AVAC’s Take on Updated WHO Guidance on Hormonal Contraception and HIV Risk

Today, the World Health Organization (WHO) released updated guidance on “Hormonal Contraceptive Eligibility for Women at High Risk of HIV”. The WHO updated guidance shifts DMPA, other progestogen-only injectables and IUDs to a MEC 1 classification, which states that the products can be used without restriction. The updated WHO recommendations follow a thorough review of the latest scientific evidence, including the recent results of the ECHO trial, which evaluated whether the risk of HIV differs with the use of three different safe and effective contraceptive methods: depot medroxyprogesterone acetate-intramuscular (DMPA-IM), also known as Depo-Provera, the copper intrauterine device (Cu-IUD) or a levonorgestrel (LNG) implant, also known as Jadelle.

About WHO’s Updated Guidance

The WHO updated guidance shifts DMPA, other progestogen-only injectables and IUDs to a MEC 1 classification, which states that the products can be used without restriction. This is a shift from the 2017 MEC 2 categorization of progestogen-only injectables, which states that the benefits of a product outweigh the theoretical or proven risks. From 2012 to 2016, DMPA and other related contraceptives were classified as a MEC 1 with a qualification—that the uncertainty around DMPA and HIV risk meant women at high risk of HIV who chose to use DMPA should receive HIV prevention services and counseling. (Click here for a background document on hormonal contraception and the WHO Medical Eligibility Criteria (MEC) system for contraceptives explains key issues in plain language.)

Now What?: AVAC’s perspective on the new WHO guidance

With this new guidance from WHO, DMPA and other progestogen-only contraceptives have their third distinct MEC classification in seven years. While the classification has changed, the context in which women receive HIV prevention and contraceptives and the number of choices available to them have not.

We are gravely concerned that this guidance will be used to justify a “business as usual” approach in which contraceptive procurement, program design, service delivery and counseling approaches go unchanged. This approach ignores women’s priorities and the clear imperative to transform services so that sexual and reproductive health and HIV concerns are addressed in the same place, at the same time, in a stigma-free environment.

The past seven years saw incremental adjustments in the range of methods available in some countries, but nothing approaching the investment and commitment needed from policy makers, funders and implementers of sexual reproductive health & rights (SRHR) and HIV services. These services continue to exist in vertical programs, even though integration is needed as an emergency response to the soaring HIV epidemic in young women—many of whom are far more concerned about avoiding pregnancy than preventing HIV.

The updated WHO guidance will simplify the messages about specific methods. However, meeting HIV and SRHR needs is a complex issue; so is the science around HIV risk and progestogen-only contraceptives. As the Civil Society Advocacy Working Group on HC-HIV noted, any increase in HIV risk associated with method use is unacceptable and the ECHO trial was not powered to eliminate the possibility of risk, but to detect with confidence a 50 percent increased hazard ratio.

This updated guidance reflects evidence on a level of risk determined by the scientific community to be relevant for public health and individuals; but women in all their diversity will want and need to be able to make their own determinations, which is why informed choice and provision of a full range of contraceptives, including alternatives to DMPA-IM, are essential.

The WHO should, with these guidelines, identify specific, actionable and monitorable ways to expand contraceptive method mix and integration of HIV, STI and SRHR products and services, sending a clear signal that the updated classification is not an excuse to preserve the status quo.

Every woman matters and no woman should have to choose between comprehensive sexual and reproductive health services and HIV prevention. Yet today, women’s access to services is under threat by funders who prioritize ideology over evidence and control over bodily autonomy. We must step up and do the challenging work of implementing women-led and -centered programs. If we don’t, the cost in lives will be even higher.

Additional Information about the ECHO Results

The ECHO trial, which released its results in June 2019, enrolled 7,829 women in eSwatini, Kenya, South Africa and Zambia. The women came from communities with high levels of HIV, but they were not recruited for the trial based on any specific risk factors for HIV. They were sexually active, and sought contraception. All of the women received HIV prevention counseling, condoms, HIV tests; a small number used PrEP, as it became available in their countries. The trial was designed with the statistical power to detect a 50 percent increase in risk associated with any method.

ECHO found no substantial difference in HIV risk among women in the trial arms. Based on the design, a smaller level of increased risk, especially below 30 percent, could not be ruled out. Though no method was associated with increased risk, the rates of HIV were alarmingly high in all groups of women: 3.8 percent across all of the participants. (This HIV incidence rate exceeds WHO’s threshold for defining populations as being at “substantial risk”, as stated in the WHO oral PrEP guidelines.) The ECHO trial also revealed concerningly high levels of other sexually transmitted infections (STIs) among women seeking contraceptive services, particularly younger women. Click here to read AVAC’s Understanding the Results of the ECHO Study.

