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Safe and effective contraceptive choices are essential for women with HIV-1 infection and at risk for HIV-1 infection. Epidemiological and laboratory-based studies suggest that hormonal contraception may influence HIV-1 transmission. Several large studies in high-risk populations indicate that hormonal contraceptive use may modestly increase the risk of HIV-1 acquisition. In addition, HIV-1-infected users of hormonal contraceptives may be more infectious to their uninfected partners, although no studies have directly measured HIV-1 transmission risk from women to men. However, several studies failed to demonstrate a link between contraceptive use and HIV-1 acquisition or transmission, and interpretation of many studies limited by methodological considerations, such as infrequent measurements of contraceptive exposure and HIV-1 status. As a result, many questions remain, and high-quality studies remain needed. It is clear that hormonal contraceptives are not protective against HIV-1 infection, and that dual protection with condoms should be the goal for women using hormonal contraception.
Nearly one-half of new HIV-1 infections worldwide are in women of reproductive age, and heterosexual intercourse is responsible for most of these transmissions1. Safe and effective contraceptive choices are essential for women who are at risk for HIV-1 and for those who are HIV-1 infected. Hormonal contraceptives, including oral contraceptive pills, injectable agents such as depot medroxyprogresterone acetate (DMPA), and hormone-impregnated implants, are used throughout the world. During the past 20 years, a number of epidemiologic studies have examined whether use of hormonal methods of contraception alters women's risk of HIV-1 acquisition. Several studies have suggested a possible link between hormonal contraceptive use and enhanced HIV-1 susceptibility, although other studies have found no such link. In 2007, Baeten et al. reviewed the available studies evaluating the associations between hormonal contraceptives and HIV-1 transmission, as well as HIV-1 disease progression2. Rather than exhaustively re-summarizing the data on the relationship between contraception and HIV-1 acquisition and transmission, here we will provide a brief overview of the potential associations between hormonal contraceptives and HIV-1 risk, and discuss gaps in knowledge and unmet research needs. The evidence relating to contraceptive use to HIV-1 disease progression risk has been recently reviewed by others and we will not discuss those studies3-5.
Epidemiologic studies of the potential link between the use of hormonal contraception by HIV-1 negative women and increased risk of HIV-1 acquisition have yielded disparate results, with some studies suggesting an association while others have not2. Methodologic considerations have likely contributed to some of these differences and have hampered the ability to directly compare these data. For instance, many studies infrequently assessed both hormonal contraceptive use and HIV-1 infection status, making it difficult to determine whether hormonal contraceptives were used at the time of HIV-1 acquisition. Of the fifteen prospective studies reviewed in 2007, only 3 assessed HIV-1 infection status at least monthly6-8, and many assessed contraceptive use only at baseline. Furthermore, differences in sexual behaviors between users and non-users of hormonal contraception may confound results, particularly in the cross-sectional studies.
Two of the largest, high-quality prospective studies to evaluate associations between hormonal contraceptive use and HIV-1 transmission highlight the difficulties in summarizing these data. In a prospective study of 1272 female sex workers in Mombasa, Kenya with monthly follow-up, both oral contraceptive pills (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.0-2.1) and DMPA (HR, 1.8; 95% CI, 1.4-2.4) were associated with greater risk of HIV-1 in analyses controlling for demographic factors, sexual behavior, condom use, and sexually transmitted infections8. In a later reanalysis, further adjustment for HSV-2 status, which was not controlled for in the original paper, did not alter these results, nor was there evidence of effect modification by HSV-2 serostatus9. In the second study, which enrolled 4439 women from family planning clinics in Uganda and Zimbabwe, women were followed at 3-monthly intervals10. Neither oral contraceptive pills (HR, 0.99; 95% CI 0.69-1.42) nor DMPA (HR, 1.25; 95% CI, 0.89-1.78) were associated with HIV-1 acquisition overall in the original analysis10. However, in the subset of women who were seronegative for HSV-2 at study enrollment, both oral contraceptive pills (HR, 2.85; 95% CI, 1.39-5.81) and DMPA (HR, 3.97; 95% CI, 1.98-8) were associated with HIV-1 acquisition10. A reanalysis of the data from this second study has recently been performed, using a different analytic methodology to better account for time-dependent confounding. In this reanalysis, a modest, but statistically significant, increased HIV-1 risk was seen for women using DMPA (HR, 1.48; 95% CI, 1.02-2.15) but not oral contraceptives (HR, 1.19, 95% CI, 0.8-1.76), and the results for both oral contraceptives and DMPA use in HSV-2 seronegative women were strengthened (oral contraceptives: HR, 2.06, 95% CI 0.75-4.92; DMPA: HR, 4.49, 95% CI, 1.98-10.17)11. In addition, younger women (≤24 years of age) using either DMPA (HR, 2.76, 95% CI 1.62-4.72) or oral contraceptives (HR, 2.02, 95% CI, 1.15-3.55) were also at increased risk of HIV-1 acquisition11.
