The Latest Study on Depo-Provera and HIV: Far More Complex Than Most Headlines Suggest

Because Depo-Provera is an important contraceptive choice and because in many parts of the world, it is the only long-acting, discreet option available to women, it is vital to take the issue of a link between HIV and hormonal contraception quite seriously while adding nuance to the discussion.

Because Depo-Provera is an important contraceptive choice and because in many parts of the world, it is the only long-acting, discreet option available to women, it is vital to take the issue of a link between HIV and hormonal contraception quite seriously while adding nuance to the discussion. Shutterstock

A newly published study by Lauren Ralph et al and an accompanying commentary in the journal Lancet Infectious Diseases is stirring up questions about the relationship between Depo-Provera, and other progestogen-only injectable contraceptives, and the risk of HIV acquisition among HIV-negative women. Based on a meta-analysis of previously published studies, the report’s authors determined that Depo use is associated with a “moderate risk” of HIV infection.

The study triggered a wave of headlines and tweets that boiled down the complexities and caveats of this analysis into an oversimplified statement: Depo increases women’s risk of HIV by 40 percent. Because Depo is an important contraceptive choice—it provides protection against unwanted pregnancy for three months after a single shot—and because in many parts of the world, it is the only long-acting, discreet option available to women, it is vital to add nuance to these headlines, while also taking the issue of a link between HIV and hormonal contraception quite seriously.

The first, and arguably most crucial, thing to understand about this new paper is that it is not based on new data, or raw information. It is simply a new analysis of a set of observational studies of rates of HIV in women using different contraceptive methods. Previous systematic analyses have included all but one of these studies; last week’s paper simply crunched those numbers, so to speak, in a new way.

About that number-crunching: Ralph’s paper concludes that those previously published studies, when analyzed as a group, suggest that there is an overall increase in risk of about 40 percent of contracting HIV associated with using Depo. The increased risk is greatest in women at “high risk” of HIV infection, which the authors define as HIV-negative women who engage in commercial sex work and/or those with known regular HIV-positive partners (women in what are known as “serodiscordant couples”). When these “high-risk” women were excluded from this meta-analysis, there was a 30 percent increase risk associated with Depo use. The study authors described this analysis as the risk for women in the “general population.”

The question of whether hormonal contraception of any kind—pills, injectables, and implants—increase HIV risk has concerned sexual and reproductive health advocates—who among other things want to simultaneously prevent HIV and ensure people can plan pregnancies—for many years. Previously published systematic reviews of observational data have examined the results from many studies and haven’t settled the question. The Ralph paper is the latest addition to this body of literature.

Like all the previous analyses, Ralph’s paper worked with existing observational data, which was gathered from studies that were either not designed to specifically address the hormonal contraception-HIV link or did not randomly assign women to use a specific method. Observational data of this kind has inherent biases—for example, women who choose a specific contraceptive method might also have other attributes that affect their HIV risk. Observational studies can try to identify factors like these, but it’s not possible to account for everything that might be in play. So although a paper like the Ralph study might be giving what looks like a precise estimate of risk associated with Depo use, it’s on the basis of studies that, by definition, lack a high degree of precision.

Previous analyses have looked at all but one of the studies included in the Ralph paper. These earlier analyses were “systematic reviews” that sifted through available studies, selected ones with high-quality evidence and analyzed the findings. The bottom line from this approach: Some observational studies did show an increased risk linked with Depo use, and others did not. In fact, the conclusions from the most recent systematic review emphasized the ongoing uncertainty around the subject and the need for all women, including those using Depo and other injectables, to be counseled and empowered to access and use male and female condoms and other HIV prevention tools.

Those systematic reviews did not perform statistical analyses that pooled all of the results of the different studies to come up with a single numerical estimate of risk. The Ralph paper did—and this is what makes it both new and particularly prone to alarmist headlines.

