I remember years ago when the dapivirine vaginal ring showed a 50% drop in HIV infections. Wow, I thought. That’s great. Cutting the risk of HIV in half!
But is that good enough?
Not, apparently, for the U.S. Food and Drug Administration (FDA). At least, not in a country that offers women 99% protection against HIV with Truvada for PrEP and with the new long-acting injectable Apretude—just one shot every two months. To put a new drug on the market, the FDA wants to see something as good as, or better than, what’s already available.
Yet, the U.S. is far behind in PrEP use given the availability, such as it is. HIV prevention workers in the United States, such as those at the Centers for Disease Control and Prevention (CDC), continue to struggle to leverage the promise of PrEP to help end the epidemic.
And both community advocates and providers say there are other issues to consider when weighing the ring—a high level of effectiveness is not the be-all and end-all for prevention.
Stopping the ring
In December, the dapivirine ring was withdrawn from FDA consideration for a New Drug Application (NDA) by the nonprofit International Partnership for Microbicides (IPM). According to IPM, “This decision was made following feedback during the agency’s review that current data are unlikely to support U.S. approval at this time given the context of the current HIV prevention landscape for women in the United States.” IPM had filed its NDA on March 9, 2021.
“IPM is disappointed that the HIV prevention portfolio in the United States will not include the monthly dapivirine ring as an option for women who cannot or choose not to use systemic PrEP but still need a way to reduce their risk of infection,” the organization reported.
“I’m really upset,” said longtime prevention advocate Jim Pickett, a member of the CROI Community Liaison Subcommittee, in a session bringing together providers and advocates. “And I think a lot of people in the United States are upset that American women, who are very vulnerable to HIV, will not have access to the ring.”
In that session, “Rings and Injectable Things: Moving from Options to Choices for HIV Prevention in Cisgender Women,” longtime advocate Julie Patterson, director of the AIDS Funding Collaborative in Cleveland, wrote in a chat box comment, “U.S. women are mad as hell that the ring is not going to be an option for us at this time.”
According to a statement issued in February by the International Community of Women Living With HIV Eastern Africa (ICWEA), “Disappointingly, the FDA decision primarily affects Black and Brown women in the U.S. as one of the communities who already have limited access to oral PrEP compared to other vulnerable groups.” The statement called for accelerated global access to the ring. “Women need more products than only limiting their choice to daily oral PrEP.”
The World Health Organization (WHO) in January of last year recommended the dapivirine ring “as an additional prevention choice for women at substantial risk of HIV infection as part of combination prevention approaches.” Following the IPM decision in December, WHO reaffirmed its support for the ring.
The dapivirine vaginal ring is made of flexible silicone and users can insert it themselves, similar to a diaphragm for birth control. The ring slowly releases the HIV drug dapivirine over the course of a month. Dapivirine is still in development and is used here as a microbicide (such as a spermicide). It’s a low dose, 25 mg. About the worst side effect that’s been experienced is that sex partners may sometimes feel the ring.
Ring research in the U.S.
In the U.S., the MTN-023/IPM 030 study reported back in 2017 at the conference of the International AIDS Society that the dapivirine ring was safe and acceptable in adolescent girls. Both blood levels and residual drug on used rings indicated high levels of adherence. Moreover, adherence to study visits was 97%.
“ ‘Can women adhere?’ We know that’s foolishness,” said Danielle M. Campbell, MPH, co-moderator of “Rings and Things,” of the question. A member of the CROI Community Liaison Subcommittee, Campbell is a sociobehavioral scientist who is both a researcher and an activist.
Adherence—the use of a medication or a product as prescribed—has been a concern of PrEP studies in women. Sometimes a significant number of women were found to have drug blood levels that were lower than needed to prevent infection.
Good adherence, however, has long been a concern in HIV in general. “Take one pill a day with or without food” may not be as easy as it sounds. It’s not just about women and HIV prevention.
Researchers worked to do more to improve adherence in women’s PrEP research. The REACH study is but one which bore good results. Overall PrEP use was higher than in previous studies.
REACH for more: vaginal ring preferred to oral PrEP
At this year’s CROI, the REACH study reported that adolescent girls and women preferred HIV prevention using a vaginal ring rather than taking daily Truvada for PrEP.
“Effectiveness is not the only variable that users care about when selecting a method,” said Kenneth Ngure, MD, of Jomo Kenyatta University School of Agriculture and Technology, in Nairobi, who presented the REACH findings at CROI and joined the “Rings and Things” session. “What REACH has taught us is that young women want choice.”
