Articles
Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial

https://doi.org/10.1016/S1473-3099(14)70937-5Get rights and content

Summary

Background

Antiretroviral pre-exposure prophylaxis (PrEP), with daily oral tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with emtricitabine, has been shown to be efficacious for HIV-1 prevention. Although the use of more than one antiretroviral agent is essential for effective HIV-1 treatment, more than one agent might not be required for effective prophylaxis. We assessed the efficacy of single-agent tenofovir disoproxil fumarate relative to combination emtricitabine plus tenofovir disoproxil fumarate as PrEP.

Methods

We did a randomised, double-blind, placebo-controlled three-group phase 3 trial of daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate PrEP in HIV-1 uninfected individuals in heterosexual HIV-1 serodiscordant couples from Kenya and Uganda. After an interim review, the trial's placebo group was discontinued and thereafter the active groups were continued, and participants initially randomly assigned to placebo were offered rerandomisation in a 1:1 ratio to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP. The primary endpoints were HIV-1 seroconversion and safety. This trial is registered with ClinicalTrials.gov, number NCT00557245.

Findings

4410 (99·6%) of 4427 couples received tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate and were followed up for HIV-1 acquisition. Of 52 incident HIV-1 infections, 31 occurred in individuals assigned tenofovir disoproxil fumarate (incidence 0·71 cases per 100 person-years) and 21 were in those assigned emtricitabine plus tenofovir disoproxil fumarate (0·48 cases per 100 person-years); HIV-1 incidence in the placebo group until discontinuation was two cases per 100 person-years. HIV-1 prevention efficacy with emtricitabine plus tenofovir disoproxil fumarate was not significantly different from that of tenofovir disoproxil fumarate alone (hazard ratio [HR] 0·67, 95% CI 0·39–1·17; p=0·16). Detection of tenofovir in plasma samples, compared with no detection and as measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the tenofovir disoproxil fumarate group (HR 0·15, 95% CI 0·06–0·37; p<0·0001) and 93% for the emtricitabine plus tenofovir disoproxil fumarate group (0·07, 0·02–0·23; p<0·0001). No significant differences were noted in the frequency of deaths, serious adverse events, or serum creatinine and phosphorus abnormalities between the two groups.

Interpretation

These results do not rule out the potential for a slight difference in HIV-1 protection with tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate, but show that once-daily oral tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate regimens both provide high protection against HIV-1 acquisition in heterosexual men and women.

Funding

Bill & Melinda Gates Foundation and US National Institutes of Health.

Introduction

Combination antiretroviral treatment is vital for individuals with HIV-1 infection, and antiretroviral medications are essential for the prevention of mother-to-child HIV-1 transmission. According to recent evidence, antiretroviral medications can also prevent HIV-1 transmission between adults, through the reduction of the infectiousness in people who are infected and as oral or topical pre-exposure prophylaxis (PrEP) in individuals who are at high risk of becoming infected with HIV-1.1, 2, 3, 4, 5, 6, 7

The results of four randomised trials3, 4, 5, 7 in diverse geographic and at-risk populations have shown that oral antiretroviral PrEP is efficacious in protecting individuals against HIV-1 infection. The efficacy of oral PrEP with tenofovir disoproxil fumarate in combination with emtricitabine has been assessed in two trials (in heterosexual men and women in Botswana and men who have sex with men from four continents),4, 5 and as single-agent therapy in one trial (in injection drug users in Thailand).7 Results of animal model studies provided early evidence that antiretroviral PrEP might be an efficacious intervention for HIV-1 prevention,8 and in subsequent studies in animals various antiretroviral agents, delivery approaches, and dosing strategies for PrEP were assessed.9, 10, 11 Data from studies of animal models with rectal viral challenge suggested that emtricitabine plus tenofovir disoproxil fumarate might provide greater HIV-1 protection than does tenofovir disoproxil fumarate alone.9 Both tenofovir disoproxil fumarate alone and emtricitabine plus tenofovir disoproxil fumarate were assessed in our trial to provide a direct comparison of these approaches, with the rationale that dual-agent versus single-agent therapy might differ in efficacy, tolerability, antiretroviral resistance in breakthrough HIV-1 seroconverters, and in costs.

