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.

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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.

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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.

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.

comment

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

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 CYP2B6 on NVP apparent oral clearance (CL/F).

They found a one-compartment model with first order absorption best described the data. For the final model (n=89) NVP CL/F (relative standard error RSE%) was 2.67 (5%) with interindividual, interoccasion variability of 30% (29%) and 32% (26%) respectively.

The apparent volume of distribution and absorption rate constant were 141L (22%) and 0.77h-1 (31%) respectively.

They reported that none of the available patient demographics were associated with NVP CL/F. Nor did they find an association between NVP CL/F and hypersensitivity or hepatitis.

Only CYP2B6 983T>C and CYP3A5*3 had an impact on NVP CL/F; reducing it by 25% in 983C heterozygotes (allelic frequency 18%) and 40% in CYP3A5*3 homozygotes (allelic frequency 5%).

They concluded that NVP exposure was not associated with the development of hypersensitivity, “which is more likely to be an immunological phenomenon.” They added that further studies are warranted to determine the mechanism of NVP hypersensitivity.

Reference:

Dickenson L et al. Population pharmacokinetic and pharmacogenetic analysis of nevirapine in hypertensive and tolerant HIV-infected patients from Malawi. 10th International Congress on Drug Therapy in HIV Infection, November 7-11. Glasgow. Poster abstract P181. Published in Journal of the International AIDS Society 2010 13(Suppl 4):P181.
http://www.jiasociety.org/content/13/S4/P181

Estimating the number of people in a country or region with undiagnosed HIV in need of ART is essential for testing and treatment programmes.

Rebecca Lodwick and colleagues from the University College London showed a simple method for making this estimate, which uses data on simultaneous HIV/AIDS diagnoses at low CD4 count.

The HIV surveillance data needed for this method are the number of previously undiagnosed people presenting with AIDS (simultaneous HIV/AIDS) in a year with CD4 count at diagnosis. The number of people with simultaneous HIV/AIDS in a CD4 stratum represents a proportion of the total undiagnosed people with CD4 count in that stratum. The proportion is equivalent to the annual incidence of AIDS in people in that stratum, which can be estimated from cohort studies.

For each stratum the number of people with undiagnosed HIV is estimated by dividing the number of people with simultaneous HIV/AIDS diagnoses (with CD4 count in the stratum) by the CD4 specific AIDS rate.

The investigators obtained an uncertainty range associated with this estimate by assuming the AIDS rate varies according to a normal distribution and the observed number of diagnoses according to a Poisson distribution. They accounted for these two sources of uncertainty simultaneously over 10,000 runs.

They illustrated this method for people with undiagnosed HIV and CD4 count below 200 cells/mm3. Using data from CASCADE the incidence of AIDS in this CD4 stratum among ART naïve patients has been estimated to be 0.25 per year (95% CI, 0.21-0.28). They used an example that supposed during the past year there were 50 simultaneous HIV/AIDS diagnoses with CD4 counts below 200 cells/mm3. Then the estimated number of undiagnosed people in this CD4 stratum would be 50/0.25=200. The estimated 95% uncertainty range would be 144-268.

They acknowledged that a potential source of bias is the possible under-diagnosis and under-reporting of simultaneous HIV/AIDS diagnoses.

They also note that the method depends on high levels of ascertainment of people presenting with simultaneous HIV/AIDS and on availability of CD4 count at diagnosis.

The investigators intend to make a SAS programme available that will perform this calculation.

Reference:

Lodwick RK et al. A method to estimate the number of people in a country or region with HIV who are undiagnosed and in need of ART. 10th International Congress on Drug Therapy in HIV Infection, November 7-11. Glasgow. Poster abstract P165. Published in Journal of the International AIDS Society 2010 13(Suppl 4):P165.
http://www.jiasociety.org/content/13/S4/P165

Lopinavir/ritonavir (LPV/RTV) is first line treatment for young children in South Africa. Concomitant treatment for TB is common in children with HIV. There is a complicated interaction between this boosted protease inhibitor and the first line TB drug, rifampicin (RIF), which reduces the bioavailabilty and Cmin of LPV by approximately 75% and 99% respectively.

Two strategies are possible to increase the LPV levels when it is dosed with RIF – either increasing the dose of RTV to a LPV:RTV 4:4 ratio or doubling the dose to a LPV:RTV ratio 8:2.

Chao Zhang and colleagues from the University of Cape Town showed a population pharmacokinetic (PK) model developed to describe the interactions between LPV, RTV and RIF in children. They used this to look at the effect of various factors (age, BSA, weight, gender, haemaglobin, albumin, ALT) on LPV and RTV PK, and make dosing recommendations for HIV/TB coinfected children receiving these drugs concurrently. [1]

In this study, 39 children with HIV only received the standard dose of LPV/RTV, 4:1, (control group); 15 coinfected children received the super-boosted dose, 4:4; and 20 the double dose, 8:2. Then 11 coinfected children received the standard dose following RIF-based treatment. Repeated sampling was performed (4-6 from each child) up to 12 hours post dose.

The children were a median age of 21 months (range 6 months to 4.5 years) and a medium weight of 10.2kg (range 5-17kg).

Using a one-compartment model with first order absorption for LPV and a one-compartment model with transit absorption for RTV, the investigators modelled the effect of RTV concentration on LPV clearance as direct inhibition with an Emax model.

The investigators found that, during concomitant treatment with RIF, the relative oral bioavailability of LPV was reduced by 79% in children receiving the twice the standard dose of LPV/RTV. RTV clearance was 18 L/h with RIF and 13L/h without.

The estimated baseline clearance of LPV, when there was no detectable RTV was 4.34 L/h. As the concentrations of RTV increased, the clearance of LPV decreased in a sigmoid relationship (EC 50, 0.051 mg/L). They found volume of distribution for LPV and RTV were 11.7 and 102 L respectively.

When the investigators performed simulations for dose optimisation during RIF-based TB treatment with a target of LPV concentrations with Cmin >1mg/L in 95% of children, they predicted doses of LPV/RTV as described in Table 1. They noted that smaller children required higher mg/kg doses of LPV/RTV, in both 4:1 and 1:1 ratios, than larger children.

Table 1: Simulation for dose optimistion of LPV/RTV during RIF-based TB treatment

comment

The same group previously presented data to show that the double dose LPV/r is not sufficient for children when coadministration with rifamipicin. [2]

The current median LPV dose using double dose strategy in this study is 23 mg/kg,

The investigators suggestion for dose adjustment in this study is much higher than double dose. Or they suggest switching to an 8 hourly dose strategy considering the adverse effect slinked to higher doses. [3]

References:

1. Zhang C et al. Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children. 10th International Congress on Drug Therapy in HIV Infection, November 7-11. Glasgow. Oral abstract O24. Published in Journal of the International AIDS Society 2010 13(Suppl 4). O223.
   http://www.jiasociety.org/content/13/S4/O24
2. McIlleron et al. Double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based anti-TB treatment. 16th CROI. February 2009, Montreal. Oral abstract 98.
   http://www.retroconference.org/2009/Abstracts/34615.htm
3. Personal communication with the author.

A poster authored by Peter Block and colleagues compared the effectiveness of efavirenz and nevirapine in a multisite cohort of South African adults attending public health facilities.

This was a retrospective analysis of routine data from 27,350 adults initiated on ART between March 2004 and March 2007 in public health facilities. Participants were a median age of 34.4 (IQR 29.4-40.8) with a median CD4 count of 113 cells/mm3 (IQR 57-165).

The investigators found, over a median follow up of 9.3 months (IQR 4.6-17.7), in multivariate analysis, participants receiving efavirenz-based combinations were more likely to achieve undetectable viral load at six months, OR 1.31 (95% CI, 1.1-1.54) and at any time between six and 36 months, OR 1.28 (95% CI, 1.16-1.41). They were also more likely to die, AHR1.24 (95% CI, 1.07-1.45) and less likely to change regimen OR 0.53 (95% CI, 0.48-0.59).

Additionally, a subset analysis of 18,527 participants for whom pregnancy and TB status were known revealed no difference in mortality risk between those receiving efavirenz and nevirapine based regimens AHR 1.17 (95% CI, 0.99-1.37).

comment

This study adds to a body of evidence showing superior results with EFV for first line ART when compared to NVP. Given the resource constraints in developing countries EFV should therefore be the preferred NNRTI for first line use. Protease inhibitors are not suitable for first line in developing countries due to increased cost. However; the possible link between EFV use in the first trimester and teratogenicity complicates its use with many women receiving EFV or initiating ART presenting only in the second trimester of pregnancy.

In the absence of suitable alternative NNRTIs or protease inhibitors, recommendations against the use of EFV in pregnancy need to be reviewed. In addition more work needs to be done to advocate for the reduction in price of suitable alternatives.

Reference:

Bock P et al. Comparing the effectiveness of efavirenz and nevirapine for first-line antiretroviral treatment amongst an adult treatment cohort from South Africa. 10th International Congress on Drug Therapy in HIV Infection, 7–11 November 2010, Glasgow. Poster abstract P10. Published in Journal of the International AIDS Society 2010 13(Suppl 4). P10.
http://www.jiasociety.org/content/13/S4/P10

This is one of the strengths of this meeting, which now has over 20,000 delegates, and many of the access-related sessions are online as webcasts and transcripts produced by the Kaiser Foundation.

A joint report from UNAIDS and Kaiser launched prior to the conference clearly and disturbingly showed that international donor funding, which now supports close to five million people on treatment, has leveled. This threatens to overturn the accumulated health benefits from the last ten years. Flat-lined funding means treatment programmes will be closed to new patients and this will have a disastrous impact on HIV prevention.

Without treatment, not only is there little incentive to test, and an increase in AIDS and death, but also the beneficial impact that antiretroviral therapy has on the risk of transmission will be reduced. And treatment is still likely to be more effective in preventing HIV than any other intervention.

This global crisis demands international support, and this involves funding. So while the US leads funding initiative, as the world’s richest country, it is just as important that other wealthy nations meet, for example, the commitments made at the G8 summit. The expense and investment in the conference itself, did not sit easily with the decision to hold the meeting in country that has not supported the Global Fund since 2002. Currently the Global Fund to Fight AIDS, TB and Malaria (GFATM) is faced with a $3 billion shortfall for 2010. Similarly, very few African nations have met their pledge in the Abuja Declaration 2001 to target at least 15% of GDP on healthcare.

The global demand for treatment challenges the concept of universal access using todays medications. Research into ARV drug delivery using nanotechnology is proceeding extremely slowly with only one abstract at this meeting, and yet this has the potential to address many obstacles to wider access. The volume of active ingredient is dramatically reduced with a nanoformulation requiring perhaps monthly dosing, both of which dramatical reduce costs.

This was a conference that highlighted access issues from a human rights perspective:

• The Vienna Declaration – is the official conference statement seeking to improve community health and safety by calling for the incorporation of scientific evidence into illicit drug policies (viennadeclaration.com).
• Many sessions addressed access to evidence-based harm reduction stategies including opioid substitution therapy (OST) and needle exchange progammes.
• Access to treatment to prevent mother-to-child transmission (PMTCT) – currently only 10–20% of HIV-positive women worldwide are able to access testing and treatment during pregnancy.
• The criminalisation of same sex relationships and discrimination against men and women whose sleep with partners of the same sex, highlighted most recently by extreme cases in Uganda, Malawi and Iran, was the focus of several sessions.

We will cover treatment access in the next issue.

In terms of medical and scientific research, there were a few important headline-grabbing studies and a good selection of interesting but preliminary research findings.

As with all meeting reports we include links to original abstracts and webcasts when available, and for this meeting we also start with a guide on how to navigate the conference website for other material.

Abstracts from the conference are published on the conference website:
http://www.aids2010.org/

Reports in this issue include:

• Navigating the conference online
• Results from the Caprisa 004 tenofovir microbicide trial
• Impact of antiretroviral PMTCT prophylaxis regimens on subsequent maternal disease progression in Kesho Bora
• Birth outcomes with antiretroviral exposure
• New WHO guidelines for children
• Scaling up: what to do first?
• Efavirenz-based regimens among women of reproductive age receiving ART in Johannesburg
• Male circumcision retains effectiveness at reducing risk of HIV infection: 54 month results
• Cambodian trial shows early ART reduces mortality in patients with very TB with very low CD4 counts
• Intensified TB case finding is feasible

Abstracts from the conference are published on the conference website:
http://www.aids2010.org/

As with previous IAS conferences, much of the conference material is available online and HTB reports include appropriate hyperlinks.

Locating the appropriate files, presentations, webcasts, transcriptions or even the basic abstracts is more challenging. Access is routed through the ‘Programme at a glance’ link on the conference homepage. This requires a free software plug-in called Silverlight, but an automatic download button should come up if you do not already have this installed.

Vienna Conference homepage

‘Programme at a glance’

The search facility requires selecting one of the seven options directly under the search bar ie to search the abstracts, you need to first click ‘abstract’ which when selected has the tiny white triangle in the red block turn to face down. Then search as you would normally by entering a keyword in the search box and clicking search. Results come up listed below.

