Scientific Data on PrEP is Promising, But Real-World Impact Still Uncertain

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Willard Cates, Jr., MD, MPH, President, Research, Family Health International, recently gave a provocative presentation at a Microbicides Trial Network meeting in Washington, D.C., providing insights about the potential public health impact of microbicides, if the scientific evidence demonstrates efficacy in preventing HIV transmission. We spoke with Dr. Cates about the challenges of translating scientific data into real-world prevention gains.

 Q: There’s a lot of excitement among AIDS experts and advocates about Pre-Exposure Prophylaxis (PrEP) to prevent HIV transmission. The main question in the advocacy community tends to be: Will we have enough resources for PrEP roll out if and when the scientific evidence shows efficacy? But your presentation suggests that our collective expectations for the public health impact of PrEP may be overblown. Is that an accurate summary or how would you characterize your bottom-line message here?

A: The bottom line is yes, that is right. We need realize that the primary place we have focused as HIV prevention scientists has been at the innovation stage–will the prevention product work or not? We haven’t gathered a lot of evidence about how things will get ramped up if effective. We’ve made many assumptions and done some creative thinking, but we haven’t generated the qualitative or quantitative data about how people would be using oral PrEP or topical microbicides in the real world. Our discussions have been largely theoretical.

Q: You use the term “prevention cascade” in the presentation, which gets at this disconnect between scientific efficacy and real-world practical impact. Can you walk us through what that prevention cascade is and what the implications are?

A: With PrEP, a simple prevention cascade model looks like this: If you have no product at all, in an HIV discordant couple, let’s assume 10 infections will occur for every 100 women exposed to HIV. If you have a PrEP product that’s 50 percent effective, you will still get 9 infections for every 100 women exposed, because only about half of those women will have access to the product, and only half of those 50 will actually use it. Even with a PrEP product that’s 80 percent effective, you still get 8 infections, because of the access and adherence barriers.

Moreover, our information in the PrEP studies is being gathered in a clinical trial setting that’s as close to perfect use and perfect access as we can expect. The participants come back to get evaluated monthly, they get regular reminders about what to do, they get a regular stock of product every month. They are supported to an extent that doesn’t exist outside this research setting. In the real world, they’re going to have to pay for the product, travel to obtain it, have it be in stock, and so on. Unfortunately reality means imperfect access and imperfect adherence.

Once you have adjusted for the prevention cascade—meaning the number of people who drop out because of adherence or access issues—the effect of PrEP or microbicides only gains us a few averted infections for every 100 exposures. What would gain us a lot more public health impact is if we were able to increase access and increase adherence.

Yet we spend all this effort and money in trials trying to get from 50 percent to 80 percent effectiveness with PrEP or microbicides.  We’re nibbling around the edges of public health impact, trying to get incremental improvements in the tools. But the number of infections prevented by any of our innovations is much more affected by access–Can the community get this prevention product? Do they use this product?–than by any marginal increase in product effectiveness.

Q: You gave a startling example of this with prevention of mother-to-child transmission (PMTCT) scale-up. It showed that with no PMTCT services at all, you get 25 HIV-infected babies for every 100 HIV-positive pregnant women. With access to highly active antiretroviral therapy (HAART), you still get 17 HIV-infected babies. Can you walk me through that–it just seems so hard to believe that you still have so many new infections with full scale-up of the most potent intervention we have.  

A: Lynne Mofenson of NIH has presented these PMTCT extrapolations in many settings. She estimates only 92 percent of women will come to the clinic in the first place. Of those, 75 percent will get tested for HIV, and of those, only 50 percent will get ARVs.  Using these access/adherence measures, she shows the difference in infections averted between single-dose nevirapine and triple-drug HAART is only two infections.

Where we are really going to get bang for the buck is by increasing those who will take up the particular intervention by going to the antenatal clinics, getting tested, and taking ARVs. Let’s say, for example, we were able to increase by 50 percent the number of women who come to a clinic for antenatal care, and then increase by 50 percent the number who get tested once there, and increase by another 50 percent those who take the ARVs if they test positive, then you’d see much greater public health gains, compared to making similar improvements with the drug regimens.

As public health people, we need to do a better job of bringing our scientific creativity to the whole field of program science. We want to increase in the real-world access to the product and improve the circumstances under which people use these prevention tools. Once we have an effective product, whether it’s condoms, PrEP, or microbicides, we need to optimize our public health bang by having that product accessed and used. This seems platitudinous, but we get so focused on the trials to show effectiveness, we neglect the factors most associated with having public health impact.

Q: So what would that mean in terms of crafting a more effective PMTCT program?

A: At the same time we’re looking at the molecular level approaches to new drug regimens, we need to think about and invest in creative approaches that will overcome some of the barriers to access and adherence. For example, we could look at providing simple ARV regimens to all pregnant women, rather than just to those who get tested and are infected. We need to look at what are the gains and risks perhaps of using such broader scale approaches. This is a new time program science.

Q: And what might that mean for PrEP roll out?

A: Now is the time to think beyond our trials. How are we really going to use a successful product? If oral PrEP is successful, who would get it? And if topical microbicides are successful, who would get them?

I used to think because the orals are so much easier to use than topicals, they would have wider application. But because of cost and resistance issues, with the possibility of intermittent use and people sharing, I now think that oral PrEP, if successful, should only focus on the highest transmission intervals and individuals–discordant couples trying to get pregnant, transient sex workers, etc.

For topicals, I’ve also gone through an evolution. Because we’re not giving it systemically, topicals are not absorbed to same level as oral medicines. We believe we’ll have fewer resistance and safety concerns. Surprisingly, topicals may even have adherence advantages. One thing we’ve found is when these trials are over, many of the women do not want to give back the product. They like the product. It gave them a power over their sexual activity, and apparently it increased their pleasure. So another approach to improving adherence is finding out what aspects of the topical microbicides made women not want to give it back at the end of trials. We can then build on those motivations as a way to ramp up the topicals.

Q: So knowing what you know now, if you were in charge of U.S. government funding for HIV prevention, what would your priorities be and why?

A: I would allocate an increasing amount of prevention resources to examining creative systems to increase the access and adherence.  We need to anticipate, if the products are effective, how we can get them to scale more quickly. We should start funding science that will address those questions now, so the evidence will guide our ability to have a faster public health impact.

The Administration is already moving in this direction. PEPFAR’s initial aim was to get treatment out quickly to those most in need. Now the emphasis is getting it out more efficiently and effectively in a way that’s going to have a public health impact, including using ART for prevention.

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