Empowering women and couples with the tools necessary to prevent unintended pregnancy and avoid sexually transmitted infections including HIV is critically important for individual and public health. Hormonal contraceptive methods are highly effective for prevention of unintended pregnancy and associated sequelae. However, some epidemiological studies suggest an association between use of specific hormonal contraceptive methods [particularly depot medroxyprogesterone acetate (DMPA)] and an increased risk of HIV acquisition in women; other studies have not reported this association . This question is critically important for women's health, particularly in sub-Saharan Africa, where high rates of HIV coincide with high use of injectable contraception . Many regions with high HIV prevalence also have high rates of unmet need for contraception, unintended pregnancy, and maternal mortality and morbidity, underlying the imperative for access to effective contraception [3,4].
Several biologically plausible mechanisms have been postulated to explain how various hormonal contraceptive methods could increase women's risk of HIV acquisition, including possible disruption of epithelial barriers, alterations in immune cell populations, or soluble inflammatory responses [5–8]. The effect of hormonal contraception on cervical immunity is influenced by the genital tract microenvironment and presence of infections . Interpretation of current data on biologic and immunologic impacts from hormonal contraceptive use is hampered by studies that fail to account for different hormones, diverse dosages, and hormonal contraceptive delivery routes . Women using particular hormonal contraceptive methods may also have other characteristics (e.g. different patterns of condom use), which could impact HIV acquisition risk.
A previous systematic review of epidemiological evidence assessed all relevant evidence published prior to 15 January 2014 . The review was conducted independently of the WHO guidance development process and served as an input into WHO deliberations related to updating the medical eligibility criteria for contraceptive use (refer to Appendix A, http://links.lww.com/QAD/A969 for current WHO guidance for hormonal contraceptive use among women at high risk of HIV) . Given the public health importance of this topic, we updated our previous systematic review to incorporate newly published, pertinent epidemiological evidence.
We conducted this systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines .
We included published primary research reports on women who were HIV-negative at baseline in longitudinal studies (observational studies or randomized trials, or meta-analyses containing data not otherwise captured in our search strategy) that measured incident, laboratory-confirmed HIV infection among women who used a specific method of hormonal contraception [injectables, oral contraceptives, implants, patches, rings, or levonorgestrel intrauterine devices (LNG-IUDs)] compared with incident HIV infections among women using a nonhormonal contraceptive method (e.g. condoms, nonhormonal IUD, sterilization, withdrawal, etc.) or no contraceptive method (henceforth, ‘hormonal contraceptive versus non-use of hormonal contraception’ comparisons). Some studies compared hormonal contraceptive users against a heterogeneous group including other hormonal contraceptive users, nonhormonal method users, and nonusers of contraception. We identified and included such studies, but considered the composition of the comparison group when assessing study quality.
We also included studies comparing incident HIV infection among HIV-negative women using a specific method of hormonal contraception against HIV-negative women using another specific method of hormonal contraception (henceforth, ‘head-to-head’ analyses) in which the comparison group did not contain nonhormonal method users or nonusers of contraception.
We excluded studies that did not report a risk estimate for the relationship between hormonal contraceptive use and HIV acquisition, cross-sectional studies, studies assessing only emergency contraception, conference abstracts, or other unpublished reports.
We retained all articles included in the previous systematic review, unless superseded by a new published analysis based upon the same data. We searched PubMed and Embase (Appendix B, http://links.lww.com/QAD/A969) for articles published in any language between 15 January 2014 and 15 January 2016, inclusive. We hand-searched reference lists of included studies. C.B.P. conducted the literature search and C.B.P., K.M.C., and P.C.H. screened titles, abstracts, and full-text manuscripts to determine inclusion using Covidence software .
Data extraction and quality assessment
We applied a study quality assessment framework used in our 2014 systematic review, with slight modifications for clarity . Briefly, studies that did not include adjustment for condom use or which had unclear measurement of exposure to hormonal contraception (refer to Appendix C, http://links.lww.com/QAD/A969 for a full explanation of the quality assessment criteria) were considered ‘unlikely to inform the primary question’. For comprehensiveness, we included all studies that met our inclusion criteria, regardless of quality. However, we focused on studies with neither of the two quality concerns noted above; we considered these studies ‘informative but with important limitations’ (IBWILs) to acknowledge that all studies to date are vulnerable to residual or uncontrolled confounding. All authors participated in confirming the study quality assessment framework and in rating the quality of each study. We adapted previously used abstraction forms that were pilot tested by all coauthors. All coauthors abstracted data from each newly included study that was considered as IBWIL. We contacted study investigators if clarifications were needed.
