HIV Prevention Vaginal Ring Withdrawn From FDA Consideration

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HIV Prevention Vaginal Ring Withdrawn From FDA Consideration

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Tosha Rogers, MD, is a one-woman HIV prevention evangelist. For nearly a decade now, the Atlanta-based ob/gyn has been on a mission to increase her gy

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Tosha Rogers, MD, is a one-woman HIV prevention evangelist. For nearly a decade now, the Atlanta-based ob/gyn has been on a mission to increase her gynecological colleagues’ awareness and prescribing of the oral HIV prevention pill. At the same time, she’s been tracking the development of a flexible vaginal ring loaded with a month’s worth of the HIV prevention medication dapivirine. That, she thought, would fit easily into women’s lives and into the toolbox of methods women already use to prevent pregnancy.

But now she’s not sure when — or if — the ring will find its way to her patients. In December, the ring’s maker, the International Partnership for Microbicides (IPM), pulled its application for FDA approval for the pre-exposure prophylaxis (PrEP) ring. Now, one year after the World Health Organization recommended the ring for member nations, there appears to be no path forward in the United States for either the dapivirine-only ring or an approach Rogers said would change the game: a vaginal ring that supplies both contraception and HIV prevention.

“It would take things to a whole other level,” she said. “It sucks that this happened, and I do think it was not anything medical. I think it was everything political.”

That leaves cisgender women — especially the Black and Latinx women who make up the vast majority of women who acquire HIV every year — with two HIV prevention options. One is the daily pill, first approved in 2012. It’s now generic but previously sold as Truvada by Gilead Sciences. The other is monthly injectable cabotegravir long-acting (Apretude). Another HIV prevention pill, tenofovir alafenamide/emtricitabine (Descovy), is approved for gay men and transgender women, but not cisgender women.

Vagina-Specific Protection From HIV

The WHO recommendation for the vaginal ring was followed last July by a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for women in low- and middle-income countries outside the European Union (EU).

The flexible silicone ring, similar to the hormonal NuvaRing contraceptive, works by slowly releasing the antiretroviral dapivirine directly into the vaginal canal, thereby protecting women who might be exposed to the virus through vaginal sex only. Because the medicine stays where it’s delivered and doesn’t circulate through the body, it has been found to be extremely safe with few adverse events.

However, in initial studies, the ring was found to be just 27% effective overall. Later studies, where scientists divided women by how much drug was missing from the ring — a proxy for use — found that higher use was associated with higher protection (as much as 54%). By comparison, Truvada has been found to be up to 99% effective when used daily, though it can take up to 21 days to be available in the vagina in high enough concentrations to protect women from vaginal exposure. And the HIV prevention shot was found to be 90% more effective than that in a recent trial of the two methods conducted by the HIV Prevention Trials Network.

This, and an orientation away from topical HIV prevention drugs and toward systemic options, led the National Institute of Allergy and Infectious Diseases (NIAID) to discontinue funding for such projects under its Microbicide Trials Network.

“Clearly you want to counsel women to use the highest efficacy method, and that is part of our label,” said Zeda Rosenberg, ScD, IPM’s founder and chief executive officer, told Medscape Medical News. “Women should not choose the ring if they can and will use oral PrEP, and I would argue it should be the same thing for [cabotegravir shots]. But if they can’t or don’t want to — and we know that especially many young women don’t want to use systemic methods — then the dapivirine ring is a great option.”

Still, Rosenberg said that the gap in efficacy, the relatively small number of women affected by HIV in the US compared with gay and bisexual men, and the emergence of products like the HIV prevention shot cabotegravir, made it “very unlikely” that FDA regulators would approve the ring. And rather than be “distracted” by the FDA process, Rosenberg said IPM chose to concentrate on the countries where the ring has already been approved or where women make up the vast majority of people affected by HIV.

Zimbabwe publicly announced it has approved the ring, and three other countries may have approved it, according to Rosenberg. She declined to name them, saying they had requested silence while they formulate their new HIV prevention guidelines. Aside from Zimbabwe, the other countries where women participated in the ring clinical trials were South Africa, Malawi, and Uganda.

“The US population…has widespread access to oral PrEP, which is unlike countries in Africa, and which would have widespread access to injectable cabotegravir,” she said. “The US FDA may not see choice in the same way that African women and African activists and advocates see the need for choice.”

But women’s rates of accessing HIV prevention medications in the US continues to be frustratingly low. At the end of 2018, just 7% of women who could benefit from HIV prevention drugs were taking them, according to Centers for Disease Control and Prevention data.

New CDC guidelines recommend clinicians talk to every sexually active adult and adolescent about HIV prevention medications at least once, and prescribe it to anyone who asks for it, whether or not they understand their patients’ HIV risks. However, research continues to show that clinicians struggle with willingness to prescribe PrEP to Black women, and the American College of Obstetrics and Gynecology’s committee opinion on managing women using HIV prevention drugs has not been updated to reflect the new guidelines. And while the HIV prevention shot is approved for women and its maker ViiV Healthcare is already initiating postmarket studies of the ring in key populations including women, there are lots of things that need to line up in order for clinicians to be willing to stock it and prescribe it to women.