The abstract books are available to download as free PDF files, but only for each day, so searching the whole conference requires repeating each search four times.

Download abstract books.

Although you can browse sessions by day and time, this is not so easy if you are looking for a specific session but don’t know when it was presented because there is not a programme that just shows the sessions. For example a search for ‘late breaker’ brings up no results whether searching ‘programme at a glance’, ‘abstracts’, or ‘oral sessions’.

If you find a session page, you then have to find and click the yellow ‘more info’ button at the bottom right of an empty box, and then you finally get to a page that makes sense. Don’t be entirely fooled. The ‘abstract’ links seems to work, but ‘slides with audio’ are not always available and the ‘powerpoint’ link doesn’t work at all. For presentation slides, scroll further down the page where slides that are available are listed under the ‘powerpoint presentations’ heading.

The audio works but you need to manually download the powerpoint slides to really follow the presentation.

To make things more confusing, some webcast presentations are provided by Kaiser Foundation on a different website.

http://globalhealth.kff.org/AIDS2010

These webcasts only show the presenter, with no slides and no easy links to slides. Although you often hear two different presentations simultaneously, this accurately captures the conference experience. Only a cloth curtain divided most session rooms, so the webcasts accurately reflect the conference atmosphere, including this difficulty.

Kaiser provide rough transcripts of the sessions that can be more useful with the slide set, than the webcast, though they are draft transcripts only.

Web access should be a leading priority for these conferences. The interface used by the Retrovirus (CROI) conference would be a much more useful model to use and would make this aspect of the meeting far more accessible, whether provided by IAS or Kaiser.

In terms of conference headlines, the biggest news came from the results of a prevention study called Caprisa 004. This study reported that a microbicide gel containing 1% tenofovir reduced the risk of infection to women when used before sex to protect against HIV by 39%. [1, 2] Previous microbicides (not using HIV drugs) have not shown a benefit, so a positive result, no matter how slight, was likely to be greeted enthusiastically. When the results were presented, the audience gave the presenters a standing ovation.

Importantly, the presenters stressed that these preliminary results justified further research. This study was based on 98 endpoints for the primary analysis and the sample size ensured that they could be 90% confident of detecting a doubling/halving in the risk (ie an OR of 2 or 0.5). However, because the endpoints are by definition fewer in subgroup analyses, the study is not powered to analyse some of those interesting results. One of the most helpful aspects of the study is that the detailed results were published in a free-access article in Science Express. [3]

The theoretical benefit from an antiretroviral microbicide is similar to the use of pre- and post-exposure prophylaxis (PrEP and PEP) but instead of taking oral drugs, applying a gel enables the active drug to be absorbed in the tissues that are first exposed to the virus. If the cells in the genital tissues have antiretroviral activity, the hope is that this will reduce the risk of infection.

As with all studies, the complexity of the results is in the details, and the presenters themselves cautioned that their results primarily signaled the urgency of running additional studies.

Women were advised to use the microbicide ‘up to 12 hours before sex’ and ‘as soon after as possible’, using a maximum of two doses in any single 24 hour period. The gel was applied with a special pre-filled applicator, similar to a tampon container.

This phase 2b study was in around 900 women aged 18–40 years, living in two districts in South Africa where the risk of HIV for women reaches 50% by the age of 24. One trial site was in urban Durban (n=278) and the second was in a rural location 90 miles from Durban (n=611). This was a double-blind study with women randomised 1:1 to either the active gel or a placebo gel. Free condoms and counselling on the importance of safe sex were provided to all women, with monthly HIV testing and monitoring.

There were significant differences between the rural and urban women. Rural women were younger (mean 23.3 vs 25.1), poorer (86% vs 69% monthly income <R1000), less likely to have a stable partner (77% vs 93%), had fewer lifetime partners (mean 2 vs 6), used condoms less consistently (22% vs 42%) and had lower HSV-2 prevalence (48% vs 60%), see Table 1. However, randomisation ensured that there was no difference in these baseline characteristics between the active and placebo group.

* NS = non significant differences

The predetermined endpoint of 98 events was reached after a mean 18 months with 1341 person years (PY) of follow-up, with a low drop-out rate (~5%).

Of the 98 women who became HIV-positive over 12–30 months, 38 were in the active gel group and 60 were in the placebo group. The HIV incidence rate per 100 PY was 5.6 (CI: 4.0, 7.7) in the tenofovir gel arm compared to 9.1 (CI: 6.9, 11.7) in the placebo gel arm (incidence ratio rate [IRR]=0.61; CI: 0.40, 0.94; p=0.017). After adjusting for baseline covariates including, age, site, anal sex history, contraceptive method, HSV-2 antibody status, and condom use, the hazard ratio was 0.63 (CI: 0.42, 0.94; p=0.025). Sensitivity analysis produced similar results. Although this fell just short of the predetermine OR of 0.50, the results remained statistically significant.

The combined rural/urban analysis produced a protection rate of 39% from using the active compared to placebo gel. However, the 95% confidence intervals are 6% and 60%. Further studies are likely to focus on dosing, adherence and other factors in order to see whether higher protection rates can be seen. Although the results were presented by site, showing effectiveness at the rural site of 43% (95%CI 5, 57; p=0.023) but not at the urban site (26%; 95%CI –59, 67; p=0.380), see Table 2. However, as the study was not designed to compare efficacy by site, while interesting, it was not powered for this comparison to be meaningful.

NOTE: Study was not powered for the subgroup analyses by site and adherence.

† Adherence could not be calculated for the 5 women who reported no sex during their follow-up in the study. NS=non significant

Adherence is essential to monitor in any intervention study, see Table 2. In Caprisa 004, the researchers determined that two applications of the gel were used for over 70% of occasions when participants had sex. While approximately 40% women reported >80% adherence, a similar proportion reported that they used the gel less than half the time. When adherence was 80% or higher (n=336), the protection increased from 39% to 54% (95%CI 4, 80; p=0.025). There appeared to be a trend between adherence and efficacy, and this is clearly plausible, though again the study was not powered for this comparison. The Science Express paper reported 38% protection (95%CI –67, 77; p=0.343) at 50–80% adherence (n=181) dropping to 28% (95%CI –40, 64; p=0.303), when less than 50% (n=367).

The mean number of sex acts in the high, intermediate and low adherence groups was 3.2, 5.0 and 6.7 per month respectively. Median adherence in the women who become HIV-positive was similar throughout the study at approximately 60%, whereas in the HIV-negative women this started at 55% and increased to 75% in the first and last six months respectively. Even with an intensive education and support programme, only a minority of women achieved >80% adherence, and these were the women who had less sex (3 times a month). Condoms were reportedly used 80% of the time, though this may have been over-reported given the rough per-exposure risk this generates for the study, which is not uncommon in prevention studies.

No serious or significant safety issues (from the 4692 reported events) were associated to using the gel in terms of side effects, including renal toxicity or in the 54 unplanned pregnancies that occurred. Mild diarrhoea was reported in 16% people using the active gel compared to 11% of the placebo group. No safety concerns in terms of flares in liver enzymes were seen relating to the use of tenofovir in the small numbers of women who entered the study with active hepatitis B (19 in the active and 15 in the placebo group) or who acquired HBV during the study (22 women, 19 or who cleared the virus without additional treatment). The concern that continued exposure to tenofovir prior to HIV being diagnosed might exert sufficient pressure to generate drug resistance was not supported in genotypic results from 35 women (no K65R, K70E or RTI-associated mutations). Of interest, the use of the active gel had no impact of viral set point after infection (4.65 vs 4.30 log; p=0.15) and participation in the study did not lead to any increase in risk behaviour.

The study also reported an impact on transmission of HSV-2, the virus responsible for genital herpes. Of the 434 women who tested negative for HSV-2 at the beginning of the study, 29 became infected in the active gel group compared to 58 in the placebo group (IR/100PY 9.9 (6.6, 14.2) vs 20.2 (15.3, 26.1). This was reported as tenofovir providing 51% protection against HSV-2 (95%CI: 22%–70%; p = 0.003). Because genital herpes increases the risk of catching HIV, these results are complicated to understand. Although tenofovir has not shown protective effects against HSV-2 in mouse and test-tube studies, drugs with a similar structure to tenofovir such as cidofovir have activity against HSV-2.

Results from the pharmacology substudy of CAPRISA 004 were presented in the same session by Angela Kashuba from the University of North Carolina. [5]

For the HIV analysis, 90 samples were available (37 active and 13 placebo in the HIV-positive women plus 24 active and 16 placebo from women who remained HIV-negative. Tenofovir levels were measured in blood plasma (BP), and cervicovaginal fluid (CVF) for all samples and additionally in vaginal and cervical tissue biopsy samples in the HIV-positive women. Plasma concentrations were minimal (<1 ng/mL), with detectable levels in only 12% of the HIV-positive women (median 0, range 0–0.1 ng/mL) a median 6 days (range 1-25) after application vs 50% of the HIV-negative women (median 0.1, range 0–0.8 ng/mL) after a median of 4.5 days (range 2–28), indicating very low systemic uptake even given the delay in sampling.

Tenofovir was more frequently detected and at higher CVF levels in the HIV-negative compared to HIV-positive women at 45% (median 1 ng/mL range 0–300,000) vs 96% (median 520 ng/mL (range 0–1,340,000), both at 4.5 days. CVF concentrations correlated well with infections and also importantly with intracellular levels of tenofovir diphosphate. This will help establish the target dose in future formulations. A separate PK study of 250 samples from 172 highly adherent HIV-negative women showed a mean half-life of about two days with most concentrations over the first few days of ~1000 ng/mL. It is important to note that there are currently no data on appropriate target levels of either tenofovir or tenofovir diphosphate and that data, as for early absorption (ie how soon before sex would you get protection?) will be the focus of the next studies. These results suggest that drug levels are a marker for adherence rather than poor absorption potentially due to interpatient variability of cellular transporters such as MRPs.

A similar relationship was observed between drug levels and acquisition of HSV-2. While oral tenofovir is not able to achieve sufficient drugs levels to suppress HSV-2 (EC50 ~10,000 ng/mL), this is possible with a topical gel. 24% of the women with levels below this became HSV-2 positive compared to only 6% of women who had levels above.

Very low levels of tenofovir found in two women in the placebo arm was explained by possible shared sexual partners.

comment

The proof of principal that an antiretroviral microbicide can protect against HIV and HSV infection is clearly important news.

The discussion in the published paper suggests that many of the infections may be due to infrequent but very high risk exposures with migrant workers and the investigators noted that the HIV incidence rate was similar in the low frequency placebo group to women who reported much more frequent sex.

In this high-risk setting, infection rates remained high in the women using the active gel (>5/100PY) and protection dropped significantly after 18 months for reasons that are unclear.

The differences in the urban/rural results may just be an issue of overall sample size (as opposed to something connected to the difference in lifetime sex partners or other factors). A good precedent for caution over the adherence analysis however comes from an earlier microbicide study. A similar adherence analysis in the phase 2b PRO2000 HPTN 035 study showed protection rates of 9%, 44% and 78% in low gel users, high gel users, and low condom/high gel users, respectively. Yet this microbicide was subsequently shown not to work.

Of note, the findings on prevention of HSV-2 transmission were more significant and robust than protection against HIV, and this will clearly be the focus for further research study.

References:

Unless otherwise stated, all references are to the Programme and Abstracts of the 17th International AIDS Conference, 18-23 July 2010, Vienna.

1. Karim QA et al. Effectiveness of 1% tenofovir vaginal microbicide gel in South African women: results of the CAPRISA 004 trial. Oral abstract TUSS0502.
   http://pag.aids2010.org/session.aspx?s=13
2. Karim SA et al. Safety of 1% tenofovir vaginal microbicide gel in South African women: results of the CAPRISA 004 trial. Oral abstract TUSS0502.
   http://pag.aids2010.org/Abstracts.aspx?SID=13&AID=17761
3. Karim QA et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science Express. Published Online 19 July 2010. Science DOI: 10.1126/science.1193748.
   http://www.sciencemag.org/cgi/content/abstract/science.1193748
4. Kashuba ADM et al. Do systemic and genital tract tenofovir concentrations predict HIV seroconversion in the CAPRISA 004 tenofovir gel trial? Oral abstract TUSS0503.

Further information: www.caprisa.org

HAART regimens used as prophylaxis during pregnancy and breastfeeding are effective in reducing mother to child transmission and are standard of care in industrialised countries.

There are some concerns, particularly since the results from the SMART study, that stopping HAART prophylaxis at the end of breastfeeding may have adverse effects on maternal health and survival.

The Kesho Bora study randomised pregnant women with CD4 counts 200-500 cells/mm3 at 28-36 weeks of pregnancy, to receive either maternal HAART (zidovudine + lamivudine + lopinavir/ritonavir to six months after delivery or breastfeeding cessation if earlier) or short- course zidovudine plus single-dose nevirapine in labour. All infants received single-dose nevirapine post partum. The results, presented at the IAS conference last year (and reported in the August 2009 edition of HTB) showed HIV transmission rates to be almost identical. [1, 2]

These data also contributed to the evidence that enabled the WHO to recommend that HIV-positive mothers or their infants take antiretrovirals while breastfeeding to prevent mother-to child transmission.

