariate analyses using logistic regression.

During this period there were 10,154 pregnancies, of which 2099 (20.7%) were sequential. Of the sequential pregnancies, 1795 were 2nd; 274 were 3rd; and 30 were 4th or 5th.

The investigators found that 100% of sequential pregnancies (n=2099) were diagnosed prior to pregnancy, compared with less than half (43.5%) of index pregnancies (n=8055), p<0.001. They noted that sequential pregnancies were more common in the more recent period evaluated (5.5% in 2000-2003 vs 66.4% in 2008-2010) and were more likely to have vaginal deliveries. Women were also more likely to be receiving HAART at conception for subsequent pregnancies, p<0.001.

In multivariate analysis adjusted for year of delivery and treatment duration, the likelihood of having a detectable viral load at delivery did not differ significantly between index and subsequent pregnancies, p=0.77. Infant HIV infection status was available for >80% of births and there was no significant difference in mother to child transmission in a multivariate model adjusted for year of delivery, treatment duration and mode of delivery.

The investigators wrote: “As the number of sequential pregnancies increases, and the treatment and management histories of women consequently become more complex, it is important that the situation be carefully monitored.”

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Good news.

Reference:

French C et al. Are sequential pregnancies in HIV-positive women associated with an increased risk of MTCT? 18th CROI, February 2011, Boston. Poster abstract 736.
http://www.retroconference.org/2011/Abstracts/40863.htm

HIV incidence infection in pregnancy is common in women in sub-Saharan Africa.

Investigators from the PEPI-Malawi trial recently developed a multi-assay algorithm (MAA) to determine incidence. They used the assay to identify women in the trial who were likely to have been recently infected with HIV at the time of delivery. They then evaluated whether those women were at increased risk of in utero mother-to-child transmission of HIV (MTCT).

Susan Eshleman and colleagues showed findings from this evaluation as a poster at CROI 2011.

PEPI-Malawi compared three infant regimens for prevention of post-natal MTCT.

The investigators obtained plasma samples from 2561 women at time of delivery. The samples were tested using the BED-Capture EIA (BED) and an avidity assay (a modified version of the BioRad HIV-1/HIV-2+0 ELISA).

For their MAA they used the following criteria to identify recently infected women:

BED<1.0 OD-n + avidity < 80% + CD4 cell count >200 cells/mm3 + HIV viral load >400 copies/mL

They indentified 73 (2.9%) women as recently infected using the MAA.

All but 9 women with non-recent infection had a BED result >1.0 and/or an avidity result >80%; 4 women with non-recent infection had a CD4 count <200 cells/mm3; and 5 had a viral load <400 copies/mL.

Of 54 women known to have non-recent HIV infection (median time since previous positive HIV test, 4.29 years, range 2.3 to 6.1 years), none were misclassified as recently infected. Nor were 9 women already receiving HAART at the time of delivery.

The recently infected group were younger, had lower parity and higher median CD4 cell count at delivery than the non recent group (all p<0.0001).

The risk of in utero MTCT was significantly higher among women identified as recently infected compared to non-recent< 17.8% vs 6.7%, p= 0.001.

In a multivariate analysis, increased risk of in utero transmission was independently associated with: recent infection AOR 2.49 (95% CI 1.30-4.78), p=0.006; viral load (per log10 increase, AOR 2.01 (95% CI 1.60-2.51), p <0.0001; and age (per 10-year increase, AOR 0.66 (95% CI 0.43-0.93), p=0.02). There was no association with CD4 count, infant gender, early presentation or infant regimen.

The investigators concluded that their results suggest recent maternal HIV acquisition is strongly associated with in utero HIV transmission independent of viral load at delivery.

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This is the first randomised trial data to show the association between recent infection and in utero transmission.

Reference:

Eshleman S et al. Women identified as recently infected at the time of delivery using a multi-assay algorithm for HIV incidence had a higher rate of in utero HIV Transmission: PEPI-Malawi Trial. 18th CROI, Boston. February 2011. Poster abstract 737.
http://www.retroconference.org/2011/Abstracts/40403.htm

Pregnant women are at greater risk both of HIV acquisition and transmission to their negative partners than non-pregnant women. This is independent to behavioural factors and is likely to have biological causes.

Jan Walters and colleagues from University of California, University of Southern California and Children’s Hospital Los Angeles hypothesised that pregnancy may cause shifts of the cerviovaginal cytokine profile that may increase the risk of infection.

Using a multiplex assay, the investigators compared concentrations of 39 immunodulatory factors in cervicovaginal lavage from 21 pregnant and 24 non-pregnant HIV negative women attending ob/gyn clinic. They measured cervical ectopy (an independent risk for HIV transmission) by planimetry. They used the same multiplex assay to determine plasma CCL22 concentrations.

They found 26/39 (66%) measured immunomodulatory factors were detectable in at least half of the tested samples. Concentrations of CCL22 were 3-fold lower in cervicovaginal lavage in pregnant women than non-pregnant women (geometric mean 30 pg/mL vs 90 pg/mL, p=0.001).

They observed a strong negative correlation of the cervicovaginal lavage CCL22 concentration with gestational age (Spearman’s rank correlation coefficient –0.49), p=0.0006. Non-pregnant women were assigned a gestational age of zero.

No other tested factors were associated in adjusted analysis.

The investigators concluded that pregnancy appears to result in reduced concentrations of the HIV suppressive cytochine CCL22 in cervicovaginal secretions, which could contribute to the increased susceptibility to HIV during pregnancy. They suggested that their hypothesis should be tested in prospective studies.

Reference:

Walter J et al. Reduced concentration of the HIV suppressive cytokine CCL22 in cervicovaginal secretions from pregnant women. 18th CROI, Boston. February 2011. Poster abstract 734.
http://www.retroconference.org/2011/Abstracts/41986.htm

The complex question of the optimal time to start antiretroviral therapy (ART) in HIV-positive patients co-infected with TB was the subject of two important presentations at a plenary session of the 18th Conference on Retroviruses and Opportunistic Infections. Diane Havlir presented the findings of ACTG’s Stride trial and Salim Abdool Karim presented the results of the SAPIT trial. [1, 2]

Stride

Havlir and colleagues conducted an open label international trial to confirm their hypothesis that in patients starting TB treatment, ART initiated within 2 weeks (immediate initiation) could reduce mortality and morbidity compared to patients starting ART within 8-12 weeks (early initiation).

Patients were randomised to immediate (405 patients) and early (401 patients) ART treatment arms. Patients had confirmed or presumed TB and a CD4 cell count <250 cells/mm3. The ART regimen for 97% of patients was efavirenz and tenofovir/emtracitabine. The TB treatment was country approved. Nearly half of the patients had confirmed TB with a median CD4 count of 77 cells/mm3 (IQR: 36-145).

The primary endpoints of the study were all cause–mortality and new AIDS-defining illnesses by 48 weeks. No data is available for after 48 weeks as patients were not followed beyond this endpoint. Secondary endpoints were safety, CD4, HIV RNA changes, TB IRIS and TB outcomes.

The proportion of AIDS or death between the immediate (12.9%) and the early (16.1%) arms were not statistically significant (p=0.45). However, a pre-specified analysis that considered patients with a CD4 cell count <50 cells/mm3 found that the proportion of patients with AIDS or death was 26.6% in the early arm compared to 15.5% in the immediate arm and this was significant (p=0.02). The majority of AIDS or death events occurred within the first 24 weeks after randomisation, with the highest proportion amongst the early arm with a CD4 count <50 cells/mm3. There was barely any difference in endpoints in the higher CD4 strata (11.5% versus 10.3% for the immediate versus early arms respectively; p=0.67).

Thirteen cases of cryptococcal disease made it the most common AIDS primary endpoint (n=63) The next two most common AIDS illness included oesophageal candidiasis (n=12) and Kaposi’s Sarcoma (n=11).

There were 31 deaths in the immediate arm versus 37 deaths in the early arm. TB was the largest contributor to deaths (21 out of 68 patients). During question time, Havlir was asked if the 14 TB-related deaths on the immediate arm versus seven in the early arm were indicative of fatal TB IRIS. She pointed out that these cases were reviewed and that they were a consequence of TB progressing in contrast to patients with IRIS who get better and then become ill again.

Twenty-one cases of AIDS-related deaths were reported and 16 non-AIDS related deaths (respiratory, renal and hepatic disease being most common). The frequency of TB IRIS in the immediate arm was 11% and 5% in the early arm (p=0.002).

In summary the investigators found that immediate ART did not overall reduce AIDS-defining disease overall and death compared to early ART, but for patients with CD4 counts < 50 cells/mm3 immediate ART reduced AIDS and mortality. Grade 3 or 4 toxicities, HIV RNA suppression rates or CD4 increase did not differ between the arms. TB IRIS was higher in the Immediate arm although it did not increase mortality. They concluded that in patients with CD4 counts <50 cells/mm3 ART should be started within two weeks.

SAPIT

Salim Abdool Karim and colleagues conducted a 3-armed open label trial called SAPiT. The sequential arm, in which patients first completed their TB treatment course and then initiated ART was stopped by the DSMB due to the significantly higher mortality in that arm. We have previously reported on this aspect of the trial. [3] This report is confined to the results of the remaining two arms.

HIV-positive patients with smear-positive TB and CD4 counts <500 cells/mm3 were randomised into an early integrated therapy arm (214 enrolled and ART initiated within four weeks of starting TB treatment) and a late integrated therapy one (215 enrolled and ART initiated within four weeks of completing the intensive phase of TB treatment). Baseline characteristics for age, gender and CD4 count were similar in both arms.

All participants attended the TB-DOTS programme at eThekwini Clinic in Durban and the study’s primary endpoints were death and AIDS defining illness.

Both arms had similar rates of AIDS defining illness or death with 18 deaths in the early arm and 19 in the late arm. The Incidence Rate Ratio (IRR) was 0.89 (95% CI: 0.44 to 1.79; p=0.73).

When the results were stratified for CD4 count of <50 cells/mm3, a 68% reduction of AIDS or death was found in the early and this approached significance (IRR: 0.32 [0.07-1.13], p=0.06). For participants with CD4 counts >50 cells/mm3 no discernable differences in AIDS/Death were noted (IRR: 1.51 [0.61-3.95], p=0.34).

In patients with CD4 counts <50 cells/mm3, the reduction in AIDS/death in the early arm overshadowed the 5-fold higher risk of IRIS (95% CI; IRR 4.7 [1.5-19.6]; p=0.01) and the increasing trend in drug switches.

HIV suppression was greater than 90% after 18 months irrespective of CD4 status. Similarly TB treatment was successfully completed in about 80% of patients with no significant differences across groups.

On the other hand in patients with CD4 counts > 50 cells/mm3 there was an IRIS rate of 15.8 person years and 7.2 in the late arm; CI: 95%; IRR: 2.2 [1.1-4.5]; p=0.02) and this was significant. Rates of drug switches were 7/100 patient years in the early arm and 1 in the late arm (CI: 95%; IRR: 6.8 [0.8-551.1]; p=0.04). The lower rates of IRIS and drug switches in the late therapy arm indicated a slight benefit to starting ART during the continuation phase of TB treatment in patients with CD4 counts >50 cells/mm3.

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The main results of both studies were similar. Immediate ART is warranted in patients with CD4 counts <50 cells/mm3 while ART for patients with CD4 counts >=50 cells/mm3 can be postponed until the continuous phase of TB treatment, but not beyond.

These studies have implications for some guidelines in high incidence countries. For example, he South African Guidelines for Antiretroviral Therapy in Adults state with respect to patients co-infected with TB state:

“[For patients with] CD4 count <200 cells/mm3: commence ART after it is clear that the patient’s TB symptoms are improving and that TB therapy is tolerated. The suggested time period to commence ART is between 2 and 8 weeks after starting TB therapy.

CD4 count 200 – 350 cells/mm3: delay ART until after the intensive phase of TB therapy (2 months) unless the patient has other serious HIV-related illness. The longer delay before commencing ART in this group is recommended to reduce the risk of shared toxicity (as the patient will then only be on fewer TB drugs) and to reduce the risk of the immune reconstitution inflammatory syndrome (see below).

CD4 count >350 cells/mm3: defer ART.”

When the guidelines are updated, the drafters will have to consider:

• Whether the recommendations be modified to explicitly state that patients with CD4 counts <50 cells/mm3 must be started immediately on ART, or does the current framing sufficiently cover that?
• Whether the recommendations be modified to initiate ART to patients with CD4 counts of 50-350 cells/mm3 only after the intensive phase?

The answers to these questions are not clear.

While the SAPIT trial included patients with CD4 counts <500 cells/mm3, there is not yet enough data on patients with CD4 counts of 350 to 500 cells/mm3 to justify a change in guidelines. Hopefully the START and TEMPRANO trials, scheduled to complete in 2015 and 2013 respectively, will help answer this question. [5, 6]

References:

1. Havlir D et al. 2011. International randomized trial of immediate vs early ART in HIV+ patients treated for TB: ACTG 5221 STRIDE study. 18th Conference on Retroviruses and Opportunistic Infections, 27 Feb to 2 March, Boston.
   http://www.retroconference.org/2011/data/files/webcast_2011.htm
2. Abdool Karim S et al. 2011. Optimal timing of ART during TB therapy: findings of the SAPiT trial. 18th Conference on Retroviruses and Opportunistic Infections, 27 Feb to 2 March, Boston.
   http://www.retroconference.org/2011/data/files/webcast_2011.htm
3. Geffen N. 2009. HIV and TB from CROI. HTB South. April 2009.
   http://i-base.info/htb-south/589/
4. Southern African HIV Clinicians Society and Department of Health. 2008. Guidelines for antiretroviral treatment in adults.
   http://sahivsoc.org/index.php?option=com_docman&task=doc_download&gid=40&Itemid=67
5. INSIGHT. Strategic Timing of Antiretroviral Treatment (START).
   http://www.clinicaltrials.gov/ct2/show/NCT00867048
6. ANRS. Early antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in HIV-infected adults (ANRS 12136 TEMPRANO).
   http://www.clinicaltrials.gov/ct2/show/NCT00495651

Medecins Sans Frontieres (MSF) have published the results of an analysis of a Lesotho cohort, comparing toxicity and regimen substitutions due to tenofovir versus AZT and d4T (stavudine). [1]

The findings of this nurse-managed community cohort study support the latest WHO guidelines that recommend the replacement of d4T with either tenofovir or AZT. This study confirmed available evidence because it showed that tenofovir has lower side effect rates. This coupled with easier dosing makes it a better option than either d4T or AZT.