We created forest plots using Microsoft Excel 2013 (Microsoft, Redmond, Washington, USA) to summarize point estimates for a given contraceptive method [i.e. oral contraceptives, injectables (nonspecified, DMPA, and norethisterone enanthate (NET-EN)), or implants]. We focus on graphics summarizing only studies considered IBWIL, but graphs depicting all studies regardless of quality are provided in Appendix D, http://links.lww.com/QAD/A969.
Most studies estimated hazards ratios using Cox proportional hazards models; some also included estimates from a marginal structural model (MSM) (for additional discussion, refer to [1,13]). A few estimated only incidence rate ratios (IRRs) (Tables 1 and 2). For clarity of presentation, we display the IRR or Cox hazards ratio, unless the MSM model generated qualitatively different estimates, in which case both Cox and MSM estimates are shown.
As in 2014, we requested disaggregated estimates from authors of new studies classified as IBWIL and which included women from South Africa (where use of both DMPA and NET-EN is common) but which did not report separate estimates for each. Disaggregated estimates have reduced statistical power but greater epidemiological and clinical value, given the potential for different biological effects by contraceptive type or formulation.
Given concerns specific to DMPA, we performed a statistical meta-analysis for the effect of DMPA versus non-use of hormonal contraception on HIV acquisition (studies that did not disaggregate injectables were not included). For maximum comparability, we included the most fully adjusted Cox hazards ratio estimates from each study, except one that reported an adjusted IRR (IRRs can be interpreted similarly to hazards ratios under certain conditions ). We log-transformed reported adjusted point estimates and 95% confidence intervals (95% CIs) to calculate standard errors using a random effects model . We assessed statistical heterogeneity using the I2 statistic . Analyses were performed using Stata (Version 13.1, College Station, Texas, USA).
Description of included studies
Twenty-two studies were included in our previous review . For this review, we screened 312 new references, assessed 14 full-text reports, and excluded four: two did not report on the association of interest [17,18] and two meta-analyses contained published data already captured by our search strategy (including them would have resulted in double-counting of data, instead they are mentioned in our discussion) (Fig. 1) [19,20].
We included 10 new reports [21–30]; one  superseded a previously included study . A large, individual participant data (IPD) meta-analysis  used raw data from 18 datasets, including seven not previously utilized to investigate the association of interest [17,32–37]. To incorporate the previously unpublished information (while avoiding double-counting from previously published studies), we requested a subanalysis restricted to data from these seven studies in a hormonal contraceptive versus non-use of hormonal contraception comparison . The IPD meta-analysis also included a head-to-head comparison that none of our included component studies had assessed; here we used results from the original article .
Table 1 describes 10 newly included studies; information on previously included studies is available elsewhere . A total of 31 studies (comprising 34 reports) were included [21–30,39–62]. Thirty assessed hormonal contraceptive versus non-use of hormonal contraception comparisons [21–29,39–62] and two assessed head-to-head comparisons [26,30].
Among 30 studies with hormonal contraceptive versus non-use of hormonal contraception comparisons, 24 included estimates specific to (or largely composed of) oral contraceptives [21–24,26,27,29,39,41–46,49–53,55–59,61,62]. Twenty-four included estimates specific to (or largely composed of) injectables [21,24–29,39–48,50–53,55,56,58,60,62] and three included implant-specific estimates [27,39,50,54]. All studies assessing DMPA assessed intramuscular DMPA, rather than the lower dose, subcutaneous formulation. No study assessed contraceptive patches, rings, combined injectables, or LNG-IUDs. Among two head-to-head studies, two compared DMPA versus NET-EN [26,30] and one compared DMPA versus combined oral contraceptives (COCs) and NET-EN versus COCs .
Hormonal contraceptive versus non-use of hormonal contraception studies considered informative but with important limitations
Of 30 hormonal contraceptive versus non-use of hormonal contraception, we rated 12 as IBWIL [21,26,27,29,39,42,43,47,51–53,55,56,58], including four newly identified studies [21,26,27,29]. Table 2 provides details on new IBWIL studies; information on previously included IBWIL studies is available elsewhere . The four new studies included a large IPD meta-analysis that assessed oral contraceptives, DMPA, and NET-EN across a range of datasets , an analysis from an 18-year cohort study of Zambian serodiscordant couples to assess oral contraceptives, DMPA, and implants , and two analyses from large microbicide trials, one assessing unspecified injectables  and the other assessing oral contraceptives, DMPA, and NET-EN . Below, we summarize results from all 12 hormonal contraceptive versus non-use of hormonal contraception studies considered IBWIL. Readers should consult the relevant tables and figures for additional detail (such as 95% CIs); descriptions below provide a succinct synthesis of the overall evidence base. We discuss studies according to whether results were significant at P less than 0.05, but acknowledge that, considered alone, P values are an imperfect indicator of significance .
