New England Journal of Medicine NOVEMBER 23, 2010

Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men

Robert M. Grant, Javier R. Lama, Peter L. Anderson, et al. for the iPrEx Study Team

Bottom Line

In this randomized, double-blind, placebo-controlled trial, daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) reduced the risk of HIV acquisition by 44% among high-risk men who have sex with men (MSM) and transgender women.

Key Findings

1. Overall, participants randomized to the FTC/TDF arm had a 44% lower risk of acquiring HIV compared to the placebo arm (95% CI, 15 to 63; P=0.005), with 36 incident infections in the intervention arm versus 64 in the placebo group.

2. Among participants with detectable plasma or intracellular study drug levels, the reduction in HIV acquisition risk was 92% (95% CI, 40 to 99; P<0.001) compared to those without detectable drug levels, highlighting the critical dependence of efficacy on adherence.

3. Serious adverse events occurred at similar rates between the two arms (P=0.57), though nausea (P=0.04) and unintentional weight loss (P=0.04) were significantly more frequent in the FTC/TDF group.

4. The study demonstrated that pre-exposure prophylaxis (PrEP) is a viable biomedical intervention that works in conjunction with a comprehensive package of HIV prevention services.

Study Design

Design

RCT

Double-Blind

Sample

2,499

Patients

Duration

21 mo

Median

Setting

Multicenter, 6 countries

Population HIV-uninfected men who have sex with men (MSM) and transgender women at high risk for HIV infection

Intervention Once-daily oral emtricitabine (FTC) 200mg and tenofovir disoproxil fumarate (TDF) 300mg

Comparator Once-daily oral placebo

Outcome Incidence of HIV-1 infection

Study Limitations

• The study relied on self-reported adherence and measurement of drug levels in a subset of participants, which may not fully capture the nuance of dosing frequency and long-term consistency.

• Effectiveness was found to be lower in some subgroups, particularly transgender women, largely linked to lower adherence levels, complicating the generalizability across all demographics.

• The study was performed in a clinical trial setting with intensive counseling and monitoring, which may not perfectly reflect real-world implementation where support services might be less frequent.

• The trial was stopped early because of the significant demonstration of efficacy, which may limit the collection of long-term data on potential late-occurring safety or resistance issues.

Clinical Significance

This landmark study established the clinical validity of once-daily oral FTC/TDF as a highly effective pre-exposure prophylaxis (PrEP) strategy to prevent HIV infection in high-risk MSM and transgender women, providing a foundation for global HIV prevention guidelines and significantly changing the paradigm of HIV care.

Historical Context

The iPrEx trial was the first successful human study of an HIV prevention strategy known as pre-exposure prophylaxis (PrEP). It addressed an urgent need to supplement traditional behavioral interventions with biomedical tools, directly leading to the subsequent FDA approval of Truvada for use as PrEP in 2012.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action of the two antiretroviral agents used in the iPrEx trial, and why were they chosen as a dual-drug combination for preexposure prophylaxis?

Key Response

Emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) are nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), respectively. They inhibit HIV-1 replication by causing chain termination during the conversion of viral RNA into DNA. They were chosen for PrEP because of their long intracellular half-lives, high potency, and a high genetic barrier to resistance compared to other single-agent options.

Resident

The iPrEx trial reported an overall efficacy of 44% in the intention-to-treat (ITT) analysis. However, efficacy was significantly higher in certain subgroups. What was the primary determinant of this efficacy gap, and how should it influence your clinical follow-up for a patient starting PrEP?

Key Response

Adherence was the primary driver of efficacy. In a case-control sub-study of the active arm, those with detectable plasma drug levels had a 92% reduction in HIV risk. Clinically, this means a resident must emphasize that PrEP is only effective if taken consistently and must implement regular adherence counseling and monitoring (e.g., every 3 months) alongside HIV and STI screening.

Fellow

In the iPrEx study, two participants in the FTC/TDF group who were found to have been acutely infected with HIV at the time of enrollment developed the M184V mutation. Discuss the clinical implications of this finding regarding 'window period' infections and PrEP initiation.