Asked how he would respond to people who question the need for a ring when a highly effective, long-acting injectable is available, Dr. Ngure replied, “It’s an interesting question and it’s something that we’ll need to think through in terms of messaging. But as you’re seeing, efficacy is not the only thing that people think about. You can have an efficacious product, but if it’s not used, then it’s worse off, probably, than a lower efficacious product that is used.”
REACH participants used both oral PrEP and the ring, for six months each. For the crossover part of the study, they were then able to continue with one or the other PrEP method of their choice. Two-thirds of the 227 participants in the crossover portion chose the dapivirine ring over oral PrEP.
Drug level testing showed some-to-high use of the ring and moderate-to-high level of oral meds. Overall PrEP use was “much higher than has been reported in other clinical trials or other implementation studies,” said Dr. Ngure. Adherence was “similarly very high for the two products.” REACH provided adherence support, such as daily text messages, that were chosen by participants from a menu of options. There was also a community workshop before the study began. Young women reported a desire for friendly clinics and friendlier providers among their preferences for PrEP delivery. The women who showed a high-level use of the oral PrEP preferred to continue using it.
The girls and women were in South Africa, Zimbabwe, and Uganda. See Late Breaker Abstract 88 at croiconference.org.
Learning from contraceptives
A lesson learned from contraceptives for women is that more choices lead to greater use, said Dominika Seidman, MD, MAS.
Dr. Seidman, an obstetrician/gynecologist and PrEP provider based at Zuckerberg San Francisco General Hospital, spoke at the “Bringing Choice to HIV Prevention” symposium at CROI.
The world of LARCs—long-acting reversible contraceptives—shows that women and providers might see choices differently.
LARCs, such as the IUD (intrauterine device), are highly effective, said Dr. Seidman. They may not require daily, weekly, or even monthly maintenance, so there’s little concern over adherence. They have an acceptable, sometimes even desirable, side effect profile. They are, as their name says, reversible. And on top of all that, they’re cost effective.
Yet, she reported, research discovered that the medical establishment, often through education campaigns, had to urge women to use LARCs. There were negative results and unintended consequences. There were high discontinuation rates, and many of the women came to distrust their providers.
Moreover, at least one study, showing providers hypothetical case studies, reported that for low-income women, the providers were more likely to recommend the use of LARCs if they were Black or Latina over low-income White women; among White women, providers were more likely to recommend long-acting methods for poor White women than for middle-income White women. The findings “demonstrated how racism and classism influence provider practices,” said Dr. Seidman.
“There are many other qualitative studies demonstrating how Black and Latinx individuals perceive subtle provider preferences, which negatively affect not only their contraceptive use but their future healthcare experiences,” Dr. Seidman said.
She quoted one woman whose doctor refused to remove her long-acting contraceptive: “My provider was really hesitant to remove the [IUD]. She kept telling me, ‘Well, we should wait three months and see if your symptoms have worsened.’ And I waited three months and she’s like, ‘Well, you should wait some more.’ And I’m like, ‘No. So take it out or I’m going to a different doctor.’” Dr. Seidman said she thinks of that story every time a patient asks her to remove an IUD.
Another woman told a researcher, “I don’t know if it makes [providers] look bad if you have an IUD removed … I don’t know if they have some chart somewhere, like a contest board in the breakroom…”
“These stories clearly come much farther down the implementation path than where we are today with PrEP,” said Dr. Seidman. “However, they provide an important cautionary tale, as the family planning community is now playing catch-up to rebuild trust and after not only exclusively emphasizing the importance of effectiveness, but also pressuring users into using methods based on the provider biases and discriminatory practices around who needs, rather than who wants, long-acting methods.”
She said that REACH shows the same concept for HIV PrEP—effectiveness is not the only thing that matters.
Nearly two years ago, in its first ever podcast, the HIV prevention advocacy organization AVAC covered the topic of partial protection. “Whether it’s condoms, a flu shot, oral PrEP, or the dapivirine vaginal ring, proven products fall short of 100 percent protections against disease, and there’s a lot to know about how and why an intervention may offer imperfect but still useful protection,” AVAC reported at the time. Asked how a product with a 50 or 60% protective effect translates into a benefit, panelist Penny Moore of the University of Witwatersrand in South Africa responded, “It’s stacking the odds in your favor.”