Is Hormonal Contraceptive Use a Factor in HIV Vaccine Trials?

By Emily Bass

The choice to use—or not use—condoms impacts enormously on women’s risk of acquiring HIV. But it is possible that other methods of contraception could also impact women’s susceptibility to HIV—for better or for worse. For example, new studies are looking at whether the diaphragm reduces HIV acquisition risk by covering the cervix, a site that is particularly vulnerable to infection. And there is a large body of data, much of it contradictory, on how hormonal contraceptives (HCs) might affect acquisition of HIV.

All of this work has implications for vaccine trials. In addition to providing ongoing condom promotion, vaccine trials also ask women participants to use an effective form of birth control to prevent pregnancy during the study. If these methods do impact on vulnerability to HIV, they could also affect analyses of vaccine efficacy, a possibility that was raised at a recent NIH-sponsored meeting on fertility regulation and HIV. [Fertility Regulation and Systemic Hormones in HIV-infected and At-Risk Women (13-14 January 2003, sponsored by the National Institutes of Health, McClean, VA)]

The meeting began with an overview of HC-HIV research by by Christine Mauck of CONRAD (Arlington, Virginia), a reproductive health research organization. Mauck traced the topic back to a 1991 study led by Frank Plummer (University of Manitoba), which found a link between longer duration of oral contraceptive (OC) use and HIV infection in a cohort of Kenyan sex workers. Follow-up research in sex workers, including studies by Julie Overbaugh (University of Washington, Seattle), confirmed this finding and extended it to injectable contraceptives (ICs) such as Depo-Provera. But other studies, including new data from serodiscordant couples cohorts in Rwanda and Zambia, and from the Rakai district community cohort in Uganda, did not find this association. Overall, Mauck said that the HC-HIV link was seen in studies of sex workers and women with multiple partners but not in studies of women recruited from family planning and antenatal clinics.

Fine-tuning Messages and Protecting Options

In the face of this contradictory data, most researchers agree that including information about potential HC-HIV interactions in family planning education could do more harm than good, by scaring women away from a birth control method that affords great privacy and autonomy.

The current popularity of HC was dramatically illustrated in a talk by Iqbal Shah (World Health Organization), who reported that in the six countries at the heart of the African AIDS epidemic—Botswana, Swaziland, Zimbabwe, Lesotho, Zambia and South Africa—66% of women who practice family planning use hormonal pills or injectables, while only 4% rely on condoms. Shah and others pointed out that this figure shows the failure to position condoms as tools for preventing pregnancy as well as STDs.

Researchers like Julie Overbaugh and Susan Allen (University of Alabama, Birmingham), a lead investigator on serodiscordant couples studies, suggest that AIDS research projects, including vaccine trials, can help develop more nuanced messages. Trial sites can work with local family planning clinics, to include IUDs, diaphragms, and other methods, and can tailor their messages depending on the study population. For instance, Overbaugh suggests that in sex worker populations, trial planners “would have to think twice about intervening to promote any kind of hormonal contraceptive use.”

A Potential Trial Variable

When a vaccine is eventually licensed, it will have to work in populations that include HC users. As Overbaugh suggests, vaccine trials can help gather data on whether and how these methods impact vaccine efficacy in preventing HIV infection or slowing disease.

The most compelling data relating to this question come from Overbaugh and her colleagues, including the Mombasa Research Team. Speaking at the recent Keystone HIV Vaccine Conference in Banff, Overbaugh reviewed data gathered from a group of female sex workers who have been followed for ten years so far. In this group, OC or IC use increases the risk of becoming HIV infected—and appears to be linked to faster rates of disease progression. In 2000, her group published data showing that many of these women were infected with more diverse viral populations than men (Nat Med 6:71;2000). Since then, she’s presented as-yet unpublished data which show a link between diversity and more rapid disease progression. This diversity is more likely to be seen in women who use hormonal contraceptives than matched peers who used other methods of birth control. Overbaugh also mentioned an earlier study showing that women who use OCs shed more virus, and that shedding increases with OC dosage.