The authors argue that the 40 percent estimate of increased risk linked to Depo use should be used to guide more precise models of the impact of Depo on HIV infections in different settings. These models calculate the relative contribution to new HIV infections given different theoretical estimates of the risk associated with Depo use. Such models have been developed to show how much of an impact Depo would have to have on HIV risk to make the number of new infections outweigh the risk of unplanned pregnancy for women. Here, too, it’s important to understand the scenarios in question. Some of the models suggest that the choice is Depo or nothing—which is not necessarily a realistic assessment.

The authors pick up on this theme, arguing that the moderate risk associated with Depo use should be weighed against the risks of maternal morbidity and mortality if Depo is “banned.” This is a misleading analysis: In the many discussions at the World Health Organization, country, and community level that have taken place in the past few years on this issue, there is no scenario or proposal in which Depo would be banned or even removed from programs without provision of a comparable alternative.

Instead, the relevant proposals and programs—as exemplified by South Africa’s new contraceptive policy—seek to expand “method mix” (the range of options women can choose from). Specifically, the proposals and programs identified by advocates, funders, and many other stakeholders focus on expanding the use of other long-acting, discreet methods such as implants and the intrauterine device (IUD) that could be used instead of Depo by women making informed choices based on what is known and unknown about all the options available.

That said, having a more precise estimate to use in models can help policymakers, communicators, advocates, and program implementers have more informed conversations about what to do given the current uncertainty. It’s also really important to remember that all of the models conclude that the question of whether Depo increases risk is of greatest relevance in East and Southern Africa, where injectable contraceptive use—Depo is often one of a very limited number of contraceptive options available—and HIV rates are both high.

Every time a new study about Depo and other hormonal contraception and HIV comes out, women ask their peers, the Internet, or the Twitterverse, what it means for them. The meta-analysis isn’t designed to provide guidance for individuals per se, and the authors steer clear of it. So we’re left with existing guidance and precedent to help make practical suggestions. A few things stand out: For the individual Depo user, the reality is that there is uncertainty about how this contraceptive method affects her risk of HIV. But there are data that suggest that Depo use might increase risk of HIV acquisition. Women who don’t know their partners’ status, or do know that they have an HIV-positive partner, or who have many partners and are concerned about HIV, should be using condoms, and this has always been the case. Women using Depo who fall into these categories can consider switching contraceptive methods if there is another one that is available that meets their needs—but it is an individual choice, and there is no normative guidance (such as from the WHO) that says what the best alternative option is.

In addition, one interpretation of the study’s results is that there is an urgent need for a trial that would use a randomized design to directly measure HIV rates of women using three different methods: Depo, the Jadelle implant, and the copper IUD. This type of trial design would eliminate many of the biases associated with observational data and could provide much-needed clarity on the issue. It would also gather data on newer methods, such as the implant, which also contain hormones. Right now, there’s no information on the implant and HIV risk.

As the study authors and the authors of the commentary acknowledge, there has been a lot of debate and discussion about such a trial. AVAC has worked in coalition with ICW East Africa, the ATHENA Network, and many other women’s organizations to articulate the urgent need for clarity on the relationship between HIV risk and Depo, and other hormonal contraceptive methods. We have articulated the need for a trial that provides clarity and shifts policy.

But this is one viewpoint. There is a robust civil society constituency following the issues around hormonal contraception and HIV. Members of this dialogue have diverse views on whether a randomized trial is the correct path. This study is a potent reminder that this issue needs all hands on deck to clarify what is known and unknown, and to help articulate that the way forward doesn’t hinge on one number, one trial, or one opinion. HIV programming and family planning must address the uncertainty with clear messages on the risks and benefits of all methods; invest in increased method mix today; and sustain investment in developing new contraceptive, HIV prevention and, especially, multi-purpose prevention options that could, in the future, reduce HIV risk and prevent unwanted pregnancies. It is a multi-faceted approach to match the multi-faceted reality of women’s health needs—that may not fit in a headline, but it’s the honest truth and an urgent priority.