How do things stand with the development of topical agents for HIV prevention? In the age of oral pre-exposure prophylaxis (PrEP) and treatment as prevention, does it matter anymore? And if lessons learned by researchers in the VOICE (Vaginal and Oral Interventions to Control the Epidemic) trial -- discussed most often in terms of its failure -- help make future HIV clinical trials more effective, can we really call it a failure?
During ID Week 2015 in San Diego, I caught up with Jeanne Marrazzo, M.D., M.P.H., a lead investigator on VOICE, and an infectious disease specialist and HIV/STI (sexually transmitted infections) researcher at the University of Washington in Seattle. See below for a webcast featuring slides and commentary from Marrazzo's engaging presentation on microbicides; and read on for her thoughts about how failure can create opportunity, why we still urgently need a topical HIV prevention method that works, and how microbicides could benefit from an image makeover.
What have we learned from the so-called "failure" of the VOICE study?
It's been an interesting time. One of the lessons learned has been that despite educating participants about what you're trying to do, it still requires a huge amount of trust for participants to actually use a study product. Building that trust is a much more complex, long-term challenge than many people who do clinical trials actually realized or anticipated.
It's not enough just to assume that, even if you do a good job with informed consent, you're going to really overcome people's concerns about using study products. One of the things that we learned in VOICE was that women really did not understand fully what the idea was behind using an anti-HIV agent as prophylaxis. That was a pretty foreign concept.
In retrospect, we were asking women to use products that are associated with profound stigma, particularly in the settings that they were living in, with the relationships they had with boyfriends, husbands, partners. I think we greatly underestimated how stigmatizing participation in a study like this could be seen to be in their context. We could have done a lot more work to figure that out, and to maybe guard against it.
The other big lesson is that women basically lied throughout the study. We asked women, both face-to-face and using audio computer-assisted self-interview, what they were experiencing in terms of adherence and how much they were taking in. Really, throughout the study, it was pretty good. At the lowest it was about an 85% level of adherence. But in reality it was about 25% adherence.
We went back and asked participants: "Why didn't you just tell us you weren't taking the product?" They said because of fear of repercussions of not taking the product, that they would get kicked out the study. And getting kicked out of the study meant that they wouldn't get contraception; they wouldn't get STI screening; and they wouldn't be seen every month, and counseled, and get an HIV test.
That was really sobering. It emphasized that it's really hard to isolate one component of everything that's going on in somebody's life, and say, "We want to study this, and this is what we're going to do" -- when, really, they've got a huge amount on their plate. There are all kinds of consequences they risk from participating.
The last thing I'd say we learned is that self-report of adherence is probably not ever going to be adequate again in any drug studies. Now, everybody is using biological markers of adherence. Even in the ASPIRE trial [A Study to Prevent Infection with a Ring for Extended Use], also known as MTN-020 -- a Phase-3 clinical trial that seeks to determine whether a woman's use of a vaginal ring containing the antiretroviral drug dapivirine is a safe and effective method for protecting against HIV when used for a month at a time], they are monitoring drugs by looking at blood levels in real time. They're not unblinding people in the study, but they're telling study sites, clinics: "You're having a problem with adherence; you've got to do this." That's going to be the future, I think.
You've got to figure out if you're studying the drug or you're studying the attempt to deliver the drug. And, really, you want to look at the drug first -- and then you work out the delivery issues. Lots of lessons.
If you had this study to do over again, what would you want to see done differently, in terms of establishing that trust?
We had extensive community involvement from an incredible community working group. Everybody was disappointed with the results, but for them it was devastating, because they had worked so hard to get community buy-in, get the word out, do educational initiatives. They were fantastic. And clearly, for that reason they were as surprised as everybody else that this didn't work.
So I think we could do more. But it is tough. I think participants need to know what happened in the previous studies, and that this can't happen again. And they need to know that trust is a two-way street. If we trust you to come and we trust you to take your meds, you trust us to give you really good care and to care about you. That has to be even more emphasized.
They also need to know that adherence is always going to be being monitored. That may change the type of person who enrolls in the study from the start. Now, that could be good or bad. Maybe you don't get as high-risk people. But those are some of the things I would do differently.
You joked during your presentation at the HIV Prevention symposium at IDWeek that some of your colleagues believe there is no point to microbicides in an era when we can conceivably stabilize the HIV epidemic with a combination of antiretroviral treatment for people living with HIV and oral PrEP for those who are HIV negative. Why do you believe we still need to pursue an effective microbicide?
