Understanding whether hormonal contraception increases the risk of incident HIV-1 infection among women is a critical public health issue. Hormonal contraception, a novelty just four decades ago, has become the norm in many countries because of its high efficacy and ease of use. Over 120 million women worldwide use hormonal contraception, and its use, especially depo-medroxyprogesterone acetate (DMPA), is increasing rapidly in many resource-limited settings [1–3]. Effective contraception has a key role to play in reducing maternal and infant mortality (by spacing pregnancies) and in allowing women a measure of control over when and how often they become pregnant. At the same time, the HIV/AIDS epidemic has reached crisis proportions in a number of sub-Saharan countries and calls for a rapid expansion of both prevention and treatment in resource-limited settings, particularly among women of childbearing age [4–6]. Despite the magnitude of the HIV/AIDS epidemic, the level of condom use among married or cohabiting couples in countries classified by UNAIDS as experiencing a generalized HIV epidemic remains very low . Most women who do use contraception rely on oral contraceptives (OC) or injectable DMPA.
A number of epidemiological studies have been conducted among women of childbearing age to examine hormonal contraception as a potential risk factor for acquiring HIV-1 infection [8–10]. Investigators have proposed several possible mechanisms for how hormonal contraception may affect HIV-1 acquisition, including physiological effects on the integrity of the vaginal epithelium (i.e., unopposed progesterone leads to increased susceptibility to vaginal SIV infection in macaque monkeys ), changes in the genital microflora , an increased likelihood of cervical ectopy , an effect on the cell-surface levels of CCR5, which is key to HIV-1 entry , and upregulation of HIV-1 gene expression . Detailed virological studies among commercial sex workers in Kenya suggested that hormone use predisposes them to the acquisition of a diverse HIV-1 virus population, which leads to higher levels of viral replication and more rapid HIV disease progression [16–18]. It is possible that these biological effects are more pronounced in young women and adolescent girls, who have been shown to be at disproportionately high risk of acquiring HIV-1 infection in sub-Saharan Africa .
To date, at least 13 published prospective studies worldwide [20–32] have reported on the association between risk of HIV-1 infection and hormonal contraception; nine of these were conducted in high-prevalence settings in sub-Saharan Africa [20–28]. Multivariate-adjusted relative risks of incident HIV-1 infection varied substantially among study populations both for OC use and for injectable hormones. Completeness of follow-up was highly variable and poor in some studies; statistical control for potentially strong confounders such as sexually transmitted diseases, number of sexual partners, and other sexual risk behavior was often suboptimal . Self-reported use of hormonal contraception and sexual behavior, even in the methodologically strongest studies, could have suffered from non-differential or differential exposure misclassification, leading to biased risk estimates and residual confounding. However, rather than dismissing the variation observed among studies, we should examine if such variation may be reflecting real differences in at-risk populations such as sex workers and adolescent girls.
In this issue of AIDS, Morrison and colleagues  describe the findings of a prospective study (> 4500 HIV-uninfected women in Uganda and Zimbabwe, aged 18–35 years) specifically designed to assess the relationship between hormonal contraception and incident HIV-1 infection. No overall association was found between use of hormonal contraception and the risk of HIV-1 acquisition, nor among the subset of participants with cervical or vaginal infections. These findings provide reassurance for women needing effective contraception in settings of high HIV-1 prevalence. However, the authors also report that among the smaller subgroup of women who were seronegative for herpes simplex virus type 2 (HSV-2) at enrollment, users of OC (adjusted hazard ratio, 2.9; 95% confidence interval, 1.4–5.8) or DMPA (adjusted hazard ratio, 4.0; 95% confidence interval, 2.0–8.0) were at increased risk of incident HIV-1 infection compared with non-users.
These findings concerning HSV-2-negative participants were unexpected and have not yet been reported by other investigators. Perhaps an important uncontrolled confounder could be responsible for the observed association between hormonal contraception and HIV infection among HSV-2-negative women in this study. Differential condom use might also confound the association with HIV incidence. HSV-2 infection has been shown to be a particularly strong risk factor for acquisition [34–37] and genital shedding [38,39] of HIV-1. Is it possible, as the authors also suggest, that HIV-1 acquisition attributable to hormonal contraception in the HSV-2-positive group (> 50% of all participants in the current study) was masked by HIV-1 seroconversion associated with HSV-2? Or, is this simply a chance finding?
A marginally higher risk for HIV-1 acquisition associated with hormonal contraception was observed among women in Uganda compared with Zimbabwe, where overall HIV-1 incidence was much higher than in Uganda . It remains possible that the ability to detect an association between hormonal contraception and risk of HIV-1 acquisition differs by the prevalence of exposure to hormonal contraception, sexual risk behaviors, other sexually transmitted diseases, and by age at exposure. Further studies in populations with different risk, using frequent monitoring and even more precise measures of contraceptive exposure and confounding variables, may help to clarify these findings. Unfortunately, no randomized clinical trial can be conducted owing to ethical and adherence issues resulting from randomly assigning women to contraceptive methods with substantially differing efficacy.
Most importantly, the study by Morrison et al.  demonstrated no overall association between use of hormonal contraception and risk of HIV acquisition among a large study population of African women with moderately high risk of HIV infection. While contraception has traditionally been the domain of family planning clinics, the findings of Morrison et al.  highlight the opportunity to integrate family planning and HIV/STD prevention, care, and treatment services, including prevention of mother-to-child HIV transmission [40–42]. Sexual activity leads to transmission of both sperm and microorganisms . Any fertility regulation counseling must be coupled with condom promotion and counseling about HIV and prevention and treatment of sexually transmitted infections. Dual protection (condom use in addition to hormonal contraception) should be recommended.
For those women already living with HIV/AIDS in sub-Saharan Africa, there is an ethical and public health imperative to offer them free, effective, and acceptable family planning services in the context of rapidly expanding HIV care and treatment services . As many more HIV-1-infected women are now accessing antiretroviral therapy, including in resource-limited settings [5,44,45], future studies will need to evaluate any possible impact of hormonal contraception on HIV-1 infectivity and viral replication among women using antiretroviral therapy. In addition, more complete data are urgently needed on the safety, efficacy, and pharmacokinetics of antiretroviral drugs when used in conjunction with hormonal contraceptives.
We acknowledge and thank the following individuals for thoughtful discussion on the issues raised in this editorial: Drs. Omotayo Bolu, Rokaya Ginwalla, Denise Jamieson, Alwyn Mwinga, Stewart Reid, Mark Shields, and Elizabeth Stringer.
Note: The findings and conclusions in this editorial commentary are those of the authors and do not necessarily represent the views of the CDC or the US Department of Health and Human Services.
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