Between January 2008 and December 2008, 1,185 adult patients (785 women) were enrolled into care and the records of 1,124 were analysed. All patients were prescribed 3TC and either nevirapine or efavirenz. Their third drug was tenofovir, AZT or d4T (at 40 mg BID dose). This period was chosen because there was overlapping use of the three drugs during this period, as d4T was phased out and tenofovir was phased in.

Nearly all patients initiated on tenofovir were given baseline renal function tests. Patients with low creatinine clearance were not initiated on tenofovir. Therefore 13 patients with severe renal insufficiency (CrCl <30 mL/min) were excluded from the analysis to avoid bias. From HAART initiation the endpoints were death, loss to follow-up or first toxicity-driven switch. Median age was 39 years. The authors noted that proportionately fewer women were initiated on tenofovir than AZT or d4T (53.5% v 89% v 78% respectively) due to misconceptions among health workers that tenofovir should not be initiated in pregnant women.

The study included 587 patients started on tenofovir, 255 on AZT and 282 on d4T with a similar median time on treatment of 483 days (IQR: 392-585), 493 days (IQR: 349–580) and 480 days (IQR: 277–610) respectively.

The overall mortality rate for the cohort was 6.5 per 100 person-years [95%CI: 5.3 to 7.9 per 100 person-years]. For patients on tenofovir, the mortality rate was 5.1 per 100 person-years [95%CI: 3.8 to 7.0), for those on AZT, 7.5 per 100 person-years [95%CI: 5.0 to 11.1] and for those on d4T, 8.3 per 100 person-years [95%CI: 5.8 to11.7]. None of these differences were significant.

The overall rate of switches due to toxicity was 8.0 switches per 100 person-years [95%CI: 6.7 to 9.6]. Based on the regimen that patients were on, this rate of switch differed significantly; for tenofovir the switch-rate was 3.0 switches per 100 patient-years [95CI%: 2.0 to 4.5]; for AZT it was 8.1 switches per 100 patient-years [95CI%: 5.4 to 12.1] and for d4T it was 18.8 switches per 100 patient-years [95CI%: 14.8 to 24.1].

The most common reason for switching regimens amongst patients on tenofovir (n=19) was renal toxicity (18 patients). For AZT (n=15) it was severe anaemia (11 patients) and for d4T (n=42) it was severe neuropathy (29 patients). Also in the d4T group 11 patients switched because of lipodystrophy and two because of severe lactic acidosis.

Tenofovir-associated renal toxicity was low and generally well managed. Of the 5% who developed toxicity, the majority had a creatinine drop of less than 10 mL/min, and all but 3 returned to normal on a subsequent measurement.”

The authors conclude that their study indicates that in resource poor settings where the detection of lactic acidosis and the monitoring of neuropathy and lipodystrophy are difficult, the use of tenofovir as the first-line option is advised.

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This study confirms expectations and adds further evidence to support the changes in WHO guidelines as well as by South Africa and other African countries in recent years.

But this study also allays a concern that renal toxicity rates from tenofovir might be unmanageably high in an African setting. In the US kidney disease is four times higher amongst African Americans than Caucasians. [2] Tenofovir’s good side-effect profile was based in large part on its use in non-African settings, though there is no evidence that tenofovir is associated with lower GFR amongst people of African descent in the US and Europe. The Lesotho study is reassuring because it confirms that the drug’s association with few side-effects can be expected in African populations as well.

References:

1. Bygrave H et al. Implementing a tenofovir-based first-line regimen in rural Lesotho: clinical outcomes and toxicities after two years. J Acquir Immune Defic Syndr. 2011 Mar 1;56(3):e75-8. PMID: 21164354
   http://www.ncbi.nlm.nih.gov/pubmed/21164354
2. National Kidney Disease Education Program. African Americans and Kidney Disease Fact Sheet.
   http://www.nkdep.nih.gov/news/campaign/african_americans.htm#1

The European Medicines Agency has completed a review of Zerit as part of the procedure for the renewal of the medicine’s marketing authorisation.

The Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the marketing authorisation for Zerit should be renewed but that the use of the medicine should be severely restricted in both adults and children.

In this context:

• Prescribers are reminded of the severe side effects seen with Zerit 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;
• Prescribers should consult the updated prescribing information and the communication letter that will be sent to them for more information;
• Patients should continue reporting any possible side effects to their doctor and should contact their doctor or pharmacist with any questions they have concerning their treatment.

Source: European Medicines Agency (EMA) (21.02.2011)

Reference:

Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 14-17 February 2011

A questions and answers document referring to this matter can be found in the following link:
http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500102227

The London HIV Consortium, the pan-London commissioning group for HIV services, has just outlined the results of the tender process for purchasing HIV drugs for the next two years. This is part of an ongoing process to manage the HIV budget within government-imposed restrictions on NHS budgets. Over two years the group is faced with having to make savings of approximately £10 million to mange the same service on a budget that has not increased in line with inflation.

This will change the way that some HIV drugs will be prescribed in London. Although there are circumstances where the choice of when to use each drug has changed, all drugs will still be available for different situations.

Initially the changes mostly affect the choice of treatment for people who are starting treatment. Most people who are currently on stable treatment will not be asked to change treatment. However, some people on stable treatment will be asked to switch one or more of their current drugs.

The main changes are:

• More people starting treatment will start with a combination of two pills rather than one pill once a day.
• Some people on current treatment will be asked to change to a similar alternative treatment.

This policy for broadly influencing prescription practice has been part of London drug commissioning for many years.

The details of these changes are explained below.

Cost is the principal reason behind the changes. Widespread cuts across the NHS include nearly all services. HIV is no different to any other service in this respect. Prescribing the most cost effective treatment first will help protect other aspects of HIV services. HIV treatment is also very individual. Treatment will continue to be individualised for each person’s circumstances.

Outline of 2011 process

This year the Consortium changed the process of purchasing drugs. This required drug manufacturing companies to tender bids for the costs of their drugs for a range of clinical settings, for example for first-line therapy or for first treatment failure etc. This process has taken several months. It has involved input from doctors from the leading HIV hospitals, pharmacists and community advocates.

The tender included the option for a sliding scale of costs if larger quantities are used.

The principles for this process are important:

• No drug will be excluded from being prescribed. The range of individual patient responses makes it likely that in some circumstances there will be a clinical need for some people to use different combinations to those recommended.
• The guidelines for use of treatment are supported by evidence. The decisions were not determined just by the cost of a drug. The decision on accepting a drug tender are dependent on them being effective and reducing the risk of side effects. The cheapest drugs were not selected if they were not as effective or had greater side effects. This process will not result in widespread use of less effective drugs simply because they are priced cheaply. However, where two options are broadly similar but have a significant difference in costs, the less expensive drug will be preferred.
• These measures are being taken due to financial constraints being imposed throughout the NHS. If HIV care does not respond by providing the cost-effective treatments, then cuts are more likely to be made in other HIV services: reduced clinic time, fewer doctors and nurses, shorter appointments and reduced monitoring.

All manufacturers had the opportunity to modify aspects of their bids to standardise them with other aspects of the tender process, especially in relation to the staggered price related to the volume of drugs purchased.

These budget estimates are dependent on reaching projected target volumes for each drug, including maintaining current drugs levels for some existing drugs. In order to reach or maintain these targets over the year, every London clinic will be working to the same guidelines. Although a clinic can prescribed outside these guidelines the drug costs for those patients will not be reimbursed by the London HIV Consortium.

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HIV care is faced with the challenge of being managed and maintained under the financial constraints being imposed on the NHS. This has to be done without jeopardising patient care and these guidelines have the potential to improve patient care in many cases.

An audit will track the outcomes from key treatment changes, initially at three-monthly intervals, to confirm that safety and efficacy is maintained.

These recommendations broadly fall within the BHIVA guidelines (though these have not been significantly revised since 2008), which include the importance of cost effectiveness when clinical data support several therapeutic choices.

HIV care remains one of the most cost-effective medical interventions. These proposed changes minimise disruptions to patient care, maintain access to high quality drugs and retain flexibility for individualised care.

Although this tender is for two years the clinical guidelines will be reviewed and changed if new research raises concerns about the clinical use of any of the preferred drugs.

What this means in practice

The recommendations for people starting treatment and people already on treatment and are summarised below.

1. Treatment-naïve patients

Preferred option:

a) Efavirenz or nevirapine plus coformulated abacavir/3TC (Kivexa)

When there are clinical reasons not to use any of these drugs, alternatives can of course be used. This includes drug resistance, concern for side effects, shift work, pregnancy, high viral load (over 100,000 for abacavir) or high risk of heart disease (a greater than 10% risk over ten years, again for abacavir). If abacavir/3TC is not appropriate tenofovir/FTC is recommended.

Alternatives:

a) Atazanavir/r is recommended as the first choice if efavirenz or nevirapine are not appropriate.

b) Tenofovir/FTC is recommended when abacavir/3TC is not appropriate.

c) Other drugs can be used when there is a clinical need. For example, alternative protease inhibitors can be used whenever these are clinically more appropriate.

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This main change for people starting treatment is that there will be more people using two pills a day rather than one. First-line treatment will still use once-daily combinations and number of daily doses is probably more important than daily pill count. All the recommended combinations are already widely used.

In practice this should not be a significant problem for most people. Most people prefer one drug to two, but there are few studies that show it makes a difference to adherence or to clinical results. While the ease of use of single-pill formulations are popular, there are little data suggesting that one vs two pills daily has a poorer clinical outcome.

When there are clinical reasons to use alternatives, these will still be used. Common reasons not to use abacavir/3TC includes a higher risk of heart disease and a viral load >100,000 copies/mL when starting treatment (based on ACTG 5202). For a few people this might also include higher lipids as tenofovir/FTC has a better lipid profile than abacavir/3TC.

Atazanavir/r is already a widely used, once-daily protease inhibitor that is generally easy to tolerate and easy to modify in case of side effects. This has the potential to improve combinations, for example for people currently taking twice-daily protease inhibitors. Switching to alternatives, including back to the original treatment is possible at all stages if this is needed.

The commissioners already influence drug prescribing. Currently there are financial incentives for clinics to start at least 85% of new patients on NNRTI-based combinations using CQUINs (DoH Commissioning for Quality and Innovations). For 2011/12 clinics that do not broadly follow the new guidelines, threatening to derail the pan-London approach, will having their drug budget witheld entirely.

2. People currently on stable treatment

a) Some people using protease inhibitor-based treatment that does not include atazanavir will be recommended to switch to using atazanavir-based combinations unless there is a clinical reason to stay on their current treatment. These reasons could include previous side effects and drug resistance. Only the protease component of the combination is being recommended to switch.

b) People currently on NNRTI-based stable treatment are not being asked to switch. People currently using Atripla will not be asked to change from Truvada (tenofovir/FTC) to Kivexa (abacavir/3TC), although they do have this option. This decision may be reviewed in the future, but is unlikely to change in the short-term. This is is dependent on clinics across London following the general guidelines for new and existing patients.

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The protease inhibitor switch may improve treatment for many people as this may include reduced doses and lower pill counts with some changes.

The staggered approach to switching people who are stable on their current treatment is dependent on clinics across London following the general guidelines for new and existing patients.

These guidelines might also prompt a review to switch patients on older treatments that are not recognised as first choice options in BHIVA guidelines.

3. Use of raltegravir

Raltegravir will still be used predominantly by people with documented triple-class resistance. It can also be used in a limited number of other situations where there is a clinical need. This includes cases where a rapid reduction of viral load is important (for example HIV diagnosis in late pregnancy) or to avoid drug interactions (for example with chemotherapy). The higher cost of raltegravir compared to other first-line and second-line drugs is the reason behind this more restricted access.

Raltegravir can be prescribed by any doctor outside of these guidelines but the cost of the treatment will have to be paid by the hospital rather than by the London Consortium.

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Raltegravir was initially developed as a treatment for people with drug resistance. It was also priced higher as a life-saving drug rather than a treatment for standard therapy. Although the cost for raltegravir has come down it is still more expensive that alternative switching options. It is disappointing that the cost of raltegravir currently limits prescribing at any treatment stage as the potential advantages of raltegravir over protease inhibitors include reduced side effects such as less impact on lipids (cholesterol and triglycerides). The disadvantages of raltegravir include fewer long-term data as it is a newer drug, needing to use twice-daily dosing, and that previous drug resistance limits the ability to switch easily from a protease inhibitor to raltegravir. Several studies have shown an increased risk of treatment failure compared to staying on a protease inhibitor.

Additional background

HIV-positive people will be able to discuss these proposals with their doctor. As with all treatment decisions, discussing options with the medical team is always recommended.

For many years, antiretroviral drugs have been bought on a pan-London basis by the London HIV Consortium as part of a way to deliver equity of care for HIV-positive people in all boroughs, independently of which London clinic they attend. Each year this group negotiates the price of each drug with each company.

While the process of drug pricing has a low profile amongst most people who use treatment, it is very complicated. The cost of a drug rarely is the same as its list price. This has led to many improvements in HIV care including greater prescribing consistency and access and use of the newest drugs. This group is as focussed on the quality of care as it is on costs, and it has developed a range of services that have improved patient care.

For example, the same London HIV Consortium are responsible for establishing the New-Fill service to correct facial fat loss in NHS clinics in London. It has also helped maintain routine services by saving costs with other initiatives such as expanding home delivery of drugs (this saves VAT costs that are otherwise charged on hospital prescribed medicines).

By ring-fencing high cost drugs for people with most extensive drug resistance, this ensured equity of access to the most extensive treatment for people whose virus was most difficult to treat.

Simon Collins is a member of the London HIV Consortium Drug and Treatment Sub-Committee.

HIV i-Base receiving no funding from the London HIV Commissioners.

References and links:

The London Consortium Drug Group included lead clinicians from London clinics, HIV-specialist pharmacists, community advocates, HIV-positive people and health commissioners. Document from the group will be posted online.
http://www.londonspecialisedcommissioning.nhs.uk/

A slide set summary of the recommendations in PDF and the Powerpoint files are available from the i-Base website.
http://www.i-Base.info/changes-to-hiv-drug-prescribing-in-london

The approval is based on one principal clinical trial (1100.1486) that demonstrated prolonged suppression of HIV-1 RNA through 48-weeks, and a supportive trial (1100.1526).

Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, nevirapine should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm3 or in adult males with CD4+ cell counts greater than 400 cells/mm3 unless the benefit outweighs the risk

The 14-day lead-in period with immediate-release nevirapine 200 mg daily dosing must be strictly followed; it has been demonstrated to reduce the frequency of rash.

If rash persists beyond the 14-day lead-in period with immediate-release nevirapine, do not begin dosing with nevirapine XR. The lead-in dosing with 200 mg once-daily should not be continued beyond 28 days, at which point an alternative regimen should be sought.

Comment

Filing in Europe for nevirapine XR has already taken place with a decision from the EMA expected in the third quarter of 2011.

Source: FDA list serve

The complete product label will be posted at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

This label change was made after review of 10 postmarketing cases with life-threatening events reported in neonates (babies less than 4 weeks old) that received Kaletra oral solution. Postmarketing life-threatening cases included cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, central nervous system depression, and respiratory complications. Of the 10 cases, there was one death due to cardiogenic shock related to a large overdose of Kaletra oral solution.

Reduced metabolism by the liver and reduced kidney function in newborns can lead to an accumulation of lopinavir (the active ingredient), as well as alcohol and propylene glycol. Preterm babies may be at increased risk for health problems because they cannot metabolise propylene glycol; this could lead to accumulation and adverse events such as serious heart, kidney, or breathing problems.

The Dosage and Administration section 2.2 and the Overdosage section 10 were revised and a new Warning and Precautions was included to describe the toxicity in preterm neonates.

Please refer to the full label for details.

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

Source: FDA listserve (24 Feb 2011).

Reference:

Kaletra (lopinavir/ritonavir) oral solution label changes related to toxicity in preterm neonates.
http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm244639.htm

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

By December 2010, programmes supported by the Global Fund were providing antiretroviral (ARV) treatment to 3.0 million people living with HIV, an increase of 20% compared to December 2009, according to data provided by the Fund. Global Fund-supported programmes were also providing directly observed therapy short course (DOTS) to 7.7 million people with TB, an increase of 28%; and had distributed 160 million insecticide-treated mosquito bed nets, an increase of 53%. In 2010 alone, 56 million bed nets were distributed. The number of malaria cases treated rose to 170 million in 2010 from 108 million in 2009, an increase of 77%.

As a result, the Global Fund says, more than 6.5 million lives have been saved. Each day, 4,400 deaths are averted.

Since the Global Fund started in 2002, programmes supported by the Fund have provided one million pregnant women with a complete course of antiretrovirals to prevent transmission of HIV from mothers to their children. In addition, 5.0 million basic care and support services have been provided to AIDS orphans and vulnerable children; 150 million sessions of HIV counselling and testing have been provided; and 2.7 billion condoms have been distributed.

The Global Fund says that it now provides one-fifth of international resources to fight AIDS, as well as 63% of international funding to fight tuberculosis and 60% of international funding to fight malaria.

Source: GFO Issue 142: 17 March 2011.
http://www.aidspan.org/gfo

The TRIPS Agreement flexibilities can be used to mitigate the impact on the production of generic drugs such as ARVs. They include:

• Compulsory licenses – these are mechanisms whereby governments or other public authorities can authorise the use of patent-protected inventions without the consent of the patent-holder, who will receive compensation royalties. Compulsory licenses can be granted based upon various grounds of interest such as public health as determined by the WTO Member themselves.
• Parallel imports – due to various market factors, companies are sometimes able to produce patented medicines at cheaper prices in certain countries. Developing countries can then buy the drugs at lower prices and import them rather than buying from domestic markets and having to pay high prices. Legally a patent can only control the price of sale within the country of manufacture. This means an intermediary could buy patented drugs in one country at a cheaper rate, import them to another country at a slightly higher price whilst still undercutting the domestic manufacturer. This is called ‘parallel importing’.
• Bolar provision/regular exception – this is a mechanism whereby a patented product can be used without authorisation to obtain the generic marketing approval prior to patent expiry. This enables generic products to enter the market immediately after patent expiry.
• Exemptions for least developed countries – in November 2005 the WTO TRIPS Council extended the time at which least developed countries are mandated to comply with the TRIPS Agreement to 1st January 2016. This is subject to further extension upon request (Article 66.1 TRIPS Agreement)

The Doha Agreement states that the TRIPS Agreement “does not and should not prevent Members from taking measures to protect public health. Accordingly while reiterating our commitment to the TRIPS Agreement, we affirm that the Agreement can and should be interpreted and implemented in a manner supportive of WTO Members’ right to protect public health and, in particular, to promote access to medicines for all.”

Several countries have begun to use the flexibilities outlined above to ensure access to cheaper generic ARVs. In 2006-2007 Thailand issued a compulsory license for efavirenz and lopinavir/ritonavir. This resulted in a tripling of the number of people using lopinavir/ritonavir despite outrage by multinational drug companies.

To enable countries which are already WTO Members to make use of the opportunities provided by TRIPS flexibilities, it is a pre-condition that they must first amend their national patent laws to incorporate the flexibilities. In 2007 a UNDP study showed that only 6 countries had incorporated the flexibilities into their legislation. A more recent study by WIPO on 142 countries revealed a vast disparity in the levels of inclusion of the TRIPS Agreement flexibilities both between countries and with regards to the different types of flexibility. For example of 112 countries with the information available, only 36 (32%) had laws allowing for with regards to parallel imports. Without these national legislative amendments, the TRIPS Agreement flexibilities will not be available for use, which in turn limits the opportunities for access to cheaper ARVs.

References:

UNAIDS Press Release:

http://www.unaids.org/en/media/unaids/contentassets/documents/pressrelease/2011/20110315_PR_TRIPS_en.pdf

UNDP report 2007:
http://content.undp.org/go/newsroom/2006/october/trinidad-property-rights-20061026.en

WIPO study report, “Patent Related Flexibilities in the Multilateral Legal Framework and their Legislative Implementation at the National and Regional Levels”:
http://www.wipo.int/meetings/en/doc_details.jsp?doc_id=131629

An overview on global antiretroviral access since 2000 based on priced reductions driven by generic drugs, the threat from patent restrictions and the new Patent Pool initiative is available online from the IAS website.

From the abstract summary:

“Global trade rules agreed upon in 1994 required many developing countries to begin offering patents on medicines for the first time. Government and civil society reaction to expected increases in drug prices precipitated a series of events challenging these rules, culminating in the 2001 World Trade Organization’s Doha Declaration on the Agreement on Trade-Related Aspects of Intellectual Property Rights and Public Health. The Declaration affirmed that patent rules should be interpreted and implemented to protect public health and to promote access to medicines for all. Since Doha, more than 60 low- and middle-income countries have procured generic versions of patented medicines on a large scale.”

“Despite these changes, however, a “treatment timebomb” awaits. First, increasing numbers of people need access to newer antiretrovirals, but treatment costs are rising since new ARVs are likely to be more widely patented in developing countries. Second, policy space to produce or import generic versions of patented medicines is shrinking in some developing countries. Third, funding for medicines is falling far short of needs. Expanded use of the existing flexibilities in patent law and new models to address the second wave of the access to medicines crisis are required.”

Reference:

Ellen ‘t Hoen et al. Journal of the International AIDS Society 2011, 14:15doi:10.1186/1758-2652-14-15.
http://www.jiasociety.org/content/14/1/15

Data are scant describing the relationship between HIV and conception.

The Women’s Interagency HIV Study (WIHS) is a multicentre US cohort of 3766 women with and without HIV. WIHS participants are broadly representative of HIV-positive women in the US. They are mostly African American and half live below the poverty line.

An analysis published ahead of print in AIDS, looked at the incidence of pregnancy and time to conception among women in this cohort between 2002 and 2009.

Women were eligible if they were 45 years or below, sexually active with male partners, or reported a pregnancy outcome within the past year, and never reported hysterectomy, tubal ligation or oopherectomy.

Overall, 1412 women were at risk from becoming pregnant during this time period. Of these, 941 (67%) were HIV-positive, and the remaining 471 (33%) were HIV-negative. During follow up, 456 women reported 766 pregnancies; 404 (53%) were among the HIV-positive women, and 362 (47%) the HIV-negative women. Interestingly, 192 pregnancies occurred at the same visit that hormonal contraception was reported.

The investigators found an overall incidence of pregnancy in this group of 1.2 (95% CI 1.1-1.3) per 100 person years.

After adjusting for age, parity, alcohol consumption, exchanging sex, number of male sex partners and contraception use in the past six months, being HIV-positive was associated with a 40% reduction in the rate of pregnancy, incidence rate ratio (IRR), 0.60 (95% CI 0.46-0.78). Also, it took 73% longer for HIV-positive women to get pregnant compared to HIV-negative women, relative time, 1.3 years (95% CI 1.35-2.36).

As would be expected, older age was also independently associated with a reduction in the incidence rate of pregnancy and the relative time to pregnancy was 30% longer in this group. Women with at least two sex partners in the past six moths had a 28% lower pregnancy rate and 64% lower time to pregnancy compared to those with only one (this was despite reporting lower baseline prevalence of contraception, 25 vs 75%, p<0.001). Women with at least three previous births conceived the fastest and had an incidence rate of pregnancy that was more than 12 times higher than those with no prior births.

Importantly, among the HIV-positive women, women with a CD4 count of 350 cells/mm3 or more had a significantly faster time to first pregnancy than those with lower CD4 counts, p<0.0073.

Reference:

Linas BS et al. Relative time to pregnancy among HIV-infected and uninfected women in the Women’s Interagency HIV Study, 2002-2009. AIDS. 2011 Mar 13; 25(5):707-711
http://journals.lww.com/aidsonline/toc/2011/03130

World Health Organisation (WHO) and national guidelines recommend universal treatment with antiretrovirals for all HIV-infected infants.

Guidelines also recommend using protease inhibitor-based treatment for children exposed to single dose nevirapine through PMTCT.

Initiation of therapy is recommended as soon as possible but there are limited data to guide treatment of very young infants.

Ellen Chadwick and colleagues from IMPAACT P1030 showed data in AIDS, published ahead of print in February 2011, from a study designed to look at the pharmacokinetics (PK) and safety of the liquid formulation of lopinavir/ritonavir (LPV/r) in HIV-infected infants starting treatment between 2 weeks and 6 months of age.

This was a prospective, open label, phase I/II study of 31 children from 17 centres in the US and Brazil treated with a high dose (300mg LPV/75mg RTV/m2 twice daily). Children were enrolled into two age groups: 14 days to 6 weeks and 6 weeks to <6 months. Children were followed until 48 weeks after the last child was enrolled.

The median duration of follow up was 123 (range 4-252) weeks. Ten (32%) children permanently discontinued the study including four before 12 months of age. Two discontinued after viral rebound to >50,000 copies/mL (weeks 43 and 176); three after parents refusal to attend study visits and/or give medication (weeks 2,42 and 145), three had non-treatment related conditions (CMV resulting in death at week 8; failure to thrive due to severe food allergy at week 70 and severe iron-deficiency anaemia at week 120) and two because their research sites closed (weeks 73 and 120).

Intensive PK sampling was performed at in 26 children at 12 months of age, pre-dose and 2, 4, 8 and 12 hours after an observed dose. Of these, 20 children had evaluable results.

The investigators found, the median AUC of the two groups was comparable at 12 months of age (99.1 ug h/mL [IQR 82.4-124.5] vs 112 ug h/mL [IQR 95.0-148.8], p=0.93). They also found a significant positive correlation of LPV trough concentration and age, p<0.0001.

By ITT analysis, at week 48, 22/31 (71%) children had a viral load <400 copies/mL; 6/10 in group 1 and 16/21 in group 2. Of these 11/15 (73%) on study treatment at 48 weeks had a viral load <50 copies/mL. Overall 29/31 (94%) children achieved a viral load <400 copies/mL while on study treatment and 19/29 (66%) children remained undetectable until the end of the study at a median of 123 (range 42-252) weeks. The children who sustained viral suppression had a higher percentage of predose time points at which concentrations exceeded the LPV target of 1 ug/ML (92 vs 71%), p=0.002.

The median baseline CD4 percentage was 35% (range 11-59%). There was a median increase of 4% (95% CI – 4 to 13%), p=0.12, among the 24 children with data available at 48 weeks and 23 (96%) had CD4 percentage >25%. Among the 19 children with follow up through 96 weeks there was a median increase of 8% (95% CI -2 to 13%), p=0.15.

The investigators noted that low LPV levels occurred at two weeks of therapy, with the lowest in infants <6 weeks of age. In this very young age group the median AUC was approximately half that seen in the older children >6 months of age. But these values were comparable between the two groups by 12 months of age and comparable to adults. They also noted that the LPV dose of 300mg/m2 is higher than the currently recommended dose for children >6 months of age.

Reference:

Chadwick EG et al. Long-term outcomes for HIV-infected infants less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral therapy. AIDS, 25(6):767-776 (13 March 2011).
http://journals.lww.com/aidsonline/toc/2011/03130

The effects of in antiretroviral (ARV) exposure through PMTCT on HIV-uninfected infants are poorly understood, particularly in resource-limited settings.

Two papers published in JAIDS report findings from sub-studies of the Mashi and Mma Bana randomised controlled PMTCT trials, both conducted in Botswana. [1, 2]

We have covered both these trials extensively in HTB, including early findings from these analyses reported at CROI 2010. [3]

Increased severe anaemia risk with HAART

Scott Dryden-Peterson and colleagues conducted a post hoc analysis of pooled data from the trials. Infants were grouped by three ARV exposure categories: infants exposed to maternal HAART in utero and during breastfeeding and one month post natal AZT (HAART-BF); infants exposed to maternal AZT in utero and 6 months postnatal AZT during breastfeeding (AZT-BF); and infants exposed to AZT in utero and formula feeding (AZT-FF).

Overall, the investigators analysed data from 1719 infants (691 HAART-BF, 503 AZT-BF and 525 AZT-FF).

