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Whether intramuscular depot medroxyprogesterone acetate (DMPA-IM) and norethisterone enanthate (NET-EN) have a differential impact on the incidence of sexually transmitted infection (STI) remains unclear. In the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, HIV-1 acquisition was higher for DMPA-IM users vs. NET-EN users. We compared DMPA-IM and NET-EN users with regard to chlamydia, gonorrhea, trichomoniasis, syphilis, and herpes simplex virus type 2 (HSV-2) infection.   Materials and Methods:  Prospective data were analyzed from VOICE, a randomized trial of HIV-1 chemoprophylaxis. Participants were evaluated annually and as indicated for chlamydia, gonorrhea, trichomoniasis, and syphilis. Stored specimens were tested for HSV-2. Proportional hazards models compared the risk of STI between DMPA-IM and NET-EN users.   Results:  Among 2,911 injectable contraception users in South Africa, 1,800 (61.8%) used DMPA-IM and 1,111 used NET-EN (38.2%). DMPA-IM and NET-EN users did not differ in baseline chlamydia: 15.1 vs. 14.3%,  p  = 0.54; gonorrhea: 3.4 vs. 3.7%,  p  = 0.70; trichomoniasis: 5.7 vs.5.0%,  p  = 0.40; or syphilis: 1.5 vs. 0.7%,  p  = 0.08; but differed for baseline HSV-2: (51.3 vs. 38.6%,  p  &amp;lt; 0.001). Four hundred forty-eight incident chlamydia, 103 gonorrhea, 150 trichomonas, 17 syphilis, and 48 HSV-2 infections were detected over 2,742, 2,742, 2,783, 2,945, and 756 person-years (py), respectively (chlamydia 16.3/100 py; gonorrhea 3.8/100 py; trichomoniasis 5.4/100 py; syphilis 0.6/100 py; HSV-2 6.4/100 py). Comparing DMPA-IM with NET-EN users, no difference was noted in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV-2 infections, including when adjusted for confounders [chlamydia (aHR 1.03, 95% CI 0.85–1.25), gonorrhea (aHR 0.88, 95% CI 0.60–1.31), trichomoniasis (aHR 1.07, 95% CI 0.74–1.54), syphilis (aHR 0.41, 95% CI 0.15–1.10), and HSV-2 (aHR 0.83, 95% CI 0.45–1.54,  p  = 0.56)].   Discussion:  Among South African participants enrolled in VOICE, DMPA-IM and NET-EN users differed in prevalence of HSV-2 at baseline but did not differ in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV-2 infection. Differential HIV-1 acquisition, previously demonstrated in this cohort, does not appear to be explained by differential STI acquisition. However, the high incidence of multiple STIs reinforces the need to accelerate access to comprehensive sexual and reproductive health services.

Prevalence and Incidence of Sexually Transmitted Infection in Injectable Progestin Contraception Users in South Africa