In an oral late breaker, Tim Farley presented findings from an evaluation of maternal HIV disease progression at 18-24 months post delivery. [3]

Disease progression endpoints were stage 4 or CD4 <200 cells/mm3 and stage 3 or CD4 <350 cells/mm3. These represent previous and current WHO thresholds for initiating antiretroviral treatment.

There were 412 women in each arm, who had received prophylaxis for a median of 6 weeks before delivery. Women receiving HAART received it for a median of 19 additional weeks during breastfeeding.

The investigators found lower rates of progression to stage 4 or CD4 200 cells/mm3 among women receiving HAART at all time points from delivery when all women were included in the analysis, p=0.003. See Table 1. But rates were similar after stopping antiretroviral prophylaxis, p=0.159. See Table 2.

They performed the same analysis censoring women with CD4 >350 cells/mm3 and there was a significant difference in progression rate from delivery, p=0.002, and no difference from stopping prophylaxis, p=0.107. See Tables 3 and 4.

A further analysis was performed looking at rates of progression to stage 3 or CD4 <350 cells/mm3 among women with CD4 >350 cells at entry. This gave differences of p=0.002 and p=0.013 from delivery and stopping prophylaxis respectively. See Tables 5 and 6.

Overall the investigators concluded that receiving maternal HAART as prophylaxis and stopping after breastfeeding did no harm compared to short course zidovudine plus single dose nevirapine. In the discussion following the presentation it was suggested that the conclusion that this strategy did “no harm” was difficult to make without having included an arm in which treatment was continued. Dr Farley agreed that this was also an important question but the study design reflects an era when even using HAART and continuing it through breastfeeding in healthier women was considered quite radical in resource limited settings.

The other important conclusion from the analysis is that the high rate of progression to CD4 <200 cells/mm3 in both arms among women with <350 cells/mm3 at entry, reinforces WHO guidance to treat from 350 cells/mm3 and emphasises the importance of early treatment initiation in pregnant women or women desiring pregnancy.

References:

1. Farley T and The Kesho Bora Study Group. Impact of triple ARV prophylaxis during pregnancy and breastfeeding compared with short-ARV prophylaxis for MTCT prevention on maternal disease progression. 18th IAS Conference, 18–23 July 2010, Vienna. Oral abstract ThLBB105.
   http://pag.aids2010.org/Abstracts.aspx?SID=644&AID=17446
2. Clayden P. Reducing HIV transmission during breastfeeding. HIV Treatment Bulletin, August 2009.
   http://i-base.info/htb/4466

In a session at the IAS 2010 conference entitled Antiretrovirals during pregnancy and breastfeeding: Importance of surveillance, data were presented describing what we know (or don’t know) about outcomes among infants exposed to antiretrovirals in utero. [1]

New data from the US was shown by George Siberry that evaluated growth parameters in tenofovir exposed infants. [2]

Lynne Mofenson provided a useful overview of the implications for women and children in developing countries. Nathan Ford presented findings from a meta-analysis looking at the safety of efavirenz in the first trimester of pregnancy (which we reported in the June 2010 edition of HTB) [3, 4, 5]. And Karen Beckerman showed data from the Antiretroviral Pregnancy Registry (APR) that looked at preterm delivery (PTD) and low birth weight (LBW) in this cohort. [6]

There was agreement among the presenters on the importance of surveillance, both from industrialised and resource-limited settings. Nathan Ford rightly pointed out that, although the largest data set contributing to their review was from the APR, the second largest set came from one centre, the Frere Hospital in South Africa. It is very likely that much important pregnancy outcome data is simply not being captured.

During discussions with the audience, Graham Taylor emphasised the role of reporting bias, particularly with respect to efavirenz. This is the only antiretroviral with preclinical primate data and in turn has the strongest FDA category and the most scrutiny in pregnancy. The point was made that the only report of myelomeningocele in the prospective reports section of the APR was of a child exposed to efavirenz during the first trimester. However, the absence of other reports of myelomeningocele in the registry, that might be expected given a general background rate in the order of 1 per 1000 births, despite almost 12,000 evaluable prospective case reports was also commented upon.

There was agreement that when a mother needs treatment for her own health the benefits of antiretrovirals in pregnancy hugely outweigh any theoretical risks.

Tenofovir exposure and low birth weight and infant growth

Preclinical studies showed that tenofovir crosses the placenta. There have been concerns that undermineralisation of foetal bones was observed in animal studies. Tenofovir use in pregnancy is on the increase but there are limited human data describing infant outcomes.

George Siberry presented data on behalf of the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of Antiretroviral Toxicity (SMARTT) study. SMARTT enrols antiretroviral exposed uninfected children in the US at two weeks of age (dynamic cohort) and at one year to 12 years of age (static cohort).

This study was conducted to evaluate the association of maternal tenofovir use and growth measures (weight, length, head circumference) at birth and at one year of age.

Maternal information is collected prospectively for dynamic cohort and retrospectively for static cohort.

In this study, LBW was defined as <2.5kg. Z-score < -1.5 was used to define small-for-age for length and HC at birth and length, weight and HC at one year.

Logistic regression models for LBW and growth outcomes were fit, controlling for potential confounders, including demographic and socioeconomic characteristics, maternal health status (CD4< 250, viral load>1000 copies/mL, genital infections) and substance use during pregnancy.

The evaluation revealed 1887 children with birth weight data for which birth length and HC measurements were available from 739 children from the dynamic cohort. Growth measurements at one year were recorded for 532 children (weight length and HC), of which 356 were from the dynamic and 176 from the static cohorts.

The investigators found that maternal tenofovir use increased from 15% in 2003 to 39% in 2009. Overall 21% of the cohort was exposed to tenofovir including 12% receiving it from the first trimester.

Among the 20% of infants with LBW, there was no difference in those exposed to tenofovir (20.7 vs 19.5%). After adjusting for confounders there remained no effect (aOR: 1.03, 95% CI 0.75-1.40, p=0.87). Neither was there an association between tenofovir use and short length or small HC at birth.

However, at one year of age children exposed in utero to tenofovir in this cohort had a marginally increased risk of low weight (aOR:1.76, 95% CI1.01-3.05).

The investigators suggested that this observation requires confirmation in further studies.

Preterm birth in the Antiretroviral Pregnancy Registry

Some reports suggest increase prevalence of PTD and LBW associated with protease inhibitor (PI) exposure, while reports from other cohorts do not.

Karen Beckerman presented data from an evaluation from the Antiretroviral Pregnancy Registry (APR) of birth weight and estimated gestational age of live births reported to this registry.

We have reported findings from the APR in previous issues of HTB. It is a prospective registry with which providers register pregnant women with antiretroviral exposure during their pregnancy and in turn provide outcome data.

In this analysis the investigators compared the prevalence of PTD at <37 and <32 weeks gestation, and LBW <2.5kg and very LBW <1.5kg among infants exposed to one antiretroviral or regimens of two or more antiretrovirals that either included a protease or did not.

Since 1989 and as of January 31st 2009 the APR had enrolled 12451 pregnancies; 426 (3.4%) had outcomes pending and 1082 (8.7%) were lost to follow up. There were 9513/10022 (95%) singleton live births with evaulable data.

Dr Beckerman reported that, in this analysis, the investigators found no differences in the prevalence of either PTD <37 weeks, 14.7% vs 13.0%, or LBW <2.5kg, 15.4% vs 16.1%, between the 1404 infants exposed to one antiretroviral compared to 8109 infants exposed to combination antiretroviral regimens.

Of those exposed to combination antiretroviral regimens, PTD <37 weeks was higher among those receiving PI-containing regimens (n=4658) compared to non PI-containing regimens (n=3451), 14.1% vs 11.8%, p=0.003, as was LBW <2.5kg p=0.001.

But PTD <32 weeks was no different between those exposed to regimens containing a PI compared to regimens without a PI, 2.3% vs 1.8%, p=0.16.

They also found that very LBW <1.5kg was more prevalent in infants exposed to PI-containing regimes compared to those without a PI, 17.4% vs 14.0%. But after controlling for race very LBW <1.5kg, for each exposure group, overlapped prevalence in the background population.

They found that there was no difference in very LBW <1.5kg in infants exposed to PI containing regimens compared to those exposed to one antiretroviral. They also found exposure to PI-containing regimens was protective against PTD <32 weeks, p=0.05.

They noted that very LBW <1.5kg was lower in all groups exposed to combination antiretroviral regimens than published reports of cohorts of HIV-exposed infants not exposed to antiretrovirals.

They concluded that optimised combination antiretroviral regimens offer profound benefit to maternal survival and vertical transmission prevention.

They added: “We hypothesise that exposure to PI could be a surrogate marker for immunologic and other factors contributing to preterm parturition and low birth weight syndromes in HIV-exposed neonates.”

comment

The debate on whether combination therapies, particularly PI-based HAART are associated with PTD continues.

Given that most of the data suggesting that there is no association has come from the US and that most of the data (85%) in the APR is also from the US, it should perhaps come as no surprise that no strong link with HAART was found.

The data suggesting a link with PTD is mostly from Europe, however in her presentation Lynne Mofenson drew attention to the recent RCT from Botswana investigating HAART during pregnancy and breastfeeding to reduce HIV transmission in which an increased rate of PTD was found in the PI-based arm compared with the triple NRTI.

References:

Unless otherwise stated, all references are to the Programme and Abstracts of the 17th International AIDS Conference, 18-23 July 2010, Vienna.

1. Antiretrovirals during pregnancy and breastfeeding: Importance of surveillance. Session WEAX01
   http://pag.aids2010.org/session.aspx?s=181
2. Siberry G et al. Safety of tenofovir use during pregnancy: associations with low birth weight and early growth in HIV-exposed uninfected infants. Oral abstract WEAX0103.
   http://pag.aids2010.org/Abstracts.aspx?SID=181&AID=5375
3. Mofenson L. Overview on antiretrovirals during pregnancy and breastfeeding: importance of surveillance and implications for developing countries. Session introduction WEAX0101.
4. Ford N et al.Safety of efavirenz in the first trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. Oral abstract WEAX0102.
   http://pag.aids2010.org/Abstracts.aspx?SID=181&AID=8350
5. Clayden P. Pregnancy outcomes with efavirenz. HTB. Volume Volume 11 Number 5/6 May/June 2010.
   http://i-base.info/htb/10464
6. Beckerman K et al. Preterm Birth (PTB), low birth weight (LBW) and fetal antiretroviral (ARV) exposure: Gestational age (EGA) and birth weight data from 10022 singleton live births (LB) reported to the Antiretroviral Pregnancy Registry (APR) 1989 through 31 January 2009. Oral abstract WEAX0105.
   http://pag.aids2010.org/Abstracts.aspx?SID=181&AID=1161

The new WHO 2010 paediatric guidelines – Antiretroviral Therapy for HIV Infection in Infants and Children: Towards Universal Access – also summarised on their website in a preliminary version for programme planning in June, were released at IAS 2010.

Lynne Mofenson provided an excellent summary of the new guidelines at the paediatric meeting and Shaffiq Essajee in the Early Infant Diagnostics (EID) session at IAS. [1,2] We will review developments in diagnostics including EID in the next issue of HTB.

When to start

Universal treatment is recommended for all infants and young children under two years irrespective of CD4 or clinical indication. The recommendation is strong for less than 12 months and conditional for 12-24 months.

Data to guide when to start for children one to five years old are scant and this is reflected in differences in recommendations between guidelines (see statement from PENTA in the comment below). After five years of age, guidance is similar to that for adults (see Table 1). Table 2 shows a comparison between the 2006 and 2010 WHO guidelines.

*CD4 percentage/absolute CD4 count mm3

Adapted from WHO 2010 revision. Essajee S.

comment

PENTA have published a letter in support of the new guidance for resource limited settings and are continuing to recommend PENTA guidance ie universal treatment for infants less than 12 months and immunological and clinical criteria for those above for treating children in Europe. In the letter they write:

“Both PENTA 2009 and WHO 2010 guidelines considered the same body of evidence, and several experts took part in the drafting of both sets of recommendations. The universal treatment of infants is based on evidence from the CHER study, children over five are treated at adult thresholds in both guidelines, based on comparisons between the HPPMCS child cohort and CASCADE adult seroconverter cohort. The recommendations for children aged between 2 and 5 are based on cohort data, largely from the HPPMCS study.

