Further evidence of an association with the injectable contraceptive, depot-medroxyprogesterone acetate with risk of HIV

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

Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM, Van Damme L, Delany-Moretlwe S, Francis SC, Friedland BA, Hayes RJ, Heffron R, Kapiga S, Karim QA, Karpoff S, Kaul R, McClelland RS, McCormack S, McGrath N, Myer L, Rees H, van der Straten A, Watson-Jones D, van de Wijgert JH, Stalter R, Low N. PLoS Med. 2015 Jan 22;12(1):e1001778. doi: 10.1371/journal.pmed.1001778. eCollection 2015.

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 1830 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 (I2 < 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 (pinteraction = 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.

Abstract [1]  Full-text [free] access [2]

Editor’s notes: As seen in the paper published this month by Ralph et al, observational studies have reported that hormonal contraception, in particular injectable progestins depot-medroxyprogesterone acetate (DMPA), may increase risk of HIV infection. This individual patient data meta-analysis adds further to the evidence. A major strength of the study is the large sample size. It provides sufficient power to examine associations between specific contraceptives and HIV risk and to investigate effect modification in pre-specified sub-group analyses. Furthermore, using individual-level data allowed a consistent approach to coding and adjustment for confounding. If the association is real, this has important implications for sexual and reproductive health in areas of sub-Saharan Africa where the incidence of HIV acquisition and unintended pregnancy is high.



Hormonal contraceptive use and women's risk of HIV acquisition: a meta-analysis of observational studies.

Ralph LJ, McCoy SI, Shiu K, Padian NS. Lancet Infect Dis. 2015 Jan 8. pii: S1473-3099(14)71052-7. doi: 10.1016/S1473-3099(14)71052-7. [Epub ahead of print]

Background: The evidence from epidemiological research into whether use of hormonal contraception increases women's risk of HIV acquisition is inconsistent. We did a robust meta-analysis of existing data to provide summary estimates by hormonal contraceptive method which can be used to inform contraceptive guidelines, models, and future studies.

Methods: We updated a recent systematic review to identify and describe studies that met inclusion criteria. To ensure inclusion of more recent research, we searched PubMed for articles published after December, 2011, using the terms "hormonal contraception", "HIV/acquisition", "injectables", "progestin", and "oral contraceptive pills". We assessed statistical heterogeneity for these studies, and, when appropriate, combined point estimates by hormonal contraception formulation using random-effects models. We assessed publication bias and investigated heterogeneity through subgroup and stratified analyses according to study population and design features.

Findings: We identified 26 studies, 12 of which met inclusion criteria. There was evidence of an increase in HIV risk in the ten studies of depot medroxyprogesterone acetate (pooled hazard ratio [HR] 1.40, 95% CI 1.16-1.69). This risk was lower in the eight studies done in women in the general population (pooled HR 1.31, 95% CI 1.10-1.57). There was substantial between-study heterogeneity in secondary analyses of trials (n=7, I2 51.1%, 95% CI 0-79.3). Although individual study estimates suggested an increased risk, substantial heterogeneity between two studies done in women at high risk of HIV infection (I2 54%, 0-88.7) precluded pooling estimates. There was no evidence of an increased HIV risk in ten studies of oral contraceptive pills (pooled HR 1.00, 0.86-1.16) or five studies of norethisterone enanthate (pooled HR 1.10, 0.88-1.37).

Interpretation: Our findings show a moderate increased risk of HIV acquisition for all women using depot medroxyprogesterone acetate, with a smaller increase in risk for women in the general population. Whether the risks of HIV observed in our study would merit complete withdrawal of depot medroxyprogesterone acetate needs to be balanced against the known benefits of a highly effective contraceptive.

Abstract access [3]

Editor’s notes: This meta-analysis has similar findings to the individual patient data (IPD) meta-analysis by Morrison et al, also published this month. The study finds that depot medroxyprogesterone (DMPA) is associated with a moderate increase in HIV risk, and little evidence of a risk associated with combined oral contraceptives or norethisterone enanthate (NET-EN). The policy implications of this finding are unclear. As with the IPD analysis, this meta-analysis is based on observational studies and does not provide conclusive evidence that DMPA causes the increased risk of HIV. However, it does provide refined estimates for modelling studies to assess the implications of possible withdrawal of DMPA on maternal and HIV-associated mortality, so that context-specific contraceptive policies can be considered.

Africa [9]
Botswana [10], Kenya [11], Malawi [12], Rwanda [13], South Africa [14], Uganda [15], United Republic of Tanzania [16], Zambia [17], Zimbabwe [18]
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