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 - 21/10/14

Doi : 10.1016/S1473-3099(14)70937-5

Jared M Baeten, ProfMD ^a,^b,^c,^⁎ , Deborah Donnell, PhD ^a,^f, Nelly R Mugo, MBChB ^a,^g, Patrick Ndase, MBChB ^a, Katherine K Thomas, MS ^a, James D Campbell, MD ⁱ, Jonathan Wangisi, MBChB ^j, Jordan W Tappero, MD ^k, Elizabeth A Bukusi, MBChB ^a,^h,^l,^m, Craig R Cohen, ProfMD ^m, Elly Katabira, ProfMB ⁿ, Allan Ronald, ProfMD ^n,^o, Elioda Tumwesigye, MBChB ^p, Edwin Were, MBChB ^q, Kenneth H Fife, ProfMD ^r, James Kiarie, MBChB ^a,^l, Carey Farquhar, ProfMD ^a,^b,^c, Grace John-Stewart, ProfMD ^a,^b,^c,^e, Lara Kidoguchi, MPH ^a, Robert W Coombs, ProfMD ^b,^d, Craig Hendrix, ProfMD ^s, Mark A Marzinke, PhD ^s, Lisa Frenkel, ProfMD ^d,^e,^t, Jessica E Haberer, MD ^u,^v, David Bangsberg, ProfMD ^u,^v, Connie Celum, ProfMD ^a,^b,^c

for the Partners PrEP Study Team

^a Department of Global Health, University of Washington, Seattle, WA, USA

^b Department of Medicine, University of Washington, Seattle, WA, USA

^c Department of Epidemiology, University of Washington, Seattle, WA, USA

^d Department of Laboratory Medicine, University of Washington, Seattle, WA, USA

^e Department of Pediatrics, University of Washington, Seattle, WA, USA

^f Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

^g Centres for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya

^h Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya

ⁱ Centers for Disease Control and Prevention, Entebbe, Uganda

^j AIDS Support Organization, Kampala, Uganda

^k Centers for Disease Control and Prevention, Atlanta, GA, USA

^l Department of Obstetrics and Gynecology, University of Nairobi and Kenyatta National Hospital, Nairobi, Kenya

^m Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA

ⁿ Infectious Disease Institute, Makerere University, Kampala, Uganda

^o Department of Medicine, University of Manitoba, Winnipeg, Canada

^p Kabwohe Clinical Research Center, Kabwohe, Uganda

^q Department of Reproductive Health, Moi University, Eldoret, Kenya

^r Department of Medicine, Indiana University, Indianapolis, IN, USA

^s Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

^t Seattle Children’s Hospital Research Institute, Seattle, WA, USA

^u Massachusetts General Hospital, Boston, MA, USA

^v Harvard Medical School, Boston, MA, USA

^* Correspondence to: Prof Jared M Baeten, International Clinical Research Center, Department of Global Health, University of Washington, Box 359927, 325 Ninth Avenue, Seattle, WA 98104, USA

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.

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Plan

Introduction

Methods

Study design and participants

Randomisation and masking

Laboratory testing

Outcomes

Statistical analysis

Role of the funding source

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Vol 14 - N° 11

P. 1055-1064 - novembre 2014 Retour au numéro

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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 - 21/10/14

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