BACKGROUND: Several observational studies have reported that HIV-1 acquisition seems to be higher in women who use depot medroxyprogesterone acetate (DMPA) than in those who do not use hormonal contraception. We aimed to assess whether two injectable progestin-only contraceptives, DMPA and norethisterone enanthate (NET-EN), confer different risks of HIV-1 acquisition. METHODS: We included data from South African women who used injectable contraception while participating in the VOICE study, a multisite, randomised, placebo-controlled trial that investigated the safety and efficacy of three formulations of tenofovir for prevention of HIV-1 infection in women between Sept 9, 2009, and Aug 13, 2012. Women were assessed monthly for contraceptive use and incident infection. We estimated the difference in incident HIV-1 infection between DMPA and NET-EN users by Cox proportional hazards regression analyses in this prospective cohort. The VOICE trial is registered with ClinicalTrials.gov, NCT00705679. FINDINGS: 3141 South African women using injectable contraception were included in the present analysis: 1788 (56.9%) solely used DMPA, 1097 (34.9%) solely used NET-EN, and 256 (8.2%) used both injectable types at different times during follow-up. During 2733.7 person-years of follow-up, 207 incident HIV-1 infections occurred (incidence 7.57 per 100 person-years, 95% CI 6.61-8.68). Risk of HIV-1 acquisition was higher among DMPA users (incidence 8.62 per 100 person-years, 95% CI 7.35-10.11) than among NET-EN users (5.67 per 100 person-years, 4.35-7.38; hazard ratio 1.53, 95% CI 1.12-2.08; p=0.007). This association persisted when adjusted for potential confounding variables (adjusted hazard ratio [aHR] 1.41, 95% CI 1.06-1.89; p=0.02). Among women seropositive for herpes simplex virus type 2 (HSV-2) at enrolment, the aHR was 2.02 (95% CI 1.26-3.24) compared with 1.09 (0.78-1.52) for HSV-2-seronegative women (pinteraction=0.07). INTERPRETATION: Although moderate associations in observational analyses should be interpreted with caution, these findings suggest that NET-EN might be an alternative injectable drug with a lower HIV risk than DMPA in high HIV-1 incidence settings where NET-EN is available. FUNDING: National Institutes of Health, Mary Meyer Scholars Fund, and the Ruth Freeman Memorial Fund