The majority of new HIV infections across the world are occurring in sub-Saharan African women, at a track of one infection per 30 seconds. We are not moving prevention fast enough to these women.
The challenge is that many of them don't know their partners are infected. So the whole idea of test-and-treat is great, if people are tested and aware and willing to be treated. But there's just such a huge reservoir of people who are undiagnosed. It's very hard for women to know that they're being exposed to HIV.
I think that it would be great if there were a vaccine. It would be great if everybody were going to use oral PrEP. But we don't have a vaccine. Oral PrEP works in women, but they've got to really be pretty clear well in advance that they're going to be exposed. It takes about three weeks, ideally, to get really good levels of tenofovir [Viread] in the female genital tract. It gets into the rectum much faster. So if you're practicing only anal sex -- especially, for example, gay men -- you can actually get away with dosing oral PrEP pretty close to sex.
Women need more time. And that is really a problem, because -- for a lot of women -- they don't have a lot of control over when they're having sex and sometimes even who they're having sex with -- let alone the whole issue of sexual assault in the more classic sense, unfortunately. I really believe an on-demand product is critical to round out all the options and expand coverage for all the potential events that could promote infection transmission.
I also really think that trying to combine it with contraception -- as with the vaginal ring -- would be pretty great. Because then you could get young women who really want to contracept, and say, "Oh, by the way, let's make sure you're protected against HIV, too."
For a lot of young women, the reality is about trying not to get pregnant. That's the first thing on their minds; it's not necessarily HIV, because you're not thinking about getting HIV when you're thinking about having sex most of the time.
For years there has been vibrant microbicide advocacy worldwide. What it would take, in your opinion or experience, to engage allies -- whether that's researchers, community partners or other stakeholders -- to participate in advocacy and amp up that sense of urgency?
The microbicide field has benefitted greatly from advocates and community involvement. In fact, I would say it's almost as robust as treatment activism -- clearly not as big, but really strong, wonderful people.
I have had many conversations where I have said I thought we needed a new name for microbicides. A lot of people are really unhappy with that. To them, microbicides are a very female-controlled thing. The whole field has grown up around advocacy for women and their right to protect themselves when they want to.
I think that's fine. We don't have to totally throw it away. But I think we need a term that will get people like my doubting colleagues -- many of whom really want to stop the epidemic; it's not that they're anti-women at all -- to say: "This is about delivering antiretroviral drugs to the right place at the right time." This can be a bridge to a vaccine. This can be a bridge to treatment as prevention. This can be a bridge to giving them a long-acting PrEP implant of some sort, or a shot. It's about getting to choices that are going to expand the period of protection for women.
I'm not sure the term resonates with the public. I mean, "microbes" is kind of a retro term, in some ways. And then you say "microbicides" -- well, what does that mean? I can't say that it's ever been a very compelling term for me.
What would you call them? Have you ever mulled over some sample new names for these agents?
I have. I think it would be important to do that with a bunch of people in the room -- especially women who are going to use the products, and scientists who are going to want to see it as a credible representation of drug delivery.
It may be a tall order. But "PrEP" is going pretty well; you could call it "topical PrEP." Topical is a little bit of a weird term. But you could just say "vaginal PrEP," or "rectal PrEP," and people would know what you're talking about. Who knows?
It seemed that people in the room at your presentation responded well to "topical peri-PrEP" -- or perhaps it was just me.
In terms of an image makeover for microbicides -- or "topical PrEP": If mainstream media were to cover this issue, what would be your dream headline for how the issue would be covered and presented to the public?
Probably it would be: "HIV Protection on Demand, When You Need It Most."
Because, again, this idea of dosing before exposure is great. But sex is very immediate -- especially risky sex. Often decisions are made in the moment.
Ideally, it would be nice if topical PrEP went along with sexual pleasure. Lubrication is generally a good thing, particularly around anal sex, but absolutely also with vaginal sex. And people actually like the lubrication effect of the microbicides.
I think if you could package this on-demand thing with increasing pleasure and, ultimately, overarching HIV/STI protection, you would have a winner. But I don't think that's the way the field has been sold.
Watch and listen to Dr. Marrazzo's presentation, "Microbicides for the Prevention of HIV -- Where Are We?" on Oct. 8 at ID Week 2015 in San Diego, Calif.
This transcript has been lightly edited for clarity.