They observed severe incident anaemia (grade 3 or 4) in 118 (7.4%) infants from birth through 6 months of age. This occurred in 82 (12.5%) infants in the HAART-BF group, 25 (5.3%) in the AZT-BF and 11 (2.5%) in the AZT-FF groups. Severe anaemia was more frequent in the HAART-BF, group compared to infants in either of the other two groups: OR 2.53 (95% CI 1.59-4.04) and OR 5.96 (95% CI 3.14-11.3) vs AZT-BF and AZT-FF respectively, both p<0.001.

They noted that different frequency of assessment between the groups (AZT-BF group had haemoglobin measured monthly) could create potential bias. There was little evidence of this though, as they did not detect significant differences in the rate of treatment-modifying anaemia between birth, 1, 3-4 or 6-7 month visits among the study groups, p=0.15.

In multivariate analysis, besides HAART-BF exposure, which remained the strongest risk factor: gestational age, per week OR 0.89 (95% CI, 0.82-0.96) p=0.005; male sex OR 1.53 (95% CI 1.03-2.27) and low maternal income <$100 a month OR 2.04 (1.12-3.71) p=0.02, were all associated with severe incident anaemia. The investigators did not find an association with maternal BMI, CD4, viral load or haemoglobin. Nor was there and association with maternal HAART regimen or duration of antenatal HAART. Infants who were small for their gestational age were not at greater risk of severe anaemia.

The majority of episodes of severe anaemia were resolved with multivitamin and iron supplements or stopping AZT but 11 infants from the HAART-BF group needed transfusion. Six infants died (1 HAART-BF, 2 AZT-BF and 3 AZT-FF), three of the infants had severe anaemia reported as cause of death. Two infants were lost to follow up before their severe anaemia was resolved.

Microcytosis and hypochromia occurred in 21.2% and 29.3% of incident anaemias with measurements available. Estimated haemoglobin iron at birth was lower for HAART-BF infants than the other two groups (p<0.001).

The investigators suggested these findings deserve further investigation and emphasised the established benefits of maternal HAART. They wrote: “Mitigating strategies such as iron supplementation to HIV-exposed breastfed infants or alternative antiretrovirals should be evaluated to maximise the benefits of maternal HAART while minimising potential risks.”

Lower weight HAART-exposed infants catch up by 6 months

Kathleen Powis and colleagues from the same group looked at the effects of in utero ARV exposure on longitudinal growth through 6 months of age in 619 HAART-exposed and 440 AZT-exposed uninfected infants from the two trials.

This was a retrospective analysis of infants carried to 37 weeks gestation or greater.

The investigators used WHO’s Child Growth Standards to calculate z-scores for an infant’s weight for age (WAZ), length for age (LAZ) and weight for length (WLZ).

They reported mean birth weights of 3.01kg and 3.15kg for HAART- and AZT-exposed infants respectively, p<0.001. HAART-exposed infants had lower values for all three z-scores at birth, all p<0.001.

HAART-exposed infants had greater improvement compared to AZT-exposed infants in WAZ from birth through 2 months, p=0.03, but the investigators observed no difference in WAZ between the two exposure groups from 3 through 6 months, p= 0.26.

Similarly, LAZ increased more in the HAART-exposed infants through 2 months, p=0.002, but this difference did not remain significant at 3 to 6 months, p=0.08.

HAART-exposed infants also had a more rapid increase in WLZ through 2 months than AZT-exposed infants, p<0.001. Between 3 and 6 months, the WLZ z-score in HAART-exposed infants declined while the AZT group had small increase. The difference in growth patterns between the two groups was significant, p=0.04.

There was no difference in wasting or stunting between groups, which occurred in about 6% and 5% of infants overall respectively.

The investigators wrote: “This analysis is the first to provide reassurance that lower birth weight associated with in utero HAART exposure does not persist during early infancy. It also highlights the importance of early and routinely scheduled health care for HAART- exposed HIV-uninfected infants.”

References:

1. Dryden-Peterson S et al. Increased risk of severe infant anaemia following exposure to maternal HAART, Botswana. J Acquir Immune Defic Syndr. Volume 56. Number 5. 15 April 2011.
2. Powis KM et al. Effects of in utero antiretroviral exposure on longitudinal growth of HIV-exposed uninfected infants in Botswana. J Acquir Immune Defic Syndr. Volume 56. Number 2. February 1, 2011.
3. Clayden P. Pregnancy outcomes in infants exposed to maternal antiretrovirals in utero. HTB. Vol 11. No 3/4 March/April 2010.
   http://i-base.info/htb/10238

In this study Truvada or placebo was being taken daily as a pre-exposure prophylaxis prevention (PrEP) treatment against HIV. When the decision to stop the study was taken, almost 2000 women from Kenya, Tanzania and South Africa were enrolled, just over half the planned number of particiapants.

These results are both extremely disappointing and surprising given that a similar study in gay men at high risk of infection (young, multiple partners and exposures, high alcohol use etc) showed a strongly protective effect. [2]

FEM-PrEP was also being run in a high-risk group: 20% of 3752 women who came forward to participant were already HIV positive when screened.

The approximate rate of new HIV infections among trial participants was 5% per year. The 56 new HIV infections were equally distributed between the active and placebo arm. Although adherence was reported at 95% similar to self-reported adherence in the iPrEX study, a pharmacokinetic sub-study in iPrEX indicated that actual adherence was far lower.

Further analyses from the study are needed to explain the starkly different results compared to iPrEX. The level of protection was expected to be similar based on systemic exposure to the same prophylactic drugs, but this would also be dependent on drug levels achieved in the genital tract.

As with all prevention studies, all participants were given support to reduce their risk of HIV, including advice to always use condoms.

References:

1. FHI statement on the FEM-PrEP HIV prevention study: FHI to initiate orderly closure of FEM-PrEP. (18 April 2011).
   http://www.fhi.org/en/Research/Projects/FEM-PrEP.htm
2. Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM. 23 November 2010 (10.1056/NEJMoa1011205). Free access:
   http://www.nejm.org/doi/full/10.1056/NEJMoa1011205

A placebo-controlled, randomised, two-period crossover study in 19 healthy HIV-seronegative women was conducted to assess the effect of raltegravir (400 mg twice daily) on the pharmacokinetics of an oral contraceptive containing ethinylestradiol and norgestimate.

The geometric mean ratio (GMR) and 90% confidence interval (CI) for ethinylestradiol when co-administrated with raltegravir relative to alone was 0.98 (0.93–1.04) for AUC and 1.06 (0.98–1.14) for Cmax. The GMR (90% CI) for norelgestromin (an active metabolite of norgestimate) when co-administered with raltegravir relative to alone was 1.14 (1.08–1.21) for AUC and 1.29 (1.23–1.37) for Cmax. There were no discontinuations due to a study drug-related adverse experience, nor any serious clinical or laboratory adverse experience.

Raltegravir had no clinically important effect on ethinylestradiol or norgestimate pharmacokinetics and no dose adjustment is required for oral contraceptives containing this combination when co-administered with raltegravir.

Source:

www.HIV-druginteractions.org (24 March 2011).

Reference:

Anderson MS et al. Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women. Br J Clin Pharmacol, 2011, 71(4): 616-620.
http://www.ncbi.nlm.nih.gov/pubmed/21395656

Several years ago, researchers led by Jason Brenchley and Daniel Douek at the National Institute of Allergy & Infectious Diseases published data suggesting an important role for microbial translocation in HIV pathogenesis. [1]

Microbial translocation is the leaking of normally friendly commensal bacteria from the gut – where they are usually contained – into the systemic circulation. Brenchley and colleagues proposed that this phenomenon contributes to immune activation in people with HIV, and thus plays a causative role in the progression of the disease.

Several subsequent studies have confirmed an association between markers of microbial translocation found in the bloodstream (e.g. the bacterial component LPS and bacterial DNA) and immune deficiency in people with HIV, including people with poor immune reconstitution on antiretroviral therapy (ART). [2]

However, these results have not ruled out the possibility that microbial translocation occurs as a result of HIV-induced immune deficiency, rather than playing a key role in causing it.

To try and gain a better understanding of the importance of microbial translocation in the pathogenesis of HIV infection, Daniel Douek has collaborated with researchers from the INSIGHT network to analyse samples from the Strategic Management of AntiRetroviral Therapy (SMART) trial. [3]

This trial randomised 5,472 people with HIV to either continuous or intermittent, CD4-guided ART, and the results showed that intermittent ART was associated with a doubling of the risk of illness and death compared to continuous treatment. [4]

During the study, 85 participants died, 142 developed major cardiovascular disease events, and 100 developed AIDS-defining events. Of these participants, 74, 120, and 81, respectively, had samples available.

Douek and colleagues used a case control study design to evaluate whether any of a suite of different markers of microbial translocation showed associations with these clinical outcomes. The same case control study design has previously been used to analyse the data from SMART, revealing a highly significant association between levels of inflammatory biomarkers and mortality. [5]

The biological markers assessed in the new study were: intestinal fatty acid binding protein (a marker of damage to cells of the gut wall called enterocytes), the bacterial product lipopolysaccharide (LPS), bacterial DNA (16S rDNA), anti-LPS antibodies (endotoxin core IgM antibody or EndoCAb) and soluble CD14 (sCD14). CD14 is a molecule expressed on monocytes that is known to be shed as a result of simulation by LPS.

The only marker that showed a correlation with a clinical outcome was sCD14; higher levels were significantly associated with an increased risk of mortality. Levels of sCD14 also correlated with the inflammatory biomarkers that have previously been associated with mortality risk in SMART. The study authors offer a variety of possible reasons why other markers of microbial translocation were not associated with clinical outcomes, and argue strongly that elevated levels of sCD14 represent a consequence of microbial translocation (even though the other markers did not correlate with sCD14). There are, however, alternate possibilities that might explain elevated sCD14 levels that are not discussed in the paper. Specifically, alpha interferon has been reported to increase levels of sCD14, and levels of this cytokine are increased in HIV infection. [6]

Furthermore, a study published last year that looked for evidence of monocyte stimulation by LPS in HIV found that the gene expression patterns of these cells were more consistent with stimulation by alpha interferon, not LPS. [7]

So while Douek and colleagues write: “these observations are consistent with a model in which HIV infection causes ongoing damage to the gut mucosa, leading to increased microbial translocation, increased systemic inflammation, and increased mortality,” this interpretation of the data seems debatable, as the elevated levels of sCD14 may not necessarily be explained solely by microbial translocation.

Coincidentally, the current issue of the Journal of Infectious Diseases includes a letter from several researchers (Andrew Redd, Ronald Gray and Thomas Quinn) highlighting the uncertainty regarding whether microbial translocation is a cause or consequence of HIV pathogenesis. They argue that the current evidence favors the view that “increased microbial translocation and LPS levels are a consequence of advanced HIV-1 disease and AIDS.” The letter closes by stressing the need for additional longitudinal studies to fully resolve the issue. [9]

Source: TAG Basic Science Blog (08 Feb 2011).

http://tagbasicscienceproject.typepad.com

References:

1. Brenchley JM et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006 Dec;12(12):1365-71. Epub 2006 Nov 19.
   http://www.ncbi.nlm.nih.gov/pubmed/17115046?dopt=AbstractPlus
2. Marchetti G et al. Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS. 22(15):2035-2038, October 1, 2008. Research Letter.
   http://journals.lww.com/aidsonline/pages/articleviewer.aspx?year=2008&issue=10010&article=00016&type=abstract
   See:
   http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2008/09/microbial-trans.html
3. Sandler NG et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis. 2011 Jan 20. [Epub ahead of print] doi: 10.1093/infdis/jiq118.
   http://jid.oxfordjournals.org/content/early/2011/01/20/infdis.jiq118.abstract
4. SMART Group. CD4+ count–guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283-2296 (November 2006)
   http://www.nejm.org/doi/full/10.1056/NEJMoa062360
5. Kuller LH et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Medicine Vol. 5, No. 10, e203 doi:10.1371/journal.pmed.0050203.
   http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050203
   See:
   http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2008/10/inflammatory-an.html
6. Carotenuto P et al. Antiviral treatment with alpha interferon up-regulates CD14 on liver macrophages and its soluble form in patients with chronic hepatitis B. Antimicrobial Agents and Chem. February 2005, p. 590-599, Vol. 49, No. 2.
   http://aac.asm.org/cgi/content/full/49/2/590
7. Rempel H et al. Interferon-alpha drives monocyte gene expression in chronic unsuppressed HIV-1 infection. AIDS. 2010 Jun 19;24(10):1415-23.
   http://journals.lww.com/aidsonline/Abstract/2010/06190/Interferon__alpha__drives_monocyte_gene_expression.3.aspx
8. Redd AD et al. Is Microbial Translocation a Cause or Consequence of HIV Disease Progression? J Infect Dis. (2011) 203 (5): 744-745. doi: 10.1093/infdis/jiq107.
   http://jid.oxfordjournals.org/content/203/5/744.extract

A study in the new issue of the Journal of Immunology suggests that triggering a cell surface molecule called toll-like receptor 8 (TLR8) may be a means to activating latent HIV infection. [1]

Erika Schlaepfer and Roberto Speck report that, in vitro, targeting TLR8 with the drug resiquimod (aka R-848) prompted HIV activity in latently infected cells of myeloid-monocytic origin (which include monocytes, macrophages, dendritic cells, microglial cells, and hematopoietic stem cells) and also had an activating effect on HIV in latently infected CD4 T cells, by causing production of the cytokine TNF-alpha. The researchers took a very preliminary look at whether individuals on HAART might be able to respond to such an approach, and found that–solely based on TNF-alpha production–their monocytes reacted to TLR8 stimulation comparably to those from HIV negative controls.

The conclusion from the findings is that “TLR8 agonists, in combination with HAART, are intriguing compounds for purging HIV from its latent reservoirs and sanctuary sites.” Schlaepfer and Speck caution, however, that “we believe that compounds, and, in particular, TLR8 agonists, acting on the latent reservoir should be given in cycles, because a longer-term administration of any such compound might be too toxic.”

Resiquimod has been studied in humans with hepatitis C infection and appeared quite potent in terms of inducing alpha interferon production (and associated side effects). [2]

The manufacturer, 3M, does not appear to be developing it further but has recently offered it to the pharmaceutical industry for license. [3]

Development of a TLR7 agonist as a hepatitis C treatment was stopped in 2007 due to toxicology studies showing “intense immune stimulation in animals.”

