The body of evidence related to hormonal contraception and HIV risk is having a growth spurt in 2015. In the beginning of January, Lauren Ralph and her colleagues published a meta-analysis of existing observational data on different contraceptive methods and rates of HIV acquisition among women. We described the approach used in this study in an AVAC blog post and a piece for RH Reality Check.

Less than two weeks later, another meta-analysis has arrived. This one comes from a team led by Charles Morrison of FHI 360 in PLoS Medicine and includes a range of collaborators including some of the researchers involved with the planned ECHO trial that proposes to directly evaluate the relationship between three different contraceptive methods and HIV risk.

The bottom line from this new study is that its findings line up with all of the available data, though with the slight nuances and variations that come with different approaches and data sets (read on for more on this). Overall, they found no evidence that oral hormonal contraceptive pills increase women’s risk of HIV. Once again, their data indicated that Depo Provera (DMPA) may potentially increase women’s risk of HIV acquisition. In this study, the findings were:

• Across all the data analyzed, DMPA was associated with an increase in women’s risk HIV acquisition by about fifty percent compared to women who were using condoms, diaphragms, sterilization, non-hormonal IUDs or no method of contraception.
• DMPA was associated with an increase in women’s risk of acquisition by about thirty to forty percent compared to women using combined oral contraceptives or the injectable NET-EN.
• Most importantly, in studies that the authors evaluated as having less methodological bias, the risk related to DMPA use was lower—only about 20 percent higher than women condoms, diaphragms, sterilization, non-hormonal IUDs or no method of contraception. Methodological bias is a major challenge for observational data, which can measure but not control for factors that might skew the outcome (e.g., the reasons a woman chooses one method versus another might also put her at increased or decreased risk of HIV).

This was one of the handful of evaluations of the relationship between NET-EN, a lower dose injectable contraceptive—and there was a slight association between NET-EN use and increased HIV risk, but it was lower than DMPA, and not statistically significant. This finding may perhaps supporting the theory that alternate dosages and formulations of DMPA might not be associated with an increase in HIV risk.

For advocates who want to get deep into the data to date, here are a few things to note about the new study (Morrison et al) compared to Ralph et al from earlier this month.

Methods and data sources:

1. The Morrison et al meta-analysis analyzes individual participant data. The researchers who did this review were able to access the data for individual participants from a range of studies. Ralph et al looked at study data and overall findings. This is the way trial data are most commonly presented—e.g., the overall findings across all participants, average ages and so on. Morrison et al, via agreement with various study investigators, went back to the original by-participant data and re-analyzed these findings. (All of the women who had participated in the original studies have given consent for this type of additional analysis to be done, though not this specific study.)
2. Morrison et al included participant data from a large study of women’s vaginal practices. This study had never published data on the relationship between hormonal contraception and HIV, so it was not been included in the other meta-analyses. Many of the other studies included have also been examined in Ralph et al and in previous systematic reviews. (Our previous blog described the difference between a meta-analysis and a systematic review.)

Findings:

1. Morrison et al found that use of DMPA was associated with increased risk of HIV acquisition, but that both the magnitiude and the statistical significance of this finding (eg the degree of confidence that it was real and not a coincidence) risk varied by the quality of the studies considered. Studies with less bias showed less associated risk, and included the possibility of no associated risk. Ralph et al found an overall association but  studies that involved women in the “general population” (not sex workers or women in serodiscordant couples) had lower risk.
2. Both Morrison et al and Ralph et al found a moderate increase in risk of HIV acquisition associated with DMPA, with a range between 20 percent and 50 percent depending on the subset of data considered. However these findings carry caveats. All conclusions to date have been drawn from observational data and have included the finding that there’s a great deal of variation depending on study quality and/or the population considered.

So, where does this leave us?

Evidence but no certainty, according to Morrison et al, who argue that these data confirm the need for a randomized trial that would seek to eliminate bias and get more clarity on three methods: DMPA, the Jadelle implant and the copper IUD.

