On July 24, the European Medicines Agency (EMA) adopted a positive opinion on the dapivirine vaginal ring for use by cisgender women ages 18 and older in developing countries to reduce the risk of HIV. The ring is an important user-controlled option for women who choose not to, or are unable to, use pre-exposure prophylaxis (PrEP).
According to the World Health Organization (WHO), at the end of 2019 there were 38 million people living with HIV worldwide. And with this positive-opinion announcement, science is bringing women closer to a future where they have additional opportunities to protect themselves from HIV. After decades of work on microbicides, activists and scientists around the world are applauding this announcement.
To learn about the positive opinion adopted by the European Medicines Agency—and more about the dapivirine vaginal ring—Terri Wilder spoke with Zeda Rosenberg, Sc.D., of the International Partnership for Microbicides (IPM), and Manju Chatani, M.P.H., of AVAC.
Rosenberg is the founder and chief executive officer of the International Partnership for Microbicides, a nonprofit dedicated to developing products that will give women the tools they need to prevent HIV and protect their sexual and reproductive health. A microbiologist, epidemiologist, and widely recognized expert in HIV prevention, Rosenberg has been on the forefront of research in biological and behavioral factors for reducing HIV transmission for over 30 years. Under her leadership, IPM developed the monthly dapivirine vaginal ring, the first long-acting HIV prevention product.
Rosenberg’s research has helped call attention to the impact of gender inequality on the HIV/AIDS epidemic and aims to empower women by expanding their options to stay HIV free on their own terms. Previously, she served as scientific director for the HIV Prevention Trials Network at Family Health International and as senior scientist at the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH). Rosenberg holds an M.S. in epidemiology and an Sc.D. in microbiology from Harvard University.
Manju Chatani joined AVAC in 2009 as senior program manager focusing on partnership management and capacity strengthening. Currently, she oversees AVAC’s Advocacy Fellows Program, coordinates activities in building civil society capacity and preparedness for microbicide introduction and other interventions that can be important to women’s HIV prevention, and is also AVAC’s liaison to several partner groups and collaborative projects. She was on the AVAC board prior to joining the staff. She cofounded the African Microbicides Advocacy Group in 2003, which she coordinated till 2008.
Prior to that, she worked with Health and Development Networks, an organization she cofounded, facilitating information-sharing among the international civil society involved in AIDS work. She has worked as a community mobilizer in Ghana, program manager in South Africa and Thailand, networking manager in Switzerland, and HIV case manager in Hawaii. Her work has been published in several peer-reviewed journals, and she has a master’s degree in public health.
Terri Wilder: Dr. Rosenberg, let’s start at the beginning. Can you talk about when and how your organization got involved in the development of the monthly dapivirine vaginal ring?
Zeda Rosenberg: Well, the when is an easy answer. The when is, for the ring, 2004-2005. A long time ago. And the why is answered more directly by talking about the whole field of microbicides, which I think was brought into being in 1990 by Dr. Zena Stein, when she issued a commentary, saying that women needed more HIV prevention options.
And so, the need for microbicides was identified back in 1990, and I think a lot of people were working very hard from that time forward to get to the place where the International Partnership for Microbicides had been established by the Rockefeller Foundation and many other donors to help focus efforts in this area. And we were able to acquire the worldwide rights, initially developed the country rights and subsequently worldwide rights, for dapivirine, a very potent antiretroviral drug, from Johnson and Johnson [J&J]. And we were able to think about formulations that could enable women to have choice in reducing their risk of HIV infection.
There were many gels, microbicide gels, in development. And we thought that we didn’t need to add to that body of work; so many people were doing a good job there. And we thought that perhaps a formulation that could help take [out] the element of remembering to use something every day, or at the time of sex, could enable some women to reduce their risk of infection.
