Morrison, Charles S. PhD; Cates, Willard Jr MD
Prevention of both unintended pregnancy and human immunodeficiency virus (HIV) are key public health priorities worldwide. These are particularly salient in regions where HIV is highly prevalent and where a large proportion of the female population is of reproductive age. Both unintended pregnancy and HIV infection are especially prevalent in sub-Saharan Africa where most (over 13 million) HIV-infected women live,1 where both fertility and maternal mortality remains high, and where contraceptive access and use are generally low. Moreover, limiting unintended pregnancies among HIV-infected women has been identified by the World Health Organization as a key strategy for the prevention of mother to child transmission of HIV.2
Hormonal methods of contraception—primarily combined oral contraceptives (COC) and injectable progestin-only contraception—are among the most widely used forms of reversible contraception worldwide. In sub-Saharan Africa, where HIV and other sexually transmitted infections (STIs) are highly prevalent, use of progestin-only contraceptives including the 3-monthly injection depot-medroxyprogesterone acetate (DMPA) and the 2-monthly injection norethindrone enanthate appears to be increasing rapidly. Thus, understanding whether women’s use of hormonal contraception, and particularly injectable progestin contraceptives, increases the risk of HIV transmission is critically important.
For the individual woman, meeting the dual objectives of fertility regulation and HIV prevention poses major challenges.3 For the HIV-uninfected woman, preventing both unintended pregnancy and HIV acquisition is paramount. However, highly effective contraceptives such as COCs and DMPA do not protect against HIV infection and condoms, which can provide dual protection against pregnancy and HIV infection, are less effective than other contraceptives for pregnancy prevention. Moreover, condoms are rarely used in primary relationships—particularly those where highly effective contraception is being used.
The situation for HIV-infected women is even more complex. They must be concerned about
* minimizing the risk of HIV transmission to a sex partner or neonate;
* whether contraception (and particularly hormonal contraception) might be related to faster progression of HIV disease;
* side effects associated with contraceptive use among HIV-infected persons;
* for women needing antiretroviral therapy (ART), whether any important interactions occur between hormonal contraception and ART. Such interactions could lead to increased side effects associated with either hormonal contraception or ART or to a reduction in either contraceptive or antiretroviral (ARV) efficacy.
The effect of hormonal contraception on the infectiousness of an HIV-infected woman is unknown. Studies that directly measure factors associated with HIV transmission efficiency, including contraception, are difficult to conduct. For example, only one study has examined whether contraceptive use by an HIV-infected woman affects HIV transmission to her male partner. The contraceptive methods compared included oral contraceptives, intrauterine devices, and no regular contraception. No difference was found in the rate of HIV seroconversion among the 151 HIV-uninfected male partners according to the contraceptive method used by the infected female partner.4 However, the logistics of enrolling HIV discordant couples and following them over a long period is extremely challenging. Moreover, studies of prevalent HIV-discordant couples may not accurately reflect the transmission dynamics of populations where acute HIV infections drive the spread of HIV.5
Because of problems in directly measuring HIV transmission risk, most studies examining HIV infectivity have relied on genital shedding of HIV as a proxy. Use of genital shedding as a proxy for infectiousness is biologically plausible and is supported by the association between plasma viral load and transmission efficiency.6 Moreover, despite the fact that approximately 20% of women will have detectable genital tract RNA despite undetectable plasma viral RNA,7 plasma viral load is generally a strong predictor of genital viral loads in women.7–11 Thus, genital shedding levels appear to be a biologic mediator between plasma viral load and sexual transmission of HIV. In addition, several recent studies12–14 show that HIV genital loads are highest during early infection, a time of known high transmission efficiency.
However, the use of HIV genital shedding as a proxy also has important limitations, especially among women. For example, although both cell-free and cell-associated virus in genital secretions (generally measured by HIV RNA and DNA, respectively) are relevant measures of infectivity, the relative importance of HIV RNA versus HIV DNA as a measure of infectivity is unknown.8,15,16 In addition, sampling of genital secretions from women is not straightforward; a number of techniques have been used, including lavage, swab, cytobrush, and snostrip, to sample either the endocervical canal, the vaginal vault, or the lateral vaginal walls. Moreover, the timing of sampling within the menstrual period, and disturbance of the cervix and vagina by the specimen collection process itself can lead to additional variability that complicates the comparison of results across studies.