The new recommendations in the WHO guidance for children between age one and five are based on programmatic considerations, in particular the ability to closely monitor a child clinically and by repeat CD4 count measurement if they are not started on ART. Such monitoring is available in Europe, and in many settings outside Europe. It is also noted that the evidence basis for these recommendations is weak or very weak, and that studies expected to publish results soon may shed more light on the subject. We endorse WHO’s recommendation to treat early where the ability to provide monitoring is limited, as well as the call for more research to provide RCT evidence for treatment initiation thresholds after infancy. We continue to recommend PENTA 2009 guidance as appropriate for European and other settings with the facility to monitor closely children in whom treatment is deferred.”

http://www.pentatrials.org/PENTA%20letter%20re%20WHO%20jul%202010.pdf

What to start with

Recommended regimens are:

• For children less than two not exposed to maternal or infant nevirapine or whose exposure status is unknown: nevirapine plus two NRTIs.
• For children exposed to maternal or infant nevirapine or other NNRTIs used for maternal treatment or PMTCT: lopinavir/ritonavir plus two NNRTIs (with the caveat that nevirapine is better than nothing).
• For children over two but under three: nevirapine plus two NRTIs.
• All others (irrespective of nevirapine exposure): nevirapine or efavirenz (efavirenz preferred for TB treatment)
• Under three and needs TB treatment: nevirapine plus two NRTIs or abacavir plus lamivudine plus zidovudine/stavudine.
• • Adolescents over 12 with hepatitis B: tenofovir plus lamivudine/emitricitabine plus efavirenz/nevirapine (can take FDC of lamivudine/emitricitabine plus efavirenz if this is available).
• Adolescents with hepatitis C: preferred regimen is efavirenz plus two NRTIs.

The guidelines also recommend a preferential order of NRTIs (zidovudine/lamivudine > abacavir/lamivudine > stavudine/lamivudine).

They recommend that any child with active TB begin TB treatment immediately and start ART in the first eight weeks of TB treatment.

For children already on ART who develop TB, they recommend that ART regimens may need to be adjusted to decrease the potential for toxicities and interactions: if on nevirapine substitute for efavirenz if over three years; if under three ensure nevirapine is at high dose (2 mg/m2) and if on lopinavir/ritonavir consider adding ritonavir to a 1:1 ratio lopinavir/ritonavir to achieve the full therapeutic dose of ritonavir.

The guidelines recommend solid in preference to liquid formulations, use of heat stable FDCs or co-packaged formulations wherever possible and dosing in accordance with WHO weight band tables.

When to switch

Switching to second line treatment is recommended when clinical, immunological or virological failures occur.

• Clinical failure is defined as the appearance (or reappearance) of WHO clinical stage 3 or 4 events at least 24 weeks on ART and child is adherent.
• Immunological failure is defined as returning to age related thresholds in a treatment adherent child: CD4 count of <200 cells/mm3 or CD4 percentage <10% for a child over two and less than five years of age; CD4 count of <100 cells/mm3 for a child of five years or more.
• Virological failure is defined as a persistent viral load above 5000 copies/mL after at least 24 weeks on ART for a treatment adherent child.

What to switch to

Choice of second line ART is dependent on the first line regimen received:

• After failure on an NNRTI: boosted PI plus 2NRTIs. Lopinavir/r is preferred.
• After failure on zidovudine or stavudine plus lamivudine: abacavir plus lamivudine is the preferred NRTI backbone, abacavir plus didanosine is an alternative.
• After failure on abacavir plus lamivudine, zidovudine plus lamivudine is the preferred NRTI backbone; zidovudine plus didanosine is an alternative.

comment

These guidelines represent a liberalisation of criteria and if they are followed should ensure that many more children are identified and treated.

They are available on the WHO website. [3]

Annexe E has updated weightband dosing tables and formulations that are needed. We also look at paediatric formulations in the TAG/i-Base Pipeline Report. [4]

References:

1. Mofenson L. What’s new in WHO Pediatric Treatment Guidelines? 2nd International Workshop on HIV Pediatrics. July 2010, Vienna, Austria.
   http://regist2.virology-education.com/2ndHIVPed/docs/I_04Mofenson.pdf
2. Essajee S. Scaling up early infant diagnosis of HIV as the bridge between prevention, care and treatment: successes, challenges and potential solutions. Special session SUSS03.
   http://pag.aids2010.org/session.aspx?s=150
3. World Health Organisation. Antiretroviral therapy for HIV infection in infants and children : Recommendations for a public health approach (2010 revision)
   http://www.who.int/hiv/pub/paediatric/infants2010/en/index.html
4. Clayden P. Paediatric antiretroviral pipeline. TAG 2010 Pipeline Report. July 2010.
   http://i-base.info/htb/13436

The revised 2009 WHO guidelines have four major changes since the 2006 edition:

• Routine CD4 counts
• Earlier ART initiation – CD4 threshold of 350 cells/mm3 from 200 cells/mm3
• Changing d4T to tenofovir in first-line regimens
• Increased number of sequential lines of treatment

In an oral session, Rochelle Walensky from Harvard presented findings from a study using a mathematical model simulated to project the clinical and economic outcomes from implementing each of these changes and combinations of these changes.

This study was designed to assist policy makers with their prioritisation process in recognition that implementing all of the guideline changes immediately poses major challenges in most resource limited settings.

The study used input data from a South African cohort with a mean age 32 years and a mean CD4 count of 375 cells/mm3 (ie healthier patients with the potential to benefit from starting earlier). Other input parameters included 24-week ART suppression rates of 75% and 78% rate of suppression at 24-weeks for first and second line ART respectively; annual costs of $36 and $135 for d4T and tenofovir respectively and 1.7-2.6% and 0.4-1.6% incidence of d4T and tenofovir related toxicity were also used.

The investigators ranked, in terms of survival and cost effectiveness, all 13 possible combinations of: (1) ART initiation at CD4 <200 cells/mL or CD4 <350 cells/mm3; (2) Replacing d4T with tenofovir; and (3) Number of available treatment regimens (1 or 2).

They examined 5-year survival, projected life expectancy and incremental cost effectiveness of different treatment scenarios. They used the WHO definition of less than 1x per capita GDP as the threshold for “very cost effective”. For South Africa this is <$5,400 per year of life saved.

The baseline assumption was that patients received a single, d4T-based ART regimen, initiated at WHO Stage III/IV.

Dr Walensky reported that the projected baseline survival was 99 months, with a 65% 5-year survival rate. Switching from d4T to tenofovir gave a modest improvement, with a 110-month life expectancy and 67% 5-year survival. Adding ART at <200 cells/mm3 to baseline gave a 116 month life expectancy and 80% 5-year survival. Adding a second line regimen increased life expectancy to 121 months but added little to 5-year survival (66%) compared to baseline. Adding ART started at <350 cells/mm3 increased life expectancy to 124 months and 5-year survival to 87%.

Stepwise additions of switching to tenofovir or adding a second-line regimen to a one line d4T-containing regimen initiated at 350cells/mm3, gave increased life expectancy of 140 and 178 months and 91% five year survival (for both changes) respectively.

Switching to tenofovir from d4T in addition to initiating at 350 cells/mm3 and adding a second-line, ie following the complete WHO revisions, increased life expectancy to 192 months with 91% 5-year survival.

Dr Walensky summarised the above results noting that the incremental life expectancy gains are maximised with the following stepwise programmatic additions: first – the expansion of ART eligibility to CD4 <350 cells/mm3 one-line (124 months); followed by the addition of second line therapy (178 months); finally followed by the replacement of d4T with and tenofovir (192 months).

When examining the incremental cost-effectiveness of alternative programmes, three were found to be economically effective: d4T 350 cells/mm3/one-line (cost-effectiveness ratio $610/year of life saved [YLS]), tenofovir/< 350 cells/mm3/one-line ($1,410/YLS), and tenofovir/<350 cells/mm3/two-lines ($2,230/YLS). The investigators noted that these results persisted despite plausible variation in efficacy and cost assumptions.

The results of this study are extremely sensitive to the price of tenofovir. A sensitivity analysis revealed a decrease in the price of tenofovir from $135 to $51 per person year would make tenofovir more effective and less costly than d4T.

Dr Walensky suggested that the limitations to this study were that it only shows results for people initiating ART and did not address people in ongoing care. Also that while the analysis looks at value for money it does not project the implications of each component of the WHO recommendations on programme budgets.

To the question “What to do first” she concluded that the decision is dependent on a country’s current policy and capacity. In countries without laboratory capacity, CD4 monitoring and ART at <350 cells/mm3 is the most crucial priority to start with. Where this is already available, replacing d4T with tenofovir are both cost effective and give survival benefits. The addition of second-line ART offers greater survival benefit but with substantial increases in total costs.

Reference:

Walensky R et al. Scaling up WHO recommendations for HIV therapy in resource-limited settings: what to do first? Oral abstract WEAE0205.

South African guidelines recommend efavirenz-based regimens as the preferred first line.

Out of concern about efavirenz use in pregnancy the 2004 guidelines only recommend its use in women of reproductive age when they are using injectable contraception plus condoms; the 2010 revision amended this to “reliable contraception”. Nevirapine is recommended for the remainder, who are “unable to guarantee reliable contraception”.

Three posters authored by researchers from the Reproductive Health Unit, University of the Witwatersrand and Johns Hopkins Bloomberg School of Public Health, showed findings from investigations into how well these guidelines were being followed, the fertility intentions of women receiving efavirenz based and other antiretroviral regimens, and whether providers discuss these issues with women of reproductive age receiving ART. [1, 2, 3]

Colleen Hanrahan and colleagues looked at the application of guidelines. This prospective cohort study enrolled non-pregnant women on ART aged 18-35 years in September 2009-January 2010 in four Johannesburg clinics. The investigators conducted baseline interviews to determine demographics, contraceptive use and the fertility intentions of the women. A record review was used to confirm ART regimens.

They classified women correctly assigned to first line regimens at baseline according to the 2004 guidelines, which were in use at the time of the evaluation, and two interpretations of the 2010 guidance, “reliable contraception”. They used logistic regression to determine predictors of “inappropriate assignment”.

The investigators reported, out of a cohort of 805 women on first line ART, 44.6% (95% CI, 41.2–48.0%) were receiving efavirenz-based regimens at baseline. Overall 26.5% (95%CI: 23.4–29.5%) of women were receiving hormonal contraception.

Of those receiving efavirenz, 90% (95% CI, 86–93%) were incorrectly assigned according to 2004 guidance, but only 11% (95% CI 9–15%) were wrongly assigned to nevirapine. These proportions reduced to 77% for efavirenz and 27% for nevirapine and 24% for efavirenz and 73% for nevirapine interpreting the 2010 guidance as using hormonal contraception and hormonal contraception or consistent condom use respectively.

In a multivariate analysis including: age, time on ART, CD4 count, number of living children, relationship and employment status and enrollment site, none were significant predictors of incorrect assignment to efavirenz. For nevirapine, each additional child gave a two-fold increase in the odds of incorrect assignment, AOR 1.95 (95% CI 1.34–2.84), p<0.001.

In a related study Sheree Schwatz and colleagues presented data from a cross-sectional analysis of the same baseline interviews to compare differences in current and future fertility intentions. This analysis included a total of 851 women; the 805 on first line regimens described above plus a small proportion (5.4%, n=46) receiving second line regimens with a boosted PI.

Multivariate analysis revealed women on efavirenz-based regimens were older and had more living children, both p<0.001. Of these 39% were either currently trying to conceive or planned to do so in the next year. Women receiving nevirapine were more likely to be currently trying to conceive than those receiving efavirenz, p=0.025, but were no more likely to plan to in the next year, p=0.17.

In the third study describing communication between providers and HIV-positive women receiving ART about fertility and reproduction, less than half (40.7%) of the 851 women enrolled reported that providers had talked to them about future pregnancy options.

Older women and those with higher income were more likely to have fertility discussions with providers in multivariate analysis whereas parity, CD4 count, time on ART, regimen, marital status or fertility intentions were not associated with the likelihood of these discussions.

The investigators also found that PMTCT knowledge was significantly higher if their providers has discussed this with them p<0.001. Only about a third (35.4%) understood that efavirenz is contraindicated if trying to conceive and this was not associated with efavirenz use, p=0.774. A small proportion (6.4%) said a provider had told then not to have more children and 36% were unsure whether their provider approved of them having children. Discussion about contraception varied by type: 93.5% of women reported that their providers had discussed male condoms, 71.6% female condoms, 45.2% injectable contraceptives, 41.6% oral contraceptives and 18.8% sterilisation.

comment

These data make the important point that no matter what labeling or guidelines recommend concerning use of efavirenz in pregnancy there is a strong likelihood that it will happen.

References:

1. Hanrahan et al. South African antiretroviral treatment guidelines for women: how well are they being followed and for whom? Poster abstract THPEO120.
2. Schwartz S et al. Fertility intentions by antiretroviral regimen among women in inner-city Johannesburg. Poster abstract THPE0784.
3. Schwartz S et al. Communication between patients and providers about HIV and fertility in inner city Johannesburg, South Africa. Poster abstract THPE0650.

A late breaker by Bailey and Colleagues presented at the International AIDS Conference reported on the follow-up to the randomised male medical circumcision trial conducted in Kisumu, Kenya, involving 2874 men aged 18 to 24 years at enrollment. [1]

The authors had previously reported a 60% protective effect of male circumcision against HIV acquisition at 24 months after enrollment, and 64% at 42 months. This poster indicates that this protective effect extends to at least 54 months after enrollment.

As of March 2010, 1552/1740 men (89%) consented to extended follow-up: 767 in the circumcision group and 785 in the control group. The age and number of sexual partners at baseline were the same in both groups. 49% (387/795) of those in the control group have been circumcised since December 2006.