That’s where the ring technology came. And the ring technology existed on the market for post-menopausal hormone replacement. And so, we were able to marry the two; we were able to marry a potent antiretroviral drug with a technology for slow-release delivery. We had to make many, many adjustments along the way. The marriage required a great deal of arrangement. And we were able to, after four tries, come up with the formulation that would get positive scientific opinion from the EMA.
TW: Manju, can you talk about the role of AVAC in microbicides and, in particular, the vaginal ring?
Manju Chatani: Sure. Advocates, in general, have been involved in this field for as long as there has been a field. As Zeda said, in 1990 Zena Stein wrote that paper calling for options. And advocates really took on that call and honed it, demanding that there are options that women can control so they won’t have to ask permission to protect their lives. Through the years and last few decades, advocates have raised the profile and the need for microbicide research, and helped to mobilize resources, demand ethical research, and that community voices have a voice in shaping the agenda and in specific protocols; and helping to communicate the field.
AVAC has participated in that throughout these years, but more so as it grew its profile from an organization that was focusing on vaccine research to one that really looked across the field and worked to support and ensure research so that new evidence-based tools find their way into policies and programs as rapidly as possible, so they get into the hands of people who need them.
In terms of the ring, again, we’ve been involved in an advocacy perspective for as long as we can talk about microbicide research has happened—in supporting it and doing all the different things. But in particular, you know, we helped to strengthen the capacity for women’s health advocates to be able to engage in this space and have built an ad hoc cohort of women’s health advocates to connect with this—and have been watching it, have been building awareness in their own countries and communities.
AVAC also worked with both IPM and the Microbicide Trials Network to do consultations to ensure that as different studies of the ring have been designed, that community input has been engaged very early on, and throughout the process; not just when results were made. We disseminated; we’ve also helped communicate the main results of different studies, ongoing research, together, again, with IPM and the MTN. But also individually with different advocates.
Of late, we’ve also—you know, we’ve donated the work AVAC does into also supporting implementation of new products and new product introduction. And so, I work with a consortium of partners and with IPM to look at staff designing and planning for introduction; to really learn the lessons from PrEP, that we don’t want to wait until the product is ready and then figure out how to produce it; and have worked with partners to speak to countries’ implementers about it and policy makers about what they need, what information they need, what kind of tools they need, what kind of modeling they need, to the point that if public opinion is recommending the approval, that they can quickly move to the next step.
TW: Dr. Rosenberg, what does it actually mean for the EMA to give the ring a positive opinion? And can you talk about the research that had to happen to get us to the point of getting that positive opinion?
Rosenberg: Certainly. We chose to go the pathway of the European Medicines Agency because they had a process called Article 58 that enabled a review of the regulatory dossier on the ring to be conducted as thoroughly as if it could be marketed in Europe, but with the caveat that we didn’t want to market it in Europe; we wanted to market the ring—or distribute the ring—in developing countries with the highest risk of HIV infection. Indeed, that is the mission of IPM as a not-for-profit organization that receives donor funds to achieve that mission.
And so, one of the very important aspects of Article 58 is that it allows the World Health Organization, WHO, to participate in the review process, as well as African national regulators who choose to observe the process. And for us, we already understood from consultations with many African regulatory agencies that what was critical for them was WHO’s feelings, thoughts, about the product; their guidelines for use on the product; and their prequalification of the product—that it was an important and high-quality product. And so, Article 58 allowed WHO to participate so that it allowed for more seamless integration of getting a positive opinion and WHO review and approval of the product.
And so, what the next steps really are for WHO now, with this positive opinion—they have already set the time for a meeting of their Guidelines Committee that will review the data on the ring and hopefully suggest revisions to the HIV prevention and treatment guidelines. That will then allow them to apply for the ring to be on the Essential Medicines List, and also for WHO prequalification.
And that time frame, because of Article 58, is a much more shortened time frame than would ordinarily occur. Because what we wanted to do was to give the African national regulatory agencies all of the information that they needed in order to review and approve the ring. So that truly is going to be the next step with the guidelines and with WHO prequalification, as well as working with WHO on a collaborative review mechanism with African governments.