Some of these unpublished data were presented by Over-baugh’s colleague Jared Baeten (University of Washington, Seattle) at the February 2003 Retrovirus meeting. In this study, women who used the injectable contraceptive DMPA (the generic name for Depo-Provera) at the time of HIV infection had a persistently higher viral set point (by 0.3 log) and faster CD4 cell count decline than those who did not use ICs. Both of these trends are associated with more rapid disease progression. Reflecting on the implications for vaccines, Overbaugh says, “Trial designers will have to include hormonal contraceptive use as a variable,” and monitor potential effects on transmission and progression.

Probing for Mechanisms

Why might hormonal contraceptives affect risk? Animal and basic science studies have provided some intriguing clues.

One early theory suggested that progesterone decreases the thickness of the vaginal membrane, which in turn facilitates HIV infection. This hypothesis has been tested in at least three primate studies, including a widely-discussed experiment by Preston Marx (Tulane University, New Orleans) in which female macaques were given implants that elevated progesterone to levels seen in the second half of the menstrual cycle. These macaques and a control group, which received placebo implants, both received a low-dose vaginal challenge. Monkeys with implants were nearly eight times more likely to become infected than the control group (which was challenged during the first half of the menstrual cycle, when progesterone levels are at their lowest.) Vaginal biopsies on a parallel set of animals showed that progesterone-treated monkeys had significantly thinner vaginal membranes.

But the explanation may not be so simple. Subsequent studies linked progesterone treatment to vaginal thinning in monkeys, but also found that monkeys, who have thinner vaginal mucosae than women, metabolize progesterone more slowly than humans. Monkeys also exhibit different tissue changes across the menstrual cycle.

Another point is that hormonal contraceptives might alter the genital tract immune milieu. Many components of this environment, including cell populations, activation markers and cytokine-secretion patterns vary across the menstrual cycle under natural hormonal regulation. Mucosal immunologist Charles Wira (Dartmouth University, New Hampshire) has found fluctuations in expression of CCR5 and CXCR4 (receptors that HIV uses to enter cells) in uterine epithelial cells across the menstrual cycle (samples obtained from patients undergoing hysterectomies).

A recent study from Manu Prakash at Imperial College, London (J Reprod Immunol 54:117;2002) showed differences in activation markers and cell populations in cervical samples from HIV- and STI-negative women (sampled at the same time in their menstrual cycles) using hormonal contraceptives, compared with those who did not. HC users had a higher level of CCR5 expression on cervical CD4 and CD8 T-cells compared to non-HC users, and a higher proportion of dendritic cells—targets for HIV infection—in the cervical epithelium.

While intriguing, these studies do not explain why HCs would be associated with HIV acquisition in some women and not in others. One theory is that sex workers have a different level of immune activation in the genital tract—perhaps due to exposure to STIs and semen from many partners—and that HCs may have a more pronounced impact in this context. New answers could come from a 6,000-women study in Uganda, Thailand, and Zimba-bwe, that will compare rates of HIV infection, pregnancy and contraceptive method-switching in women using both HCs and condoms and those using condoms alone.

As these population-based data are being gathered, Wira advocates a complementary focus on hormones and local immune responses in vaccine trials. “If you’re trying to interfere with infection in a setting where the immunologic parameters vary, then of course these variations need to be considered.”  •

The Female Genital Tract: A Glossary

Ectocervix: a zone of tissue on the outer cervix; thicker than the endocervix and with a squamous epithelial layer contiguous to the vaginal mucosae. Endocervix: a zone of tissue characterized by a thin columnar epithelial layer containing target cells for HIV, including macrophages and dendritic cells. Endocervical secretions are sampled using “SnoStrips” or swabs; cell samples are obtained using cytobrush, which dislodges cells within the cervical canal. Lower reproductive tract: vaginal canal and cervix (uterine opening). Upper reproductive tract: uterus, ovaries and fallopian tubes. Vaginal Mucosae: highly heterogeneous tissue of the lower reproductive tract; top layer (vaginal epithelium) containing squamous cells (see ectocervix) and a range of immune cells, such as dendritic cells and macrophages, although at lower proportions than in the endocervix. The epithelial surface is covered in mucins, IgA, IgG (components of the adaptive immune system) and innate defense components.