The number of HIV seroconversions by 54 months of follow-up was 39 in the circumcised group and 79 in the uncircumcised group (RR = 0.34; 95%CI: 0.23-0.51). The estimated cumulative incidence [95% CI] at 54 months was 4.0% [95%CI: 2.8-5.7] in the circumcised group and 10.6% [95%CI: 8.2-13.6] in the uncircumcised group (p<0.0002, RR=0.36; 95%CI: 0.24-0.55). The annualised incidence in the circumcised group was 0.91 per 100 person-years and 2.45 per 100 person-years in the uncircumcised group (p=0.0007).

The authors conclude that they found that the 60% protective effect of circumcision against HIV acquisition over 24 months is sustainable, and possibly strengthened, over 54 months of study. They write that these results provide support for policy makers, donors and implementers to scale up comprehensive, safe, voluntary medical male circumcision in appropriate regions as rapidly as possible.

comment

This important finding demonstrates the lasting preventative effect of voluntary male medical circumcision. On 14 July the Bophelo Pele Male Circumcision Project in Orange Farm, one of the sites for the other two randomised controlled trials that showed the efficacy of circumcision, announced that they had reached the milestone of 20,000 safe circumcisions.

This intervention has long-term efficacy and has been proven that it can be conducted at scale and safely. It is therefore sensible to roll it out in areas with large heterosexual epidemics. It needs to be scaled up across sub-Saharan Africa.

References:

1. R.C. Bailey et al. 2010. The protective effect of adult male circumcision against HIV acquisition is sustained for at least 54 months: results from the Kisumu, Kenya trial. XVIII International AIDS Conference, Vienna, July 18-23. Late breaker poster FRLBC101.
   http://pag.aids2010.org/Abstracts.aspx?SID=643&AID=17707
2. Bophelo Pele Male Circumcision Project. 2010. 20 000 safe circumcisions performed in Orange Farm.

Blanc and colleagues presented the results of CAMELIA, a randomised open-label controlled trial in Cambodia. The trial’s purpose was to determine when to initiate ART in patients with TB with low CD4 counts. They randomised patients to either receive treatment at two weeks after commencing TB treatment (ie during the intensive phase) or eight weeks (ie during the continuation phase). [1] The SAPIT trial, also discussed in this issue, is still examining this question but the SAPIT cohort has a much higher mean CD4 count.

CAMELIA was designed as a superiority trial to answer the question of the best timing for the introduction of ART in patients with TB with CD4 counts ≤ 200 cells/mm3. All patients were ART-naive at trial entry. The primary endpoint was survival at the end of the trial.

661 patients with suspected TB were randomised, 332 to the early arm and 329 to the late arm. A high proportion of patients turned out to be culture positive for tuberculosis in both arms (282 in the early arm and 294 in the late one).

The patients were all very sick with no difference between the two arms. The median CD4 count was 25 cells/mm3, median viral load was 5.60 log copies, and the median BMI was 16.7. Of the 645 patients, 587 had (at least) pulmonary TB and 13 cases (2%) of MDR TB were identified.

There was a 34% reduction in mortality in the early arm: 59 deaths versus 90. The mortality rate in the early arm was 8.28 per 100 person years (IQR: 6.42 – 10.69) and 13.77 per 100 person years (IQR: 11.20 – 16.93) in the late arm (p=0.002).

IRIS occurred more frequently (p<0.0001) in the early arm, 4.03 per 100 person-months, (IQR 3.34-4.86) compared to the late arm, 1.44 per 100 person-months (IQR 1.09 – 1.91). It occurred about 2 to 3 weeks after starting ART in both arms, but was easily managed.

More than 95% of patients had an undetectable viral load at week 50. The median CD4 cell count at week 50 had increased by 114 cells/mm3 and this had increased to 200/mm3 by the end of the trial.

comment

This trial provides convincing evidence that patients with TB with low CD4 cell counts should be placed on treatment immediately upon diagnosis. One of the main concerns with early initiation of ART in such patients is the concern about IRIS. Since the patients in this trial are on average more immuno-compromised than those in SAPIT and would therefore be expected to have higher rates of IRIS, it is not clear if they can be any valid reason left for delaying ART in any group of patients with TB with CD4 counts <350 cells/mm3. The DSMB for the SAPIT study should meet to consider the implications of this data on SAPIT.

Reference:

F.X. Blanc et al. Cambodian Early vs. Late Introduction of Antiretrovirals. XVIII International AIDS Conference, Vienna, July 18-23. Late Breaker Session B-1.
http://pag.aids2010.org/PAGMaterial/aids2010/ppt/113126_10013/final.pptx

A late breaker at the International AIDS Conference by Shapiro and colleagues presented the results of a project to trace the contacts of patients with TB in Northwest Province, South Africa. Based on an aerial photograph in the presentation, data was collected from five sites separated by a total approximate distance of 50km. [1]

The authors studied whether intensified case-finding (ICF) in household contacts of known TB patients is a feasible strategy for a high-TB, high-HIV prevalence settings. They also compared the strategy of testing for TB in the households of contacts versus randomly selected households. By way of background, a meta-analysis by Morrison and colleagues in 2008 of household contact tracing in low and middle-income countries found that 4.5% [95%CI: 2.1-2.5] of household contacts of known TB patients also had active TB. Just over 51% had latent TB [95%CI: 50.6-52.2]. But there was substantial heterogeneity across the studies.

In this study by Shapiro, 800 people were screened. Of these, 723 patients with active TB were enrolled over seven months. These are referred to as the index cases. Of these, 607 (84%) were HIV-positive and the HIV statuses of another 28 (4%) were unknown. The basis for TB diagnosis was as follows: 163 had tested smear-positive, 16 were smear-negative but culture-positive and the remainder were diagnosed using clinical criteria and chest x-rays. Three (0.4%) had MDR TB. Each index had an average of four household contacts. A total of 2 812 household contacts were screened for TB.

The mean age of the index cases was 38 (IQR: 18-91) compared to the mean age of 23 (IQR: 0-92) in the household contacts (p<0.01). Of the index cases, 78% were unemployed versus 61% of the household contacts (p<0.01). There were no significant differences between the two groups in sex (about 43% female). A quarter of participants lived in shacks.

A total of 2 146 (76%) household contacts gave sputum for analysis and 164 (8%) were diagnosed with TB. Of these, 95 were confirmed and 69 were probable cases. Of the 666 (24%) who did not give sputum, 60 were already on TB medication. The TB statuses of the other 606 were unknown.

Amongst the household contacts, 205 (7%) were already known to have HIV and of these, 99 were already on ART. Another 1 610 (57%) agreed to voluntary counselling and testing and 164 (10%) tested HIV-positive. Of these, 32 (19%) of these had a CD4 below 250 cells/mm3 and were referred for ART.

154 (94%) of the 164 household contacts with TB were smear-negative and culture-positive. Only 18 (11%) of these had TB symptoms. Five (3%) had MDR TB, 22 (13%) were HIV-positive and four (18% of HIV-positive cases) had CD4 counts <250 cells/mm3 (p<0.01 for all of these compared to the index cases).

A random sample of 350 households was compared to the contact households. Table 1 below shows that they were significantly less likely to have TB. At least one case of TB was found in 138(19%) contact households versus 4(1%) in the randomly selected households.

The authors conclude that undetected TB and HIV are highly prevalent in the households of known TB patients. The undetected TB in contacts is more likely to be in HIV-negative and asymptomatic individuals than in patients who present to care for TB diagnosis and treatment.

The authors suggest that intensified case-finding in household contacts of TB patients resulted in accelerated detection of both TB and HIV in undiagnosed contacts. They explain that their study demonstrated that household contact-tracing is feasible and acceptable in a high TB/HIV burden setting and should be considered as an approach to addressing the co-epidemics.

comment

This is an excellent study that shows the feasibility and usefulness of contact tracing. The contacts on average appear to have been in an earlier stage of active TB. Consequently, an additional advantage of tracing contacts is that they would be treated earlier thereby potentially preventing significant TB transmissions.

The authors are planning to present a cost-effectiveness analysis. It would be surprising if contact-tracing were not cost-effective compared to random household selection. What will be particularly interesting to see is the cost per TB case diagnosed. Interestingly, 81% of contact households did not have TB. It would be very useful if criteria could be found that identify contact households with a higher probability of having someone with TB. If such criteria could be found, an algorithm for contact-tracing could potentially be found that reduces the cost of contact-tracing and requires fewer human resources to speedily identify people with TB.

The meta-analysis by Morrison and colleagues indicates that there is significant heterogeneity amongst contacts. Therefore it would be useful if this study was replicated in several other communities in Southern Africa, possibly as part of a pilot contact-tracing programme.

While contact-tracing will cost money and require an additional intervention to be placed on health systems, the extensive benefits that are likely to accrue from it probably make it worthwhile. Southern African governments should give serious consideration to massive contact-tracing operations.

References:

1. Shapiro AE et al. Targeting at-risk households: intensified case-finding for TB and HIV in contacts of TB patients in South Africa. XVIII International AIDS Conference, Vienna, 18–23 July 2010. Late breaker poster FRLBC106.
   http://pag.aids2010.org/Abstracts.aspx?SID=643&AID=17517
2. Morrison J et al. Tuberculosis and latent tuberculosis infection in close contacts of people with pulmonary tuberculosis in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Infect Dis. 2009 Jan; 9(1):3-4.
   http://www.ncbi.nlm.nih.gov/pubmed/18450516

The 17th Conference on Retroviruses and Opportunistic Infections (CROI), one of the most important annual HIV meetings, was held this year from 16-19 February. As with previous meetings, much of the conference is published online including all abstracts and webcasts of oral presentations including poster discussions.

Making this scientific content available without login or subscription is itself a significant achievement. It is a model for broadening access to medical research to a degree that is currently unmatched by any other meeting.

The webcasts this year include oral presentations, poster discussions, the opening lectures and the pre-meeting set of training workshops for young investigators.

The conference website also includes a searchable abstract database.

We encourage readers to view these lectures directly.

http://www.retroconference.org/2010/Abstracts/38289.htm

http://www.retroconference.org/2010/data/files/webcast_2010.htm

Lectures are also available as audio downloads and podcasts which include slides as audiobooks.

Our first articles covering this meeting are:

• Treatment reduces infections by over 90%: a theme that is here to stay
• ACTG 5205: atazanavir/ritonavir vs efavirenz in treatment naïve patients
• Pipeline compounds and new approaches to treatment
• Clinical benefits of stopping smoking: CVD and CHD risk returns to that of ‘previous smoker’ in HIV-positive people within three years
• HIV increases the risk of lung cancer, independent of smoking status
• HIV-positive people in the HOPS cohort have 4-fold risk of fracture compared to general population in the US
• OCTANE 2: nevirapine and lopinavir/r are similar when used with tenofovir and FTC in treatment-naïve women
• HIV incidence and retesting in pregnancy
• Efavirenz use in pregnancy and birth outcomes
• Pregnancy outcomes in women using non-AZT HAART in Europe
• When should HAART be initiated in pregnancy to achieve an undetectable viral load?
• Pregnancy outcomes in infants exposed to maternal antiretrovirals in utero
• Maternal TB, HIV and pregnancy
• Botswana IPT trial: Continuous isoniazid superior to 6 months short course

More to follow next issue…

CROI was important this year because of the profile given to further studies supporting the role of treatment as prevention. Together they support the argument that universal treatment is perhaps the most powerful prevention tool we are likely to have for many years, perhaps with the potential to even eradicate the virus on a population level.

In a lecture prior to the main conference, Brian Williams from the South African Centre for Epidemiological Modelling and Analysis, Stellensbosch, detailed the modeling data for the direct and indirect impact of ARVs on prevention, [1] elaborating on the research paper published last year in the Lancet. [2]

At its most optimistic, this includes the potential for universal treatment to eliminate new infections in South Africa within 5-10 years on a cost neutral budget, at the same time saving millions of lives (and preventing millions of new infections). The science on which the model is based shows an impact on dramatically reducing infections that few can ignore.

The epidemiology for the model included low HIV infectivity (~0.001 per heterosexual encounter), 10-fold individual variability in infectivity, a slow epidemic doubling time (~1-3 years), a long period of potential infectiousness (5-15 years) and an average case reproduction number (~7 additional people infected per case): leading to a calculation showing that virtual eradication of HIV could be achieved if transmission could be reduced by 7-fold.

Viral load is commonly reduced by 10,000 times on treatment, and although infectivity reduces in smaller proportions (roughly in relation to the cubic root of viral load), the net impact of treatment on infectivity was estimated to be a 96% reduction.

The impact on reducing TB and for continuous treatment after pregnancy were also included, and for interventions based only on PrEP alone or in combination with ARVs. For South Africa, the model was based on a conservative treatment programme, treating at a CD4 count of 200 cells/mm3, but similar costs and benefits were shown when starting universal treatment at 350, 500 or even at diagnosis. The initial outlay (an adjusted US $60 billion) was compensated by lower cost of hospitalisations and reduced new infections, and saved an additional 3 million lives over 40 years, at stable costs.