TW: Manju, I know that AVAC works internationally. And I’m wondering if you could share some perspective, or maybe even a story, about an activist, particularly in Africa, that’s really been working hard to get us to this point in history.
Chatani: That’s a hard question, Terri. Because now I have to choose between stories. Because there are so many inspirational stories of women who have been focusing on this and using it.
I won’t give you a story, but I’ll tell you that when the EMA opinion finally came out—and I say finally because a number of us were watching that space for two years, I think, waiting for that opinion and for the next steps; and there was an impromptu celebratory phone call. And there were advocates from South Africa, from Zimbabwe, from Uganda, really claiming part of this step and what it means, and really owning it. It was really a different experience than some of the other recent results that have sometimes, to be honest, thought of to have much higher efficacy. And I think that’s part of the ownership that so many advocates have felt.
So, I will tell you that there is a young woman. She’s 24 and from Zimbabwe. She was an AVAC Advocacy Fellow in 2019. And she was, unbeknownst to us (and I think unbeknownst to IPM), called by WHO to give testimony during the EMA meeting to discuss the ring and anything about giving it a positive opinion.
And so, she talked to me about what she wanted to talk about. She said what the ring was really important for was to give young women choice, and that right now, the only choice young women have is merely to choose—you know, for something they can control, it’s just really—oral sex. Because with condoms, whether it’s female or male condoms, they have to negotiate. But even oral sex is not for everyone.
And she used herself as an example, and she said, “You know, when I was younger, I was too afraid to use anything else. And I would use a condom. And now, it feels like oral sex; it seems like what everyone is pushing.” But she said, “I hate taking efavirenz. And I actually don’t want something in my body all the time. And so the ring gives me that option. And the ring gives me choice. And that’s what young people want. We want choices. Because we won’t need the same product all the time.”
And it was really good to hear that from a young woman. And it resonates to what we hear in the contraceptive field. Allow me to just also tell you a story of a ring participant. This was a trial participant, you know, in one of the ring studies. And she is a huge champion.
I was in a discussion group where a researcher asked her, “So you’re very excited.” And you know, this researcher works in a different field; it was at a conference. And the researcher asked her, “So, you’re excited about the ring. That’s great. But what if there is a new product which is more efficacious, like an injectable?”
And she said, “I don’t like injections. And I think injectables; you get more options. It goes right into your bloodstream. And that’s good for people who have many ways they can get HIV.” She said, “But for me, I have only one way I can get HIV. And so for me, the ring works. And I know that the medicine won’t stay in my body all the time. And, yes; I understand about its effectiveness. And it’s fine with me, to pick something I can use. And I don’t have to ask permission every time. I don’t need to talk about it but once.”
And she has continued to be a voice in this space. In fact, she was on our webinar, as well, talking about this.
And I bring up those two stories because I think, going forward into this introduction phase, it’s going to be essential to include the voices of trial participants who have actually been in these studies, who have used the ring, who will tell us how much they need—how easy it was for them; how it works with their life.
And for young women, who we really are looking to support in making decisions about protecting themselves that work for them; these are folks who are more recent in their advocacy. But these are some of the things we have to continue to relate.
TW: Dr. Rosenberg, I have a lot of questions about the actual ring. So, I’m just going to throw out a couple of questions to you. How does the ring actually work? What is the dosage of the medicine? What is the ring made out of? How do you actually put it in your vagina?
And I guess the other thing is: What is dapivirine?
Rosenberg: OK. Well, we’ll start with the drug; and that is dapivirine. The drug that is in the vaginal ring is a highly potent antiretroviral drug that, in very small amounts, can be very highly effective in the test tube against HIV.
It is very inexpensive to make, which is one important aspect of it—because we knew that this ring needed to be affordable and accessible to women in resource-poor settings. And it is put into, mixed into, liquid silicone, which is kind of like a rubber. It is mixed in with the silicone and it’s given a catalytic agent that helps it solidify.