Neither of two IBWIL studies assessing levonorgestrel-based implants (Norplant or Jadelle) [27,39,54] suggested a statistically significant increased risk of HIV. Point estimates ranged from adjusted hazards ratio (adjHR) 0.96 to 1.60; 95% CIs were wide.
Of 11 IBWIL studies assessing oral contraceptives [21,26,27,29,38,39,42,51–53,55,56,58], one reported a marginally significant increase in risk (adjHR: 1.46, P = 0.05); 10 reported nonsignificant estimates ranging from adjusted incidence rate ratios (adjIRR) 0.66 to adjHR 1.80 (Fig. 2). One study disaggregated COCs and progestin-only pills (POPs); point estimates were similar and nonsignificant (adjHR: 0.86 and 0.98, respectively) .
Of 12 IBWIL studies assessing injectables (DMPA, NET-EN, or a mix of both) [21,26,27,29,38,39,42,47,51–53,55,56,58], nine provided DMPA-specific estimates and three provided estimates for unspecified injectables. Five studies reported a statistically significant increase in risk with either unspecified injectables  or DMPA [21,26,38,39,52,53], although the point estimate in one was not statistically significant in a Cox proportional hazards model  (Figs. 3 and 4). Point estimates from Cox models from these five studies ranged from adjHR 1.45 to 2.04 (Figs. 3 and 4) [21,26,38,39,42,52,53]; the largest estimate under an MSM model was 2.19 . Among seven studies reporting nonstatistically significant results, point estimates ranged from adjIRR 0.46 to adjHR 1.34 (both DMPA-specific) [27,29,47,51,55,56,58]. None of six studies assessing NET-EN reported statistically significant increases in HIV risk: point estimates ranged from adjHR 0.87 to adjIRR 1.76 (Fig. 5) [21,26,38,47,51,55,56].
Head-to-head studies considered informative but with important limitations
No head-to-head comparison studies were available in the previous review . Both newly included head-to-head studies were considered IBWIL (Tables 1 and 2) [26,30]. Both reported a statistically significant increased risk of HIV for DMPA use (adjHR: 1.32 and 1.41) versus NET-EN use [26,30]. The IPD meta-analysis also compared each injectable against COCs, reporting significantly increased risk for DMPA versus COCs (adjHR: 1.43, 95% CI: 1.23–1.67) and a borderline nonsignificant increased risk for NET-EN versus COCs: adjHR 1.30 (0.99–1.71) (Fig. 6) .
Ten estimates, from nine published studies with DMPA-specific estimates versus non-use of hormonal contraception [21,27,39,42,47,51,53,55,56] and a subanalysis of previously unpublished information from an IPD meta-analysis , were included in our meta-analysis of the effect of DMPA on HIV acquisition (Appendix D, Fig. 5, http://links.lww.com/QAD/A969). The overall effect estimate was 1.40 (95% CI: 1.23–1.59) with an I2 of 0%, indicating minimal quantitative heterogeneity.
One study reported increased HIV risk with DMPA and oral contraceptives in younger (18–24 years) but not older women ; eight studies reported no effect modification by age [21,27,29,39,42,47,51,56]; most studies reported no effect modification by herpes simplex virus type 2 (HSV-2) status [21,29,39,42,51], whereas two reported effect modification in opposite directions [One observed higher HIV risk with DMPA in HSV-2 seronegative women (Morrison et al.) and the other observed higher HIV risk with DMPA (versus NET-EN) in HSV-2 seropositive women (Noguchi et al.).]. Two studies reported no effect of modification by study site [21,30], one reported greater risk for oral contraceptives and DMPA in a Ugandan site versus a Zimbabwean site . A study in serodiscordant couples reported no effect modification for genital ulceration, inflammation, viral load of HIV-positive partner at baseline, or fertility intentions . Another study reported no effect modification by reported condom use at baseline, participant behavioral risk, or prevalent chlamydia or gonorrhea .
