Oral Tenofovir/FTC for Pre-Exposure Prophylaxis: The iPrEx Study

In the first-ever efficacy trial of antiretroviral-based pre-exposure prophylaxis, once-daily oral tenofovir significantly reduced the risk for HIV acquisition among men who have sex with men.
The use of antiretroviral therapy (ART) for HIV prevention holds great promise, as demonstrated by two major trials this year: First, the CAPRISA 004 study demonstrated a 39% reduction in the risk for HIV acquisition among women who used a 1% tenofovir vaginal gel both shortly before and shortly after sex (JW AIDS Clin Care Jul 26 2010). Second, a phase II study demonstrated the safety of oral tenofovir monotherapy as pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) (Abstract FRLBC102, AIDS 2010). Now, results are available from iPrEx, the first-ever efficacy trial of ART-based PrEP.
Nearly 2500 HIV-negative MSM in South America, the U.S., Thailand, and South Africa were randomized 1:1 in double-blinded fashion to receive once-daily oral tenofovir/FTC or placebo. Both groups received condoms and intensive counseling regarding sexual risk behavior, and every 4 weeks, underwent rapid enzyme-linked immunosorbent assay (ELISA) testing. All participants were screened and treated for urethral sexually transmitted infections (STIs) and syphilis at study entry, every 24 weeks on-study, and for any clinical suspicion of STIs.
During 3324 person-years of follow-up (median, 1.2 years), 36 incident HIV infections were identified in the tenofovir/FTC group versus 64 in the placebo group, for a relative risk reduction of 44% (95% confidence interval, 15%–63%). As was seen in CAPRISA 004, efficacy was strongly related to product use, with risk reductions as follows:

• 32% (95% CI, –41%–67%) at adherence levels <50%
  
• 50% (95% CI, 18%–70%) at adherence levels 50%
  
• 73% (95% CI, 41%–88%) at adherence levels 90%
  

Adverse events and discontinuations were similar between groups, except for an early excess of nausea and weight loss in the tenofovir/FTC group. Serum creatinine elevations occurred in 25 patients in the tenofovir/FTC group versus 14 in the placebo group (P=0.08); all were resolved upon drug discontinuation. Risk compensation (an increase in high-risk sexual behavior in response to perceived protection from the intervention) was not observed in either treatment group.
Viral set points and CD4-cell counts were similar throughout follow-up between patients who seroconverted in the tenofovir/FTC group and those who did so in the placebo group. No drug resistance was observed among those who seroconverted on-study. A nested case-control analysis indicated that most seroconversions within the tenofovir/FTC group likely occurred when the drug was not detectable in plasma or intracellular compartments.
Comment: Although the overall efficacy of PrEP in this study (44%) is disappointing compared to projected estimates, the results demonstrate proof-of-principle and suggest that greater efficacy is possible with higher adherence levels. Interestingly, the case-control analysis hints that taking the drug shortly before exposure might be more relevant to efficacy than overall adherence levels are. Ongoing trials exploring different preparations, components, and intervals of ART within various at-risk populations will help clarify the optimal use of ART as a prevention tool. In the meantime, decisions about policy around ART as prevention — and about the obligations of research teams to offer PrEP and/or tenofovir-based microbicide gel as part of future prevention trials — just got exponentially more complicated.
— Raphael J. Landovitz, MD
Dr. Landovitz is Assistant Professor, Division of Infectious Diseases, Center for Clinical AIDS Research and Education, University of California, Los Angeles. He reports no conflicts of interest.
Published in Journal Watch HIV/AIDS Clinical Care November 23, 2010

Citation(s):

Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010 Nov 23; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa1011205)

Michael NL. Oral preexposure prophylaxis for HIV — Another arrow in the quiver? N Engl J Med 2010 Nov 23; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMe1012929)