The liquid is first poured into these ring molds. And it is catalyzed, and it hardens. It ends up being a very flexible, circular, white ring that contains this drug, dapivirine.
The ring can be easily twisted into kind of a figure-8 shape and inserted by the woman into her vagina. When it is inserted correctly, it just goes in. It doesn’t have to be fitted; it’s one size fits all. It kind of untwists and expands, and it is placed high up in the vagina. It is not felt by the woman at all. And it is rarely if ever felt by the male partner during sex. Many men reported feeling it, but only after they were told it was there. When they didn’t know it was there, most men didn’t feel it.
It slowly releases the drug dapivirine into the surrounding tissue in the vagina so that it saturates the tissue in the vagina, so that when a woman has vaginal sex, and HIV comes in during sex, it gets into vaginal cells. But this drug prevents the virus from replicating so it cannot set up an initial vaginal infection.
So, that is the goal; it’s to have a lot of drug at the site of infection, where the virus first enters the body. And very little drug goes throughout the bloodstream. It really does stay locally—which is why I think some of the women were saying they really didn’t want to have a drug in them all the time. The drug is there, but it’s in vaginal tissue. It’s not circulating at high levels, or even modest levels, around the body. It gets absorbed at very, very low levels.
And so, its systemic side effects are negligible, if any; and even local side effects were not observed in the trials. So it has a very good safety profile, as seen through all of the studies. And we’re very happy about those findings.
TW: Is there a reason why—and I don’t obviously know the science behind why dapivirine was chosen; but is there a reason why Truvada wasn’t used? Or another medicine?
Rosenberg: Well, the reason why dapivirine was used is because it was so inexpensive to make, highly active in very low quantities, and is part of a class of drugs called nonnucleoside reverse transcriptase inhibitors that were already used successfully for prevention of mother-to-child transmission.
And so, that was why this was chosen for use. We also knew that there were many other people who were looking at Truvada as a possible HIV prevention drug. For the most inexpensive ring technology, dapivirine works well. Truvada requires, because it is very water soluble; it requires a different kind of ring technology.
And so, we were going for something that was the simplest and most cost-effective product, with a highly active antiretroviral drug that had been originally developed as a therapeutic, along with other NNRTIs from J&J, but was considered almost too easy to copy from a patent-protection side. And for us, that was not an issue. Because if someone can make dapivirine easier and cheaper, that would be great. We’re a nonprofit. We just wanted to be able to make the most effective product at the lowest cost.
TW: Got it. I’m also curious about Descovy. Did you consider that? Or is anybody else considering it as a vaginal ring? Would it work as a vaginal ring?
Rosenberg: There are people who have been looking at Descovy. We did not because, again, we started this work in 2004-2005. And Descovy was not yet there.
TW: Got it. And what is the dosage of dapivirine in the ring?
Rosenberg: There is 25 mg of dapivirine in the ring. And the ring is intended to be used for a month at a time. The woman inserts it on Day 1 and removes it on Day 28 or 29 or 30. And, over the course of the month, it releases approximately 4 mg to 5 mg of drug. And you have to have a certain level of drug in the ring to almost be able to push the drug out of the ring. So, not all 25 mg of the drug comes out; only 4 mg to 5 mg of the drug comes out.
We are also now developing a ring that may be useful for three months at a time, if a woman doesn’t feel the need to change her ring every month, which would be her choice. But that’s a ring that would be in development further on that will likely have, you know, several hundred milligrams of drug.
TW: Manju, can you talk about why it’s important for women to have access to this HIV prevention tool? And what will be some important educational messages for women who may consider using it in the future?
Chatani: Thank you for that question. I think that the dapivirine vaginal ring is really great for women who need it, want it, and will use it. I think the one thing that sustains its use for a long time is that there are no magic bullets. And yet, every time there’s a tool people act like that’s the one that’s going to change the epidemic.
