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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.
Lancet Infect Dis. 2014 Nov; 14(11):1055-1064.LI

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.

Authors+Show Affiliations

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: jbaeten@uw.edu.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.Department of Global Health, University of Washington, Seattle, WA, USA; Centres for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.Department of Global Health, University of Washington, Seattle, WA, USA.Department of Global Health, University of Washington, Seattle, WA, USA.Centers for Disease Control and Prevention, Entebbe, Uganda.AIDS Support Organization, Kampala, Uganda.Centers for Disease Control and Prevention, Atlanta, GA, USA.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.Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA.Infectious Disease Institute, Makerere University, Kampala, Uganda.Infectious Disease Institute, Makerere University, Kampala, Uganda; Department of Medicine, University of Manitoba, Winnipeg, Canada.Kabwohe Clinical Research Center, Kabwohe, Uganda.Department of Reproductive Health, Moi University, Eldoret, Kenya.Department of Medicine, Indiana University, Indianapolis, IN, USA.Department of Global Health, University of Washington, Seattle, WA, USA; Department of Obstetrics and Gynecology, University of Nairobi and Kenyatta National Hospital, Nairobi, Kenya.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 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.Department of Global Health, University of Washington, Seattle, WA, USA.Department of Medicine, University of Washington, Seattle, WA, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.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.Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.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.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

25300863

Citation

Baeten, Jared M., et al. "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." The Lancet. Infectious Diseases, vol. 14, no. 11, 2014, pp. 1055-1064.
Baeten JM, Donnell D, Mugo NR, et al. 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;14(11):1055-1064.
Baeten, J. M., Donnell, D., Mugo, N. R., Ndase, P., Thomas, K. K., Campbell, J. D., Wangisi, J., Tappero, J. W., Bukusi, E. A., Cohen, C. R., Katabira, E., Ronald, A., Tumwesigye, E., Were, E., Fife, K. H., Kiarie, J., Farquhar, C., John-Stewart, G., Kidoguchi, L., ... Celum, C. (2014). 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. The Lancet. Infectious Diseases, 14(11), 1055-1064. https://doi.org/10.1016/S1473-3099(14)70937-5
Baeten JM, et al. 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;14(11):1055-1064. PubMed PMID: 25300863.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Baeten,Jared M, AU - Donnell,Deborah, AU - Mugo,Nelly R, AU - Ndase,Patrick, AU - Thomas,Katherine K, AU - Campbell,James D, AU - Wangisi,Jonathan, AU - Tappero,Jordan W, AU - Bukusi,Elizabeth A, AU - Cohen,Craig R, AU - Katabira,Elly, AU - Ronald,Allan, AU - Tumwesigye,Elioda, AU - Were,Edwin, AU - Fife,Kenneth H, AU - Kiarie,James, AU - Farquhar,Carey, AU - John-Stewart,Grace, AU - Kidoguchi,Lara, AU - Coombs,Robert W, AU - Hendrix,Craig, AU - Marzinke,Mark A, AU - Frenkel,Lisa, AU - Haberer,Jessica E, AU - Bangsberg,David, AU - Celum,Connie, AU - ,, Y1 - 2014/10/07/ PY - 2014/10/11/entrez PY - 2014/10/11/pubmed PY - 2015/2/25/medline SP - 1055 EP - 1064 JF - The Lancet. Infectious diseases JO - Lancet Infect Dis VL - 14 IS - 11 N2 - 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. SN - 1474-4457 UR - https://www.unboundmedicine.com/medline/citation/25300863/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1473-3099(14)70937-5 DB - PRIME DP - Unbound Medicine ER -