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)

Interim Guidance: Preexposure Prophylaxis for the Prevention of HIV Infection in Men Who Have Sex with Men

The iPrEx study was conducted in Peru, Ecuador, Brazil, Thailand, South Africa, and the United States. Eligible participants were consenting HIV-uninfected men and male-to-female transgender adults (aged ≥18 years) who reported sex with a man and reported engaging in high-risk sexual behaviors during the preceding 6 months, and had no clinical contraindication to taking a combined formulation of 300 mg TDF and 200 mg FTC (TDF/FTC).*

LINK: http://www.cdc.gov/mmwr/pdf/wk/mm6003.pdf

HIV/AIDS Clinical Care / Guía del CDC para profilaxis pre exposición para HSH

HIV/AIDS Clinical Care

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HIV/AIDS Clinical Care for February 14, 2011 CLINICAL PRACTICE GUIDELINE WATCH Interim CDC Guidance on Pre-Exposure Prophylaxis for HIV Prevention in MSM Free! February 14, 2011 | Raphael J. Landovitz, MD, MSc In the wake of the iPrEx study, the CDC offers some general guiding principles for the implementation of pre-exposure prophylaxis. Reviewing: Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep 2011 Jan 28; 60:65 SUMMARY AND COMMENT What's the Best Way to Measure ART Adherence? February 14, 2011 | Keith Henry, MD The matter is neither simple nor settled. Reviewing: McMahon JH et al. Clin Infect Dis 2011 Feb 15; 52:493 SUMMARY AND COMMENT More Evidence that Treatment Interruptions Are Not SMART February 14, 2011 | Yasir Ahmed, MD, and Helmut Albrecht, MD Intermittent antiretroviral therapy results in inferior CD4-cell recovery and increased rates of opportunistic infections and death, compared to continuous therapy. Reviewing: Kaufmann GR et al. AIDS 2011 Feb 20; 25:441 SUMMARY AND COMMENT Not So Fast: Hepatitis B Vaccination in HIV-Infected Patients February 14, 2011 | Rajesh T. Gandhi, MD An accelerated vaccination schedule improves compliance but sacrifices efficacy in those with CD4 counts <500 cells/mm3. Reviewing: de Vries-Sluijs TEMS et al. J Infect Dis 2011 Jan 25; SUMMARY AND COMMENT Pulmonary Disease in HIV February 14, 2011 | Paul E. Sax, MD Both infectious and noninfectious pulmonary diseases were more common among HIV-positive patients than among HIV-negative controls. Reviewing: Crothers K et al. Am J Respir Crit Care Med 2011 Feb 1; 183:388 SUMMARY AND COMMENT Starting and Switching Antiretroviral Therapy in Children February 14, 2011 | Holly Rawizza, MD First-line PI- and NNRTI-based therapies offer equivalent virologic efficacy in children without prior exposure to NNRTIs. However, when failure occurs, an immediate switch is necessary for those on NNRTIs. Reviewing: The PENPACT-1. (PENTA 9/PACTG 390) Study Team. Lancet Infect Dis 2011 Feb 1; SUMMARY AND COMMENT HIV and Stroke February 9, 2011 | Rajesh T. Gandhi, MD The proportion of hospitalized stroke patients who are HIV-infected is increasing; multiple reasons are likely. Reviewing: Ovbiagele B and Nath A. Neurology 2011 Feb 1; 76:444 Free Full-Text Article Clinical Practice Guideline Watch Interim CDC Guidance on Pre-Exposure Prophylaxis for HIV Prevention in MSM In the wake of the iPrEx study, the CDC offers some general guiding principles for the implementation of pre-exposure prophylaxis. The iPrEx study recently demonstrated proof-of-principle for the efficacy of oral chemoprophylaxis in preventing HIV infection among men who have sex with men (MSM). Daily tenofovir/FTC (Truvada) was associated with a 44% reduction in the risk for HIV acquisition, relative to placebo; efficacy was strongly associated with medication adherence (JW AIDS Clin Care Nov 23 2010). These results are tremendously exciting, but many questions remain about the appropriate use of pre-exposure prophylaxis (PrEP) in real-world clinical settings. On January 28, 2011, the CDC offered some interim guidance. The key points are as follows: PrEP should be considered for use only in MSM who are at ongoing high risk for HIV acquisition. PrEP candidates should undergo conventional HIV antibody testing to ensure that they are HIV-negative. Those with signs or symptoms of acute HIV infection should undergo viral-load testing or nucleic acid amplification testing (NAAT). All candidates should be screened for other sexually transmitted infections (STIs) and for hepatitis B. Tenofovir/FTC, dosed at 1 tablet daily, is the only currently recommended PrEP regimen. It should not be used in people with creatinine clearance <60 mL/minute. PrEP should be prescribed for only 3 months at a time, to ensure appropriate follow-up. Every 2 to 3 months, PrEP recipients should receive HIV antibody testing, counseling regarding risk reduction and medication adherence, and assessment for possible signs and symptoms of STIs. STI testing should be conducted every 6 months. Serum creatinine levels should be assessed 3 months after PrEP initiation and then yearly. HIV antibody testing should be performed at discontinuation of PrEP. Comment: These guidelines provide basic recommendations for clinicians who are interested in implementing PrEP based on the data that are currently available. The recommendation for follow-up every 2 to 3 months is clearly a concession to the reality that monthly follow-up (as was done in iPrEx) is unlikely to be feasible or practical outside the research setting. Many prevention experts will also take issue with the instruction to provide baseline viral-load testing and NAAT only to candidates who are clinically symptomatic; in the iPrEx study, investigators inadvertently enrolled 10 individuals with acute HIV infection, presumably because they were asymptomatic. Given the resistance consequences of missing such infection, one could argue that if an individual is at sufficient risk to warrant PrEP intervention, he should be screened at baseline with both HIV antibody testing and viral-load testing or NAAT. Alternatively, the fourth-generation HIV test that involves both antigen and antibody detection could be employed as a compromise between sensitivity and cost for detection of acute infection. More formal PrEP guidelines from the U.S. Department of Health and Human Services and the FDA are eagerly anticipated and are likely to include guidance on the type of provider that should be prescribing PrEP, application to other populations, and longer-term safety follow-up. — Raphael J. Landovitz, MD, MSc 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 February 14, 2011 Citation(s): Centers for Disease Control and Prevention (CDC). Interim guidance: Preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. MMWR Morb Mortal Wkly Rep 2011 Jan 28; 60:65. (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6003a1.htm) Medline abstract (Free)

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