The discussion after the presentation stressed the need for pilot operational research on each aspect of a universal treatment model, including willingness to test, virological response rates with earlier treatment, the actual impact on transmission – and the need to develop new heath structures to allow such scale-up.

A first step in confirming treatment reduces HIV transmission in real world settings was shown in results from the Partners in Prevention HSV/HIV Transmission (PARTNERS) Study in over 3400 serodifferent heterosexual couples in seven southern African countries (Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia).  The HIV-positive partner was a man in 32% and a woman in 68% of couples. [3]

This study previously reported that HSV therapy with daily acyclovir failed to protect against HIV infections, explained by a massive increase in localised CD4 target cells, and persistence for up to two months after the healing of HSV lesions.

All HIV-positive partners entered the study with CD4 counts >250 cells/mm3 and were not on treatment. Over two years, approximately 10% of study participants required HIV treatment for their own care, and this allowed for the HIV transmission rates to be compared by use of ARV treatment. Intensive risk reduction support was supplied throughout the study, to minimise HIV risk for the HIV-negative partners.

People with more advanced HIV at baseline were more likely to start treatment; with higher baseline viral loads (mean 4.4 vs 3.9 log copies/mL, p<0.001), and lower CD4 counts (375 vs 540 cells/mm3, p<0.001). A higher proportion of men than women (12% vs 9%, p=0.01) strated treatment, at slightly lower median CD4 counts (192 vs 204 cells/mm3, p=0.05). People starting treatment were also older (mean 35.2 vs 32.7 years, p<0.001).

ART was initiated at CD4 counts <200 cells/mm3 in 52% patients, between 200 and 349 cells/mm3 in 33%, and >350 cells/mm3 in 15% (30% of this group were for prevention of mother to child transmission).

New HIV infections were detected in 151 of the HIV-negative partners, over 24 months of follow-up, with testing and prevention support provided every 3 months. Phylogenetic analysis suggested that slightly less than one third (43/151) of the infections were not from the relationship partner. Five cases were excluded from the transmission analysis due to uncertain use of ARVs.

This left an overall transmission rate in 103 remaining transmissions of 2.1%.

Of these, 102/103 were in the non-ARV group (102/4558 person years; rate 2.24 95%CI 1.82-2.72) compared to 1/103 from partners using ARV treatment (1/233 person years; rate 0.37 95%CI 0.09-2.04). This produced an unadjusted relative risk of 0.17 (p=0.037), which became even more significant when adjusting for time on study and CD4 count, showing a 92% reduction in risk: RR=0.08 (95%CI 0.002, 0.57, p=0.004).

The single transmission case occurred in someone whose partner started treatment 18 days before the 9 month assessment, when they were still HIV-negative (details on whether this was by HIV-antigen or PCR testing were not provided), but who seroconverted by the month 12 evaluations. Viral load was undetectable at month 12 in the HIV-positive partner.

Details on CD4 count in the HIV-positive partner showed transmissions at all CD4 levels, with a considerably higher risk when the partner had a count <200 cells/mm3 (rate = 8.79 vs 2.79 at 200-350 and 1.7 at 350-500).

This is likely to be an indirect marker of higher viral load relating to more advanced infections, but surprisingly, the presentation provided no further information on viral load levels of the source partner, other than showing that after a median of 7 months treatment (IQR 3-12months) the median viral load dropped to undetectable, indicating excellent responses.

Importantly, and perhaps showing the positive results from the behavioural interventions, the percentage of visits at which people reported unprotected sex dropped from 6.2% to 3.7% at the pre- and post-treatment visits, respectively, with no change in frequency of sex.

Two other studies at CROI, in a largely MSM population in San Francisco, supported the impact of ARVs to reduce transmission.

Moupali Das-Douglas and colleagues from the San Francisco Department of Public Health and the University of California presented results from a model that estimated values for average and total community viral load (CVL) from 2004-2008 and then compared these with the expected and actual number of new diagnoses over the same period. [4]

Average CVL was defined as the mean of the most recent viral load of all reported HIV-positive individuals in a particular population, divided by the number of reported HIV-positive individuals in the population. Total CVL was the sum of the most recent viral loads of all HIV-positive individuals in a particular population.

The context for this study was an effective ‘test and treat’ programme that from 2004 to 2008 increased the percentage of MSM testing within 12 months from 65% to 72% and within 6 months from 41% to 53%. The percentage of HIV-positive MSM unaware of their status dropped from 24% to 14.5% (comparable UK figures vary from 30-50%). By 2008, 90% of patients in care were on HAART, with 72% virologically suppressed (<75 copies/mL).

The decreases in mean CVL and reductions in actual diagnoses (from 798 in 2004 to 434 in 2008) were both statistically significant (p=0.005), as were the decreases in total CVL (p=0.019) and percentage of virologically suppressed patients (p=0.002). The presentation acknowledged that a limitation in these results is that cases may be diagnosed chronic rather than new infections, which was addressed in methodology for expected and actual incidence rates.

However, using a more conservative meta-regression analysis (different to the reported abstract), the 30% reduction in CVL and almost 40% reduction in incidence (rather than cases) was not significant (p=0.3) due to the degree of imprecision in the estimates.

While this makes it too early to link CVL with incidence, the reductions in newly diagnosed and reported cases, at the same time as increased testing, greater ARV coverage and greater virological suppression strongly support close following of subsequent data from this model.

In a related poster, Edwin Charlebois and colleagues modeled the impact of earlier treatment and broader test and treat programmes in San Francisco, suggesting that HIV prevalence could fall from the current 25% to around 10% by 2030 if the programme shifted to universal test and treat. [5]

As this issue of HTB went to press, a policy shift in San Francisco to offer HIV treatment to all newly diagnosed patients, regardless of CD4 count or viral load, was announced by public health officials. [6]

comment

The positive correlation between viral load and risk of transmission for every route, whether sexual, from shared injection equipment, during pregnancy, at birth and from breast milk, and from needle stick exposure to health workers, is now convincingly demonstrated.  For some of these transmission routes, antiretroviral treatment to reduce viral load is already widely used to reduce transmission (principally for mother to child transmission, PEP and PEPSE).

Treatment dramatically extends life, reduces morbidity and should now be additionally valued for reducing transmission. An estimated 70% of HIV-positive people globally in need of immediate treatment for their own care are still unable to access it.

References:

Unless stated otherwise, all references are to the Programme and Abstracts of the 17th Conference on Retroviruses and Opportunistic Infections. 16-10 February 2010, San Francisco. All oral abstracts are available as webcasts.

http://www.retroconference.org

1. Williams B and Dye C. Put your money where your model is: ART for the prevention and treatment of HIV/AIDS.  Webcast: Guiding the global response. Tuesday 2.30pm.

http://www.retroconference.org/2010/data/files/webcast_2010.htm

2. Granich RM et al. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. The Lancet, Volume 373, Issue 9657, p48-57, 3 January 2009. doi:10.1016/S0140-6736(08)61697-9.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61697-9/abstract

3. Donnell D et al. ART and risk of heterosexual HIV-1 transmission in HIV-1 serodiscordant African couples: a multinational prospective study. 17th CROI 2010. Oral abstract 136.

http://www.retroconference.org/2010/Abstracts/39222.htm

Webcast: New Insights into Transmission and Acute Infection. Friday 9.30am.

http://www.retroconference.org/2010/data/files/webcast_2010.htm

4. Das-Douglas M et al. Decreases in community viral load are associated with a reduction in new HIV diagnoses in San Francisco. 17th CROI 2010. Oral abstract 33.

http://www.retroconference.org/2010/Abstracts/38232.htm

Webcast: Testing and Transmission. Wednesday 9.30am.

http://www.retroconference.org/2010/data/files/webcast_2010.htm

5. Charlebois E et al. Effect of Expanded ART Strategies on the MSM HIV Epidemic in San Francisco. 17th CROI 2010. Poster abstract 996.

http://www.retroconference.org/2010/Abstracts/39042.htm

6. San Francisco endorses starting HIV treatment immediately after diagnosis. (5 April 2010)

http://www.aidsmeds.com/articles/treatment_HIV_diagnosis_1667_18253.shtml

The few randomised clinical trials using currently licensed antiretrovirals worth highlighting from CROI partly stood out because there were fewer comparative studies that at previous CROI meetings. Of these, ACTG 5205, and its metabolic sub-study ACTG 5224s, generated most attention.

ACTG 5205

ACTG 5205 enrolled over 1850 treatment naïve patients from 2005-7 and followed them through to September 2009. The study was designed to compare efavirenz to atazanavir and tenofovir/FTC to abacavir/3TC by randomising equally to one of four groups. Patients were stratified by baseline viral load (above vs below 100,000 copies/mL). [1, 2]

Baseline demographics included 83% men/17% women; 40% white (non-Hispanic), 33% black, 23% Hispanic; median age 38 years median viral load ~50,000 copies/mL, and median CD4 230 cells/mL, Primary efficacy endpoints were time to confirmed virological failure (>1,000 copies/mL) at or after 16 weeks and before week 24 or viral load >200 copies/mL at week 24. Safety endpoints included time to first grade 3/4 event or laboratory abnormality at least one grade higher than baseline (excluding unconjugated hyperbilirubinaemia). Tolerability was assessed as time to change of treatment.

In February 2008, following a DSMB review, patients with baseline viral load >100,000 copies/mL who were using abacavir/3TC were unblinded and recommended to change to tenofovir/FTC due to significantly poorer virological responses. [3, 4]

Interpreting the final results now is further complicated because HLA-B*5701 testing was not available when the study started. Also, and perhaps more surprisingly, baseline resistance testing was performed in less than half the study group. In practice, this means that the most relevant results from the whole study relate to the comparisons between efavirenz vs atazanavir/r.

Using the primary virologic endpoint, there were no significant differences between atazanavir/r and efavirenz with either abacavir/3TC (HR 1.13, 95%CI 0.82–1.56) or tenofovir/FTC (HR 1.01, 95%CI 0.70, 1.46). The differences for the safety endpoint report benefits for atazanavir/r over efavirenz only with abacavir/3TC (HR 0.81, 95%CI 0.66–1.0; p=0.05), probably driven by a caution over management of rash and a potential hypersensitivity reaction when NNRTIs are prescribed with abacavir. This was seen even more in the tolerability analysis (HR 0.69, 95%CI 0.55, 0.86; p=0.0008).

Cardiovascular and renal events, non-AIDS malignancies and bone fractures were broadly similar in each group.

Again, as seen in other PI vs NNRTI studies, patients with virological failure were significantly more likely to develop resistance on the NNRTI compared to the PI regimen (approximately 60% vs 20% of virological failures included >1 major mutation in the efavirenz vs atazanavir/r group respectively).

The only signficant differences in CD4 responses were seen when atazanvir/r group was compared to efavirenz, but only when tenofovir/FTC was used as the nucleoside backbone (+252 vs +221 cells/mm3 at 96 weeks, p=0.002).

Lipid differences were more complicated, and while statistically significant for some values, may or may not be of clinical relevance.

In an on-treatment analysis at week 48, efavirenz was consistently associated with significantly greater increases in total cholesterol, LDL and HDL regardless of nucleosides (all comparisons p<0.001, except LDL with TDF/FTC, p=0.002). Increases were also consistently greater with abacavir/3TC compared to tenofovir/FTC. There were no significant differences for triglycerides although there was a trend for greater increases with atazanavir/r compared to efavirenz, when used with tenofovir/FTC (p=0.07). Despite this, there were no significant differences in total cholesterol:HDL ratio in any comparisons.

Finally, creatinine clearance dropped by approximately -3.0 mL/min at week 96 (as-treated analysis) when atazanavir/r was used with tenfovir/FTC compared to slightly higher increases in the other three groups (p<0.001). These differences were described as modest and <5% of patients in any arm experienced changes of greater than 25% decline.

ACTG 5224s

The metabolic substudy ACTG 5224s provided data on bone mineral density (BMD) and limb fat changes in 269 patients in ACTG 5202 (approximately 65 from each of the four comparative regimens). [5, 6]

Exclusion criteria for the substudy included diabetes or other complications including use of medication related to bone or body composition. DEXA evaluations (whole body and bone) were taken at baseline and at 24, 48 and 96 weeks, then annually. CT abdominal scans were taken at baseline and at week 96.

When no interaction was seen between either the RTI component or third drug components, factorial analyses were performed comparing pooled results for each dual RTI, and for atazanavir/r to efavirenz.

Primary endpoints included percentage changes in hip and lumber spine between the two RTI components, and changes of >10% loss of limb fat. Secondary analysis included fracture rates and the same bone and fat changes in the PI vs NNRTI groups.

Baseline demographics broadly reflected the main study and were balanced between groups. Of note, baseline rates of osteopenia (T-score <1.0) were 35% at lumbar spine and 23% at the hip.