It should be noted that very few studies had sufficient statistical power to detect the 50-80% increased risk of HIV-1 infection suggested by the Mombasa study of high-risk sex workers2, 8. In fact, studies of high-risk populations, such as sex-workers, have generally shown that hormonal contraception use is associated with elevated risk of HIV-1 acquisition7, 8, 12, 13. In several studies, the risk of HIV-1 acquisition in high-risk women may be higher in users of DMPA than in users of oral contraceptive pills7, 8, 14. Additional evidence that hormonal contraceptives may increase risk of HIV-1 acquisition in high-risk women comes from the observation that women who use hormonal contraceptives are more likely to become simultaneously infected with more than one variant of HIV-1 (Odds Ratio [OR], 2.7; 95% CI, 1.3-5.6)15. Therefore, messages about the potential risks associated with hormonal contraceptives may have to be tailored to the population.
In order to more clearly establish the role of hormonal contraceptives in altering the risk of HIV-1 acquisition, future studies must be carefully designed to account for potential confounders and bias, including sexual habits, condom use, and other behaviors that might affect HIV-1 acquisition risk. Such studies must be sufficiently powered to detect as modest as a 50% increase in HIV-1 infection incidence, and should carefully assess hormonal contraceptive use, HSV-2 status, surrogate markers of risk, and HIV-1 infection status at multiple, frequent timepoints during the follow-up period. Ideal groups to study would include adolescents, who are at high risk of HIV-1 acquisition yet there is little available data, and discordant couples, in whom precise measurement of transmission rates from infected male partners to uninfected female partners can be determined.
To date, only one study has directly evaluated the effect of hormonal contraception on female-to-male HIV-1 transmission. This study of 563 HIV-1-discordant European couples found no association between hormonal contraceptive use in the index case and increased risk of transmission to the uninfected male partner16. To demonstrate that contraceptive use increases risk of sexual HIV-1 transmission required longitudinal studies of HIV-1 infected women and their initially-uninfected sexual partners, and establishment of such cohorts has been logistically challenging17. Thus, most studies of HIV-1 infectiousness have instead evaluated HIV-1 shedding in genital tract secretions as a surrogate marker of infectivity18, 19. In cross-sectional studies, hormonal contraceptive use appears to be associated with increased shedding of HIV-1 DNA, but not RNA, in the genital tract20-22. The only prospective study to measure HIV-1 RNA and DNA levels before and after initiation of hormonal contraceptives confirmed the findings of the cross-sectional studies: ~2 months after initiation of hormonal contraceptives, endocervical HIV-1 DNA, but not RNA, levels were increased23.
The reasons why contraception may increase genital HIV-1 DNA, but not RNA levels, have not been elucidated, though it is tempting to speculate that hormonal contraceptives promote recruitment of resting T cells and/or macrophages, which might be HIV-1-infected but unlikely to produce large amounts of virus. Consistent with this hypothesis, hormonal contraceptive use has been associated with increased recruitment of CCR5-expressing T cells into the genital tract24, although the activation state of these cells is not known. It is therefore important that future studies evaluate the subsets of immune cells recruited to the genital tract in women on versus not on hormonal contraceptive methods and the activation status of genital immune cells. Such studies should consider the effects of both oral contraceptives and DMPA, as these agents may differ in their effects. Studies of discordant couples would be particularly valuable, because genital HIV-1 RNA and DNA levels in the infected partner could be measured and directly correlated with transmission risk. Thus, in addition to improving our understanding of the effects of hormonal contraceptives, such studies will shed light on mechanisms of HIV-1 transmission in general by allowing determination of whether infected cells (measured as HIV-1 DNA) or cell-free virus (measured as HIV-1 RNA) are a better correlate of transmission.