A New Oral PrEP Strategy Is On the Horizon, But Who’s Going to Get It?

Earlier this month, a new daily oral PrEP strategy using F/TAF (brand name Descovy), inched a step closer to availability—though not necessarily for all people who need it. It’s a mixed moment. More strategies are good, but it is unacceptable to skimp on research in ways that leave women or any other population out. The history of the AIDS epidemic is, in part, the history of moving ahead based on research in the bodies of people assigned male at birth—to the detriment of essential knowledge about what works for cis (and trans) women and transmen. This blog provides information on what happened at an Antimicrobial Drugs Advisory Committee meeting on F/TAF for PrEP, convened by the US regulatory body, the Food and Drug Administration (FDA)—and what needs to happen next.

What’s the New Strategy?

Gilead Sciences, the developer and patent holder for Descovy (F/TAF), submitted an application to license F/TAF as a daily oral PrEP strategy for HIV prevention. TAF and TDF (TDF is one of two drugs in the combination TDF/FTC that the FDA approved for PrEP in 2012) represent different prodrug versions of the same compound, tenofovir (TFV). A prodrug is a drug that works only after our bodies have processed, or metabolized, it. It gets activated as our bodies break it down. Many drugs just start working without this activation step, but tenofovir is not absorbed well without this step. TAF is similar to TDF in many ways, but TAF gets metabolized inside cells not the blood. Cells are where the drug needs to be to stop HIV from establishing infection. This difference—being activated at the site where protection is needed, versus in the blood—means that people need a lower dose of F/TAF compared to TDF/FTC to achieve protective drug levels. This also translates to a smaller pill for F/TAF.

How Is F/TAF Different from the Already-Approved TDF/FTC?

Gilead claims that the lower circulating blood levels for F/TAF (described above) might reduce the risk of some of the side effects seen with daily oral TDF/FTC for PrEP (as well as for treatment, for which both drugs have been approved). These include bone density loss and kidney function issues. While the side effect profiles of the two drugs are different, AVAC and other activists have pushed against any claims that F/TAF is “better PrEP”. We welcome strategies that reduce pill size and that may lower toxicities and side effects (less tenofovir in the blood could mean less risk of renal toxicity and bone density loss, both possible with long-term TDF use). But, we don’t want Gilead or anyone else to argue that F/TAF is “better” or “safer” PrEP unless the data clearly show that. As we wrote to the FDA, “Any claims of superiority of F/TAF are an overstatement of the data and, more importantly, will cause enormous confusion among both users and providers of PrEP… All labeling and marketing materials should clearly state these as equivalent daily oral PrEP options.” Click for more on concerns about how Gilead described F/TAF from AVAC, and the Treatment Action Group (TAG) and PrEP4All.

What Happened at the August 7th Hearing?

Gilead presented data from the Phase III DISCOVER trial of daily F/TAF as PrEP amongst men and transgender women who have sex with men. It showed that daily F/TAF is as safe and effective as daily TDF/FTC for HIV prevention in these populations. There is no similar efficacy trial amongst cisgender women, but Gilead did present data, including from a small USAID-funded pharmacokinetic study from research NGO CONRAD, that Gilead hoped would allow extrapolation of efficacy to support a PrEP indication for F/TAF in cisgender women. This CONRAD study of daily oral F/TAF in 72 HIV-negative cisgender women measured the levels of tenofovir (TFV) in the blood among participants. In that study, participants taking F/TAF for PrEP had protective levels of TFV in their blood. (This blood level—associated with a greater-than-90% reduction in risk of HIV acquisition—derived from efficacy trials of TDF/FTC in cisgender women.) The vaginal tissue concentrations in samples in the CONRAD study, though, did not allow the FDA to make any conclusions about protective levels for F/TAF. Since there is no consensus about which levels—blood or tissue—matter most in predicting efficacy, the FDA presentation found it could not conclude that this extrapolation was justified.

AVAC and partners, including TAG and PrEP4All, attended the Advisory Committee and submitted both written comments and presented during the open session of the meeting. The key points from AVAC’s testimony are at the end of this update; additional background materials from the meeting, including submissions from a number of organizations and individuals can be found here.

How Did the Committee Vote?

The Advisory Committee overwhelmingly voted to recommend F/TAF for PrEP in men who have sex with men (MSM) and transgender women by a vote of 16-2. But the committee split 10-8 against recommending F/TAF for PrEP in cisgender women. The panel’s recommendations are advisory to the FDA but are usually followed by the agency. This means that the FDA could approve F/TAF as PrEP for MSM and transgender women, without approving it for use in cisgender women. FDA is expected to announce its decision in early October.

