Hormonal contraception for women at risk of HIV infection.

rationaleThere is controversy about a possible link between hormonal contraception, specifically injectable depot medroxyprogesterone acetate (DMPA) and HIV acquisition. Following the results of a large randomised controlled trial, there is a need to update the previous version of this Cochrane review.

objectivesTo determine the effects of hormonal contraception on HIV acquisition in women who live in settings with high HIV prevalence. SEARCH

methodsWe searched CENTRAL, MEDLINE, Embase, SCOPUS, Global Index Medicus and trial registries (together with reference checking, citation searching and contacting study authors), to identify studies up to 13 September 2023. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) comparing hormonal contraception with non-hormonal or other methods of contraception for women at high risk of HIV. OUTCOMES: Outcomes of interest were HIV acquisition, pregnancy, discontinuation of method, amenorrhoea, adverse events and condomless sexual activity. RISK OF BIAS: We used the Cochrane risk of bias 2 tool to assess bias in the RCTs. SYNTHESIS

methodsWe synthesised results for each outcome using random-effects meta-analysis where possible and meaningful. We assessed the certainty of evidence with GRADE. INCLUDED STUDIES: We included four trials with 9726 participants, conducted across four countries. SYNTHESIS OF

resultsDMPA injection compared to copper intrauterine device (IUD) DMPA compared to copper IUD likely results in little to no difference in HIV acquisition (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.82 to 1.26; 2 RCTs, n = 6417; moderate-certainty evidence), resulting in one more woman per 1000 acquiring HIV (from 9 fewer to 13 more). DMPA compared to copper IUD results in a slight reduction in pregnancy (RR 0.53, 95% CI 0.39 to 0.71; 1 RCT, n = 5216; high-certainty evidence), resulting in 21 fewer women per 1000 becoming pregnant (from 27 to 13 fewer). DMPA compared to copper IUD results in a reduction in discontinuation of method (RR 0.50, 95% CI 0.40 to 0.62; 1 RCT, n = 5216; high-certainty evidence) and in adverse events (RR 0.53, 95% CI 0.38 to 0.75; 1 RCT, n = 5216; high-certainty evidence). In the DMPA group 'any unprotected sex' was reported at 66.4% of follow-up visits, compared to 70.9% in the copper IUD group. Levonorgestrel (LNG) implant compared to copper IUD LNG compared to copper IUD likely results in little to no difference in HIV acquisition (RR 0.84, 95% CI 0.66 to 1.06; 1 RCT, n = 5159; moderate-certainty evidence), resulting in nine fewer women per 1000 acquiring HIV (from 18 fewer to 3 more). LNG compared to copper IUD likely results in a slight reduction in pregnancy (RR 0.67, 95% CI 0.51 to 0.89; 1 RCT, n = 5220; moderate-certainty evidence), resulting in 15 fewer women per 1000 becoming pregnant (from 22 to 5 fewer). LNG compared to copper IUD likely results in little to no difference in adverse events (RR 0.85, 95% CI 0.63 to 1.14; 1 RCT, n = 5220; moderate-certainty evidence) and discontinuation of method (RR 1.03, 95% CI 0.87 to 1.24; P = 0.71; 1 RCT, n = 5220; moderate-certainty evidence). DMPA injection compared to LNG implant DMPA compared to LNG probably slightly increases HIV acquisition (RR 1.25, 95% CI 0.98 to 1.58; 1 RCT, n = 5144; moderate-certainty evidence), resulting in 11 more women per 1000 acquiring HIV (from 1 fewer to 26 more). DMPA compared to LNG probably results in little to no difference in pregnancy (RR 0.78, 95% CI 0.56 to 1.09; 1 RCT, n = 5222; moderate-certainty evidence), resulting in seven fewer women per 1000 becoming pregnant (from 13 fewer to 3 more). DMPA compared to LNG reduces adverse events (RR 0.63, 95% CI 0.44 to 0.90; 1 RCT, n = 5222; high-certainty evidence), and discontinuation of methods (RR 0.48, 95% CI 0.39 to 0.60; P < 0.00001; 1 RCT, n = 5222; high-certainty evidence). No included studies in the above comparisons measured amenorrhoea. In the DMPA group 'any unprotected sex' was reported at 66.4% of follow-up visits, compared to 69.4% in the LNG implant group. DMPA injection compared to NET-EN injection The evidence is very uncertain about the effect of DMPA compared to NET-EN on HIV acquisition (RR 0.67, 95% CI 0.19 to 2.35; 1 RCT, n = 450; very low-certainty evidence) resulting in nine fewer women per 1000 acquiring HIV (from 22 fewer to 36 more); and pregnancy (RR 2.03, 95% CI 0.19 to 22.19; 1 RCT, n = 449; very low-certainty evidence), resulting in five more women per 1000 becoming pregnant (from 4 fewer to 94 more). DMPA compared to NET-EN probably increases amenorrhoea (RR 1.12, 95% CI 0.89 to 1.41; P = 0.33; 1 RCT, n = 449; moderate-certainty evidence). Discontinuation of methods was not measured. AUTHORS'

conclusionsHIV incidence was high in all groups, regardless of contraceptive used, as would be expected in a setting with high HIV prevalence. All contraceptives used in the included studies are widely used and known to prevent pregnancy. When comparing different contraceptive methods, DMPA injections compared to copper IUD may result in little to no difference in HIV acquisition and result in a slight reduction in pregnancy. LNG implants compared to copper IUDs likely result in little to no difference in HIV acquisition and in a slight reduction in pregnancy. DMPA injections compared to LNG implants likely result in a slight increase in HIV acquisition and likely result in little to no difference in pregnancy. The evidence is very uncertain about the effect of DMPA compared to NET-EN on HIV acquisition and pregnancy. HIV acquisition and pregnancy are important outcomes that have a long-lasting impact. Access to safe, effective contraception is important for women wanting to prevent unplanned pregnancies, as pregnancies have long-lasting physical, social and economic ramifications. Evidence from included studies shows that across groups, many participants report engaging in condomless sexual activity, even when living in high HIV prevalence settings. HIV prevention methods such as pre-exposure prophylaxis and HIV education remain crucial in the fight against HIV.

fundingThis Cochrane review had no dedicated funding. REGISTRATION: Protocol available via (DOI: 10.1002/14651858.CD015701).