Mascolini: Have you or any providers you know in the area actually prescribed PrEP for anyone?
Landovitz: I've prescribed it to one man in a serodiscordant couple outside of a study context. We have a growing number of people enrolling in the HPTN 069 study2 for whom we've prescribed PrEP. Because HPTN 069 is a fairly intensive study, these are largely people in serodiscordant relationships or individuals who want to give back to the community by furthering research about PrEP and who simultaneously perceive themselves to be at high risk of HIV acquisition. But that view is a little bit skewed because our clinical practice does not see uninsured patients and so does not reflect the evolving US epidemic.
Mascolini: You've reported frequent substance abuse in your population of HIV-uninfected MSM. Will you be less likely to prescribe PrEP for men with substance abuse problems?
Landovitz: That's an extremely challenging question. In LA methamphetamine appears to be driving a large portion of the MSM HIV epidemic, so stimulant users may be a population for whom PrEP could be particularly effective, if there were a way to deploy it successfully and safely. My group and some of my colleagues have done some pilot work trying to use postexposure prophylaxis in stimulant users for exactly that reason.5 We found that you can get PEP time-toinitiation and adherence rates in methamphetamine users comparable to those in the general population by combining PEP with a contingency management program in which people are given voucher-based incentives to abstain from stimulant use during the course of PEP treatment.
But we're still struggling to figure out how to optimize a PrEP regimen that requires daily adherence in a population with clear adherence challenges. Most people assume that the poor antiretroviral adherence we see in HIV-positive substance users will also be true in an HIV-uninfected population of substance users. I think it's an unanswered question that needs to be studied. For now, I would personally be reluctant to prescribe PrEP for this population outside of a study context because we're so acutely aware of how adherence-sensitive the efficacy of this intervention is.
Mascolini: How will you consider kidney and bone risk factors when deciding whether to prescribe Truvada PrEP?
Landovitz: I think that's a critical question. The phase 3 randomized PrEP data raise some serious concerns about both those safety areas. [See the following article in this issue.] The 1% loss in bone mineral density over 1 year recorded in some trial participants is extremely concerning in a healthy population, especially considering the poor adherence rates in PrEP trials. What would be the rate of bone mineral density loss in a more adherent population? I don't think we know.
I think PrEP trial data on bone mineral density changes would give a provider pause in using Truvada-based PrEP in someone with risk factors for low bone mineral density. Perhaps PrEP candidates with these risk factors should receive up-front vitamin D and calcium supplementation, and maybe they need more frequent DEXA scans during PrEP use. But I think we don't know exactly how to use these diagnostic tools to stratify people. It's an important area of research that needs to be clarified before Truvada PrEP is implemented in a widespread way.
The risk of renal toxicity with Truvada PrEP is also an unanswered question. All of the randomized controlled PrEP trials selected extremely healthy populations with excellent baseline renal function. I don't think we know what the renal adverse event rate is going to be in real-world populations. Even the PrEP demonstration projects rolling out now are going to have fairly restrictive creatinine clearance and glomerular filtration rate criteria for entry, so they will still not give a full picture of the toxicity spectrum. But toxicity results from these projects should be closer to what we will see in practice because the study populations will be a little more diverse. We're hoping to enroll 30% to 40% African Americans in our demonstration project, and African Americans have increased rates of hypertension and baseline renal dysfunction. So we hope to get a broader experience with how Truvada PrEP may affect HIV-uninfected African Americans at risk.
I think it's incumbent on those who are running these demonstration projects to build in careful safety monitoring that will provide a full and clear picture of toxicity now that the efficacy of this intervention has been established.
Mascolini: How do you counsel PrEP candidates on the importance of adherence?
Landovitz: I think it's really challenging. We're partnering with some of the smartest adherence experts in the country and the ones with the most experience in biomedical prevention-related adherence. We're working with Rivet Amico from the University of Connecticut, who was the adherence and behavioral specialist in the iPrEx study. So we're benefitting from her longitudinal experience with that group.
We need to be very careful to explain to PrEP candidates that all available data strongly suggest that the medication works best when taken every day. For that reason we cannot recommend that people skip any doses. At the same time we want people to report their medication-taking behavior realistically because we want to understand why people do or don't take the medication regularly. The best and most honest information we can provide is that the medication does not work if you don't take it, and that the more regularly you take it, the better it works.
Mascolini: What are you saying to PrEP candidates about condom use?
Landovitz: I fear that many individuals will look at PrEP as an alternative to condoms. Mathematical models clearly suggest that if individuals choose to use PrEP only and not use condoms, there is the potential for an increase in HIV incidence.6,7 I find that frightening.
We have to remind everyone that no prevention intervention is 100% effective and the best way to protect oneself is to use condoms and to consider PrEP a back-up strategy if a condom fails or for whatever reason doesn't get used in a particular instance. But PrEP should not be thought of as a substitute for the protection afforded by condoms. If that weren't compelling enough, many other infections that can be transmitted sexually are not prevented by PrEP.
Mascolini: Do you want to add anything on concerns or observations you may have on how PrEP may be used in practice?
Landovitz: The biggest concern I have that I'm hearing from communities is that disparities between those who have access to HIV care and treatment and those who don't will only be enlarged by the medicalization of HIV prevention. There is concern that those disparities will widen the chasm between racial and ethnic communities who do and do not have access to HIV care and treatment.
I think it's critical for those of us who are studying and considering how to implement PrEP to make sure that doesn't happen. Partnership with communities in the study and dissemination of PrEP information is the only way to ensure it's done equitably. I'm far from saying that we in LA have found the optimal or even the right way to do that. But that is one of our main missions in reaching a comprehensive understanding of how to use this intervention.
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