What to Watch For

  • The FDA decision. Their decision is expected approximately two months from the time of the Committee meeting and vote. Advisory Committees provide the FDA with independent advice, but final decisions are made by FDA. The FDA could accept the Committee’s recommendation to approve F/TAF for MSM and transgender women (but not cisgender women), approve a label for all people at risk, or deny Gilead’s application altogether. Typically, the FDA accepts the Committee’s recommendation.
  • Regulatory filings in Europe and Africa, and WHO prequalification and guidelines. The DISCOVER study included sites in Europe, and Gilead will presumably be filing with the European Medicines Agency (EMA) for registration, and/or with national regulatory agencies in Europe.

    Will Gilead file for an MSM and transgender women indication for F/TAF in Africa, and would that make F/TAF use unsafe given the rampant homophobia and stigma still present in many communities?

    If registration will only be in Europe and the US, will Gilead file for WHO prequalification, which would allow F/TAF to be purchased by PEPFAR or the Global Fund? And how would WHO modify its PrEP guidance if F/TAF is approved by the FDA?

  • Safety and effectiveness data in cisgender women. Whether the FDA approves F/TAF for cisgender women or not, there is an urgent need to collect more data in cisgender women, as well as other populations that were not represented well or at all in the DISCOVER trial. AVAC has argued for full approval, with a clear requirement for Gilead to develop and implement a robust post-marketing research agenda to provide data on safety and effectiveness among cisgender women. Gilead has heard collective deep disappointment with their decision not to test F/TAF as PrEP in ciswomen—will they now act?
  • Pricing of F/TAF. Branded TDF/FTC, or Truvada, is shortly coming off patent in the US, finally opening the US market to generic TDF/FTC. What will this mean for pricing for branded F/TAF? The list price in the US for F/TAF is currently identical to TDF/FTC, but the generic price for F/TAF is unknown. It should be less expensive to produce F/TAF because it uses less active drug. Even so, Gilead will likely price it above, and possibly well above, the generic price for TDF/FTC. For public agencies, which still fund the majority of PrEP use either through programs like PEPFAR, national insurance schemes or health programs, any significant cost difference may lead them to stick with TDF/FTC. Gilead’s pricing of Truvada, which has limited PrEP uptake in the US, has been under criticism and legal challenge from groups like PrEP4All.

AVAC’s Bottom Line

  • The available data support approval of F/TAF as an additional non-inferior oral PrEP option. While Gilead representatives and researchers did present data at IAS 2019 that F/TAF was superior in safety and possibly in efficacy to F/TDF, claims of superiority of F/TAF are an overstatement of the available data and could cause confusion among both users and providers of PrEP. An indication that claims superiority could cause actual harm as potential TDF/FTC users delay initiation or current TDF/FTC users abandon PrEP use until F/TAF is later available. We were pleased that in their comments, the members of the Advisory Committee reinforced this view that if approved, F/TAF should not be marketed as superior to TDF/FTC.
  • We support labeling that includes cisgender women as a population that can benefit from F/TAF as PrEP. F/TAF and TDF/FTC represent different tenofovir prodrugs. Gilead did not plan an efficacy trial in cisgender women, hoping that bridging data would be sufficient. There are differing views about which biologic samples matter most in bridging across populations, but the data that were presented do, in our minds, support a label that includes cisgender women. While the Advisory Committee did not vote in favor of recommending F/TAF as PrEP for cisgender women, the comments from the committee members (irrespective of how they voted) did highlight the importance of requiring Gilead to collect this data in the most ethical and expeditious manner.
  • Any indication should be subject to specific post-marketing surveillance, Phase 4 studies and a robust Risk Evaluation and Mitigation Strategy (REMS). We know from earlier oral PrEP trials [of daily TDF/FTC] that efficacy in cisgender women can have wide confidence intervals. Recent data about lipid and weight-gain side effects of TAF compared to TDF, especially in women and individuals of African descent, make strict post-marketing surveillance critical. And, these post-marketing plans should also include other populations (e.g., adolescents and transgender men) that were not part of the DISCOVER trial.
  • Given the fundamental need for additional prevention options for cisgender women, AVAC believes the insufficient process for collecting data in Gilead’s product development plan for F/TAF thus far could be major setback in HIV prevention, and we join the chorus of advocates who are disappointed at Gilead’s lack of commitment to robust testing of this drug for PrEP in cisgender women. This is a unique situation, given that TAF is closely related to TDF, and not an entirely new product. Approving oral F/TAF for PrEP on the limited data is warranted in this case, but should not be the standard by which additional, novel PrEP options are tested and approved. We urge the FDA to hold product developers to a higher standard in drug development plans that will gain sufficient data across a range of populations in a timely and efficient manner, and in advance of regulatory submissions. Robust data across a range of populations at risk of infection must continue to be the standard, so that product development and regulatory approval can lead more seamlessly to acceptance, uptake and adherence by all populations who can – and should – benefit from innovation.

