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How PrEP Will Roll Out in Practice (Slowly, so Far)
An Interview With Raphael J. Landovitz, M.D., M.Sc.

By Mark Mascolini

Winter 2012

Raphael J. Landovitz, M.D., M.Sc.

Raphael J. Landovitz, M.D., M.Sc., Assistant Professor of Medicine, Division of Infectious Diseases, Center for Clinical AIDS Research & Education; Co-Director, Combination Prevention Core, UCLA Center for HIV Identification, Prevention, and Treatment Services, David Geffen School of Medicine at UCLA, University of California, Los Angeles

In his 16 years as a physician and clinical investigator, Dr. Landovitz has earned a strong reputation for his research on medical prevention of HIV infection and the impact of such interventions on risk behavior. As co-director of the Combination Prevention Core at the Center for HIV Identification, Prevention, and Treatment Services and the UCLA Center for Clinical AIDS Research & Education, he conducts research through the HIV Prevention Trials Network (HPTN) and the AIDS Clinical Trials Group (ACTG), which awarded him the John Carey Young Investigator Award in 2010. Dr. Landovitz holds an undergraduate degree from Princeton University and earned his MD from Harvard Medical School and his MSc from UCLA. Before moving to Los Angeles, he served as chief resident at Brigham and Women's Hospital in Boston and medical co-director of the Vietnam-CDC-Harvard Medical School-AIDS-Partnership (VCHAP), which trains Vietnamese physicians in HIV care and treatment. (He speaks Vietnamese and Spanish.) Dr. Landovitz heads the Los Angeles County PEP Demonstration Project and collaborates with the City and County of Los Angeles, and Friends Community Center. His innovative work in HIV prevention includes prevention practices among gay men who use GRINDR (a GPS-based networking application MSM use to find sex partners) and combination HIV prevention with postexposure prophylaxis and contingency management for substance use among methamphetamine-using men.

Mascolini: Can you summarize the demographics, sexual behaviors, and substance use habits of HIVpositive and negative populations you care for and study in Los Angeles?

Landovitz: Our clinic cares for about 900 HIVinfected men and women on the west side of Los Angeles. We're broadening the scope of our care and research involving HIV-uninfected individuals at risk for HIV infection. With the medicalization of HIV prevention, we're working to learn how to best deliver prevention and care services as the domain of who provides prevention care continues to evolve.

Our clinic's HIV-infected population is approximately 42% non-Hispanic white, 34% African American, and 22% Latino. Although I don't have aggregate data on sexual and drug use behavior for this patient population, I can give you some data from certain studies we've done in people with HIV: 44% of that population had ever used any illicit substances, and 36% reported ever having used stimulants. In terms of sexual risk behavior, about 30% of that study population reported some unprotected sexual activity with a partner of unknown HIV status in the last year.

For the HIV-negative but at-risk individuals we see, I can cite some data from studies of people who requested HIV postexposure prophylaxis (PEP) at our community-based program. That population is almost 95% male, and 85% men who have sex with men (MSM). Almost two thirds, 62%, sought PEP after receptive anal intercourse. This population is 48% Caucasian, 35% Latino, and 8% African American.


PrEP Interest and Uptake in Los Angeles

Mascolini: Do HIV-negative at-risk men in your area know about PrEP and do they want to try it?

Landovitz: We have had very few requests for PrEP in our clinic. I've surveyed other HIV providers on the west side of Los Angeles, and they too have had precious few requests for PrEP. We were a little surprised by that. The majority of these few requests have come from men who are in serodiscordant relationships and seem to keep their fingers on the pulse of what's current.

Here is Los Angeles we've only recently begun to be involved in clinical trials of PrEP. We were not part of the iPrEx trial in MSM1 or the early open-label study that came out of iPrEx, the iPrEx OLÉ rollover protocol. The HPTN 069 protocol comparing PrEP regimens containing tenofovir/emtricitabine to maraviroc-containing regimens2 (Table) is the first clinical study activity in Los Angeles. In the wake of the iPrEx results, we've had a number of community forums and engagement meetings to disseminate the results and initiate discussion about how PrEP could or should be used in the context of larger prevention programming.


HPTN 069: Safety and Tolerability of Four PrEP Regimens in MSM

Status

  • Recruiting
  • Estimated primary completion date January 2014

Primary outcomes

  • Occurrence of grade 3 or 4 adverse events through 48 weeks
  • Tolerability as assessed by time to permanent discontinuation of treatment through 48 weeks

PrEP regimen arms

  • Maraviroc plus emtricitabine (FTC) placebo plus tenofovir (TDF) placebo orally once daily
  • Maraviroc plus FTC plus TDF placebo orally once daily
  • Maraviroc plus FTC placebo plus TDF orally once daily
  • Maraviroc placebo plus FTC plus TDF orally once daily

Key inclusion criteria

  • Born male and 18 or older at screening
  • Receptive or insertive anal intercourse without condoms with at least one HIV-infected male partner or male partner of unknown HIV status within 3 months of study entry
  • Creatinine clearance 70 mL/minute or higher
  • No alcohol or substance use that the investigator believes would interfere with the study

Key exclusion criteria

  • One or more reactive HIV test results at screening or enrollment
  • Use of antiretrovirals for PEP or PrEP within 90 days before study entry
  • Ongoing intravenous drug use
  • Weight over 300 pounds

