Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis

Abstract

Background: Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.

Methods and findings: Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I(2) < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (p(interaction) = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship.

Conclusions: This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

Fig 1. Flow diagram of studies included in individual participant data meta-analysis of hormonal contraception and HIV acquisition.

Fig 2. Multivariable associations between hormonal contraceptive use and HIV acquisition by study, with non-hormonal-contraceptive group as the reference.

(A) aHRs for COC use versus no HC use—primary model. (B) aHRs for DMPA use versus no HC—primary model. (C) aHRs for NET-EN use versus no HC—primary model. Individual study results from Cox regression modeling. Pooled aHRs from random effects meta-analysis adjusted for age, married/living with partner, number of sex partners, condom use, and region (east Africa, southern Africa, and South Africa). Each horizontal line represents the 95% confidence interval around the HR. Shaded areas represent the comparative weight of each study. No estimate was possible if there were not events in the specified contraceptive group. NA, not applicable.

Fig 3. Multivariable associations directly comparing different hormonal contraceptives and HIV acquisition by study.

(A) aHRs for DMPA versus COC use—primary model. (B) aHRs for NET-EN versus COC use—primary model. (C) aHRs for DMPA versus NET-EN use—primary model. Individual study results from Cox regression modeling. Pooled aHRs from random effects meta-analysis adjusted for age, married/living with partner, number of sex partners, condom use, and region (east Africa, southern Africa, and South Africa). Each horizontal line represents the 95% confidence interval around the HR. Shaded areas represent the comparative weight of each study. No estimate was possible if there were not events in the specified contraceptive group.