From where Dázon Dixon Diallo sits, the decision to withdraw the ring from FDA consideration and the FDA’s seeming argument that the epidemiology in the US doesn’t warrant the ring’s approval, is a slap in the face to the Black women who have led the movement to end HIV in the US for decades.

“No matter how you slice it, we’re talking about Black women, and then we’re talking about brown women,” said Dixon Diallo, executive director of the nonprofit SisterLove. “The value [they place on us] from a government standpoint, from a political standpoint, from a public health standpoint is just woeful. It’s woeful and it’s disrespectful and it’s insulting and I’m sick of it.”

“America Sneezes and Africa Catches a Cold”

When she first heard the decision to pull the ring from FDA consideration, Yvette Raphael, the South Africa-based executive director of Advocates for the Prevention of HIV in Africa, started asking, “What can we do to help our sisters in America get this ring?” And then she started worrying about other women in her own country and those nearby.

“The FDA plays a big role,” she said. “You know, America sneezes and Africa catches a cold.”

She worries that IPM’s decision to withdraw the ring from FDA consideration will signal to regulators in other countries either (a) that they should not approve it or (b), in countries where it’s already been approved but guidelines have not been issued, that they won’t invest money in rolling it out to women in those countries — especially now with the US approval of the prevention shot. In much of Africa, ministries of health prefer to provide injectable contraception, often giving women few or no other options. But women, she said, think about more than administration of the drug. They look at if it’s an easier option for them to manage.

“This is a long journey, an emotional one too, for women in South Africa, because the idea of a microbicide is one of the ideas that came directly from women in South Africa,” she said. “[The jab] can be seen as a solution to all. We can just give jabs to all the women. And after all, we know that women don’t adhere, so we can just grab them.”

Rosenberg pointed to the positive opinion from the EMA as another “rigorous review” process that she said ought to equally influence ministries of health in countries where women tested the ring. And she pointed to the WHO statement released last month, the same day as IPM’s announcement that it was withdrawing the ring from FDA considerations, recommitting the ring as a good option in sub-Saharan Africa: “The US FDA decision is not based on any new or additional data on efficacy and safety,” it stated. “WHO will continue to support countries as they consider whether to include the [dapivirine vaginal ring]. WHO recognizes that country decision-making will vary based on their context and that women’s voices remain central to discussions about their prevention choices.”

Dual Action Ring on the Horizon, but Not in US

What this means, though, is that the next step in the ring’s development — the combination dapivirine ring with contraceptive levonorgestrel (used in the Mirena intrauterine device) — may not come to the US, at least for a long while.

“It’s not out of the question,” Rosenberg said of conducting HIV/pregnancy prevention ring trials in the US. “But without the approval of the dapivirine-only ring by FDA, I imagine they would want to see new efficacy data on dapivirine. That is a very difficult hill to climb. There would have to be an active control group [using oral PrEP or injectable cabotegravir], and it would be very difficult for the dapivirine ring to be able to go head-to-head for either non-inferiority and certainly for superiority.”

The study would need to be quite large to get enough results to prove anything and IPM is a research organization, not a large pharmaceutical company with deep enough pockets to fund that, she said. Raising those funds “would be difficult,” she added.

In addition to NIAID discontinuing its funding for the Microbicides Trials Network, a new 5-year, $85 million research collaboration through USAID hasn’t slated any money to fund trials of the combination HIV prevention and contraceptive ring, according to Rosenberg.

But that doesn’t mean avenues for its development are closed. NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is currently funding a phase 1/2 trial of the combination ring, and IPM continues to receive funding from research agencies in Germany, the Netherlands, Denmark and Ireland. And this means, she said, that the EU — not the US — is where they would seek approval for a combination ring first.

That leaves Rafael and Dixon Diallo debating how to work together to push the FDA —and maybe IPM — to reconsider the ring. For instance, Dixon Diallo suggested that instead of seeking an indication for all women, the FDA might consider the ring for women with very high risk of HIV, such as sex workers or women with HIV positive partners not on treatment. And she said that this has to be bigger than HIV prevention. It has to be about the ways in which women’s health issues in general lag at the FDA. For instance, she pointed to the movement to get contraceptive pills available over the counter, or fights against FDA rulings on hormone replacement therapy, or fights for emergency contraception.

In the meantime, ob/gyn Rogers is expecting access to the ring to follow a similar path as the copper IUD, which migrated to the US from Europe, where it has been among the most popular contraceptive methods for women.

“Contrary to what we may think, we are not innovators, especially for something like this,” she said. “Once we see it is working and doing a good job — that women in Europe love it — then someone here is going to pick it up and make it as if it’s the greatest thing. But for now, I think we’re going to have to take a back seat to Europe.”

Dixon Diallo reports receiving fees from Johnson & Johnson, ViiV Healthcare, and Gilead Sciences. Rosenberg and Rogers have disclosed no relevant financial relationships.

Heather Boerner is a science journalist based in Pittsburgh, Pennsylvania. Her book, Positively Negative: Love, Pregnancy, and Science’s Surprising Victory Over HIV, came out in 2014.

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