Key Response

This finding highlights the risk of selecting for drug-resistant mutations when NRTIs are used as monotherapy or dual-therapy in the setting of undiagnosed acute HIV infection. It necessitates the use of high-sensitivity HIV testing (such as 4th generation antigen/antibody assays or viral load testing) prior to PrEP initiation to ensure the patient is truly HIV-negative, particularly if they report recent high-risk exposure.

Attending

Critics of the iPrEx trial were concerned about 'risk compensation'—the idea that patients might increase high-risk sexual behaviors because they felt protected by the medication. How did the study's behavioral data address this, and how do you teach this concept to trainees?

Key Response

The study actually observed a decrease in self-reported high-risk behaviors and an increase in condom use in both the placebo and active arms over time. This suggests that the intensive prevention package (counseling, testing, and STI treatment) provided during the trial mitigated risk compensation. This is a vital teaching point: PrEP should be framed as a component of a comprehensive sexual health package, not a standalone 'magic bullet'.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The iPrEx trial demonstrated a significant discrepancy between self-reported adherence (over 90%) and objective biomarker data (approximately 50% drug detection). What are the implications of this 'social desirability bias' for the design and statistical power of future HIV prevention trials?

Key Response

This discrepancy indicates that self-reported data is an unreliable surrogate for drug exposure, potentially leading to underpowered trials if the effect size is calculated based on reported rather than actual use. Future trials must incorporate objective adherence measures, such as intracellular tenofovir-diphosphate levels in dried blood spots or hair samples, to accurately model the dose-response relationship and ensure robust ITT vs. per-protocol interpretations.

Journal Editor

As a reviewer, how would you evaluate the generalizability of the iPrEx findings given the heterogeneous inclusion of both men who have sex with men (MSM) and transgender women (TGW)? What specific data would you request regarding the TGW subgroup?

Key Response

A critical reviewer would flag that while the study was inclusive, the TGW subgroup was relatively small and potentially underpowered for a standalone efficacy analysis. Furthermore, biological factors such as drug-hormone interactions and different tissue distribution (rectal vs. vaginal) could affect outcomes. An editor would push for a stratified analysis by gender identity to ensure the 44% overall efficacy isn't masking significantly lower protection in a specific high-risk sub-population.

Guideline Committee

Based on the iPrEx trial and subsequent evidence, how does the level of recommendation for TDF/FTC as PrEP compare to newer formulations like TAF/FTC for MSM populations in current clinical guidelines?

Key Response

iPrEx provided the foundational Level 1A evidence for TDF/FTC. Current CDC and WHO guidelines strongly recommend TDF/FTC for MSM. While the DISCOVER trial later showed TAF/FTC is non-inferior to TDF/FTC for MSM and TGW, TDF/FTC remains a primary recommendation due to its long-term safety data and availability as a lower-cost generic. However, TAF/FTC is preferred for those with pre-existing renal disease or osteoporosis, reflecting the evolution of guidelines from the iPrEx baseline.

Clinical Landscape

Noteworthy Related Trials

2011

TDF2 Study

n = 1,219 · NEJM

Tested

Daily oral TDF/FTC

Population

Heterosexual men and women in Botswana

Comparator

Placebo

Endpoint

HIV-1 acquisition

Key result: Daily TDF/FTC demonstrated a 62.2% reduction in HIV acquisition among heterosexually active men and women.

2012

Partners PrEP Study

n = 4,758 · NEJM

Tested

Daily oral TDF or TDF/FTC

Population

HIV-uninfected adults in HIV-discordant heterosexual couples

Comparator

Placebo

Endpoint

HIV-1 acquisition

Key result: Daily oral TDF and TDF/FTC reduced the risk of HIV acquisition by 67% and 75% respectively compared to placebo.

2015

PROUD Study

n = 544 · Lancet

Tested

Daily oral TDF/FTC

Population

Men who have sex with men (MSM) at high risk for HIV

Comparator

Deferred PrEP (wait 12 months)

Endpoint

HIV-1 infection

Key result: Daily TDF/FTC resulted in an 86% reduction in HIV incidence among high-risk MSM in a real-world clinic setting.

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