Within the IPD meta-analysis, assessment for effect modification was conducted with information from all 18 studies (some of which were also included in our review). No evidence of interaction was reported with any method for age (15–24 versus >25 years), HSV-2 status at baseline, or HIV incidence in population (low versus high) . Increased HIV risk was observed for COC use in East Africa (adjHR: 1.58, 95% CI: 1.19–2.09) but not South Africa or Southern Africa, and for DMPA use in east and South Africa (adjHR: 2.09, 95% CI: 1.68–2.80; adjHR: 1.30, 95% CI: 1.11–1.53), but not Southern Africa. Populations that reported engaging in transactional sex work had an increased HIV risk with COCs (adjHR: 1.51, 95% CI: 1.09–2.10) unlike populations without transactional sex work. Finally, smaller point estimates were observed among studies deemed by the investigators as at lower risk of methodological bias: adjHR for DMPA: 1.22 (95% CI: 0.99–1.50) and adjHR for NET-EN: 0.67 (95% CI: 0.47–0.96). Table 3 details how the IPD meta-analysis investigators defined lower risk of bias in comparison with our quality criteria.
Interpretation of overall results
As in our 2014 review, current data do not suggest an increased risk of HIV acquisition among women using oral contraceptives . Extremely limited data do not suggest a statistically significant increased risk of HIV acquisition among users of levonorgestrel implants; no data are available regarding etonogestrel implants. In 2014, one of five studies that was considered IBWIL suggested an increased risk of HIV acquisition with NET-EN injectables . In this updated review, that study was replaced by a larger, more sophisticated analysis of the same dataset , and increased HIV risk was no longer observed. Thus, currently available data for injectable NET-EN use do not suggest an association with HIV acquisition in women.
Although concerns around confounding in observational data remain relevant, newly available evidence regarding injectable DMPA use increases concern about a potential causal association with HIV acquisition. Twelve studies considered IBWIL assessed DMPA or nondisaggregated injectables compared with non-use of hormonal contraception; four or five (depending on the statistical model considered) reported statistically significant increased risks of HIV acquisition, ranging from adjHR 1.45 to 2.04 in Cox models (or 2.19 in MSM models). Among four newly included studies, two reported statistically significant increased risk (adjHR: 1.45 and 1.69), including one very large study  and a subanalysis of a large IPD meta-analysis . A smaller study among serodiscordant couples  reported a nonsignificant estimate of adjHR 1.34, and data from a microbicide trial also had a nonsignificant estimate of adjHR 1.17 but did not disaggregate between injectables . Head-to-head comparisons were newly available and may be less confounded by unmeasured or residual behavioral differences than comparisons from hormonal contraceptive versus non-use of hormonal contraception studies, particularly if groups compared in head-to-head studies use different types of the same delivery method (i.e., injectable DMPA versus injectable NET-EN) . A head-to-head analysis of VOICE data reported a 41% increased risk of HIV acquisition in DMPA versus NET-EN users . In the IPD meta-analysis , DMPA use was associated with a significantly increased risk of HIV acquisition of 30–40% when compared with either NET-EN or COC use. Comparing NET-EN against COC users suggested higher risk with NET-EN, though this was not statistically significant at P less than 0.05 (P = 0.055). Although residual confounding cannot be ruled out in any observational study, several recently published studies suggesting an increased risk of HIV acquisition among DMPA users had few limitations apart from being observational (Table 2).
Recent analyses contradict the hypothesis that differential over-reporting of condom use by hormonal contraceptive users explains observed associations between hormonal contraceptive use and HIV infection in some studies . However, the possibility remains that certain confounders are specific to DMPA users. In South Africa (where both DMPA and NET-EN injectables are used), studies suggest that women perceive DMPA and NET-EN differently, and providers may preferentially prescribe different injectable types to specific subpopulations, which could result in confounding specific to injectable type [30,65,66]. Although beyond the scope of this review, emerging evidence related to DMPA and HSV-2 acquisition must also be considered [67,68].
Taken together, the new evidence points toward heightened concerns that the association between DMPA use and HIV acquisition may not be fully explained by confounding or other methodological problems. In contrast, additional reassuring evidence of no significant association for other hormonal contraceptive methods (oral contraceptives, NET-EN, and implants) is newly available. If the association between DMPA and HIV acquisition risk is causal, meta-analyses, including our own, suggest a likely increase in risk of hazards ratio 1.5 or less.
The quality of epidemiological evidence on this issue has improved over time. Several newly published studies used recent analytic recommendations  or other innovative analytic techniques. For example, Crook et al. conducted a particularly thorough exploration of statistical methodology and incorporated multiple sensitivity analyses to assess the robustness of their findings, Morrison et al. contributed substantial new data in a carefully conducted IPD meta-analysis, and Noguchi et al. examined an alternative comparison group (NET-EN users).
