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

Jared M Baeten; Deborah Donnell; Nelly R Mugo; Patrick Ndase; Katherine K Thomas; James D Campbell; Jonathan Wangisi; Jordan W Tappero; Elizabeth A Bukusi; Craig R Cohen; Elly Katabira; Allan Ronald; Elioda Tumwesigye; Edwin Were; Kenneth H Fife; James Kiarie; Carey Farquhar; Grace John-Stewart; Lara Kidoguchi; Robert W Coombs; Craig Hendrix; Mark A Marzinke; Lisa Frenkel; Jessica E Haberer; David Bangsberg; Connie Celum; Partners PrEP Study Team

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

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

Lancet Infect Dis. 2014 Nov;14(11):1055-1064. doi: 10.1016/S1473-3099(14)70937-5. Epub 2014 Oct 7.

Authors

Jared M Baeten¹, Deborah Donnell², Nelly R Mugo³, Patrick Ndase⁴, Katherine K Thomas⁴, James D Campbell⁵, Jonathan Wangisi⁶, Jordan W Tappero⁷, Elizabeth A Bukusi⁸, Craig R Cohen⁹, Elly Katabira¹⁰, Allan Ronald¹¹, Elioda Tumwesigye¹², Edwin Were¹³, Kenneth H Fife¹⁴, James Kiarie¹⁵, Carey Farquhar¹⁶, Grace John-Stewart¹⁷, Lara Kidoguchi⁴, Robert W Coombs¹⁸, Craig Hendrix¹⁹, Mark A Marzinke¹⁹, Lisa Frenkel²⁰, Jessica E Haberer²¹, David Bangsberg²¹, Connie Celum¹⁶; Partners PrEP Study Team

Affiliations

¹ Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA. Electronic address: [email protected].
² Department of Global Health, University of Washington, Seattle, WA, USA; Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³ Department of Global Health, University of Washington, Seattle, WA, USA; Centres for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
⁴ Department of Global Health, University of Washington, Seattle, WA, USA.
⁵ Centers for Disease Control and Prevention, Entebbe, Uganda.
⁶ AIDS Support Organization, Kampala, Uganda.
⁷ Centers for Disease Control and Prevention, Atlanta, GA, USA.
⁸ Department of Global Health, University of Washington, Seattle, WA, USA; Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya; Department of Obstetrics and Gynecology, University of Nairobi and Kenyatta National Hospital, Nairobi, Kenya; Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA.
⁹ Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA.
¹⁰ Infectious Disease Institute, Makerere University, Kampala, Uganda.
¹¹ Infectious Disease Institute, Makerere University, Kampala, Uganda; Department of Medicine, University of Manitoba, Winnipeg, Canada.
¹² Kabwohe Clinical Research Center, Kabwohe, Uganda.
¹³ Department of Reproductive Health, Moi University, Eldoret, Kenya.
¹⁴ Department of Medicine, Indiana University, Indianapolis, IN, USA.
¹⁵ Department of Global Health, University of Washington, Seattle, WA, USA; Department of Obstetrics and Gynecology, University of Nairobi and Kenyatta National Hospital, Nairobi, Kenya.
¹⁶ Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁷ Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
¹⁸ Department of Medicine, University of Washington, Seattle, WA, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
¹⁹ Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
²⁰ Department of Laboratory Medicine, University of Washington, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA; Seattle Children's Hospital Research Institute, Seattle, WA, USA.
²¹ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

Abstract

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.

Publication types

Clinical Trial, Phase III
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenine / adverse effects
Adenine / analogs & derivatives*
Adenine / therapeutic use
Adult
Anti-HIV Agents / adverse effects
Anti-HIV Agents / therapeutic use*
Deoxycytidine / adverse effects
Deoxycytidine / analogs & derivatives*
Deoxycytidine / therapeutic use
Double-Blind Method
Drug Therapy, Combination / adverse effects
Drug Therapy, Combination / methods
Emtricitabine
Female
HIV Infections / prevention & control*
HIV Infections / virology
HIV-1 / drug effects
Humans
Kenya
Male
Organophosphonates / adverse effects
Organophosphonates / therapeutic use*
Placebos / administration & dosage
Pre-Exposure Prophylaxis / methods*
Tenofovir
Treatment Outcome
Uganda

Substances

Anti-HIV Agents
Organophosphonates
Placebos
Deoxycytidine
Tenofovir
Emtricitabine
Adenine

Associated data

ClinicalTrials.gov/NCT00557245

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding