Crook, A., Ford, D., Gafos, M., Hayes, R., Kamali, A., Kapiga, S., Nunn, A., Chisembele, M., Ramjee, G., Rees, H., & McCormack, S. (2014). Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial. Human reproduction (Oxford, England), 29(8), 1810-1817. https://doi.org/10.1093/humrep/deu113
Crook A, Ford D, Gafos M, Hayes R, Kamali A, Kapiga S, et al. Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial. Hum Reprod. 2014;29(8):1810-1817. doi:10.1093/humrep/deu113
Crook, Angela, et al. "Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial." Human reproduction (Oxford, England), vol. 29, no. 8, 2014, pp. 1810-1817.
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Do injectable and oral contraceptives increase the risk of human immunodeficiency virus (HIV) acquisition in women?
Summary Answer
After adjusting for confounders, evidence of a significantly increased risk of HIV remained for women using injectable depo-medroxyprogesterone (DMPA) (hazard ratio = 1.49, 95% confidence interval (1.06-2.08)) but not for injectable norethisterone-enanthate (Net-En) or oral contraceptive pills (OC).
What Is Known Already
An association between the use of some types of hormonal contraception (HC) methods and an increased risk of HIV, possibly through changes in the genital tract environment and alterations in the immune response, has been previously observed, although not consistently. A recent systematic review of these studies has highlighted the need for more definitive evidence.
Study Design, Size, Duration
A secondary data analysis of the MDP301 phase 3 microbicide trial was conducted to estimate the effects of use of different methods of HC on the risk of HIV acquisition in women. HIV-negative women (n = 8663) with a median age of 28 years were included in the analysis; 382 HIV seroconverted by 52 weeks follow-up; 10% of women-years were lost to follow-up before 52 weeks.
Participants/Materials, Setting, Methods
Contraceptive use was reported at each 4-weekly visit. Cox proportional hazards (PH) models were used to estimate the effects of baseline and current use of injectable DMPA, injectable Net-En and OC compared with no HC, on the risk of HIV, adjusting for baseline and time-updated covariates. Causal effects for 52 weeks of HC use compared with no HC were estimated in a weighted Cox model, censoring women at deviation from baseline HC use (or non-use) or pregnancy.
Main Results and the Role of Chance
At baseline, 2499 (29%) women were on DMPA, 1180 (14%) on Net-En, and 1410 (16%) on OC; 3574 (40%) not on HC, started HC in follow-up. Adjusted hazard ratios (HR) for baseline HC use, compared with no HC, were 1.38 (95% confidence interval (CI) 1.07-1.78) for DMPA; 1.18 (0.86-1.62) for Net-En and 0.97 (0.68-1.38) for OC. The estimated causal effects of DMPA and Net-En over 52 weeks were: HR = 1.49 (95% CI 1.06-2.08) and HR = 1.31 (95% CI 0.62-1.61), respectively.
Limitations, Reasons for Caution
A main limitation of the study was that it was a secondary analysis of data from a study that was not designed to investigate this question. Despite our best efforts, we cannot exclude residual confounding to explain the effect of DMPA.
Wider Implications of the Findings
The results of this study should be reviewed by the World Health Organization to determine whether current recommendations on the use of DMPA in settings with high HIV prevalence require modification.
Study Funding/Competing Interests
MDP is a partnership of African and European academic/government institutions with commercial organizations, which is funded by the UK Government (DFID and MRC), with support from IPM and EDCTP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Morrison CS et al., 2015·PLoS Med·Free full text on PubMed Central
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. 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. 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.
To investigate the association between hormonal contraceptives and risk of HIV-1 seroconversion and prevalence of other sexually transmitted infections.
Prospective cohort. The study population was 2,236 HIV-negative women who were screened in a biomedical intervention trial in Durban, South Africa. The association between the use of hormonal contraceptives and risk of HIV-1 seroconversion was modeled using Cox proportional hazards regression analysis. Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections were assessed using logistic regression models. Hormonal injectables were the most common method of contraceptives (46.47%) followed by condom use (28.04%). Overall, compared with women who reported using condoms or other methods as their preferred form of contraceptive, those who reported using hormonal contraceptives (injectables and oral pills) were less likely to use condoms in their last sexual act. Using hormonal injectables during the study was significantly associated with increased risk for HIV-1 infection [adjusted hazard ratio 1.72, 95% confidence interval (CI) 1.19-2.49, P = 0.005]; hormonal injectables were also significantly associated with higher prevalent of C. trachomatis infections (adjusted odds ratio 2.46, 95% CI 1.52-3.97, P < 0.001). Hormonal injectables are highly effective and well tolerated family planning methods and have played an important role in reducing unplanned pregnancies and maternal and infant mortality. However, they do not protect against HIV-1 and other sexually transmitted infections. This study reinforces the importance of comprehensive contraceptive counseling to women about the importance of dual protection, such as male condoms and hormonal contraceptives use.