AVAC and partners continue to work together to understand these findings, communicate them and to advocate for research, policies and programs that expand women’s range of contraceptive choices in the context of informed choice.

The European AIDS Treatment Group and AVAC organized an unprecedented three-day workshop: New Developments in HIV Prevention. The EATG-AVAC collaboration is an attempt to update EATG members on the latest developments in biomedical HIV prevention approaches; facilitate the exchange of state-of-the-art information on HIV prevention research topics between researchers and the community; and strengthen local and regional advocacy efforts in the area of HIV prevention R&D and related national/EU policies and funding.

Leading European advocates and researchers filled a Brussels conference room to discuss the latest scientific achievements in vaccines, treatment as prevention and ARV-based prevention in all its forms, and how to translate advances in science into infections averted in Europe and beyond. Representatives of several pharmaceutical companies were also on hand to provide their perspectives.

In addition to comprehensive updates on product pipelines across the prevention research landscape, the group is actively discussing the anticipation of the first data from European oral PrEP trials and the implications for PrEP access in Europe. Results from both the UK PROUD and French IPERGAY studies are scheduled for presentation at next month’s CROI conference.

Leading up to this meeting, EATG and AVAC hosted a webinar series in advance of the meeting so participants could bone up on new biomedical prevention developments. A meeting report and PowerPoint presentations will be available soon; in the meantime, get daily updates from the meeting and download the presentations from EATG member Tamas Bereczky’s blog.

In addition to our P-Values posting yesterday, AVAC’s Emily Bass also wrote a longer piece for the Reproductive Health Reality Check blog, which contains expanded analysis and information. Read it here and remember to check the blog and join our Advocates’ Network for continued updates and ways to engage on this issue.

A newly published analysis by Lauren Ralph et al and an accompanying commentary in the journal Lancet Infectious Diseases is stirring up questions about the relationship between DMPA (brand name 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 state that DMPA 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 over-simplified statement that DMPA increased women’s risk of acquiring HIV by about 40 perent. This isn’t precise or true. Because DMPA is an important contraceptive choice – it is discrete and provides protection against unwanted pregnancy for three months after a single shot – and because in many parts of the world, DMPA is the only long-acting, discrete option available to women, it is really important 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 important thing to understand about this new paper is that it is not based on new data. It is a new analysis of a set of observational studies of rates of HIV in women using different contraceptive methods. All but one of the studies included in the analysis here has been included in previous systematic reviews. (There is a difference between previous systematic reviews and the statistical meta-analysis used in this paper… more on that follows!)

The bottom line is that this conclusion is not based on new information; it just crunched the numbers in a different way.

Here are some key points to help advocates read, analyze and act on the latest information.

About the data analyzed and the methods

• The study by Ralph et al is different from previously published papers for two main reasons. First: It is a statistical meta-analysis, rather than a systematic review. Second: It includes one recent paper that was published after the most recent systematic review. What do these terms mean?
• Systematic reviews, as the name implies, typically involve a detailed and comprehensive plan and search strategy for identifying and synthesizing all relevant studies on a particular topic.
• A meta-analysis involves using statistical techniques to combine data from multiple studies (such as those identified in a systematic review) into a single quantitative estimate or summary effect size.
• Conducting a meta-analysis of observational data can be a controversial technique to use. There is often disagreement about whether it is or is not appropriate to combine studies into a single estimate. Some experts have argued that this approach can result in “spurious precision”, since the summary estimate will only be as good as the studies combined to produce it.
• What does these terms mean in the context of the new paper?
• Previously published systematic reviews have identified all of the studies that exist at a particular time on this issue. The most recent systematic review published in October 2014 by Polis et al. is available online. That systematic review concluded that the relationship between injectable hormonal contraception and HIV risk is inconclusive. It recommended that women choosing progestin-only injectable contraceptives such as DMPA or NET-EN should be informed of the current uncertainty regarding whether use of these methods increases risk of HIV acquisition. It also emphasized that users of DMPA and other injectables should be empowered to access and use male and female condoms and other HIV prevention tools. Messages and programs that support “dual protection” (against unwanted pregnancy and infection with HIV and other STIs) should be provided to all women at risk of HIV.
• Prior systematic reviews of the HC-HIV acquisition question have carefully described the methods, results and interpretation of the body of evidence, but they deliberately chose not to have crunched the numbers from all of the studies together, due to methodological concerns with that approach. A meta-analysis is when the number-crunching happens. That’s what makes the Ralph meta-analysis new.
• The Ralph meta-analysis includes one new study (Crook et al 2014) that was published subsequent to the most recent systematic review.
• All of the studies considered in the systematic reviews and in this meta-analysis are observational. None of these studies randomly assigned women to different methods, they could have biased results (women who choose a specific contraceptive method might have other factors that affect their HIV risk that the study doesn’t pick up on).
• The studies that were considered include:
• Data gathered from studies that were designed to answer other questions (e.g. a study looking at herpes treatment in serodiscordant couples that also documented women’s contraceptive use).
• Prospective studies that followed women who had chosen different contraceptive methods and gathered information about HIV rates among women using different methods.