But we believe that the more people who use products means there are more to choose from. And we’ve seen that in the contraceptive field. That’s why we’ve been fighting for choice for a long time. But not just choice of all products—a choice of long-acting, shorter-acting, systemic, and non-systemic, so that we are really trying to find products that fit into the lives of people. And lives of women. We believe that this is one product that, for some people, could be really important.
The concept of women controlling themselves is also critical. Now, that doesn’t mean that we’re encouraging people not to talk to their partners. But for women who are unable to negotiate, for women who it’s more difficult, this is really an excellent option.
Often, people talk about the ring that, even if you do need to negotiate; the negotiation happens once. Like Zeda said, in research, many men didn’t know it was there until their partners actually told them. So there’s a discretion. Using a discreet product is also important. The long-acting part, for a month—you put it in, and you don’t have to think about it—is really important.
All of that, in a really powerful drug, and really effective. But it’s only as effective as the consistency of use. And what we’re seeing with PrEP rollout is there are women, and young women, in particular, who do have difficulty using it. So, for those people who can’t use it, this is an excellent option. And, again, talking about the young woman I described earlier: Choice is essential. So, these are some of the reasons.
What’s interesting about the ring for us as well is that it’s a platform for some of the multipurpose prevention technologies that are in the field. We know that there is a ring in research that will have both contraceptive and dapivirine, and that will be released at the same time.
So, ensuring that this platform gets through for the future, as you can see, is critical. Because that’s what we always learn from women: that it would be great if there was one product that did both things, so that they wouldn’t have to continually be thinking about protecting—you know, the contraception and HIV prevention. And if it could be in the same space that we receive the same drug, or in the same device; that would be excellent.
So that’s another reason. And the truth is, the infection rates in women are really just really high. If we looked at 10 to 13 years ago, the MIRA study showed HIV infection in a population of 4%. We saw those same numbers in the ECHO trial, and also in the vaccine trials earlier. This was in [HIV Vaccine Trials Network study] 702.
In the last decade, we haven’t been able to bring down that generalized infection rate. So we need to do new things. We need to introduce new things. We need to really give women choices so that they can take things that will work in their life. And then to give them some of the reasons. And I think that the vaginal ring could be an important tool and provide an option for women to choose.
TW: I’m just curious, Dr. Rosenberg: Are there any medications that a woman could be taking while the ring is in her that could have a contraindication that would be important to know about?
Rosenberg: Because so little drug is absorbed into the bloodstream systemically, there is no contraindication to systemic use of products. We also looked at the possible interaction of dapivirine with some locally administered antifungal medications, yeast medications; as well as antibacterial medications. It appears that they can be used without concern. Although it’s always a better option, perhaps, for women with yeast infections or others to take more active oral medications, as they do in the developed world.
But no; there are no contraindications to its use, with the exception of HIV infection. We don’t want products that contain antiretroviral drugs—like Truvada, or dapivirine, or any other antiretroviral drugs—to be used for prevention when a person is already HIV [positive].
TW: As I’m listening to the two of you speak, I can’t help but think about when the, quote, female condom came to market. I’m wondering if there’s any possibility that people might try to use this ring for anal sex and put it in their rectum, even though it was created for vaginal use. And what might that look like? What can potentially happen if it is used that way?
Rosenberg: Well, the ring has not been tested anally. And so, I think that it will be clearly stated on the label that it should not be used anally. It is only intended for vaginal use.
And since we haven’t tested it, there’s no way to know whether there could be any protection. But it was really designed to be comfortably used vaginally.
TW: Has there been any kind of projections on cost? Will it require a prescription, versus over the counter? I’m just kind of curious about those logistical questions about cost; how do you get it, how will it be packaged? That kind of thing.
Rosenberg: Well, it’s intended to be packaged as either a single ring or as three rings in one box. And, again, because it is likely that quarterly or every three months, HIV testing will be needed before a woman gets another set of three rings. So that would be the packaging.