Reproductive factors associated with HIV genital shedding are of special interest. Monkey studies have suggested that animals treated with progesterone that become infected with HIV have higher levels of viremia than infected animals not treated with progesterone.32 17–19 Additionally, genital shedding among women appears to be mediated by the menstrual cycle (and highest during the luteal phase when progesterone predominates).20,21 This offers support for the hypothesis that hormonal contraception might influence HIV plasma and genital viral loads.16
Results of previous studies on the impact of hormonal contraceptive use on HIV genital shedding have been conflicting. Three cross-sectional studies from Kenya have examined the association between hormonal contraceptive use and genital shedding of HIV DNA from the endocervix (using cervical swabs). Two of these studies found a statistically significant increased proportion of women with shedding of HIV DNA among COC users compared with women not using hormonal contraception,22,23 whereas the third study did not find a statistically significant association.24 In addition, one of these studies found an increased proportion of DMPA users who shed HIV DNA compared with nonhormonal users.22 A cross-sectional study from the United States found no association between hormonal contraceptive use and the proportion of women who shed HIV RNA.9 A prospective study conducted in Kenya among family planning clients found a modest but statistically significant increase in the proportion of women shedding HIV DNA 2 months after, compared with before, initiation of hormonal contraception.15 However, no difference occurred in the temporal concentration of cervical HIV RNA. Finally, we found no statistically significant association between either COC or DMPA use and the proportion of women with cervical RNA shedding during early HIV infection.13
The report by Clark in this issue of Sexually Transmitted Diseases addresses the issue of whether use of hormonal contraception is associated with an increase in genital shedding of HIV among women. The study included 126 women at baseline, about half of whom were also using ARV therapy. One hundred eight of these women were followed over a 3-month period. The authors compared whether hormonal contraception was associated with whether (or not) a woman had detectable genital shedding of HIV RNA (dichotomous outcome). Unfortunately, the study did not include large numbers of women using hormonal contraception (n = 32). Although most were using DMPA, the numbers were not large enough to consider the effects of specific forms of hormonal contraception (e.g., oral contraceptives, DMPA, etc.).
Both in the baseline (OR = 0.60, 95% CI 0.16–2.29) and in the longitudinal analysis (OR = 0.59, 95% CI 0.13–2.72), hormonal contraception was not significantly associated with the proportion of women with detectable genital tract shedding of HIV RNA. Only 36% of the 126 women had any detectable genital RNA shedding and ARV therapy decreased the likelihood of genital shedding (OR = 0.25, 95% CI 0.11–0.54). Plasma HIV RNA was significantly associated with vaginal HIV RNA (P < 0.01) but the correlation was only moderate (Pearson’s r = 0.25). Two women (both taking ARVs) had detectable HIV genital RNA but nondetectable plasma HIV RNA.
Strengths of the Clark article include (a) the longitudinal (as well as the cross-sectional) nature of the analyses, (b) its contribution to the relatively scarce database from women in developed countries, (c) that it included women both using and not using ARVs, and (d) that the analyses adjusted for a number of possible confounding variables. Weaknesses of the analyses include (a) the relatively small number of hormonal contraceptive users (and the corresponding lack of precision in effect estimates), (b) that different types of hormonal contraception (e.g., combined vs. progestin-only methods) could not be examined individually, (c) that the analyses considered only whether HIV RNA was detectable and not the effect of hormonal contraception on genital RNA levels, (d) that the number of women with detectable HIV DNA was not assessed, and (e) that only 74 of 126 women (59%) were included in the 3-month assessment.
This study confirms previous research suggesting that hormonal contraceptive use is not associated with genital shedding of HIV RNA.9,15 However, the study does not provide any data to confirm or dispute the previous finding that hormonal contraception may be associated with the shedding of HIV DNA. Thus, current data suggest that hormonal contraception does not appear to increase HIV replication in the genital compartment, but may be associated with increased recruitment of HIV-infected cells from systemic compartments15 and possibly from the endometrium.25
The Clark study had a lower proportion of women with detectable HIV RNA (36%) and a lower correlation between genital and plasma RNA levels than some previous studies.9,15 A number of possible explanations could explain these differences. First, it is likely that the sampling technique—sampling from the vaginal vault with a Dacron swab—affected the measurement. Previous studies have generally shown lower levels of detectable shedding with vaginal when compared with endocervical sampling. Other possibilities include differences in the timing of the sampling within the menstrual cycle and differences in the study populations particularly the levels of concurrent STIs, the use of ARV therapy and the stage of HIV disease.
What are future research needs in the area of contraception and HIV transmission? First, we should exploit any existing partner studies to examine the role of contraception in female to male HIV transmission. However, the number of partner studies is likely to be small, particularly those that document sizeable numbers of female to male HIV transmission events. Thus, longitudinal cohort studies to compare genital shedding levels before and after women initiate contraception and using measures of both genital HIV RNA and DNA will also be important. Long-term studies can also consider the effect of contraception during different stages of HIV infection (early infection, chronic infection, using ARVs). Likewise, studies that include more women using specific hormonal methods are important to assess the impact of each hormonal method independently. As has been found with contraceptive research, the effect may differ depending on the presence of estrogen and the types of progestins used. Finally, accurate measurements of contraceptive use (including precise starting and stopping dates) and of potentially important confounders including sexual behaviors, concurrent STIs, and pregnancy status are critical.
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