Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana

N Engl J Med. 2012 Aug 2;367(5):423-34. doi: 10.1056/NEJMoa1110711. Epub 2012 Jul 11.

Abstract

Background: Preexposure prophylaxis with antiretroviral agents has been shown to reduce the transmission of human immunodeficiency virus (HIV) among men who have sex with men; however, the efficacy among heterosexuals is uncertain.

Methods: We randomly assigned HIV-seronegative men and women to receive either tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or matching placebo once daily. Monthly study visits were scheduled, and participants received a comprehensive package of prevention services, including HIV testing, counseling on adherence to medication, management of sexually transmitted infections, monitoring for adverse events, and individualized counseling on risk reduction; bone mineral density testing was performed semiannually in a subgroup of participants.

Results: A total of 1219 men and women underwent randomization (45.7% women) and were followed for 1563 person-years (median, 1.1 years; maximum, 3.7 years). Because of low retention and logistic limitations, we concluded the study early and followed enrolled participants through an orderly study closure rather than expanding enrollment. The TDF-FTC group had higher rates of nausea (18.5% vs. 7.1%, P<0.001), vomiting (11.3% vs. 7.1%, P=0.008), and dizziness (15.1% vs. 11.0%, P=0.03) than the placebo group, but the rates of serious adverse events were similar (P=0.90). Participants who received TDF-FTC, as compared with those who received placebo, had a significant decline in bone mineral density. K65R, M184V, and A62V resistance mutations developed in 1 participant in the TDF-FTC group who had had an unrecognized acute HIV infection at enrollment. In a modified intention-to-treat analysis that included the 33 participants who became infected during the study (9 in the TDF-FTC group and 24 in the placebo group; 1.2 and 3.1 infections per 100 person-years, respectively), the efficacy of TDF-FTC was 62.2% (95% confidence interval, 21.5 to 83.4; P=0.03).

Conclusions: Daily TDF-FTC prophylaxis prevented HIV infection in sexually active heterosexual adults. The long-term safety of daily TDF-FTC prophylaxis, including the effect on bone mineral density, remains unknown. (Funded by the Centers for Disease Control and Prevention and the National Institutes of Health; TDF2 ClinicalTrials.gov number, NCT00448669.).

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenine / adverse effects
  • Adenine / analogs & derivatives*
  • Adenine / therapeutic use
  • Adolescent
  • Adult
  • Anti-Retroviral Agents / adverse effects
  • Anti-Retroviral Agents / therapeutic use*
  • Bone Density / drug effects
  • Contraception Behavior / statistics & numerical data
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Drug Resistance, Viral
  • Drug Therapy, Combination
  • Emtricitabine
  • Female
  • HIV Infections / prevention & control*
  • HIV Seropositivity
  • HIV-1* / genetics
  • HIV-1* / isolation & purification
  • HIV-2 / genetics
  • HIV-2 / isolation & purification
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Organophosphonates / adverse effects
  • Organophosphonates / therapeutic use*
  • Proportional Hazards Models
  • RNA, Viral / blood
  • Sexual Behavior / statistics & numerical data
  • Tenofovir
  • Viral Load
  • Young Adult

Substances

  • Anti-Retroviral Agents
  • Organophosphonates
  • RNA, Viral
  • Deoxycytidine
  • Tenofovir
  • Emtricitabine
  • Adenine

Associated data

  • ClinicalTrials.gov/NCT00448669