About the findings

• The Ralph meta-analysis concludes that there was evidence of a “moderate increase” (40%) in HIV risk in the ten studies of DMPA use that were combined. There was no evidence of increased HIV risk associated with oral hormonal contraceptive pills or in other progestin-only injectable contraceptives (e.g. NET-EN). The meta-analysis of all the studies yields an overall increase in risk of about 40 percent or a hazard ratio (HR) of 1.40.
• The increased risk is greatest in women at “high risk” of HIV infection, which the authors define as women who engage in commercial sex work and/or those who are in serodiscordant couples. A sub-analysis that excluded data from high risk women found a 30% increase, or HR of 1.30 among women in the “general population.”
• The authors note that “Meta-analyses of observational studies, like observational studies themselves, are inherently prone to bias and cannot be used to address whether the association between hormonal contraception and HIV is causal”. This caution is consistent with previously published systematic reviews of observational data, in which authors have deliberately chosen not to quantitatively combine estimates.

About the authors’ interpretation and conclusion

• The authors argue that the estimate of increased risk (40% or an “odds ratio” of 1.40) should be used to guide more precise models of what it would mean if DMPA does, in fact, increase HIV risk. These models calculate the relative contribution to new HIV infections given different theoretical estimates of the magnitude of risk associated with DMPA use. All of the modeling studies conclude that the question of whether DMPA increases HIV risk is of greatest relevance in Eastern and Southern Africa, where injectable contraceptive use and HIV rates are both high.
• The authors also argue that that the moderate risk associated with DMPA use should be weighed against the risks of maternal morbidity and mortality if DMPA is “banned”. This is a misleading statement. In the many discussions at WHO, country and community levels that have taken place in the past few years on this issue there is no scenario or proposal in which DMPA would be banned or even removed from programs without provision of a comparable alternative. 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, discrete methods, such as implants and the intrauterine device (IUD), that could be used instead of DMPA by women making informed choices based on what is known and unknown about all the options available.
• The authors argue that the findings “emphasize an immediate need” to look more closely at how DMPA use might impact risk among women in serodiscordant relationships and/or women engaged in sex work. They suggest additional analyses of existing data in these populations, but don’t suggest a change in policy or messaging.