What’s New on AVAC.org and PrEPWatch.org

We don’t want you to miss a host of resources posted in recent weeks on AVAC.org and PrEPWatch. In case you missed them, these tools and resources will sharpen your take on the field.

Reporting on Global HIV Prevention

Check out these reports—recently published by AVAC and partners—for updates on funding trends in prevention and cure R&D, as well as a fresh look at places that have beaten back HIV with existing interventions:

Smarter Rollout

These articles and tools support advocates, implementers and decision-makers working on PrEP rollout today with an eye on future interventions tomorrow:

  • Reaching and Targeting More Effectivley: The application of market segmentation to improve HIV prevention programmes, by AVAC’s Anabel Gomez and others, and published in the Journal of the International AIDS Society, explores how to leverage the power of market segmentation for the promotion and uptake of primary prevention.
  • Just updated in July, AVAC’s Global PrEP Tracker on PrEPWatch.org provides the latest data on programs, number of enrollments by country, regulatory status and more.
  • A User’s Guide to PrEP Tools offers a handy table to navigate the many tools produced by different organizations to support policy makers, implementers, providers and others on PrEP access, uptake and continuation. Use this table to learn more about these tools, who they’re designed for, and when to use them.
  • The PrEP4Youth video series of public service announcements encourages adolescent girls and young women in South Africa to consider PrEP as an HIV prevention method. Created by the OPTIONS Consortium in collaboration with the South African National Department of Health, these videos feature popular actresses and put young women at the center with short empowering messages.

Apply to be an AVAC Fellow in 2020

AVAC would like to remind you that our call for applications for the 2020 class of AVAC Fellows is open until September 20. We encourage you to learn more about the program and share this information with your network!

Ushering in the Next Decade of the Fellows Program: Apply now to become a 2020 Fellow

AVAC is pleased to announce its call for applications for the 2020 Advocacy Fellows—leading us into the next decade of the program!

DOWNLOAD APPLICATION MATERIALS HERE.

The submission deadline for Advocacy Fellows applications is 20 September.

Seventy Fellows have moved through the program in its first 10 years, many of whom have gone on to become leaders in the HIV movement in their communities, countries and globally. As AVAC prepares for our 2020 Fellows Program, watch this space for information about activities and an evaluation marking 10 years of impact on HIV prevention advocacy and to chart the way forward for the program.

About the Program

AVAC’s Advocacy Fellows Program launched in 2009 to expand the capacity of advocates and organizations to accelerate, shape and monitor biomedical HIV prevention research and implementation worldwide. At AVAC, we believe effective and sustainable advocacy grows out of work that reflects organizational and individual interests, priorities and partnerships. The Fellows Program is guided by these principals.

The Advocacy Fellows Program supports emerging and mid-career advocates as they design and implement advocacy projects focused on HIV prevention research and implementation activities in their countries and communities. These projects address locally identified gaps and priorities. Fellows receive training, full-time financial support and technical assistance to plan and implement a targeted one-year project within host organizations working in HIV or related advocacy. Host organizations are critical partners in the program and Fellows’ projects can be an opportunity for an organization to further develop its own work in this field.

The Fellows Program focuses on low- and middle-income countries where clinical research on new biomedical HIV prevention options or HIV cure is planned or ongoing, or where there is demonstrated need for implementation of proven interventions including the integration of HIV and sexual and reproductive health.

HIV Prevention Research Advocacy Fellows are:

  • Emerging or mid-career community leaders and advocates involved or interested in advocacy around HIV prevention.
  • Individuals with some experience or education in the areas of HIV and AIDS, public health, international development or women’s rights.
  • Key populations such as young women, sex workers, gay men, other men who have sex with men, transgender people, people who inject drugs and those living with HIV.
  • Based in low- and middle-income countries where biomedical HIV prevention or cure clinical research is planned and/or where implementation of multi-intervention prevention packages is planned, ongoing or emerging.
  • Fluent English speakers.

Learn More

Prospective applicants or host organizations who want to learn more or have questions are encouraged to:

  • Watch two videos featuring past Fellows reflecting on their experience here and here.
  • Download the 2020 Advocacy Fellows Information Packet and application materials here.
  • Visit AVAC’s Fellows page for more information on the application process and to learn more about current and alumni Fellows.
  • Email the team at fellows@avac.org.
  • Listen to the recording of the 22 August informational conference call with the AVAC Fellows Team to learn more about the program.

Applications are due by 20 SEPTEMBER.

Please share this information with your networks and we look forward to receiving your application.