Unraveling the divergent results of pre-exposure prophylaxis trials for HIV prevention

Abstract

Although the balance of recent evidence supports the efficacy of antiretroviral (ARV)-based pre-exposure prophylaxis (PrEP) against HIV-1 infection, recent negative trial results are perplexing. Of seven trials with available HIV endpoints, three different products have been tested: tenofovir 1% vaginal gel, oral tenofovir disoproxil fumarate (TDF) tablets, and TDF/emtricitabine tablets. Six of these trials were conducted exclusively in sub-Saharan Africa; all found the products to be well tolerated, and four demonstrated effectiveness. Furthermore, the HIV Prevention Trial Network (HPTN) 052 trial recently confirmed that antiretroviral treatment leads to 96% reduction in transmission to HIV-negative partners in HIV-serodiscordant couples. These results, along with human and animal data, provide substantial evidence for the efficacy of antiretroviral-based HIV prevention. Yet assessment of oral TDF/emtricitabine in the FEM-PrEP study and of oral and vaginal tenofovir in the Microbicide Trial Network (MTN)-003 trial (VOICE) was stopped for futility. How do we make sense of these discrepant results? We believe that adherence is a key factor, although it cannot be the only factor. Expanding upon a recent editorial in the Lancet, we discuss the impact of suboptimal product adherence on PrEP efficacy in the context of variable drug concentration at the exposure site, integrity of the vaginal epithelium, and the role of acute infection.

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

“…Excluding two trials discontinued due to nonefficacy, PrEP has been found to reduce the risk of HIV acquisition by 39%–86% (McCormack et al., 2015; van der Straten, Van Damme, Haberer, & Bangsberg, 2012), and a recent meta‐analysis found that PrEP reduces HIV risk by 51% compared to placebo (Fonner et al., 2016). Further, as PrEP efficacy hinges vitally on drug adherence (McCormack et al., 2015; van der Straten et al., 2012), the efficacies reported in clinical trials may be biased due to inflated access to drugs and medical care. We therefore consider low, medium and high PrEP efficacy estimates of 0.2, 0.5 and 0.8, respectively.…”

Neuropsychiatric effects of tenofovir in comparison with other antiretroviral drugs

“…19 Recent studies (CAPRISA004, iPrEX, TDF2, Partners for PrEP) have investigated the use of TDF in noninfected adults for PreP of HIV infection primarily through sexual contact. [20][21][22][23][24] In the CAPRISA004 study, the use of 1% TFV gel by noninfected women with high risk for HIV exposure reduced risk of HIV acquisition by 39%. 21 The studies of oral TDF/FTC (iPREX and TDF2) reported 44% and 62% efficacy in preventing HIV transmission, respectively.…”

Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1

“…In particular, PrEP using tenofovir with or without emtricitabine has demonstrated a protective efficacy of ∼40-70% in persons at high risk for HIV-1 infection; however, other studies using the same drugs have demonstrated no efficacy in similar populations. Higher efficacy would be expected if patients could better adhere to the prescribed regimen (14)(15)(16); however, the practical reality is that adherence on a daily basis is difficult, especially when patients are feeling well, regardless of the level of risk for HIV-1 infection.…”

“…Structural knowledge of such Abs in complex with the viral envelope (Env) glycoprotein gp120 (2,3,(7)(8)(9)(10) has raised the hope that immunogen design can be facilitated through a process of reverse vaccinology (11). In the meantime, alternative strategies for HIV-1 prevention are being pursued, including "treatment as prevention" (12), vaginal microbicides (13), and preexposure prophylaxis (PrEP) based on daily administration of antiretroviral drugs (14)(15)(16). In particular, PrEP using tenofovir with or without emtricitabine has demonstrated a protective efficacy of ∼40-70% in persons at high risk for HIV-1 infection; however, other studies using the same drugs have demonstrated no efficacy in similar populations.…”