About what should happen next

• These findings are not news in and of themselves. They identify the same trend seen in some individual studies and utilize the same information as in previously-published systematic reviews. However, each time a study or analysis is published on this issue, particularly when the results suggest a significant effect, in a zone of such uncertainty—it triggers fresh discussion and debate. There have already been a range of media reports focusing on the “40 percent” figure and suggesting that this is now the definitive estimate of HIV-related risk for injectable HC users. In light of this publication, it would be appropriate for the WHO to re-convene an expert stakeholder group to review both current recommendations and communications strategies regarding DMPA and similar products with a particular focus on the countries in East and Southern Africa where rates of HIV and DMPA use are high.
• The study and the accompanying commentary reference, without naming, the proposed ECHO trial that would use a randomized design to directly measure rates of HIV in women using three different methods: DMPA, the Jadelle implant and the copper IUD. 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 DMPA and other hormonal contraceptive methods. We have articulated the need for a trial that provides clarity and is able to influence policy. It is critical that the ECHO team engage with civil society stakeholders to explore the understanding and implication of this paper as part of a broader discussion about the planned launch of the trial later in 2015.
• During the recent “summit” of the FP2020 initiative (the global family planning initiative that aims to increase women’s access to contraception worldwide), FP2020 leadership indicated that it would await and follow the results of the ECHO trial as well as country and WHO guidance. It is invaluable to the field for FP2020 to convene a meeting of family planning policy makers and implementers in potentially-affected countries to discuss existing plans, proposed expansion of method mix and processes for interpreting and acting on these results.
• There is a robust civil society constituency following the issues around HC-HIV. Members of this dialogue have diverse views on whether a randomized trial such as ECHO is on the critical path—but are united in the need for family planning and HIV programming to:
  • Address the uncertainty with clear messages on knowns and unknowns, risks and benefits of all methods;
  • Invest in increased method mix today; and
  • Sustain investment in developing new contraceptive, HIV prevention and, especially, multipurpose prevention options that could, in the future, reduce HIV risk and prevent unwanted pregnancies.

AVAC will continue to work with partners to distill new findings, convene dialogues with scientists and other partners and ensure that an informed advocacy voice helps guide decisions in this key area. To get involved and hear what’s next, watch this space or contact us.

It is sometimes said in our field that clinical trial protocols are too complex for community members to review. But we also say research should not go forward without the approval of the community. How can community members, activists, and other people whose primary expertise might not be clinical research provide meaningful input into protocols and broader research agendas? The Community Research Advisors Group (CRAG) has released a new tool to help with this challenge. Take a look here at A Protocol Review Companion for Activists.

Mark S. King of MyFabulousDisease.com published a piece in The Body listing 15 HIV advocates worth watching in 2015. The list includes AVAC’s 2014 Fellow Yvette Raphael of South Africa.

In the city of Midrand Gauteng in South Africa, Yvette Raphael stays busy running her catering company. “I do it because I love making people happy and every meal is prepared with love,” she says. Love is also something Yvette shares generously with her extended family, including three young girls living with HIV for whom she serves as guardian and mentor.

None of these responsibilities, though, have kept her from becoming an emerging voice for women living with the virus.

Diagnosed with HIV in 2000, Yvette contributes to a number of national and global efforts, including working in support of the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), the Campaign to End AIDS, and serving as a 2014 AIDS Vaccine Advocacy Coalition (AVAC) Fellow associated with Johns Hopkins University. Her influence is growing faster than a baking souffle.

“Yvette is a rare breath of fresh activism in a time in the AIDS movement that needs more advocacy and policy change, not less,” said Dazon Dixon Diallo, founder of Sisterlove and one of the preeminent global voices for HIV among women. “She comes to the movement with a fierce brilliance and a fearless voice for women, youth and the African LGBTQ community. Yvette is a young, single mother who works hard to defend and protect the human rights of all, especially young girls. She rocks on all fronts!”

Click here to read about the other 14 advocates!

In an article for HIV Plus Magazine, Charles Stephens, founder of the Counter Narrative Project and a member of AVAC’s PxROAR advocacy cadre, talks about the importance of gay black men remembering “our legacy” related to HIV and AIDS and stigma and discrimination.

“The black gay male experience is profoundly alienating,” says Charles Stephens in front of a packed audience…

“As black gay men, more often than not, we are denied a history, denied a culture, and often represented in the most narrow and simplistic forms. We are robbed of our lovely complexity far too often in mainstream culture, and that is in itself a form of violence. To strip someone of their complexity is to strip them of their humanity.”

The article also talks about the black gay male experience in the US as it relates to the broader LGBT agenda of marriage equality. Read more.

AVAC would like to wish our advocates and friends from across the globe a Happy New Year! The Weekly NewsDigest will return to its regularly scheduled delivery this Friday.

Here’s to much success this New Year!