Source: TAG Basic Science Blog (23 Mar 2011).

http://tagbasicscienceproject.typepad.com

References:

1. Schlaepfer E, Speck RF. TLR8 activates HIV from latently infected cells of myeloid-monocytic origin directly via the MAPK pathway and from latently infected CD4+ T cells indirectly via TNF-alpha. Journal of Immunology, April 1, 2011, vol. 186 no. 7 4314-4324.
   http://www.jimmunol.org/content/186/7/4314.abstract
2. Pockros PJ et al. Oral resiquimod in chronic HCV infection: safety and efficacy in 2 placebo-controlled, double-blind phase IIa studies. J Hepatol. 2007 Aug;47(2):174-82. Epub 2007 May 4.
   http://www.ncbi.nlm.nih.gov/pubmed/17532523
3. 3M press release. Immune response modifiers from 3M available for the pharmaceutical industry. (2 Dec 2010).
   http://solutions.3m.com/wps/portal/3M/en_WW/DrugDeliverySystems/DDSD/technology-solutions/tlr-agonists/?PC_7_RJH9U523080CC0IA3DRQB50OJ0_assetId=1273663090851
4. Development discontinued for ANA975, an early stage compound for treatment of hepatitis C virus infection. (July 2007)
   http://www.drugs.com/news/development-discontinued-ana975-early-stage-compound-hepatitis-c-virus-infection-6604.html

Toward the end of last year, a group of Italian researchers led by Barbara Ensoli published some limited data from an ongoing trial of a therapeutic HIV vaccine [1], and issued a press release to draw attention to the paper. [2]

The resulting press coverage was generally favorable. Somewhat lost in the discussion of the results was the fact that they were obtained in an “ad hoc exploratory interim analysis,” which is generally considered to be a dubious and unreliable way to analyse trial data. The vaccine candidate contains the Tat protein from HIV-1, and Ensoli’s group has been developing it for many years now. The question of whether the approach has any potential has been controversial [3]; a macaque study suggesting protection against SHIV was not confirmed [4] and there have also been reports of disputes about the vaccine’s development among the Italian research community. [5]

In light of this background, trumpeting the results of an ad hoc exploratory interim analysis via press release seems an imprudent strategy for the researchers to pursue.

The trial described in the paper is not placebo controlled, which adds to the challenge of trying to interpret the results. Because there is no control arm, comparisons in the paper are made between vaccine recipients and HIV positive individuals enrolled in “a parallel prospective observational study at the same sites.” Most of the immunological analyses reported in the paper involve small subsets of the 87 participants, but it is not clear how these subsets were selected. The primary aim of the trial is to compare the immunogenicity (ability to induce anti-Tat immune responses) of two different doses and two different dosing schedules of the vaccine. The secondary aim is monitor safety. The trial protocol, which is included in the supporting information for the paper, does not make reference to the conduct of ad hoc exploratory interim analyses or their publication.

Amidst this sea of caveats, the researchers report that the higher vaccine dose was more immunogenic but no significant differences were apparent between the 3-dose and 5-dose immunisation schedules. The vaccine was also found to be generally safe and well tolerated. From these top-line results, the paper descends into murky sub-analyses suggesting that the vaccine may have decreased CD8 T cell activation, both increased and decreased in CD4 T cell activation (depending on the marker), increased regulatory CD4 T cells, increased CD4 T cells and B cells, decreased CD8 T cells and natural killer cells, and altered representation of different memory T cell subsets. None of the reported analyses are statistically corrected for the multiple comparisons being performed.

Although the suggestion that therapeutic vaccination might reduce immune activation in HIV is not unprecedented, there is a discomforting gap between the murkiness of the methodology and the breezily conclusive title of the paper: “Therapeutic Immunisation with HIV-1 Tat Reduces Immune Activation and Loss of Regulatory T-Cells and Improves Immune Function in Subjects on HAART.” The only way to show whether the vaccine can achieve these outcomes is with a randomised placebo-controlled study. [6]

Source: TAG Basic Science Blog (24 Jan 2011).

http://tagbasicscienceproject.typepad.com

References:

1. Barbara Ensoli et al. Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART. PLoS ONE 5(11): e13540. doi:10.1371/journal.pone.00135.
   http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0013540
2. National AIDS Centre press release. HIV/AIDS: Interim analysis of phase II trial of TAT vaccine in HIV-infected patients. (11 Nov 2010).
   http://www.hiv1tat-vaccines.info/publications/Press%20release.pdf
3. Aurelio Cafaro et. Al, Control of SHIV-89.6P-infection of cynomolgus monkeys by HIV-1 Tat protein vaccine Nature Medicine 5, 643 – 650 (1999) doi:10.1038/9488:
   http://www.nature.com/nm/journal/v5/n6/abs/nm0699_643.html
4. Xiaoping Liang et al. Vectored Gag and Env but not Tat show efficacy against Simian-Human Immunodeficiency Virus 89.6P challenge in mamu-A*01-negative rhesus monkeys. J Virol. 2005 October; 79(19): 12321–12331. doi: 10.1128/JVI.79.19.12321-12331.2005.
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1211517/?tool=pubmed
5. Jon Cohen. Feud over AIDS vaccine trials leads prominent Italian researchers to court. Science 10 August 2007: Vol. 317 no. 5839 pp. 738-739 DOI: 10.1126/science.317.5839.738
   http://www.sciencemag.org/content/317/5839/738.summary
6. Fernandez-Cruz E et al. 3-year evaluation of a therapeutic vaccine (HIV-1 Immunogen) administered with antiretrovirals versus antiretroviral therapy alone in patients with HIV chronic infection. Int Conf AIDS. 2002 Jul 7-12; 14: abstract no. ThOrA1482.
   http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102254982.html

A recent post covered a review by Beth Jamieson and Tammy Rickabaugh describing the parallel effects of HIV infection and aging on the pool of naïve T cells in humans. [1]

Three recent papers address different aspects of naïve T cell loss, including the first study to document a decrease in this population in people with chronic hepatitis C infection.

In PLoS One, Beth Jamieson’s group reports on a study of naïve CD4 T cell levels in younger (20-32 years) and older (39-58 years) individuals with untreated HIV infection, compared to age-matched HIV-negative controls. [2]

The researchers use a cell surface marker named CD31 to discriminate between naïve CD4 T cells that have recently been produced by the thymus (CD31+) and those that have proliferated in the circulation (CD31-). Consistent with previous studies, HIV infection had a strong effect on naïve CD4 T cell levels that was additive to that seen in aging; the absolute number of CD31+ naïve CD4 T cells in the younger individuals mirrored those measured in HIV-negative controls who were 17-28 years older. While both HIV infection and aging were associated with declines in CD31+ naïve CD4 T cell numbers, loss of CD31- naïve CD4 T cells was only observed HIV infection; in this case the effect was independent of aging as the absolute loss was similar in both the younger and older HIV-positive participants. In a separate longitudinal analysis of the effects of antiretroviral therapy, CD31+ naïve CD4 T cells achieved levels comparable to age-matched controls after two years of treatment. However, CD31- naïve CD4 T cell levels remained significantly reduced.

The researchers also evaluate telomere lengths in both naïve CD4 T cell subsets, finding them to be reduced both as a result of HIV infection and aging; as was seen for CD31+ naïve CD4 T cell numbers, the effects were additive. Jamieson and colleagues conclude by suggesting that their results likely explain why disease progression occurs more rapidly among HIV-positive individuals over the age of 50, because this older population already has reduced numbers of naïve CD4 T cells, making the impact of HIV infection more severe. They also note that incomplete recovery of naïve CD4 T cells may play a role in increasing the risk of aging-associated diseases in people with HIV.

One commonly cited causative mechanism of naïve T cell depletion in HIV is the persistent activation of these cells, which leads to their differentiation into memory cells. Another contributing factor is lymphoid tissue fibrosis (a type of scarring damage associated with immune activation & inflammation). Naïve T cells continually recirculate through lymphoid tissue and depend on signals received in that environment for their survival.

A recent study by Ming Zeng and colleagues delves into this link between lymphoid tissue fibrosis and naïve T cell loss in both SIV and HIV infection. [3]

The researchers find that fibroblastic reticular cells (FRC)–which form the pathways along which T cells travel in lymph nodes–are the major source of IL-7, a cytokine essential for naïve T cell survival. Fibrotic damage (measured by the accumulation of collagen) is shown to disrupt the FRC network and therefore impede the ability of T cells to access IL-7, causing an increase in T cell apoptosis. Both naïve CD4 and CD8 T cells are affected. Additional studies reveal that the loss of T cells in turn exacerbates the damage to FRCs by reducing the production of a cytokine called lymphotoxin-É¿, which is vital for maintaining FRC networks. The results suggest that there is a vicious cycle in which fibrosis damages FRCs, which causes T cell loss, which then further exacerbates FRC loss.

Continuing their investigative work, Zeng et al look for a source of collagen and find that production of the cytokine TGF-beta by regulatory T cells is increased in HIV, and TGF-beta induces collagen production by fibroblasts. In lab experiments, the antifibrotic drug pirfenidone blocks TGF-beta signaling and reduces collagen production, leading the researchers to conclude that this drug may deserve consideration as an adjunctive therapy for promoting immune reconstitution in HIV.

Lastly, a study published in the 1st March issue of the Journal of Infectious Diseases demonstrates that another persistent chronic infection, hepatitis C, can accelerate naïve CD4 T cell loss. The authors conclude that their findings provide an explanation for the reduced response to vaccinations observed in people with chronic HCV. [4]

Source: TAG basic science blog (17 Mar 2011)

http://tagbasicscienceproject.typepad.com

References:

1. Jamieson B and Rickabaugh T. A challenge for the future: aging and HIV infection. Immunol Res. 2010 Aug 24. [Epub ahead of print]
   http://www.springerlink.com/content/np150557h6u06316/
   See
   http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2010/09/losing-immunological-naivete.html
2. Rickabaugh TM et al. The Dual Impact of HIV-1 Infection and Aging on Naïve CD4 T-Cells: Additive and Distinct Patterns of Impairment. PLoS One. 2011 Jan 26;6(1):e16459.
   http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0016459
3. Zeng M et al. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 . J Clin Invest. doi:10.1172/JCI45157.
   http://www.jci.org/articles/view/45157
4. Yonkers NL et al. Reduced Naive CD4 T Cell Numbers and Impaired Induction of CD27 in Response to T Cell Receptor Stimulation Reflect a State of Immune Activation in Chronic Hepatitis C Virus Infection. J Infect Dis. 2011 Mar;203(5):635-45. Epub 2011 Jan 10.
   http://jid.oxfordjournals.org/content/203/5/635.abstract

A study led by Hiroyu Hatano from Steve Deeks’s group at UCSF reports that adding the integrase inhibitor raltegravir (Isentress) to a standard antiretroviral (ART) regimen failed to reduce residual HIV replication, or the HIV reservoir, in a group of individuals with suboptimal CD4 count increases despite prolonged HIV suppression. The intensification approach also did not significantly increase CD4 T cell counts or reduce levels of immune activation, which the authors note adds to the evidence that low-level HIV replication is unlikely to be a major cause of suboptimal CD4 T cell gains in people on ART. [1, 2]

Interestingly, a secondary analysis–conducted in collaboration with Barbara Shacklett’s laboratory at UC Davis–revealed a novel association between the magnitude of HIV Gag-specific CD8 T cell responses in gut-associated lymphoid tissue (GALT) and the size of the HIV reservoir (as measured by proviral DNA in peripheral blood mononuclear cells). Hatano and colleagues caution that the findings are preliminary and require confirmation by larger studies, but also write: “approaches aimed at expanding HIV-specific CD4+ and CD8+ T cell responses in the gut mucosa may accelerate clearance of the viral reservoir. The next logical step would be to pursue therapeutic vaccine studies using HIV vaccines that elicit strong mucosal T cell responses in HAART-treated patients.”

Coincidentally, a paper that appeared online today in the journal Blood describes an approach to augmenting HIV-specific CD8 T cell immunity in GALT. [3]

The researchers sampled HIV-specific CD8 T cells from individuals on ART, expanded them in the laboratory, and then re-infused them. Persistence up to 84 days was documented, as well as trafficking to GALT. Many of the cells displayed a “central memory” phenotype, which is believed to be important due to the ability of these cells to self-renew and proliferate robustly upon encountering antigen. Although the infusion approach has practical limitations, the study authors suggest that their results imply that vaccination strategies aiming to boost systemic and GALT HIV-specific CD8 T cell responses are worth pursuing.

Source: TAG basic scieince blog (21 Mar 2011)

http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2011/03/intensifying-treatment-does-not-reduce-hiv-reservoirs-but-gut-immune-responses-may-have-a-role-to-pl.html

References:

1. Hatano H et al. A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis. (2011) 203 (7): 960-968. doi: 10.1093/infdis/jiq138
   http://jid.oxfordjournals.org/content/203/7/960.abstract
2. Schulze zur Wiesch J et al. Hide and seek… can we eradicate HIV by treatment intensification? J Infect Dis. (2011) 203 (7): 894-897. doi: 10.1093/infdis/jiq150
   http://jid.oxfordjournals.org/content/203/7/894.extract
3. Chapuis AG et al. HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo. Blood, prepublished online March 21, 2011; DOI 10.1182/blood-2010-11-320226.
   http://bloodjournal.hematologylibrary.org/cgi/content/abstract/blood-2010-11-320226v1



Besides informative regular posts, the website contains a database called “Quackbase”. This is updated with new unsubstantiated claims made in the South African media.

The strap line of the site is “Helping you make informed choices about health care.” So the site aims to publish articles that are informative, factual and largely free of rhetoric. The site recognises that we are all taken in by quackery sometimes and so it’s aimed at helping people make informed choices, not at being smug about quackery (as many anti-quack websites seem to be). Examples of articles published so far are:

The website is managed by Nathan Geffen, who sometimes writes for HTB. He is looking for additional writers, so if you’re a keen quackbuster or have an interesting tale of quackery to tell, do get in contact with him via the contact form of the website.

http://www.quackdown.info

Tracy Swan’s 2011 Hepatitis C Treatment Pipeline Report produced by the Treatment Action Group in New York is a must-read. This clear concise and comprehensive overview of research shows that hepatitis C treatments in 2011 have a similarly dramatic potential as HAART had for HIV in 1996.