Comparative Studies · Contraception Versus Fertility Awareness
To evaluate the effect of hormonal contraception including combined oral contraceptives (COCs), and the injectable progestins depo-medroxyprogesterone acetate (DMPA) and norethisterone enanthate (Net-En) on the risk of HIV acquisition among women in South Africa. We analyzed data from 5567 women aged 16-49 years participating in the Carraguard Phase 3 Efficacy Trial. Participants were interviewed about contraceptive use and sexual behaviors and underwent pelvic examinations and HIV testing quarterly. We used marginal structural Cox regression models to estimate the effect of hormonal contraception exposure on HIV acquisition risk among women overall and among young women (16-24 years) in particular. Two hundred and seventy participants became HIV-infected (3.7 per 100 woman-years); HIV incidence was 2.8, 4.6, 3.5 and 3.4 per 100 woman-years in the COC, DMPA, Net-En and nonhormonal contraceptive groups, respectively (P = 0.09). The adjusted hazard ratios (AHRs) were 0.84 [95% confidence interval (CI) 0.51-1.39], 1.28 (95% CI 0.92-1.78) and 0.92 (95% CI 0.64-1.32) among COC, DMPA and Net-En users, respectively, compared with the nonhormonal group controlling for covariates. Age modified the effect of hormonal contraception on HIV acquisition risk; among young women, the AHRs were 1.02 (95% CI 0.46-2.28) for COCs, 1.68 (95% CI 0.96-2.94) for DMPA and 1.36 (95% CI0.78-2.35) for Net-En users. In this study conducted among South African women, hormonal contraception did not significantly increase the risk of HIV acquisition. However, the effect estimate does not rule out a moderate increase in HIV risk associated with DMPA use found in some other recent studies.
Heffron R et al., 2012·Lancet Infect Dis·Free full text on PubMed Central
Hormonal contraceptives are used widely but their effects on HIV-1 risk are unclear. We aimed to assess the association between hormonal contraceptive use and risk of HIV-1 acquisition by women and HIV-1 transmission from HIV-1-infected women to their male partners. In this prospective study, we followed up 3790 heterosexual HIV-1-serodiscordant couples participating in two longitudinal studies of HIV-1 incidence in seven African countries. Among injectable and oral hormonal contraceptive users and non-users, we compared rates of HIV-1 acquisition by women and HIV-1 transmission from women to men. The primary outcome measure was HIV-1 seroconversion. We used Cox proportional hazards regression and marginal structural modelling to assess the effect of contraceptive use on HIV-1 risk. Findings: Among 1314 couples in which the HIV-1-seronegative partner was female (median follow-up 18·0 [IQR 12·6-24·2] months), rates of HIV-1 acquisition were 6·61 per 100 person-years in women who used hormonal contraception and 3·78 per 100 person-years in those who did not (adjusted hazard ratio 1·98, 95% CI 1·06-3·68, p=0·03). Among 2476 couples in which the HIV-1-seronegative partner was male (median follow-up 18·7 [IQR 12·8-24·2] months), rates of HIV-1 transmission from women to men were 2·61 per 100 person-years in couples in which women used hormonal contraception and 1·51 per 100 person-years in couples in which women did not use hormonal contraception (adjusted hazard ratio 1·97, 95% CI 1·12-3·45, p=0·02). Marginal structural model analyses generated much the same results to the Cox proportional hazards regression. Interpretation: Women should be counselled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, especially injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk. Non-hormonal or low-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1. US National Institutes of Health and the Bill & Melinda Gates Foundation.
Combined oral contraceptives (COC) and depot-medroxyprogesterone acetate (DMPA) are among the most widely used family planning methods; their effect on HIV acquisition is not known. To evaluate the effect of COC and DMPA on HIV acquisition and any modifying effects of other sexually transmitted infections. This multicenter prospective cohort study enroled 6109 HIV-uninfected women, aged 18-35 years, from family planning clinics in Uganda, Zimbabwe and Thailand. Participants received HIV testing quarterly for 15-24 months. The risk of HIV acquisition with different contraceptive methods was assessed (excluding Thailand, where there were few HIV cases). HIV infection occurred in 213 African participants (2.8/100 woman-years). Use of neither COC [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.69-1.42] nor DMPA (HR, 1.25; 95% CI, 0.89-1.78) was associated with risk of HIV acquisition overall, including among participants with cervical or vaginal infections. While absolute risk of HIV acquisition was higher among participants who were seropositive for herpes simplex virus 2 (HSV-2) than in those seronegative at enrolment, among the HSV-2-seronegative participants, both COC (HR, 2.85; 95% CI, 1.39-5.82) and DMPA (HR, 3.97; 95% CI, 1.98-8.00) users had an increased risk of HIV acquisition compared with the non-hormonal group. No association was found between hormonal contraceptive use and HIV acquisition overall. This is reassuring for women needing effective contraception in settings of high HIV prevalence. However, hormonal contraceptive users who were HSV-2 seronegative had an increased risk of HIV acquisition. Additional research is needed to confirm and explain this finding.