Mean values for BMD at lumbar spine dropped in all groups over the first year of treatment and then recovered by about 50% over the subsequent year. These declines were more significant in the tenofovir/FTC compared to abacavir/3TC (approximately -3.5%% vs -1.5% at week 96, p=0.004) group and in patients using atazanavir/r compared to efavirenz (-3.2% vs -1.7, p=0.035).

Tenofovir/FTC was associated with a greater drop in hip BMD at 96 weeks compared to abacavir/3TC (-4.0% vs -2.6%, p=0.025) with no difference between atazanavir/r and efavirenz (p=0.59, each approx -3.0%). Early declines in hip BMD did not appear to reverse over time.

Fracture rates were similar in all groups, with an incidence of 1.7 per 100 patient years, all of which were reported as traumatic (ie expected in general life). No difference by regimen was seen in the main study (where 12% of fractures were without trauma).

Changes in fat distribution was complicated by the study decision to select a relatively marginal 10% cut-off for fat loss as the endpoint. No differences were seen between arms using this criteria (approximately -16%), with a post-hoc analysis using >20% reported in <5% patients with no clear RTI or third drug association.

Absolute mean values increased in both RTI arms (approximately +1 kg gain, no statistical difference) but this was higher in the atazanavir/r vs efavirenz groups (approximately +2 kg vs +1 kg;  +30% vs +15%, both p=0.008).

Trunk fat increases were similar in each RTI group, but atazanavir/r had greater increases at 96 weeks compared to efavirenz (approximately +2.4 kg vs +1.2 kg, p=0.023).

comment

The clearest outcome from these complicated results is likely to be a stronger recommendation for atazanavir/ritonavir as a clinical option in for first-line therapy.

Absolute differences in side effects, tolerability and metabolic differences are more complicated to interpret in clinical terms, even when they are statistically significant, but would be a factor to consider in individual patients at higher risk.

The reductions in bone mineral density in all groups are concerning, especially given the high percentage of patients with low levels at baseline. While fracture rates in this study were low, other studies at CROI suggested that the concern that ageing will uncover reduced BMD as a greater complication in HIV-positive people compared to the general population, may, unfortunately, be well founded.

Fat changes are difficult to interpret given the choice of endpoint for fat loss, although ~5% patients lost >20% fat across all arms. The significant increases in trunk fat, largely interpreted as a return to health effect, were based on DEXA results. The analysis of CT results, not included in the CROI presentation, is needed to determine whether this is an accumulation of visceral or subcutaneous fat.

References

Unless stated otherwise, all references are to the Programme and Abstracts of the 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco.

All oral abstracts are available as webcasts.

http://www.retroconference.org

1. Daar E et al. ACTG 5202: Final results of ABC/3TC or TDF/FTC with either EFV or ATV/r in treatment-naive HIV-infected patients. 17th CROI 2010. Oral abstract 59LB.

http://www.retroconference.org/2010/Abstracts/39789.htm

2. Webcast: Advances in ART. Wednesday 9.30am.

http://www.retroconference.org/2010/data/files/webcast_2010.htm

3. US study changes use of abacavir/3TC in naïve patients with viral load >100,000 copies/mL based on DSMB recommendation. HIV Treatment Bulletin, April 2008.

http://i-base.info/htb/1811

4. Sax P et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009;361. DOI: 10.1056/NEJMoa0906768.

http://www.ncbi.nlm.nih.gov/pubmed/19952143

5. McComsey G et al. Bone and limb fat outcomes of ACTG A5224s, a substudy of ACTG A5202: a prospective, randomized, partially blinded Phase III trial of ABC/3TC or TDF/FTC with EFV or ATV/r for initial treatment of HIV-1 infection. 17th CROI 2010. Oral abstract 106LB.

http://www.retroconference.org/2010/Abstracts/39788.htm

6. Webcast: Complications of HIV and ART. Thursday 9.30am.

http://www.retroconference.org/2010/data/files/webcast_2010.htm

There were fewer presentations at this years meeting on either new drugs or comparative studies between existing drugs. While the missing studies were very noticeable, this is probably more due to the recent approval of several new drugs over the last two years.

It may be significant though that most of the notable studies were nearly all included in one oral abstract session. [1]

QUAD, elvitegravir and cobicistat

New clinical data was presented on the integrase inhibitor elvitegravir, in combination with a new pharmacokinetic booster from Gilead called cobicistat (previously GS-9350), both coformulated with tenofovir/FTC in a four-in-one tablet called Quad. [2]

When Quad was compared to Atripla (efavirenz + tenofovir + FTC), over 80% of patients in each group had undetectable viral load (less than 50 copies/mL) after 24 weeks. However, mean  baseline viral load was <40,000 copies/mL, and it was only >100,000 copies/mL in 25% of patients. In this Phase 2 study, patients in the Quad group (n=48) became undetectable more quickly than those on Atripla (n=23), as was seen with raltegravir. For example, after 8 weeks, about 80% people were undetectable with Quad compared to about 50% with Atripla.

While Quad was better tolerated in terms of not having efavirenz-related side effects, a caution due to the impact of cobicistat on reducing estimated glomerular filtration rate (eGFR) – but not actual GFR – suggests that management of renal toxicity may have to be handled differently.

Results from a second Phase 2 study were presented in the same oral presentation, this time comparing the new booster (n=50) to ritonavir (n=29), each in combination with atazanavir, tenofovir and FTC. [2]

No differences were seen in efficacy or tolerability between the two boosters. Unlike ritonavir, cobicistat has no antiretroviral activity.

In summary, results were sufficiently encouraging for both QUAD and cobicistat to be taken into larger Phase 3 studies.

Compounds in earlier development

A dose-finding Phase 1 study of a CCR5-inhibitor in development with Tobira Pharmaceuticals under the compound name TBR-652. The compound has a plasma half-life of 35-40 hours allowing once-daily dosing and although metabolised by CYP and non-CYP pathways is neither and inducer or inhibitor of CYP P450. [3]

These first results in 54 HIV-positive patients produced median viral load reductions of 1.7 log with the 50, 75 and 150mg doses after 10 days monotherapy. Although baseline viral load was lower in the 150mg group (median 4.0 logs, compared to 4.5 and 4.6 logs in the 50mg and 75mg groups), all patients using the 75mg dose had >1.0 log reductions. Patients were treatment-experienced (off treatment for at least 6 weeks), CCR5-naïve and CCR5-postive. No dose-related or serious side effects were reported, though the study was only in about 50 people.

Side effects were mild (none reported at the 75mg dose) and included nausea, diarrhoea, headache and fatigue in greater frequency at the 100 and 150mg – although many of these were reported as being associated with one patient with a concomitant infection.

Very little new information was available for the new integrase inhibitor in development with Shionogi and GSK called S/GSK1349572. [4] Although included in the oral session, this was more a product overview, adding no new in vivo data to that presented at the IAS meeting in Cape Town last year. [5]

Results from a pooled analysis of 721 treatment experienced patients in the unfortunately named Victor-E 3 and 4 Phase studies, presented by Joe Gathe, disappointingly found to too little difference compared to placebo for the troubled CCR5-inhibitor vicriviroc to continue to be taken forward for further development. In a modified ITT analysis the percentage of patients with undetectable viral load (<50 copies/mL) at 48 weeks was 64% and 61% in the vicriviroc and placebo groups respectively (p=0.6). [6]

The presentation suggested this was because of more effective background drugs were available for patients to construct optimum background therapy (approximately 65% had >3 active drugs), for the third agent to show significant advantages. A prespecified sub analysis showed that 70% of people randomised to the vicriviroc arms who had <2 active drugs achieved <50 copies/mL compared to 55% of the placebo group, and an indication that this was significant. As the vicriviroc group had fewer active drugs at baseline, this potentially obscured a difference in activity between the two arms.

While safety was apparently similar, during the questions, we learned that there were 7 vs 0 deaths in the vicriviroc and placebo arms respectively, not apparently significant after adjusting for time on treatment.

Despite the early promise, it looks likely that the development of this compound will now be put on hold. [6]

Preliminary studies looking at a handful of other targets and approaches, including attempts to target latently infected cells were presented as posters.

Frauke Christ and colleagues from University of Leuven, Belgium, detailed potential compounds from a new class of integrase inhibitor, called LEDGINS, that would not bind at the active site, and therefore not be cross-resistance to raltegravir or elvitegravir. These potential molecules, 2-(quinolin-3-yl)acetic acid derivatives, were designed by rational drug design, and identified after screening 200,000 molecules. [7]

Stephen Mason presented preclinical results on two early compounds that could interfere with the assembly and stability of the capsid core, that are in development at Boehringer Ingleheim. These compounds interrupt the process for assembling new virus and were shown to have activity against resistant HIV from other classes. [8]

Many presentations reiterated that eradication with current drugs is not possible, due to the inability to recognise latently infected resting cells. Even after many years of maximally suppressive therapy, it is well established that viral load rapidly rebounds to pretreatment levels, potentially within weeks of discontinuing treatment.

At least five new types of treatment are the focus of research on how to target latently infected cells. These include cellular restriction factors – human proteins that reduce HIV replication and that can help or block infections – such as tetherin, a protein that blocks HIV release, APOBEC3, an immunity gene that has anti-HIV activity, and TRIM5-alpha, a protein that in some monkeys protects against HIV infection, and that gene therapy could perhaps be modified to adapt the related human protein. Zinc finger inhibitors that can knock out CCR5 were included in other presentations, although this potential target that has been on the outer radar of investigative treatment for at least 15 years.

References

Unless stated otherwise, all references are to the Programme and Abstracts of the 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco.

1. Webcast: Advances in ART. Wednesday 9.30am.

http://www.retroconference.org/2010/data/files/webcast_2010.htm

2. Cohen C et al. Single-tablet, fixed-dose regimen of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 achieves a high rate of virologic suppression and GS-9350 is an effective booster. 17th CROI 2010. Oral abstract 58LB.

http://www.retroconference.org/2010/Abstracts/39864.htm

3. Palleja S et al. Safety and efficacy of TBR 652, a CCR5 antagonist, in HIV-1-infected, ART-experienced, CCR5 antagonist-naïve patients. 17th CROI 2010. Oral abstract 53.

http://www.retroconference.org/2010/Abstracts/37579.htm

4. Johns B et al. The discovery of S/GSK1349572: a once-daily next generation integrase inhibitor with a superior resistance profile. 17th CROI 2010. Oral abstract 55.

http://www.retroconference.org/2010/Abstracts/37960.htm

5. First results of new integrase compound: GSK1349572. HTB October 2009.

http://i-base.info/htb/5976

6. Gathe J et al. Phase 3 trials of vicriviroc in treatment-experienced subjects demonstrate safety but not significantly superior efficacy over potent background regimens alone. 17th CROI 2010. Oral abstract 54LB.

http://www.retroconference.org/2010/Abstracts/39832.htm

7. Christ F et al. First-in-class inhibitors of LEDGF/p75-integrase interaction and HIV replication. 17th CROI 2010. Oral abstract 49.

http://www.retroconference.org/2010/Abstracts/37630.htm

8. Titolo S et al. Discovery of potent HIV-1 capsid assembly inhibitors. 17th CROI 2010. Oral abstract 50.

http://www.retroconference.org/2010/Abstracts/38238.htm

An analysis from the D:A:D study, presented as an oral session, reported that HIV-positive people who stop smoking can expert similar direct health benefits to HIV-negative people.

Kathy Petoumenos from the University of New South Wales, Sydney, looked at rates of cardiovascular disease before and after stopping smoking in over 27,500 HIV-positive patients from Europe, the US and Australia, who had smoking status recorded in the prospective D:A:D cohort study.

The group looked at four endpoints: fatal and non-fatal myocardial infarction (MI), a broader definition of coronary heart disease (CHD), cardiovascular disease (CVD) combining CHD and stroke, and all cause mortality. Event rates were calculated for never smokers (n=8,920), ex-smokers at D:A:D study entry (n=6,265), current smokers (n=11,951), and smokers who stopped during D:A:D follow-up (n=8,197).

Current smokers were more likely to be male (77%), white (70%), infected through IV drug use (32%) and HCV-positive (34%), but CD4, viral load, BP, lipids and ARV-exposure were broadly similar between groups.

Incidence rate ratios (IRR) were determined adjusting for age, sex, cohort, calendar year, antiretroviral treatment, family history of CVD, diabetes (men and women), and time updated lipids and blood pressure assessments. Mortality endpoint also adjusted for HCV, HBV, mode of HIV exposure, ethnicity and incidence of CVD during follow-up.

Up to February 2008, there were 432 (MI), 600 (CHD), 746 (CVD) and 1902 (mortality events) endpoints. Crude event rates were 2.85, 3.96, 4.94, and 12.45 per 1000 person years respectively.

With never-smoked as the reference, increased risks rates were 1.73 and 3.40 for previous- and current-smokers respectively. Rate ratios for patients who had stopped smoking for <1, 1-2, 2-3 and >3 years follow-up since quitting, were 3.73, 3.00, 2.62 and 2.07 respectively, compared to never-smokers. This showed significant reductions within a year of stopping that continued to reduce over subsequent years. A similar pattern was seen for CHD and CVD, and although these were not significant at all timepoints, this is likely to be related to the lower number of events in some groups and the lower number of people who stopped smoking more than two years ago. The protective trend here is clear and important (see Table 1).