Issues covered include diagnostics, drug resistance,  access to, and delivery of treatment, and population-specific focus on the new HCV drugs, as well as research recommendations.

FDA approval of two hepatitis C-specific protease inhibitors, the first of the coming wave of oral antiviral drugs, is anticipated later this year. Dozens of other drugs are in development.

Download
http://cts.vresp.com/c/?TreatmentActionGroup/b5f575334e/9e21c20d7a/9ae5755cb4/id=4416

Tomescu C et al. Clinical & Experimental Immunology. Published online: 17 March 2011. DOI: 10.1111/j.1365-2249.2011.04379.x

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2249.2011.04379.x/full

The description of highly exposed individuals who remain seronegative (HESN) despite repeated exposure to HIV-1 has heightened interest in identifying potential mechanisms of HIV-1 resistance. HIV-specific humoral and T cell-mediated responses have been identified routinely in HESN subjects, although it remains unknown if these responses are a definitive cause of protection or merely a marker for exposure.

Approximately half of HESN lack any detectible HIV-specific adaptive immune responses, suggesting that other mechanisms of protection from HIV-1 infection also probably exist. In support of the innate immune response as a mechanism of resistance, increased natural killer (NK) cell activity has been correlated with protection from infection in several high-risk cohorts of HESN subjects, including intravenous drug users, HIV-1 discordant couples and perinatally exposed infants.

This review highlights the most current evidence in HESN subjects supporting the role of epithelial microenvironment and the innate immune system in sustaining resistance against HIV-1 infection.

The authors argue that as a front-line defence the innate immune response determines the threshold of infectivity that HIV must overcome to establish a productive infection.

Effectiveness and cost effectiveness of expanding harm reduction and antiretroviral therapy in a mixed HIV epidemic: a modeling analysis for Ukraine

Alistar SS et al.

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000423

A cost-effectiveness study by Sabina Alistar and colleagues evaluates the effectiveness and cost effectiveness of different levels of investment in methadone, ART, or both, in the mixed HIV epidemic in Ukraine.

A randomised controlled trial comparing the effects of counseling and alarm device on HAART adherence and virologic outcomes

Chung MH et al.

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000422

Michael Chung and colleagues show that intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure, whereas use of an alarm device had no effect.

HIV-1 drug resistance emergence among breastfeeding infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention of mother-to-child transmission: a secondary analysis

Zeh C et al.

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000430

Analysis of a substudy of the Kisumu breastfeeding trial by Clement Zeh and colleagues reveals the emergence of HIV drug resistance in HIV-positive infants born to HIV-infected mothers treated with antiretroviral drugs.

Triple-antiretroviral prophylaxis to prevent mother-to-child HIV transmission through breastfeeding—the Kisumu breastfeeding study, Kenya: a clinical trial

Thomas TK et al.

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001015

Timothy Thomas and colleagues report the results of the Kisumu breastfeeding study, Kenya, a single-arm trial that assessed the feasibility and safety of a triple-antiretroviral regimen to suppress maternal HIV load in late pregnancy.

Hepatitis B and HIV Coinfection
http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-05-03-04

Hepatitis C and HIV Coinfection
http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-05-03-05

Immunisations and HIV Coinfection
http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-03-01-08

Conference reports also include exciting news on a new TB medication and diagnostic test (from the 41st Union World Conference on Lung Health); early data, presented at Glasgow, suggesting boosted PI monotherapy maintenance may not be a viable option in settings without access to viral load monitoring and promising results from the Caprisa 004 microbicide trial.

We also include a report from the iPrEX study and a summary of US CDC preliminary guidance for use of PrEP.

Richard Jeffery’s basic science reports include the published results from the single case of functional cure in an HIV-positive man who received stem-cell transplantation from a donor with the delta-32 deletion.

As usual, we don’t have room for all of our reports here, further conference reports and other news from HTB can be found on our website.

Happy reading!

Polly Clayden, HIV i-Base

Thirty years into the history of the epidemic, the 1st International Workshop on HIV and Women was convened in Washington by Virology Education at the beginning of January 2011.

This meeting included some excellent overviews and all the slides are online.

http://www.virology-education.com/index.cfm/t/Workshop_materials/vid/7F5C7280-BB2F-AFB8-9E1C67CB7C0278B1

Many of the presentations underlined how little we know. In her talk on HIV Treatment in Women, Kathleen Squires reminded us that from 1987–1990 only 6.7% of the 11,909 participants in ACTG trials were women. Despite increased representation by women, most studies since 1990 lack statistical power to definitively answer many important questions. And a meta-analysis of antiretroviral registrational trials from 2000–2008, showed that only 20% of 22,411 participants overall were women.

The good news is that the number of HIV-positive women participating in trials is increasing although sex/gender based analyses are relatively uncommon. Most analyses show higher discontinuation rates in women, although the factors that drive this are unclear.

In the session on pharmacokinetics, Angela Kuasaba described “what is important?” with regards to drug exposure in women. Whether increased drug exposure may translate to better efficacy or more adverse events; dosing in pregnancy and post partum; interactions with progestins and oestrogens and oral and topical concentrations when using antiretrovirals in prevention all need to be better characterised.

Quarraisha Abdol Karim looked at where we are with microbicides and Glenda Gray at the challenges a woman faces in her lifetime living with HIV from adolescence, through pregnancy, ageing and menopause.

The slides from all the lectures are worth looking at for anyone wishing to learn about or get an update on the current state of the art.

Overall this meeting is a welcome addition to the conference calendar and will provide researchers with a dedicated forum to present their work (and perhaps drive more research), as there are still many unanswered questions. At the moment, making recommendations concerning HIV treatment and women is often an exercise in how many different ways can you say, “there are no data”.

Articles from this meeting in this issue of HTB include:

• Lopinavir/ritonavir: women versus men
• Quality of life in the GRACE study
• Antiretroviral pharmacokinetics in women with undetectable viral load
• No association between bone mineral density and lipodystrophy in women receiving antiretroviral therapy
• The impact of antiretroviral treatment on fertility intentions in South Africa

Lopinavir/ritonavir (LPV/r) is used frequently in pregnancy and in second line regimens in resource limited settings.

An FDA meta-analysis showed that women made up only 21% of overall participants in phase 2-4 HIV studies from 2000-2006. LPV/r (Kaletra) was approved in 2005.

The originator manufacturer, Abbott, performed a meta-analysis from company data to provide some information on the efficacy, safety and tolerability of LPV/r in women compared to men.

Ashwaq Hermes presented findings from this analysis of seven randomised controlled trials that met the following inclusion criteria: prospective adult trials using the standard dose as part of a three drug regimen with available data to 48 weeks on viral load, CD4, adverse events and discontinuation rates.

The investigation included 2022 trial participants. Of these, 492 were women (286 treatment naïve and 206 experienced) and 1530 were men (1137 naïve and 393 experienced).

Treatment naïve women, treatment naïve men and treatment-experienced women were all younger, having mean ages of 39.2, 38.2 and 38.7 years respectively, than treatment-experienced men, who had a mean age of 41.6 years. White participants made up a greater proportion of both groups of men compared to women, 76.4 vs 48.3 and 58.5 vs 37.9, in the treatment naïve and experienced groups respectively. More treatment-experienced men had a CD4 count of <50 cells/mm3 at baseline, 12.6 vs 5.8. All comparisons p<0.05.

Intent-to-treat analysis revealed similar proportions of women and men with viral load <50 copies/mL at 48 weeks: 69 vs 74% in treatment naïve women and men, p=0.73, and 52 vs 57% in experienced women and men, p=0.3. Mean increases in CD4 count from baseline were also similar between sexes at 48 weeks: 209 vs 200 cells/mm3 in naïve women and men, p=0.42 and 138 vs 123 cells/mm3 in experienced, p=0.253.

Incidence of moderate to severe adverse events also did not differ greatly overall between sexes: 34.3 vs 34.9% in treatment naïve women and men, p=0.89, and 28.2 vs 25.4% in experienced women and men, p=0.495. Although there was a significant increase in the incidence vomiting, 6.6 vs 2.4%, and dyspepsia, 2.3 vs 0.7%, in naïve women compared to men, both p<0.05. Laboratory abnormalities were again similar overall, but with a greater incidence of raised triglycerides (>750 mg/dL) in 7.2 vs 1.4% in treatment-naïve and 7.6 vs 2.0% in treatment-experienced men vs women, respectively (both p<0.05).

When the investigators looked at overall rates of discontinuation of treatment for any reason, they found that these were greater in treatment-naïve women compared to men, 21.7 vs 15.4%, p=0.013. Lost to follow up made up a high proportion of this group, 8.7 vs 4.1%, of women compared to men, p=0.004.

Among experienced women and men, the overall rates of discontinuation were similar: 23.8 vs 21.9%, p=0.608.

Discontinuation due to adverse events was greater in treatment naïve women compared to men: 8.7 vs 5.2%, p=0.034. However, these rates were similar among the treatment experienced group: 7.8 vs 4.6% of women compared to men, p=0.136.

Dr Hermes noted that the older gel formulation was used in the treatment naïve trials whereas the tablet formulation was used in the trial of treatment-experienced patients.

The investigators concluded that this analysis revealed no substantial overall differences between women and men with regards to efficacy, safety and tolerability. They are continuing their evaluation of these data.

comment

Overall this meta-analysis of seven randomised controlled studies including 492 women and 1530 men did not find significant differences in virological or immunological response or overall incidence of adverse events.

Although there are always difficulties with interpretation with any post hoc analysis it seems a good idea for companies to look at their own data in this way.

Reference:

Hermes A et al. Efficacy, safety and tolerability of lopinavir/ritonavir in HIV-infected women: results of a meta-analysis of 7 prospective, randomised clinical trials through 48 weeks. 1st International Workshop on HIV and Women. 10–11 January 2011, Washington. Oral abstract O_17.

One study that was designed to enroll and evaluate a high proportion of women was the Gender, Race And Clinical Experience (GRACE) open label trial of darunavir/ritonavir (DRV/r)-based regimens. [1]

This trial also included a high proportion of black participants and everyone was treatment experienced.

Of the 429 people enrolled, 66.9% were women, 61.5% black, 22.4% Hispanic and 15.2% white.

This trial found significant differences in discontinuations with substantially more women than men discontinuing for reasons other than virological failure, 32.8% vs 23.3%, p=0.042. A higher proportion of black participants did not complete the study compared to hispanic or white participants.

Intent-to-treat analysis showed 50.9% of women compared to 58.5% men had viral load <50 copies/mL at week 48, p=0.067. In the analysis that censored the patients that discontinued for reasons other than virological failure, the response rate was 73.0 in women compared to 73.5% in men, p=0.44.

Health-related quality of life (HRQoL) measures are used to quantify the physical and mental aspects of being HIV-positive that can have an impact on someone’s overall well being. Several studies have demonstrated a correlation between HRQoL and survival of people with HIV.

Judith Feinberg reported the HRQoL results by sex and race from the GRACE study. [2]

HRQoL was measured by the validated Functional Assessment of HIV Infection (FAHI) questionnaire. This was completed at baseline, at weeks 4, 12, 24 and 48 (or when a participant left the study, if they discontinued early).

FAHI consists of 47 questions to measure aspects of physical, emotional, functional and social well-being, and cognitive functioning. The total score (range 0-176, higher scores better) is calculated as the sum of the scores from the five subscales.

The investigators also conducted some post hoc analyses to look at factors associated with an improvement in scores. Analyses were performed on the observed population.

The total FAHI scores at baseline were 118.1 (n=423) overall, 116.8 (n=283) women and 120.8 (n=140) men. They were 119.5 (n=261), 114.1 (n=94) and 119.5 (n=64) for black, Hispanic and white ethnicity respectively.

The overall score of the total population improved significantly by week 4, with a mean increase from baseline of almost 30%, p<0.05. By week 12, near maximum changes of just over 70% were achieved overall and these remained consistent through to week 24 and week 46. Patterns of improvement were similar for men and women, but improvements were greater for women, with over 80% at 48 weeks, than men whose improvement was less than 60%. Black participants also demonstrated greater improvement in total FAHI score that either Hispanic or white participants.

The investigators found that patients with lower baseline HRQoL scores were significantly more likely to discontinue the study than those who scored higher, p=0.044. They noted that this is the first time lower baseline HRQoL has predicted study discontinuations.

In order to assess whether the QoL improvement was due to participants with lower HRQoL scores discontinuing early, the investigators conducted a sensitivity analysis evaluating only those who completed the study. They found, the baseline value with patients who discontinued excluded was 120.1 and the total FAHI score still improved to the same extent from baseline to 48 weeks compared to the total study population, p<0.05.

Multivariate analysis identified four factors that were significantly associated with the improvement in FAHI score over 48 weeks: lower baseline FAHI score, p<0.001; lower baseline CD$ count, p=0.0077; virological response, p=0.0045 and the timepoint of analysis (total FAHI score increased over time. Neither sex nor ethnicity was independently found to be associated.

The investigators concluded that HRQoL improved significantly for the study population overall and that sensitivity analysis suggests that this was not due to people with low HRQoL scores discontinuing the trial.

The largest improvements in total FAHI scores were seen in women and black participants, despite these two groups having lower virological response rates and higher discontinuation rates when compared to men and to Hispanic and white patients, respectively.

“In future, it may be possible to identify patients with a higher risk of discontinuation based on their baseline HRQoL scores; these patients could then be more closely monitored and supported, potentially improving retention.”

comment

These are interesting findings and GRACE must be applauded for conducting this study in harder to reach trial populations.

Gender sub-analyses from ARTEMIS and CASTLE trials also show similar virological response between women and men.

References:

1. Currier J et al. Sex-based outcomes of a single-group trial. Annals of Internal Medicine. Volume 153. Number 6. 21 September 2010.
2. Feinburg J et al. Association of sex and race with health-related quality of life in patients treated with darunavir/ritonavir-based therapy in the GRACE trial. 1st International Workshop on HIV and Women. 10–11 January 2011, Washington. Oral abstract O_15.

Although some studies have shown higher antiretroviral concentrations in women versus men, data are limited.

Mona Loufty presented findings from a Canadian study to look at whether or not non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) drug levels are significantly higher in women compared to a largely male historical population. This analysis also examined whether or not there was an association between weight and drug concentrations.