The methodological contribution of three newly published meta-analyses varied. In addition to the IPD meta-analysis included in our review , two meta-analyses [19,20] utilized data already included as primary studies in our systematic reviews (thus, adding no information beyond that already included in this review). Although all three meta-analyses reported summary estimates for DMPA similar to our own (hazards ratio 1.4–1.5), one of the excluded meta-analyses contained no assessment of study quality and included several studies with serious methodological limitations , which raises particular concern in the context of meta-analysis of observational data (Table 3) . Both excluded meta-analyses [19,20] double-counted  data by inclusion of both Wand and Ramjee  and Crook et al.. We generated a meta-analytic estimate for DMPA, but recommend that such results be interpreted with caution, given the potential for spurious precision in meta-analyses of observational data . The I2 value for our meta-analysis suggested minimal statistical heterogeneity, but qualitative differences between study populations and methods remain an important consideration . That said, estimates from all four meta-analyses are similar, despite inclusion of slightly different component studies .
Previous reviews have addressed key methodological considerations about this body of literature, including potential for confounding, frequency, and accuracy of variable measurement, considerations related to ‘direct’ and ‘total’ effects, potential for publication bias, and limitations of individual studies, such as failure of some studies to disaggregate by specific hormonal content or formulation (e.g., most studies assessing oral contraceptives failed to disaggregate estimates by COCs or POPs) [1,72]. Our study quality framework is necessarily subjective, and we encourage continued discussion on how best to evaluate study quality in this body of evidence.
There remain no data on use of contraceptive patches, rings, or hormonal IUDs and HIV acquisition in women. For implants, very limited data pertaining to levonorgestrel implants do not suggest increased risk, but more information is needed. In comparison, a larger amount of data are available for oral contraceptives and are generally reassuring. A growing number of studies have assessed injectable NET-EN, and although still limited, data are generally reassuring. For injectable DMPA, although some new, high-quality studies do not report a statistically significant increased risk of HIV acquisition, other new data, including studies directly comparing DMPA and NET-EN, tend to strengthen concerns about DMPA. If the association between DMPA and HIV acquisition risk is causal, data suggest a likely increase in risk of hazards ratio 1.5 or less. Several new studies have used recently proposed recommendations for analysis or other innovative methodological approaches , although as with all observational data, the possibility of uncontrolled or residual confounding remains. The growing, generally reassuring evidence about other hormonal contraceptive methods, including other injectables like NET-EN, stands in contrast to the DMPA-specific findings. An important next step is for WHO to determine whether these concerns warrant a reconsideration of global guidance for DMPA. Modeling studies can be useful in understanding net health impacts of various policy responses in different epidemiological contexts, including the risk of HIV, maternal mortality and morbidity, and access to alternative contraception and HIV prevention methods [2,73–76].
We are grateful to Sharon Achilles for her thoughtful input related to describing potential biological mechanisms, and to all study investigators who provided additional information about their analyses. WHO provided support for the writing of this systmatic review and for the writing group to attend a working meeting in Geneva, Switzerland in October 2015. D.J.W. was partially funded by NIH DP2-HD-08-4070. The review was conducted independently of the WHO guidance development process; and conclusions represent the independent opinions of the authors. The findings and conclusions in this article do not necessarily reflect the positions and policies of the donor.
Role of authors: The World Health Organization (J.N.K. and P.S.S.) initiated the idea to conduct this systematic review update. C.B.P. led the conduct of the systematic review, including conducting the systematic literature search and drafting the manuscript. C.B.P., K.M.C., and P.C.H. screened titles, abstracts, and full-text manuscripts to determine study inclusion. S.J.P. conducted the statistical meta-analysis. All coauthors (C.B.P., K.M.C., P.C.H., S.J.P., T.C., J.N.K., D.J.W., and P.S.S.) participated in framing the study question, developing the quality criteria, abstracting study information and assessing study quality, interpreting the data, and contributing to the writing and editing of the manuscript.
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the Guttmacher Institute, the Centers for Disease Control and Prevention, the World Health Organization, the National Institutes of Health, or other institutions with which the authors are affiliated.
Conflicts of interest
C.B.P. worked at USAID between 2011 and 2014, led previous systematic reviews on this topic, and participated in preliminary discussions considering the ECHO trial. P.C.H. served as a reviewer for potential funders of the ECHO protocol to inform their funding decision. S.J.P. participated in the inception of the ECHO trial. T.C., J.N.K., and P.S.S. are current members of the ECHO trial consortium. We do not feel that participation in these activities influenced our work on this systematic review. K.M.C. and D.J.W. have nothing to declare.
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