Although current smokers were at 28% higher risk of mortality, with no difference between never- and former-smokers, no clear reductions were seen during follow-up since stopping, with all confidence intervals crossing 1.0, even in a sub-group at higher risk of CVD-related mortality (in patients older than 50 years).

Table 1: Incidence rate ratios by baseline smoking status and time since quitting

* Non significant (CI crossed 1.0)

An explanation for the higher rates seen in the most recent (< 1 year) quitters was explained by the likelihood that a medical incident could have been the prompt needed to stop smoking. This group would therefore be at higher risk compared to current smokers (who would have been symptomatic). This was supported by the cause of mortality being more likely to be HIV/AIDS in the never smoked group with higher rates of non-AIDS malignancies seen in the previous and stopped groups.

The study has limitations in the amount and type of data that were collected on smoking (e.g. no start/stop dates or pack-year data). However, the significant reductions on CHD with each year after stopping smoking should support cessation programme for HIV-positive people, a greater percentage of whom smoke than the general population.

comment

This is the first time that the clinical benefits of stopping smoking has been reported in HIV-positive people and these findings should not be taken for granted.

Each year, HIV-positive people are advised on the importance of modification of lifestyle for ‘healthy options’ related to the complicated etiology of cardiovascular health and any study that can show tangible benefits is important.

This is particularly important given the higher rates of lung cancers reported in other studies. Keith Sigel and colleagues reported that HIV is an independent risk factor for lung cancer after adjusting for smoking (IRR 1.80; 95%CI 1.28 2.15). [2]

Edgar Simard from the US National Cancer Institute, reported a 3-fold observed incidence of lung cancer in HIV-positive patients within 3-5 years of an AIDS diagnosis compared to the general population (and increasing cumulative incidence). [3]

Meredith Shiels and colleagues reported that lung cancer was one of the cancers that was being diagnosed at an earlier age in HIV-positive compared to HIV-negative people, and that this 3-4 year difference was statistically significant after adjustment for multiple comparisons (p<0.001). [4]

References

Unless stated otherwise, all references are to the Programme and Abstracts of the 17th Conference on Retroviruses and Opportunistic Infections. 16-10 February 2010, San Francisco. All oral abstracts are available as webcasts.

http://www.retroconference.org

1. Petoumenos K et al. Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the D:A:D study. 17th CROI, 2010. Oral abstract 124.

http://www.retroconference.org/2010/Abstracts/38289.htm

2. Sigel K et al. HIV infection is an independent risk factor for lung cancer. 17th CROI, 2010. Oral Abstract 30.

http://www.retroconference.org/2010/Abstracts/38365.htm

3. Simard E et al. Cancer incidence and cancer-attributable mortality among persons with AIDS in the US. 17th CROI, 2010. Oral abstract 27.

http://www.retroconference.org/2010/Abstracts/38173.htm

4. Shiels M et al. Do people with AIDS develop cancer at younger ages than the general population? 17th CROI, 2010. Poster 757.

http://www.retroconference.org/2010/Abstracts/37914.htm

Keith Sigel and colleagues presented an analysis from the US Veterans Ageing Cohort Study Virtual Cohort (VC) on the relationship between HIV and lung cancer. [1]

The advantages of this database included size, smoking status data from a related health survey and a matched HIV-negative control group, although this was an almost exclusively (98%) male study. Median age was 47 years and ethnicity was approximately 40% white, 40% black. 10% Hispanic and 10% other. Approximately 30% were current smokers, 15% recently quit (< 1 year), 25-50% distantly quit (> 1 year) and 20% of HIV-positive compared to 25% of HIV-negative had never smoked.

The analysis compared over 3,700 HIV-positive and nearly 10,000 HIV-negative patients (contributing 28,500 and 76,800 person-years of follow-up respectively).

Lung cancer was defined using International Classification of Diseases (ICD-9) codes and Incidence Rate Ratios (IRR) were adjusted for age, race, smoking exposure, and Chronic Obstructive Pulmonary Disease (COPD).

The overall incidence of lung cancer per 100 person years was 0.26 compared to 0.16 in the HIV-positive vs HIV-negative groups (unadjusted IRR 1.5, 95%CI 1.2–2.0). Results from the adjusted analysis are detailed in Table 1.

Table 1: Adjusted IRR for lung cancer multivariate model including all covariates

* Reference = white race; ** Reference = never smoked.

The authors concluded that the incidence of lung cancer was significantly increased in HIV-positive men in their group, even after adjusting for smoking exposure.

comment

This study reported slightly lower rates of increased risk of lung cancers in HIV-positive individuals compared to rates that were 2- to 6-fold higher in earlier studies, that also adjusted for smoking status. [2, 3, 4]

While the approximate 2-fold increased risk associated with HIV was significant and is important, the presenter emphasised the 10-fold higher risk for current smokers (that was halved to around 5-fold for former smokers who had quit more than one year earlier).

References

Unless stated otherwise, all references are to the Programme and Abstracts of the 17th Conference on Retroviruses and Opportunistic Infections. 16-10 February 2010, San Francisco. All oral abstracts are available as webcasts.

http://www.retroconference.org

1. Sigel K et al. HIV infection is an independent risk factor for lung cancer. 17th CROI, 2010. Oral Abstract 30.

http://www.retroconference.org/2010/Abstracts/38365.htm

2. Cadranel J et al. Lung cancer in HIV infected patients: facts, questions and challenges. Thorax 2006; 61:1000-1008.

http://thorax.bmj.com/content/61/11/1000.abstract

3. Engels EA et al. Elevated incidence of lung cancer among HIV-infected individuals. J Clin Oncol 2006; 24 (9); 1383-1388. (March 2006).

http://jco.ascopubs.org/cgi/content/abstract/24/9/1383

4. Kirk GD et al. HIV infection is associated with an increased risk for lung cancer, independent of smoking. Clin Inf Dis 2007; 45:103-110.

http://www.journals.uchicago.edu/doi/abs/10.1086/518606

Over the last ten years HTB has reported numerous studies of lower bone mineral density and higher rates of osteopenia and osteoporosis in HIV-positive people compared to rates in age- and gender-matched general population.

While some research groups cautioned that their findings might not translate into higher fracture rates, most others suggested that ageing was likely to compound this risk and that it would be only a matter of time before the additional impact of HIV might be seen.

Two studies at CROI unfortunately suggest that these concerns are likely to be real.

Christine Dao from the US CDC in Atlanta and colleagues presented an analysis of fracture rates from 1994-2008 in over 8,400 HIV-positive patients followed in the HIV Outpatients (HOPS) Cohort and compared this to rates from non-HIV US inpatient (NHDS) and outpatient (NHAMCS) surveys that were weighted to make inferences to the US general population.

Only first fractures were included from HOPS and adjusted Hazard Ratios (AHR) were calculated controlling for age and gender. As fracture data were not comprehensively collected in HOPS prior to 2000, the presentation focused on fractures from around 5800 patients seen at least annually over the last eight years.

Baseline characteristics at first visit included: 79% male; 52% non-Hispanic white, 38% non-Hispanic Black; median (IQR) age 40 years (34-46), median BMI 24.4 (22.3-27.4); median time since diagnosis 5.3 years (1.3-9.9). Three-quarters of patients were treatment-experienced with median viral load (for the cohort) of 1,300 (<400-35,560) copies/mL.

Approximately 4% patients (236/5826) experienced a fracture at median age 45 years (38-51), roughly in proportion to baseline characteristic of race and gender, although only 51% of fractures were in treatment-experienced patients.

Gender-adjusted rates were restricted to patients aged 25-54, representing most HIV-positive individuals and showed not only an increase in fracture rates over time from about 55 to 85/10,000 PY, p=0.01 (compared to stable rates at around 30/10,000 PY in general population outpatient data). The rate in HIV-positive people was stable from 2002-2008 (and was approximately 4-fold higher).

Fractures at fragility sites (wrist, vertebra, femoral head) occurred at higher rate in both HIV-positive men and women compared to the general population, and are detailed in Table 1.

Factors independently associated with increased risk of fracture (adjusted HR: 95%CI) included: age >47 years (1.6; 1.0–2.5, p<0.05); nadir CD4 <200 cells/mm3 (1.6; 1.1–2.3, p=0.04); HCV coinfection (1.6; 1.1–2.3, p=0.01); diabetes (1.6; 1.0–2.6, p<0.05); and history of substance use (1.5; 1.0–2.3, p<0.05).

Limitations of the study included the use of different data collection systems for the HIV-positive and general population groups, no data linking bone mineral density to fracture risk, and whether this increase was due to an increase in events or a potential improved reporting.

Table 1: Percentage of fractures by anatomic site in adults 25-54 years old (HOPS 2000-2008)

Importantly, they also stressed that the actual event rate remained low, even though the relative rate was significantly higher.

Nevertheless, the researchers concluded that HOPS patients experienced higher rates of fracture compared to the general US population, that this rate increased over time and included a higher percentage of fragility fractures; and that in addition to known risk factors, low CD4 nadir was also associated with increased fracture risk.

Julie Womack and colleagues from the Veterans Ageing Cohort Study (VACS) presented results from men in the largely male VA cohort, focusing on the prevalence and incidence of fragility fractures (ie associated with minimal or no trauma, and with low bone mineral density). [2]

The VACS is a prospective observational cohort of about 40,000 HIV-positive veterans matched 1:2 by age, sex and site to around 80,000 HIV-negative controls. This analysis only included first fracture. Wrist fractures and compound fractures were excluded because of the higher likelihood of being related to trauma.

Multivariable models were adjusted for HIV status, race, enrollment date, age, coinfection, BMI and corticosteroid use, with additional adjustment for baseline CD4 and ARV use in HIV-positive patients.

During a median follow-up of 8 years (range 4-11), 952 fractures (644 hip and 308 vertebral) fractures were recorded, with an unadjusted incidence of 16 vs 11/10,000 PYFU in the HIV-positive vs HIV-negative groups. Fractures occurred at a mean age of 55 years (SD+11).

Prevalence results showed that across all ages only hip fractures occurred at a significantly higher rate in the HIV-positive vs HIV-negative groups (p<0.0001), with a difference developing and widening from age 40 onwards. Although vertebra fractures were generally similar in both groups, the rate in HIV-positive men increased significantly in men over 70 years who were HIV-positive.

After adjustment for cofactors (AHR; 95%CI), including Caucasian race (1.79; 1.57–2.03), BMI <19 (2.50; 1.54–4.05), alcohol use (H1.79; 1.47–2.18), pulmonary disease (1.38; 1.10–1.73), cerebrovascular disease (2.16; 1.54–3.02), and peripheral vascular disease (1.64; 1.10–2.44), the HIV effect was reduced, though still significant (1.38; 1.18–1.60). Similar ratios applied for the full model and HIV-positive only model.

The presentation also discussed management and this was picked up in the question session afterwards. Prevention is stressed for all patients. Clinical assessment for fracture risk was recommended for patients aged 40-50 and DEXA indicated when HIV is not the only risk factor.

Several members of the audience commented that they would encourage broader use of DEXA scans, especially given the high rates of other risk factors, including higher rates of smoking, alcohol use and low testosterone.

Although ARV use was not found to be significant in this study, another question from the audience suggested that this was unlikely to be a reliable conclusion, as the study defined exposure by baseline use of d4T, tenofovir, PIs or NNRTIs, rather than looking at cumulative exposure more commonly adopted in most studies.

Finally, a third presentation in the same oral session reported fracture incidence in a retrospective analysis in about 2400 women (approxiamtely 1700 HIV-positive, 700 HIV-negative) in the Women’s Interagency HIV Study (WIHS). Of note, this study also collected data on smoking, opiate/cocaine use and vitamin D/calcium supplementation.

Fractures occurred in 148 (9%) HIV-positive women vs 47 (7%) HIV-negative women producing incidence rates of 1.79 vs 1.41/100 PY, respectively (p=0.13 NS). Analysis by fracture site also showed no significant difference in rates by HIV status. In the multivariate analysis, HIV status remained non-significant, with only age, race (being Caucasian), HCV coinfection and serum creatinine only showing positive relationship to increased fracture rate. The only determinants of time to fracture in HIV-positive women were age (per 10 years older HR 1.2; 95%CI 1.0–1.5, p=0.047) and previous AIDS defining illness (HR 1.9; 95%CI 1.3–2.7, p=0.0008), but not CD4 count or ARV use.

Although no impact of HIV was seen over five years of follow-up the limitations of this study was that this was broadly a pre-menopausal patient group and in a modest sample size. Also, approximately 50% women had high BMI which is associated with protecting bone density and strength.

The conclusion included recognition that fracture risk could increase in HIV-positive post-menopausal women, given that oestrogen has a protective effect and other studies have already highlighted the lower levels of bone mineral density in HIV-positive women.

References

Unless stated otherwise, all references are to the Programme and Abstracts of the 17th Conference on Retroviruses and Opportunistic Infections. 16-10 February 2010, San Francisco. All oral abstracts are available a