Results presented at CROI 2013 underscore some of the barriers to pre-exposure prophylaxis.
Studies presented at CROI 2013 remind us that, as prevention goes biological, human behavior still determines outcomes.
FINAL VOICE RESULTS
VOICE (MTN 003) was a five-arm, randomized, double-blind, placebo-controlled, phase IIB trial designed to assess the safety and efficacy of oral tenofovir, oral tenofovir plus FTC, and tenofovir 1% vaginal gel (TFV) used daily to prevent sexual transmission of HIV in women. The trial began in September 2009 and enrolled 5029 sexually active women (median age, 25; 51% younger than 25; 21% married) at 15 sites in South Africa, Uganda, and Zimbabwe. At baseline, 17% of participants reported anal sex, and 85% reported vaginal sex with condoms. In 2011, the vaginal gel and oral tenofovir arms were stopped after interim reviews indicated that these strategies, although safe, were no better than placebo in preventing
HIV acquisition (JW AIDS Clin Care Oct 3 2011 and Dec 5 2011).
Final results of the study, including the results of the tenofovir + FTC arm, were presented at CROI 2013 [Marrazzo J et al. Abstract 26LB]. Overall retention in the study was excellent (91%); HIV incidence was 5.7 per 100 person-years (ranging from 0.8 to 9.9 per 100 person-years across sites), with no significant difference across study arms; and pregnancy incidence was 7.4%, with no difference across study arms. All three product arms failed to show efficacy. The underlying reason appears to be adherence. In a subset analysis of tenofovir levels, less than one third of participants in any of the active drug arms had detectable tenofovir levels in blood, suggesting that most study participants simply did not take the product. Being married, being older than 25, and reporting a primary male partner older than 28 were associated with having detectable tenofovir levels — in other words, with adherence. The disappointing results of this well-designed and complex study are a sobering reminder that biomedical prevention, at this point, depends on high levels of adherence to daily medication. Why study participants across 15 different sites failed to take their assigned drugs despite high risk for HIV is an unanswered question.
MORE FROM IPREX
The randomized phase of the iPrEx trial, which ended in November 2010, showed pre-exposure prophylaxis (PrEP) with oral tenofovir + FTC to be effective among men who have sex with men (MSM). Thereafter, participants were offered enrollment in the open-label phase of the study (iPrEx OLE). Enrollment occurred between June 2011 and June 2012, allowing researchers to study HIV seroconversion among high-risk individuals after they had stopped PrEP [Grant R et al. Abstract 27]. Of 1770 MSM enrolled in iPrEx-OLE, 91% came from iPrEx; of these, 86% were HIV seronegative at the end of the randomized phase. Results showed that the difference in HIV seroconversion incidence between participants formerly enrolled in the placebo arm and those in the active arm (4.11 and 3.24 per 100 person-years, respectively) was not statistically significant. Unprotected anal intercourse and younger age were risk factors for seroconversion. This study suggests no excess incidence after stopping PrEP with tenofovir + FTC. However, it also highlights the extremely high incidence of HIV infection among MSM and reminds us of the urgent need for effective prevention interventions for this population.
GSK744
Over the years, we have learned much about PrEP from studies in nonhuman primates. Investigators from research centers in New York and Louisiana and from industry presented data on the use of a novel integrase inhibitor (GSK744LAP), a dolutegravir analogue with pharmacological properties (plasma half-life, 21–50 days) that allow for monthly or quarterly intramuscular injections [Andrews C et al. Abstract 24LB]. In this study, eight male macaques were each given two injections of GSK744LAP 4 weeks apart and then challenged intrarectally each week with SHIV — a monkey virus (SIV) modified to contain the same outer protein as HIV — for up to eight exposures. Eight macaques injected with placebo and similarly challenged became infected after a median of two rectal exposures, but all eight treated macaques were protected. This study suggests that long-acting agents such as this drug may offer novel opportunities for HIV prevention.
DATA FROM HPTN 052
HPTN 052 is a phase III randomized trial designed to assess whether ART can prevent HIV transmission in HIV-serodiscordant couples. In April 2011, the review board overseeing HPTN 052 recommended that interim study results showing a 96% reduction in HIV transmission be made public. Subsequently, all participants in the treatment-delay arm were offered ART. At this year's CROI, researchers presented data on the number of participants who accepted or declined ART and the reasons for declining [Batani J et al. Abstract 550]. Among the 584 participants in the delay arm who had not started ART, 81% accepted and 19% declined. The most common reasons given for declining ART were not being ready to start therapy and believing their CD4-cell counts were too high. These findings are not entirely surprising. Despite the many "reasonable arguments" about why people should initiate ART for personal and community reasons, the reality is that many patients remain skeptical about starting ART when they have high CD4-cell counts and feel well. Understanding how to overcome such barriers will be critical to the success of the "test-and-treat" approach to HIV prevention.