To evaluate the effect of oral and injectable hormonal contraception on the risk of HIV acquisition among women in South Africa and Zimbabwe.
Secondary data analysis of 4913 sexually active women aged 18-49 years followed for up to 24 months in the Methods for Improving Reproductive Health in Africa (MIRA) phase III effectiveness trial of the diaphragm and lubricant gel for HIV prevention. Participants were interviewed quarterly about contraception and sexual behavior and were tested for pregnancy, HIV, and other sexually transmitted infections. We used a Cox proportional hazards marginal structural model, weighted by the inverse probability of hormonal contraception use, to compare the risk of HIV acquisition among nonpregnant women reporting use of combined oral contraceptive pills (COC), progestin-only pills (POP), and/or injectable hormonal contraception to women not using these methods. During the study, 283 participants seroconverted. Use of oral contraceptives (POP or COC) was not associated with HIV risk [adjusted hazard ratio (HRa) = 0.86, 95% confidence interval (CI) 0.32, 1.78]. Injectable hormonal contraception was associated with a small nonsignificant risk of HIV infection (HR(a) = 1.34, 95% CI 0.75, 2.37). The effect of injectable hormonal contraception was similar in the unweighted site-adjusted only (HR(a) = 1.32, 95% CI 1.00, 1.74) and baseline factor adjusted models (HR(a) = 1.27, 95% CI 0.94, 1.72). In this study, oral contraceptives were not associated with HIV acquisition. There is substantial uncertainty in the effect of injectable hormonal contraception on HIV risk. These findings underscore the importance of dual protection with condoms and the need for diverse contraceptive options for women at risk of HIV infection.
Ralph LJ et al., 2015·Lancet Infect Dis·Free full text on PubMed Central
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. 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, I(2) 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 (I(2) 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. None.
Many women using hormonal contraceptives are also at risk of sexually transmitted HIV infection, but data are mixed on whether hormonal contraception increases women's risk of HIV. We investigated associations between HIV incidence and use of combined oral contraceptives (COC), norethindrone enanthate (NET-EN) or depot medroxyprogesterone acetate (DMPA) in a cohort of South African women. Participants were 4200 HIV-negative women aged 35-49 years enrolled into a cervical cancer screening trial. At enrollment, women were tested for sexually transmitted infections and reported on their sexual behaviour and contraceptive use. During the 24 months of follow-up, women reported on their sexual behaviours and contraceptive use and underwent repeat HIV testing. During the 5010 person-years of follow-up, 111 incident HIV infections were observed (HIV incidence, 2.2 infections/100 person-years). At enrollment, 21% of women reported using hormonal contraception, primarily DMPA (14% of all women) or NET-EN (5%). After adjusting for sexual risk behaviours and sexually transmitted infections, the incidence of HIV was similar among women using COC, NET-EN or DMPA compared with women not using any hormonal method [incidence rate ratios and 95% confidence intervals, 0.65, 0.16-2.66; 0.79, 0.31-2.02 and 0.96, 0.58-1.59, respectively]. There was also no association between increased duration of DMPA use and HIV incidence (P-value for trend, 0.51). These findings contribute to the evidence from general population cohorts of women that hormonal contraceptive use is not associated with increased risk of HIV acquisition. Nonetheless, family planning services are an important venue for HIV prevention activities.
Angela M Crook, Deborah Ford, Mitzy Gafos, Richard Hayes, Saidi Kapiga, Andrew Nunn, Helen Rees, Sheena McCormack, Maureen Chisembele, Anatoli Kamali, Gita Ramjee
A Crook, Debbie Ford, Deb Ford, D Ford, M Gafos, Rick Hayes, Dick Hayes, Rich Hayes, R Hayes, S Kapiga, Andy Nunn, Drew Nunn, A Nunn, H Rees, S McCormack, M Chisembele, A Kamali, G Ramjee
PMID 24838704 24838704 DOI 10.1093/humrep/deu113 10.1093/humrep/deu113 Crook et al. 2014, Crook 2014
Cite this article
Crook, A., Ford, D., Gafos, M., Hayes, R., Kamali, A., Kapiga, S., Nunn, A., Chisembele, M., Ramjee, G., Rees, H., & McCormack, S. (2014). Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial. Human reproduction (Oxford, England), 29(8), 1810-1817. https://doi.org/10.1093/humrep/deu113
Crook A, Ford D, Gafos M, Hayes R, Kamali A, Kapiga S, et al. Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial. Hum Reprod. 2014;29(8):1810-1817. doi:10.1093/humrep/deu113
Crook, Angela, et al. "Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial." Human reproduction (Oxford, England), vol. 29, no. 8, 2014, pp. 1810-1817.
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