In our previous report from our multisite, randomised, double-blind, three-group, placebo-controlled phase 3 trial, we compared daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate as PrEP in African heterosexual men and women who were at high risk of HIV-1 acquisition because they had an HIV-1 infected sexual partner (the Partners PrEP Study).3 An interim review showed that PrEP afforded protection against HIV-1 transmission, as assessed with prespecified efficacy thresholds. The trial's placebo group was discontinued and the results were reported: the efficacy for prevention of HIV-1 transmission with tenofovir disoproxil fumarate was 67% and that with the coformulation was 75%, but the difference between tenofovir disoproxil fumarate alone versus in combination with emtricitabine was not significant (p=0·23).3 The active groups were continued thereafter, and the participants who were initially randomly assigned to placebo were offered rerandomisation to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP to gather additional comparative safety and efficacy data related to single-agent versus dual-agent PrEP. We report the efficacy of single-agent tenofovir disoproxil fumarate in relation to dual-agent emtricitabine plus tenofovir disoproxil fumarate as PrEP for HIV-1.

Section snippets

Study design and participants

Between July 3, 2008, and Nov 30, 2010, heterosexual couples who were HIV-1 serodiscordant (ie, one member was HIV-1 infected and the other was not infected) were enrolled from nine research clinics in Kenya and Uganda, as described previously.3, 12 Eligible couples were sexually active and intending to remain as a couple. HIV-1 seronegative partners had normal renal function, were not infected with hepatitis B virus, and the women were not pregnant or breastfeeding.

An independent data and

Results

At the initial randomisation, 4747 couples were enrolled: 1584 assigned to tenofovir disoproxil fumarate, 1579 to emtricitabine plus tenofovir disoproxil fumarate, and 1584 to placebo. Of the 1584 HIV-1 uninfected individuals initially randomly assigned to placebo, 1502 were alive and had not seroconverted to HIV-1 and of these 84 (6%) were deemed ineligible to receive active PrEP—77 pregnant and breastfeeding women (which were exclusion criteria for provision of PrEP in the study protocol) and

Discussion

The results of this study suggest that once-daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate have comparable HIV-1 protective efficacy and safety. HIV-1 protective efficacy in intention-to-treat analyses compared with placebo in previous studies ranged from 44% to 75%, with no clear differentiation in efficacy estimates for tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate.3, 4, 5, 7 Notably, the protective

References (30)

  • JG Garcia-Lerma et al.

    Intermittent prophylaxis with oral truvada protects macaques from rectal SHIV infection

    Sci Transl Med

    (2010)
  • A Mujugira et al.

    Characteristics of HIV-1 serodiscordant couples enrolled in a clinical trial of antiretroviral pre-exposure prophylaxis for HIV-1 prevention

    PLoS One

    (2011)
  • Joint United National Programme on HIV/AIDS (UNAIDS), AVAC. Good participatory practice: guidelines for biomedical HIV...
  • Ethical considerations in biomedical HIV prevention trials

    (2007)
  • P Ndase et al.

    Successful discontinuation of the placebo arm and provision of an effective HIV prevention product after a positive interim efficacy result: the partners PrEP study experience

    J Acquir Immune Defic Syndr

    (2014)
  • Cited by (87)

    • Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection

      2020, Cell Reports Medicine
      Citation Excerpt :

      Complete sample size information is listed in Table 1. Tenofovir levels were measured in the serum for the GMS A and GMS B studies as previously described.57 Samples from the treatment arm without detectable tenofovir were removed, as was one post-treatment sample, where drug was unexpectedly detected.

    View all citing articles on Scopus
    View full text