Defining the mechanisms by which hormonal contraceptives alter HIV-1 acquisition and transmission risk may provide insight into the somewhat inconsistent epidemiologic data and suggest new approaches to understanding this challenging field. Several potential mechanisms by which hormonal contraceptives could influence HIV-1 transmission are summarized in Figure 1. Hormonal contraceptives are thought to have a myriad of effects, including introducing structural changes in the genital tract, altering immune responses, changing the vaginal flora, and increasing risk of sexually transmitted infections.
Hormonal contraceptive use has been associated with two major structural changes in the genital tract. The first is cervical ectopy, or extension of the endocervical columnar epithelium onto the exocervical face25. Cervical ectopy, in turn, is associated with increased susceptibility to HIV-126. It will be valuable for future studies to directly evaluate whether cervical ectopy is associated with an increased recruitment of CD4+CCR5+ HIV-1 target cells and/or other inflammatory markers in the vagina.
The second genital tract alteration that is associated with hormonal contraceptive use is thinning of the vaginal epithelium. In animal models, progesterone administration results in thinning of the vaginal epithelium and marked increase in SIV susceptibility27. Topical estrogen cream reverses these changes in animals28. However, in studies of women, conflicting results have been observed regarding the effects of progesterone on the vaginal epithelium29, 30, and thus it is not clear how applicable the animal models are to transmission to women. It will therefore be important for future studies to evaluate the effects of both estrogen and progesterone on vaginal and cervical structure in women.
Hormonal contraceptives may also alter immune responses that could protect from HIV-1 and potentially directly promote HIV-1 replication at a local and systemic level31-35. Hormonal contraception is associated with increased inflammation in the genital tract, including an increase in the number of CCR5-expressing T cells36, 37. This inflammation and recruitment of potential HIV-1 target cells could increase the risk of HIV-1 acquisition in uninfected hormonal contraceptive users. However, it should be noted that the association between inflammation and HIV-1 transmission is currently not well understood. It is therefore critical that future studies establish which markers of inflammation, if any, are associated with increased risk of HIV-1 acquisition. As with studies of the structural effects of hormonal contraceptives, such studies would shed considerable light on the general mechanisms of HIV-1 transmission in addition to increasing our understanding of the effects of hormonal contraceptives. In addition, in HIV-1-infected hormonal contraceptive users, recruitment of infected cells could also increase their risk of transmitting HIV-1 to their uninfected partners.
Hormonal contraceptive use is associated with increased risk of cervical sexually transmitted infections and inflammation, particularly Chlamydia and non-specific cervicitis8, 24, 36-42. In HIV-1-unifected women, this increased risk of genital tract infection may increase the risk of HIV-1 acquisition; in HIV-1 infected women, increased genital HIV-1 shedding as a result of genital infections may increase their risk of transmitting HIV-1 to their uninfected partners18, 43, 44. In addition, hormonal contraceptives do appear to increase the risk of yeast vaginitis, and decrease the number of protective H202 producing lactobacilli, both of which could enhance HIV transmission7, 30, 45, 46. Overall, the data supporting many of these mechanisms are limited, making it difficult to determine which, if any, of these mechanisms are actually relevant to HIV-1 transmission. It will be important for future studies to determine which immune cells and mediators are recruited into the genital tract during different genital infections, which may shed light on some of the disparate results.
Safe and effective contraceptive choices are essential for women with HIV-1 infection and at risk for HIV-1 infection. Epidemiological and laboratory-based studies suggest that hormonal contraceptive use may modestly increase the risk HIV-1 acquisition in uninfected women and could increase the risk of HIV-1 transmission to uninfected partners of HIV-1-infected women. However, not all studies have supported a link between hormonal contraceptive use and HIV-1 transmission, and methodological considerations have limited the clarity of the data. As a result, many questions remain (Table I), and high-quality studies of this important issue remain needed. It is clear that hormonal contraceptives are not protective against HIV-1 infection, and that dual protection with condoms should be the goal for women using hormonal contraception.
We would like to thank Julie Overbaugh for helpful comments on the manuscript and funding from NIH grants R01 AI38518 and K08 AI0684241.