“In the face of a stable HIV epidemic among women, contraceptives are not the driver of substantial HIV risk,” said Renee Heffron, Ph.D., of the University of Washington, at the Conference on Retroviruses and Opportunistic Infections (CROI). This was shown by the ECHO trial in southern Africa, where seroconversion rates were similar across the study’s three arms of long-acting birth control methods: injections of depot-medroxyprogesterone acetate (DMPA-IM, Depo-Provera), a levonorgestrel contraceptive implant, or an intrauterine device. While results from that study and the controversy surrounding it were already reported last year, this year researchers presented a number of substudies that explored biologic changes related to contraceptives, both in HIV-negative cisgender women and in women living with HIV.
Rubina Bunjun, Ph.D., of the University of Cape Town, South Africa, reported that cervical samples from 72 women showed Th17 cells, a type of inflammatory cytokine, that were more activated in those on DMPA-IM compared to those in the other two study arms. General genital inflammation was higher among women using the IUD compared to those in the other two arms, another substudy among 190 women showed, according to Ramla F. Tanko, Ph.D., also from the University of Cape Town. However, greater inflammation did not affect seroconversion rates in either substudy.
Other changes to the vaginal environment, however, may make a woman more susceptible to acquiring HIV. In general, a lactobacillus-dominant environment helps keep virions, including HIV, out, while a more diverse set of bacteria increases the risk of seroconversion two- to fourfold, explained Caroline Mitchell, M.D., of Massachusetts General Hospital. That susceptibility is likely related to mucosal inflammation, which can counteract the benefits of pre-exposure prophylaxis (PrEP). “Inflammation totally overwhelms any protective benefit of tenofovir,” Mitchell said.
However, some birth control products may actually improve the vaginal environment. A combination estrogen/progestin vaginal ring studied in women taking atazanavir (Reyataz) or efavirenz (Sustiva, Stocrin) and in an HIV-negative control group was associated with a lactobacillus-heavy vaginal community, Nicole Tobin, M.D., of the University of California, Los Angeles, reported. When the ring was removed after three weeks, the diverse bacteria associated with a higher risk for HIV acquisition returned.
Bacterial vaginosis can also increase susceptibility to HIV when samples are exposed to the virus in a lab dish, Marla Keller, M.D., of the Albert Einstein College of Medicine, explained. Once the vaginosis was treated, susceptibility dropped. “These findings have implications for adolescents and women of color, who have higher rates of a non-lactobacillus-dominant microbiome,” she concluded.
Most studies on sex differences in HIV acquisition are conducted among cisgender women, Eileen P. Scully, M.D., Ph.D., of Johns Hopkins University, noted. “Hormones, environment, and epigenetics all contribute to sex differences,” including those in HIV acquisition, she explained. There is little data on how these interactions play out in transgender women. Despite women’s high HIV burden, few are included in clinical trials. “We need policy support for representation of women, with specific enrollment goals by sex and gender, and also trial structures that incentivize the enrollment of women,” she demanded.
One case in point was the recommendation issued after the safety signal on dolutegravir (Tivicay, DTG) was published. At the time, it appeared that infants born to mothers taking dolutegravir were at greater risk for neural tube defects. The World Health Organization recommended that women should use that antiretroviral only if reliable contraception was available, but no data on interactions between the HIV drug and common contraceptives were available, Kimberly Scarsi, Pharm.D., of the University of Nebraska, said.
Given the variety of antiretrovirals and birth control options, one or two studies won’t be enough to cover the possible interactions. “One size doesn’t fit all,” she noted, and data from one study cannot be extrapolated to other contraceptive products.
Non-oral contraceptives, such as a vaginal ring, are not necessarily free of interactions, either. For example, in a Kenyan study, hormonal implants failed to prevent pregnancy in women who were taking efavirenz-based antiretroviral therapy at 2.6 times the rate of those on nevirapine (Viramune)–based treatment. At that time, efavirenz was recommended as first-line antiretroviral therapy in South Africa. Study results and other issues led to an increase in requests for early removal of the implant, for which the South African health care system was ill-prepared, explained Gregory Petro, M.B.Ch.B., of the University of Cape Town.
One takeaway from the experience is that rollout of an implant—be it to prevent pregnancy, HIV acquisition, or both—must include planning for its removal. Furthermore, multilingual and multicultural information must be provided to allow women to make an informed choice about their birth control, he demanded.
Women not only need the information, they also need to be able to choose freely, added Wame Jallow of the International Treatment Preparedness Coalition, who is based in Botswana. Recently, the South African Commission for Gender Equality found that women living with HIV had been coerced into signing documents that permitted them to be sterilized when they gave birth. Beyond that extreme, stigma and discrimination from health care workers, pressure to use whatever contraceptive method is in stock, inaccessibility of long-acting contraceptive methods, and other issues are common, Jallow’s survey of 198 women living with or vulnerable to HIV found. Participants recommended meaningful involvement by affected women at all levels, from policy to the design of individual trials; integrated, one-stop sexual health and reproductive services with sufficient stock of various options; and non-judgmental family-planning information for women living with HIV, among other things.
After the study of interactions between efavirenz and contraceptive implants, the South African government recommended that women using that birth control method be instead prescribed dolutegravir. That antiretroviral not only does not reduce hormone levels from implants, but may actually increase them, Rena Patel, M.D., M.P.H., of the University of Washington in Seattle, reported. The pharmacokinetic PARVI study included 195 women on two different doses of efavirenz or on dolutegravir, as well as an HIV-negative control group. All participants were using a contraceptive implant, either with etonogestrel or levonorgestrel. While etonogestrel concentrations were higher in the plasma of women taking dolutegravir than in the HIV-negative group, this presented no safety or tolerability problems.
Results are reassuring so far, said Patel, although analysis of the other groups in the trial is still ongoing. She called on researchers and others “to advocate alongside women living with HIV in asking our institutions, such as the FDA and pharmaceutical companies, to study a broader range of contraceptive methods prior to clinical approval” to avoid a repeat of the problem with efavirenz and hormonal implants.