This was a cross-sectional study conducted at 14 sites across Canada. Women, 18 years and above, on their first antiretroviral regimen, receiving current agents at standard doses (atazanavir, atazanavir/r, lopinavir/r, efavirenz or nevirapine- containing regimens), with an undetectable viral load <50 copies/mL were included.

Timed blood samples for Cmin and Cmax occurred weekly for three weeks. Demographic and clinical data were also collected.

Each individuals median Cmin and Cmax were used to calculate the ratio to the published population’s mean values for the antiretroviral.

Data from 79 women were included in the analysis. They were a median age of 41 (IQR 36-48) years, had been receiving HAART for a median of 21 (IQR 8-45) months and had a median CD4 cell count of 484 (IQR 380-620) cells/mm3.

Median antiretroviral Cmin and Cmax ratios to population mean were 1.22 (p<0.01) and 0.83 (p=0.01) respectively. With 32.2% and 8.9% with values %>1.5 population mean. See table 1 for Cmax and Cmin ratios by antiretroviral.

In linear regression models, including age, ethnicity, CD4 and weight, the investigators found no variables correlated with Cmin or Cmax ratios. They noted that both ratios were highly variable within and between women in this cohort.

They also noted that the study was limited having no real time male control group, inclusion criteria that resulted in limited range in the covariates and possible selection bias due to the commitment required for participation.

They suggested that these pharmacokinetics may result in better viral suppression in women and that women with side effects may benefit from drug level monitoring if drug concentrations may be the culprit.

comment

As Angela Kashuba discussed in her overview, it seems sex/gender based differences in PK are often subtle and may disappear with weight adjustment.

Although these differences may have a small impact at population level, for some individuals they could be significant and TDM may be useful here. However, nuanced drug dosing is challenging (and not feasible in settings with limited resources).

Reference:

Loutfy M et al. Antiretroviral pharmacokinetics in HIV-positive women with full virological suppression on current regimens. 1st International Workshop on HIV and Women. 10-11 January 2011, Washington. Oral abstract O_22.

A number of studies have found an association between lipodystrophy and bone mineral density.

Rebecca Hicks presented data from a study of 47 HIV-positive women enrolled from the Maple Leaf Medical Clinic and Sunnybrook Health Services Clinic in Toronto. The study was conducted to examine the potential correlation between lipodystrophy and reduced bone mineral density (BMD) in women receiving antiretroviral treatment.

This was a cross-sectional study and participants were 18 years or older, on stable HAART for at least two months, not pregnant, and had a DXA BMD test.

The women completed a questionnaire that collected demographic data and information on the presence and severity of lipodystrophy. Lipodystrophy was diagnosed according to the HIV Outpatient Study criteria. Women were considered to have lipodystrophy if they had at least one severe symptom of fat redistribution, or at least two symptoms with one being of at least moderate severity.

Data on DXA BMD test results, osteoporosis risk factors and fracture history were collected from patient charts. A z-score was used to measure BMD (> –2.5 classified as low bone mass).

Almost half (25/47) of the women evaluated met the study definition for lipodystrophy. There were no significant differences in age, 42 vs 39 years, p=0.42; ethnicity 72 vs 68%, were black, p=0.73; duration of HIV infection, 7 vs 8 years, p=0.73, duration of HAART, 3 vs 4 years, p=0.75 or current CD4 count 500 vs 540 cells/mm3, between those with or without lipodystrophy respectively.

The investigators found similar BMD z-scores at the L1-L4 location, –0.60 vs –0.52, p=0.86; femoral neck –0.22 vs 0.05, p=0.44 and total hip –0.48 vs –0.58, p=0.83 in women with and without lipodystrophy.

Multivariate analysis adjusted for age (–0.036, 95% CI –0.094–0.023, per 10 years, p=0.222) and ethnicity (0.133, 95% CI 0.036–0.231 for black vs other, p=0.009), in which only ethnicity remained significant, revealed no association between lipodystropy and femoral neck BMD z-scores (0.014, 95% CI –0.072-0.100) p=0.744.

The investigators suggested this finding that lipodystrophy and reduced BMD were not associated with each other in this study may have been due to reduced power caused by small sample size. They noted that as BMD was significantly associated with black ethnicity, with 70.2% of the sample population identifying as black, the results may have been skewed.

comment

These data were hard to interpret, particularly as the investigators used a definition of lipodystrophy that did not differentiate between fat loss and fat gain.

Reference:

Hicks R et al. Pilot study exploring the association between bone mineral density and lipodystrophy in HIV-positive women taking antiretroviral therapy. 1st International Workshop on HIV and Women. 10–11 January 2011, Washington. Oral abstract O_15.

There is limited information about the impact of expanding access to HAART in settings with limited resources and large epidemics on women’s reproductive decisions and outcomes.

Angela Kaida showed findings from an investigation conducted to assess whether the use and duration of HAART was associated with: fertility intentions, contraception use and method preference, and the incidence of live birth, among women attending the Perinatal Research Unit (PHRU) in Soweto, South Africa.

The study was cross-sectional and used an interviewer-administered survey and a case note review. A total of 751 women, aged 18-49, took part. Of these, 253 had received HAART for a median duration of 31 months. The mean CD4 count was 406 cells/mm3 and 81% had undetectable viral load (group 1). A further 249 women were also HIV-positive but HAART-naïve, with a mean CD4 count of 351 cells/mm3 (group 2). A reference group included 249 HIV-negative women (group 3).

Multivariate analysis (n=674) revealed HIV-positive women were nearly 60% less likely to report fertility intentions than HIV-negative women but the difference between those receiving treatment and naïve women was modest. With HIV-negative women as reference, the investigators reported adjusted odds ratio (AOR) 0.35 (95%CI 0.21-0.60) and AOR 0.4 (95% CI 0.23-0.69) for women HAART-naïve and receiving HAART respectively.

When the investigators looked at the prevalence of contraceptive use among non-pregnant sexually active women (n=563) in this cohort, they found that use was high–nearly 80%, compared to an average of just over 60% among South African women in general. Women receiving HAART were significantly more likely to use contraception: 86% of women receiving HAART, 82% of HAART-naïve women and 69% of HIV-negative women reported contraceptive use, p<0.001. Multivariate analysis, compared to HIV-negative women, found AOR 1.59 (95% CI 0.88-2.85) and AOR 2.40 (95% CI 1.25-4.62) for women HAART-naïve and receiving HAART respectively. The investigators also noted that women receiving HAART were more likely to use dual contraception.

Finally Dr Kaida presented preliminary data from an assessment of lifetime incidence of live birth by time period. For this analysis each participant (n=748) contributed woman-years of follow up based on dates of HIV diagnosis and starting HAART (for those who had). With the HIV-negative time period as a reference, this analysis showed a 69% higher incidence of live birth in the HAART naïve time period than the HIV-negative period—adjusted relative risk (ARR) 1.69 (95%CI 1.48–1.93)—but 66% lower in the period when women received HAART, ARR 0.34 (95% CI 0.23–0.49).

The investigators suggested that this study highlights the potential value of improved integration between HIV prevention, testing and HAART services with sexual and reproductive health programming.

Reference:

Kaida A et al. The impact of expanding access to HAART on fertility intentions, contraceptive use and fertility among women in an HIV hyper-epidemic setting. 1st International Workshop on HIV and Women. 10–11 January 2011, Washington. Oral abstract O_09.

The theme this year was “TB, HIV and Lung Health: From Research and Innovation to Solutions” pointing to the need for new drugs and vaccines, but also for the resources and policies required to put these new tools to use to help some of the poorest citizens, where demand and need is the greatest.

Approximately 2500 delegates attended from over 100 countries.

An impressive programme of webcasts from the meeting ensure that most of the oral sessions can now be viewed online, including slide presentations.

http://uwclh.conference2web.com/content/all#/?groups=3

The programme and abstract book from this meeting can also be downloaded from the conference website.

http://www.worldlunghealth.org/confBerlin/index.php?lang=en

Articles from this conference in this issue of HTB include:

• Faster conversion rates with TMC-207 versus placebo plus OBT for the treatment of MDR-TB
• Xpert MTB-RIF validation study from Tanzania
• Gene Xpert demonstrates good sensitivity and specificity but at high cost

TMC207 is the first in a new class (diarylquinoline) of anti-tuberculosis (TB) drugs to inhibit mycobacterial ATP synthase. It has the potential to improve treatment of both drug-sensitive (DS) and multidrug- resistant (MDR) TB.

In an oral presentation, David McNeely first provided some background information on this drug. [1] TMC-207 previously increased culture conversion by approximately 40% in MDR TB patients in an 8-week trial (see below). These findings were published in the NEJM and we reported them in the August 2009 issue of HTB. [2, 3]

He also showed several key pharmarmacokinetic findings from the phase 1 trials. These were: a positive food effect with TMC-207 giving a two-fold increase in drug exposure when taken with a meal; coadministation of rifampicin lowers TMC207 levels by 50% and coadministartion of lopinavir/ritonavir (LPV/r) modestly increases TMC-207 exposure by 22%. Unpublished information on nevirapine shows a similar interaction. These data suggest the potential to administer the drug with antiretrovirals. Dr McNeely noted that this did not occur in the early trials in patients, as this information was not available. The drug also has a long terminal half-life and does not reach steady state by day 14.

He reported that, to October 2010, 595 participants had received TMC-207 in all trials: 217 healthy volunteers; 147 DS and MDR-TB patients (79 for 24 weeks). There is also an open label trial (Breathe) in which 231 MDR TB patients have been enrolled that is ongoing.

In the second part of this presentation, Andreas Diacon showed findings from TMC-207 C208 stage 2. This randomised, double-blind, placebo-controlled trial is in two stages. It is conducted in patients with newly diagnosed smear positive pulmonary MDR-TB. Following a one-week washout period, patients were randomised to receive optimised background therapy (OBT) plus TMC-207 or placebo.

TMC-207 was dosed at 400mg once daily for 14 days and then 200mg TIW (three times a week).

In Stage 1, conducted in South Africa, 47 patients received 8 weeks of TMC207 (n=23) or placebo (n=23). They then continued their MDR-TB treatment with background regimen alone. All stage 1 patients have completed the trial. Stage 1 found a significant increase in the proportion of culture negative subjects among those who received TMC207 compared to placebo (48% vs. 9% at week 8). There was a 58% reduction in mean time to culture conversion in those who received TMC-207 compared to placebo.

In Stage-2, 161 patients were randomised to receive 24 weeks of either TMC207 or placebo added to the same 5-drug background regimen. All stage 2 patients have completed 24 weeks of TMC207/placebo plus OBT. They are now completing 18–24 months treatment with 2nd line TB drugs (without TMC207/placebo).

Stage 2 was a multi country trial conducted in Brazil, India, Latvia, Peru, Phillipines, Russia, South Africa and Thailand.

The objective was to demonstrate superiority of TMC-207 compared to placebo at 24 weeks. The primary endpoint was time to sputum culture conversion (MGIT). Participants who discontinued during 24 weeks were considered failures irrespective of their culture status at time of discontinuation.

The secondary endpoint was culture conversion rates at 24 weeks.

At baseline about 65% of patients were men, with a median age of 33 years, 85% were HIV-negative and they weighed about 53kg. Patients had confirmed resistance to isoniazid and rifampicin and had not received second line TB treatment previously. HIV-positive patients had a CD4 count greater than 300 cells/mm3 and were not receiving antiretroviral treatment. No patient had significant extrapulmonary TB or other illness.

Of the total randomised patients (80 TMC-207, 81 placebo), 160 were included in the ITT analysis (one patient randomised to the TMC-207 arm, did not receive study drug). The researchers also conducted a modified ITT analysis of 132 patients. Exclusions included, non-MDR patients (4 TMC-207 and 8 placebo), XDR patients (3 TMC-207 and 4 placebo) and patients, for whom, culture results were not evaluable.

OBT was a 5-drug standardised background regimen: ethionamide, pyrazinamide, ofloxacin, kanamycin and terizodone/cycloserine.

Dr Diacon noted that there were high rates of baseline resistance to kanamycin at baseline among patients from European sites. He also noted worryingly high rates of resistance to pyrazinamide across all sites. In vitro evidence suggests there may be good synergy between TMC-207 and pyrazinamide.

Adverse events were similar across both groups. None were serious and discontinuations were unrelated to the study drug.

He reported that the addition of TMC-207 to a 5-drug OBT regimen resulted in faster culture conversion within 24 weeks, p=0.003. It also gave a shorter median time to 50% culture conversion of 12 vs 18 weeks. And there was a higher sputum conversion rate at 24 weeks of 79 vs 58%, p=0.008.

comment

These results are very promising and phase 3 trials will begin this year. Discussions between Tibotec and regulatory authorities in the US and Europe are ongoing and data should be submitted to the FDA and EMA for accelerated or conditional approval this year.

Demand for early access to this drug is already considerable. Activist organisations published an open letter to Tibotec calling for expanded access. This letter was handed over at the beginning of the World Lung conference at which the presentations discussed here were made. The company has committed, both in a teleconference on 7 January and in the OpenForum meeting in Addis Ababa in August 2010, to accelerate access. In countries that have a regulatory framework for pre-registration access, such as South Africa, this will be the preferred method. Although expanded or accelerated access has been the norm for HIV drugs, TMC 207 could set precedence for these strategies with TB drugs. Tibotec needs to maintain a balance between making it available fast to those in greatest need and ensuring it is used judiciously.

Tibotec intends to carry out a trial that will collect safety data in countries that do not provide for pre-registration access and this will allow drug-resistant patients with limited options to access TMC207. Quite reasonably, Tibotec is concerned that it only partners with health-delivery institutions that are capable of ensuring high adherence. There are also plans to include TMC207 in studies with the investigational drug in development from Otsuka Pharmaceuticals, OPC-67683. This is a nitroimidazole and is in phase 2b. It is especially important that OPC-67683 or other drugs under investigation for DR-TB, such as PA-824, become available soon after TMC207, so as to reduce the risk of continuously adding TMC207 to potentially failing second-line regimens and consequently risking a high rate of TMC207 resistance.

