Partners PrEP Study: Oral TDF or TDF - FTC Significantly Reduces the Risk of HIV-1 Acquisition among Heterosexual Men and Women in Serodiscordant Relationships

Introduction

Pre-exposure antiretroviral prophylaxis is a potential HIV-1–prevention strategy for those not yet infected with HIV-1.

Aim

To study the effect of daily oral tenofovir disoproxil fumarate (TDF) or tenofovir disoproxil fumarate–emtricitabine(TDF-FTC) for pre-exposure prophylaxis (PrEP) against HIV-1 acquisition among East African heterosexual men and women in HIV-1–serodiscordant relationships.

Patient Profile

• For the HIV-1–seronegative partners
  • Age greater than or equal to 18 and less than or equal to 65 years
  • Satisfactory renal function
  • No infection with hepatitis B virus
  • Satisfactory hepatic function
  • Sexually active and
  • Not pregnant or breast-feeding
  • Seronegative participants for HIV-1 had monthly visits.
• For HIV-1–seropositive partners
  • Age more than or equal to 18 years
  • Sexually active
  • CD4 cell as per the then guidelines and were not receiving antiretroviral therapy (ART) as per the national guidelines
  • Partners seropositive for HIV-1 were followed quarterly
  • CD4 counts were acquired every 6 months
  • Once eligible for the initiation of ART according to national guidelines they were actively counseled to initiate treatment and referred to local clinics.
• Additionally, all couples received a comprehensive package of HIV-1 prevention services

Methods

• Multisite
• Phase 3
• Randomized, double-blind, three-group, placebo-controlled trial
• Enrolled 4,758 couples and followed 4,747 couples from July 2008 through November 2010 from nine sites in Kenya and Uganda
• Partners seronegative for HIV-1 were randomized in a 1:1:1 ratio as follows:
  • Once-daily TDF 300 mg, (n=1584)
  • TDF–FTC(300-200mg), (n=1579)
  • Placebo (n=1584)

Study End Points

• The primary end point was seropositivity in partners previously seronegative for HIV-1

Results

Baseline characteristics were similar across the three study groups.

• Among participants seropositive for HIV-1
  • The median CD4 count was 495 cells/ mm³
  • 80% had a CD4 count of 350 cells or more per mm³
  • The median plasma HIV-1 RNA level was 3.9 log10 copies/mL
• Of the 82 HIV-1 infections that occurred after randomization
  • 17 in TDF arm
  • 13 in TDF/FTC arm
  • 52 in placebo arm
• In the TDF group, HIV-1 acquisition risk reduced by 67%  (P < .0001) and 75% in the  TDF/FTC group (P < .0001) which is illustrated in the graph below.

• Both, the single-drug and 2-drug regimens were associated with significant reduction in HIV-1 acquisition vs placebo in both men and women
• Efficacy with TDF was 71% in women (P = .002) and 63% in men (P = .01)
• Efficacy with TDF/FTC was 66% in women (P = .005) and 84% in men (P<.001)
• No HIV resistance developed after randomization
• Retention and pill-count adherence were high
  • TDF was detected in 82% of samples from randomly selected participants
  • Detectable TDF levels were associated with a reduction in the relative risk of HIV-1 infection of more than 85%
• No significant differences in key safety parameters were observed between PrEP regimens and placebo
• At enrollment, 27% HIV-1uninfected partner reported having sex without a condom with their HIV-1 infected partner during the prior month which decreased during the follow-up period to 13% at 12 months and 9% at 24 months, respectively and was similar across the study groups
• There were no significant differences in the frequency of deaths, serious adverse events, or serum creatinine or phosphorus abnormalities across the study groups
  • Neutropenia was seen more commonly in the TDF–FTC group (17% of participants with a grade 1 or 2 event and 1% with a grade 3 or 4 event) than in the TDF group (15% of participants with a grade 1 or 2 event and 1% with a grade 3 or 4 event) or the placebo group (12% of participants with a grade 1 or 2 event and 1% with a grade 3 or 4 event)
  • Active study medications were associated with modestly increased reports of gastrointestinal side effects and fatigue as compared with placebo, primarily during the first month of administration

Conclusion

• In this study of heterosexual serodiscordant couples, once-daily oral TDF and TDF–FTC was associated with risk reductions against HIV-1 infection when provided in combination with other HIV-1 prevention services.
• Both TDF and TDF–FTC showed significantly, and a comparable degree of, HIV-1 protection for both women and men.

N Engl J Med; 2012; 367:399-410