We are working very hard at getting the cost down as low as possible. Currently it is approximately $7 to $8 a ring. We will try very hard; with higher volumes, we know that we can get that cost down by a few dollars. And then, with even higher volumes, we believe that the cost of the ring could be as low as $3 a ring—somewhere in that area—at the loading dock.
The goal, of course, of the three-monthly ring, would be to even drive the annual cost down lower. Because the cost of the drug is so low, a three-month ring would likely not be much more than a one-month ring in cost. And then you’d only need four of those a year, rather than 12 of the monthly rings. So, our goal was to drive this down as low as possible. And we’re working with the manufacturer and looking at different kinds of technologies to drive that down.
One of the very nice features of the ring is that it has a very long shelf life—four to five years—so that rings can be made in quantity and not have to be used immediately. That’s also one of its very important features.
TW: And how will it come packaged; will it require a prescription?
Rosenberg: Ah, the prescription. Likely yes, because it is a new chemical entity and it’s its first introduction to the market. And there will, of course, need to be pharmacovigilance when a product is first introduced. Usually products are granted non-prescription status after a lot of experience with the product.
TW: Great. And Manju, I’m going to ask you the final question, which is: What can activists be doing right now to push this forward, not only in countries with higher incidence of HIV; but I’m also thinking about the United States and for women at risk, particularly in the South, which is actually where I’m from?
Chatani: Thank you for the question, Terri. So, one thing we’re delighted about is that IPM is going to submit to the FDA, as well, for regulatory approval. And that will give advocates in the U.S. [a chance] to really push after that for availability in the U.S. of the ring. You know, if it gets a positive approval from the FDA. So that is a case that we are seriously watching. And we’ll be on hand when the FDA makes this decision. Because that will be a green light for advocacy in the U.S., to move along that path.
But, you know, in general, there are real paths in Africa, as well. There are many things advocates can do now. And one is to track the regulatory process.
It’s great that WHO is committed to this and has already called for a date. But the community wants really stakeholders to also be part of that decision-making; and also an update in the guidelines.
Advocates can really call for any research agenda from there, on the post-authorization research or any implementation research happening, to happen in a real-world setting. So, at the same time, we can understand the best ways for participants to access the ring are from places they already go to—family planning clinics, youth centers—and really ensure that post-authorization research really gets community-based input in the design.
We need to prioritize access. Oral PrEP and the dapivirine ring can be great options for women; but they can only be options if they’re available in this program. So, we need to demand that policymakers and funders move really quickly to integrate the ring into country-entitled prevention guidelines and prevention programs.
Funding is critical, and as soon as WHO and the national guidance documents support the introduction, that’s when we need PEPFAR guidance and the Global Fund Technical Review committee to encourage proposals for reintroduction as part of broader packages for services for women. We have to continue to advocate and support this data for programs that offer oral PrEP to women. If we really care about women’s prevention, we have to ensure that they are accessing—for those women who are accessing PrEP now.
And we have to also really keep a keen eye that we are learning the lessons from oral PrEP rollout as we develop use of the ring. And that includes moving faster and moving through roadblocks. And I say that, knowing that COVID gives us, this context gives us, special challenges.
And we have to engage user voices early when we design programs. And not only when we’re halfway down the road. This is an important time for us to really intensify our advocacy for integrating HIV prevention and sexual reproductive health services and messages. This means re-envisioning programs. It means developing customized trainings for health care workers. It also means targeted funds.
And, at the same time, we have to keep the pressure for a robust research pipeline. You know, women want, they need, and they deserve choices for HIV prevention. And so, it’s important that we are continuing to improve on products available, improve on programs that are delivering options to women; but continue to find products that will work for women, as well.
TW: Great. Well, thank you so much to both of you for your work and taking the time to speak with me today. I just want to mention that if people want to learn more about the International Partnership for Microbicides they can visit them at ipmglobal.org. And if folks want to learn more about AVAC, they can go to avac.org.
Thank you both!