References:

1. McNeeley D et al. TMC-207 versus placebo plus OBT for the treatment of MDR-TB: a prospective clinical trial. The International Journal of Tuberculosis and Lung Health. S3 41st Union World Conference on Lung Health. 11-15 November 2010.
   http://uwclh.conference2web.com/content/187
2. Diacon AH et al. The diarylquinoline TMC207 for multidrug-resistant Tuberculosis. NEJM. 2009 June 4. 360, 2397-2405. (4 June 09).
   http://content.nejm.org/cgi/content/abstract/360/23/2397
3. Geffen N. TMC207 reduces time to sputum conversion in phase II trial on patients with drug-resistant TB. HIV Treatment Bulletin. August 2009.
   http://i-base.info/htb/4403

The Xpert MTB-RIF assay (Xpert, described in detail in the article below) gained a lot of attention at this meeting.

This is a cartridge-based, real-time PCR test with automated sample processing, amplification, detection of M. tuberculosis and resistance to rifampicin (RIF).

Andrea Rachlow presented data from an evaluation study of this test performed in Tanzania.

This study enrolled 292 consecutive symptomatic patients. These patients were classified as TB positive or negative following results of sputum smear, culture on solid and liquid media on three different sputum samples (plus chest X-ray and HIV test), and sustained recovery after two months follow-up.

Stored samples were then tested with the Xpert (three frozen, untreated sputum samples per patient).

The investigators reported, that of 69 culture-positive TB cases, Xpert detected 88.4% (95% CI 78– 95%). Sensitivity was notably different between smear-positive and only culture-positive patients, with sensitivities of 98% and 61% respectively.

Among all TB negative patients, Xpert detected one positive result (99% specificity). One of the samples from 45 patients that were culture-positive for non-tuberculous mycobacteria (NTM) also tested positive with Xpert.

Additionally, the test performed well in HIV-positive patients (n=50) with 88% sensitivity and 89% specificity.

The investigators noted that the test is easy to use and the short time to a result could mean avoidance of loss to follow up during the diagnostic process, which could result in a 5-15% decrease in TB deaths worldwide.

They added that further studies are required to confirm the tests performance on fresh sputum samples and on other clinical material.

Reference:

Rachlow A et al. Detection of TB using the Cepheid Xpert MTB/RIF® Assay: a clinical validation study from Tanzania. The International Journal of Tuberculosis and Lung Health. FA-101098-13
http://uwclh.conference2web.com/content/667

Further information:

http://www.treatmentactiongroup.org/press.aspx?id=4320

http://www.tac.org.za/community/node/2962

We published a report on the Gene Xpert in the April 2010 edition of HTB South. [2] Catherine Boehme of FIND and her colleagues have since published the test results of Cepheid’s Gene Xpert TB diagnostic technology in the NEJM. [1] This device aims to diagnose TB and determines rifampicin resistance in less than two hours. Preliminary results have been good. This study confirms that this device has high sensitivity and specificity in a variety of settings in both HIV-positive and HIV-negative patients and in culture-positive sputum-negative patients.

Over 1,800 patients were screened at five sites located in Lima, Baku, Cape Town, Mumbai and Durban. 1,730 patients were able to provide three sputum samples with sufficient volume and were consequently eligible for the study. Of these, 268 were excluded from final analysis, 115 because they were culture-negative and suspected of MDR TB while receiving treatment, 28 because three or more of their cultures were contaminated, 23 because they had growth of non-MTB only, 10 because they had indeterminate phenotypic rifampicin results, 39 because they were smear-positive but culture-negative, seven because they had suspected culture cross-contamination and 46 because they died or were lost to follow-up.

Of the 1,462 included in the main analysis 741 were culture-positive, of whom 567 were smear-positive and 174 were smear-negative. Of the 721 culture-negative cases, 105 had clinical TB and 616 did not have TB (as determined by a clinical review committee).

As explained in our previous article the Gene Xpert consists of a computer installed with Cepheid’s proprietary software and a machine –the smallest of which is about the size of a desktop computer– that takes cartridges loaded with sputum and reagents. The cartridges consist of a syringe barrel, a sonicator dome, a reverse-transcriptase PCR tube and a rotary valve. The smallest version of the machine takes four cartridges. The highest capacity one apparently contains 100 cartridges. As explained below, two or even three cartridges might be needed for a patient.

The screening results and consequent inclusion and exclusion criteria of patients in various analyses is complicated in this study. Table 1 presents an overview that readers can refer to when reading the remainder of this summary.

Table 1: Screening results. Adapted from Boehme et al.

TB sensitivity and specificity

With one sputum sample, the Gene Xpert had a sensitivity of 92% for all culture-positive specimens. This increased to 96% for two samples and 98% for three. Specificity on non-TB cases was 99% with one sputum sample, declining marginally to 98% with three samples. However, for culture-positive, sputum-negative specimens, sensitivity using one sputum sample was 73% rising to 90% with three samples. No site had a sensitivity lower than 83% for culture-positive, sputum-negative specimens.

Further details including confidence intervals are provided in Table 2.

Table 2: Sensitivity and specificity of Gene Xpert on culture-positive patients and culture-negative patients not treated for TB. Adapted slightly from Boehme et al.

Sensitivity was 94% in HIV-positive patients with pulmonary TB versus 98% in HIV-negative patients (p=0.02). Of the 105 patients with culture-negative samples excluded from the main analysis but who had clinical signs of TB, 29.3% had positive results on the Gene Xpert.

Rifampicin sensitivity and specificity

Of the 723 culture-positive patients correctly identified as having TB by the Gene Xpert, 720 were tested phenotypically for rifampicin resistance (for the remaining three, the Gene Xpert gave indeterminate resistance results). The Gene Xpert identified 200 out of 205 rifampicin resistant specimens correctly for a sensitivity of 98%. It identified 505 out of 515 rifampicin sensitive specimens correctly for a specificity of 98%.

Details of resistance testing with confidence intervals are presented in table 3.

Table 3: Sensitivity and specificity of Gene Xpert on phenotypically determined rifampicin susceptibility. Adapted from Boehme et al.

The authors also did a second analysis that included the results of gene sequencing of the 15 discrepant results between phenotyping and the Gene Xpert. After three of these were excluded from analysis because sequencing gave indeterminate results, sensitivity was 99.1% [95%CI: 96.6-99.7] (209/211 correct) and specificity was 100% [95%CI: 99.2–100.0] (506 correct).

Importantly, 195 out of 200 of the rifampicin resistant specimens were also resistant to isoniazid. This suggests that rifampicin resistance is a good predictor of MDR TB in practice.

In 115 patients, excluded from the main analysis in the study, who were culture-negative but who were diagnosed with MDR TB and consequently received treatment, 51 had positive results on the Gene Xpert. Rifampicin resistance was detected in eight. Interestingly, the authors note that all eight patients were later started on second-line therapy by physicians unaware of the results of the Gene Xpert results.

comment

These results are promising. The Gene Xpert is much easier to use than sputum microscopy. It has a high sensitivity and specificity and appears to be better than culture in a subset of patients who are culture-negative but nevertheless have TB. It has high sensitivity and specificity for detecting rifampicin resistance. The diagnostic can be used in facilities that offer consistent electricity supply. One drawback, as with most TB diagnostics, is that patients need to provide sputum and preferably as many as three samples.

But the main obstacle to wider use of the Gene Xpert will be its price. The cheapest machine reportedly costs $20,000. Each cartridge costs approximately $20. There is a great need for better TB diagnostics primarily in poor communities. Pressure needs to be exerted on Cepheid to bring down the price of this system, which was in any case developed with substantial public investment. Conversely pressure needs to be placed on international TB bodies to fund the implementation of diagnostics such as this one in resource-poor settings.

References:

1. Geffen N. 2010. Cepheid Gene Xpert diagnostic technology for TB. HTB South April 2010.
   http://i-base.info/htb-south/960/
2. Boehme C et al. 2010. Rapid Molecular Detection of Tuberculosis and Rifampin Resistance. NEJM September 2010.
   http://www.nejm.org/doi/full/10.1056/NEJMoa0907847

This year the conference abstracts are already posted online as a supplement to the Journal of the International AIDS Society (Volume 13, Supplement 4).

http://www.jiasociety.org/supplements/13/S4

In the references to our reports we include both the conference abstract numbers and the IAS publication link.

A PDF file of the abstracts is also available (direct download):
http://www.biomedcentral.com/content/files/pdf/1758-2652-13-S4-full.pdf

Approximately 200 posters are online as PDF files, categorised by general topics, and posted to the ‘webcast’ pages of the conference website. A few webcasts are included in this selection.

http://www.hiv10.com/webcastsearch.asp

Reports in this issue include:

• Virological findings from the SARA trial of boosted protease inhibitor monotherapy
• Nevirapine exposure was not associated with hypersensitivity in patients from Malawi
• Estimating the number of people in a country or region with HIV who are undiagnosed and in need of ART
• Pharmacokinetics of lopinavir/ritonavir in combination with rifampicin based TB treatment in children
• Efavirenz versus nevirapine based first line treatment in a South African cohort

There is currently an interest in using boosted protease inhibitor monotherapy as a maintenance strategy in resource rich countries.

A pilot substudy of the DART trial, Second-line Anti-Retroviral therapy in Africa (SARA), randomised 192 patients who had received 24 weeks of lopinavir/ritonavir-based (LPV/r) second-line combination therapy to either continue on this combination or to receive LPV/r maintenance monotherapy. Prior to the switch, DART patients had taken first line therapy for a median of 4.4 years.

Data were presented as a late breaker poster at IAS 2010 suggesting few differences between the two groups in CD4 increases or adverse events in the short term. [1] At week 24 the mean CD4 gain was 48 vs 42 cells/mm3 in the combination and monotherapy arms respectively. For those completing 72 weeks the gains were 159 vs 153 cells/mm3.

No real-time virology was performed in DART but plasma samples were stored from: time at switch to second line, time of SARA randomisation, 24-weeks after SARA randomisation and latest time point (35-107 weeks after SARA randomisation).

Dave Yirrel presented results at Glasgow 2010 from a retrospective analysis of viral load, measured by Roche Amplicor v1.5 on the stored samples. In addition, genotype resistance was assessed on samples with viral load >1000 copies/mL at 24 weeks. Analyses were intent to treat. [2]

The median CD4 counts overall were 86 cells/mm3 at switch to second line and 245 cells/mm3 at SARA randomisation. The majority of patients (86%) had received a triple nucleoside first line regimen and the remainder two nucleosides and an NNRTI. At SARA randomisation 22% were receiving LPV/r + 2/3 NRTIs, 15% LPV/r + NNRTI and 62% LPV/r + NNRTI + NRTI. Of those with viral load measurements 135/173 (77%) had viral load <50 copies/mL.

The investigators found a higher proportion with undetectable viral load among patients on combination therapy compared to monotherapy at week 24, p=0.007. They reported 77% (70/91) vs 60% (66/94) had viral loads <50 copies/mL and 94% vs 84% had viral load <1000 copies/mL.

Among the small number of patients for whom 96-week data were available for analysis, the proportion with rebound to >200 copies/mL was greater in the monotherapy than combination therapy arm: 50% vs 20% (n=7 per arm). This difference was similar among those with rebound >1000 copies/mL: 40% vs 10% (n=7 in the monotherapy and , n=8 in the combination therapy arms).

Genotype results from the patients with viral load >1000 copies/mL at 24 weeks showed 0/5 patients with major protease inhibitor mutations of those in the combination therapy arm and 4/16 (of 19 patients with rebound to 1000 copies/mL) in the monotherapy arm.

The investigators concluded that, over the relatively short period of follow up (median 60 weeks) since SARA randomisation, there was an increase in low level viraemia with monotherapy compared to combination therapy, but no evidence of systematic increase in viral load after loss of suppression.

The EARNEST trial due to start next year will provide data on the long-term effectiveness of PI maintanance monotherapy in this setting. [3]

comment

Neither the numbers involved, nor the duration of the trial make it possible to make any definite conclusion from these data. But it does seem that boosted PI monotherapy may not be a viable option in settings without access to viral load monitoring.

References:

1. Gilks CF et al. Boosted protease inhibitor monotherapy as maintenance Second-line Anti-Retroviral therapy in Africa: a randomised controlled trial (SARA). 18th International AIDS Conference. 18-23 July, 2010. Vienna. Poster abstract LBPE16.
   http://pag.aids2010.org/Abstracts.aspx?AID=17479
2. Pillay et al. Virological findings from the SARA trial: boosted PI monotherapy as maintenance second-line ART in Africa. 10th International Congress on Drug Therapy in HIV Infection, November 7-11. Glasgow. Oral abstract O20. Published in Journal of the International AIDS Society 2010 13(Suppl 4). O214.
   http://www.jiasociety.org/content/13/S4/O20
3. Europe – Africa Research Network for Evaluation of Second-line Therapy (EARNEST) study.
   http://earnest.cineca.org/index.php

Although there is a risk of hypersensitivity, nevirapine (NVP) is used widely in first line regimens in resource- limited settings.

The relationship between drug exposure and hypersensitivity with NVP is unknown. It is possible that it is influenced by the effect of polymorphisms in CYP2B6 and CYP3A5 on drug metabolism.

Laura Dickenson and colleagues from Malawi and Liverpool showed findings from a study designed to develop a population pharmacokinetic (PK) model for NVP serum concentrations, and, in turn, to determine the impact of patient demographics, hypersensitivity and genetics on the PK of the drug.

The population PK model included 180 drug-naïve HIV-positive patients (of which 101 were women), starting NVP-based treatment at Queen Elizabeth Central Hospital, Malawi between March 2007 and September 2008. At the time of PK sampling, they were a median age of 34 years old, with a median CD4 cell count of 156 cells/mm3 (range 1-812). The median duration of treatment was 6 weeks (1-26). Twenty-five patients were hypersensitive and 23 coinfected with hepatitis B or C.

The investigators performed rich and sparse sampling in 40 and 140 patients respectively. PK data were available for single nucleoside polymorphisms (SNPs): CYP3A5*6, CYP3A5*3, CYP2B6 983T>C, CYP2B6 516G>T and CYP2B6 785A>G in 89/180 patients. Genotyping was performed using Sequenom iPLEX.

The investigators used non-linear mixed effects modelling (NON-MEM, VI 2.0) to investigate the effects of patient demographics, hypersensitivity, hepatitis and CYP3A5 and C