Participating sites

  • California: UCLA Care Center, Los Angeles; San Francisco Vaccine and Prevention Center
  • Maryland: Johns Hopkins Adult AIDS Center, Baltimore
  • Massachusetts: Fenway Institute, Boston
  • New York: Cornell University, New York City
  • North Carolina: University of North Carolina, Chapel Hill; Wake County Health and Human Services, Raleigh
  • Ohio: Case Western Reserve University, Cleveland
  • Puerto Rico: Puerto Rico-AIDS
  • Pennsylvania: Hospital of the University of Pennsylvania, Philadelphia; University of Pittsburgh
  • Washington, DC: George Washington University
  • Washington State: University of Washington, Seattle

For detailed study information and study site contacts: www.clinicaltrials.gov/ct2/show/study/NCT01505114


We've done some combination prevention work at two community-based sites in Los Angeles, one at the Gay and Lesbian Center and one at the Oasis Clinic, which is in South LA. As part of this work, we developed a community-based 1-year nonoccupational PEP demonstration project that we parlayed into an ongoing public health service delivery program sponsored by the Division of HIV/STD Prevention (DHSP) in the County Department of Public Health. We are ramping up a PrEP demonstration project that will be deployed at those sites, but it has not begun yet.

Our PEP work indicates that 3% to 5% of PEP users asked for PEP more than once, and we think those people are excellent candidates for PrEP. In my mind PEP should be a one-time emergency intervention after a condom breaks or isn't used in a particular situation. The counseling that surrounds an episode of PEP should help prevent someone from ever requiring PEP again, and certainly not to require PEP frequently. I believe recurrent PEP users would be better served by PrEP. At the same time, we have to continue studying this recurrently at-risk population -- to understand how to modify the behaviors that cause them to be persistently at risk and allow potential PrEP users to come off PrEP, because nobody wants to be on PrEP forever.

Mascolini: Have you and your colleagues figured out how to make PrEP part of your practice, and have you established any sort of PrEP use protocol?

Landovitz: We've talked about how PrEP might be part of larger HIV prevention programming. I think we all agree that PrEP should not be seen or promoted as an isolated intervention: PrEP may be an appropriate adjunct to other prevention efforts and may be appropriate for certain targeted populations, but we should not prescribe PrEP and send people off with the impression that PrEP alone is sufficient to mitigate HIV acquisition risk.


We're trying to funnel any PrEP referrals to providers who have kept up on the literature and have a comprehensive understanding of combination prevention programming. Such programming might involve referring people to other services, including mental health services, substance use treatment services, and intimate partner violence services. At the same time, we believe combination prevention includes condom provision and education and adherence counseling. In that context we can do some risk stratification for who appears to be at ongoing risk for HIV acquisition despite other interventions and then consider PrEP as an adjunct to all these other efforts.

I'm one of those people handling PrEP referrals, and so far I've seen two consultations for preexposure prophylaxis since the FDA approval of Truvada for PrEP. So at least in a controlled medical environment on the west side of LA, we're not seeing a lot of demand for PrEP.

Mascolini: Do you think this low demand means PrEP candidates are on an early part of the PrEP learning curve, or does it mean people just aren't interested in taking a pill to prevent HIV infection?

Landovitz: It's probably multifactorial. I think people are probably much less interested in taking a daily pill, and some adherence data from the placebocontrolled iPrEx,1 Partners PrEP,3 and TDF24 trials bear this out. [See the first article in this issue.] Others may believe it's just not feasible to take a daily HIVprevention pill for any number of reasons.

My personal feeling is that there's not going to be widespread uptake and interest in PrEP -- at least in the MSM communities who dominate the epidemic on the West Coast -- until a PrEP agent is available in a depot or sustained-release formulation. My experience talking to patients and interacting with other providers suggests that the analogy to women taking daily birth control does not appear to be a compelling one for gay men. So I think the game changer will be a depot or long-acting formulation -- or at the very least a much more sophisticated understanding of what sort of more intermittent dosing might be effective and safe.

Mascolini: What proportion of PrEP candidates you see have insurance that will pay for PrEP?

Landovitz: In our PEP experience with HIV-negative but at-risk people, 60% of those seeking PEP at our community-based sites are uninsured. Our PEP demonstration project is designed to have no cost to people seeking that service. I suspect this PEP population is similar to our potential PrEP population. People who are well-informed early adopters, who have private insurance and private doctors, will access PrEP in those contexts and aren't waiting for a publicly funded demonstration project.

Considering Substance Abuse and PrEP Side Effects

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.

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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.


Talking to PrEP Candidates About Adherence and Condoms

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.


References

  1. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587-2599.
  2. ClinicalTrials.gov. Evaluating the safety and tolerability of antiretroviral drug regimens used as pre-exposure prophylaxis to prevent HIV infection in men who have sex with men.
  3. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399-410.
  4. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423-434.
  5. Landovitz RJ, Fletcher JB, Inzhakova G, Lake JE, Shoptaw S, Reback CJ. A novel combination HIV prevention strategy: post-exposure prophylaxis with contingency management for substance abuse treatment among methamphetamine-using men who have sex with men. AIDS Patient Care STDS. 2012;26:320-328.
  6. Gomez GB, Borquez A, Caceres CF, et al. The potential impact of pre-exposure prophylaxis for HIV prevention among men who have sex with men and transwomen in Lima, Peru: a mathematical modelling study. PLoS Med. 2012; 9: e1001323.
  7. Abbas UL, Anderson RM, Mellors JW. Potential impact of antiretroviral chemoprophylaxis on HIV-1 transmission in resource-limited settings. PLoS One. 2007;2:e875.




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