Ethics and PrEP: Jay and Gostin in JAMA

A short piece covering issues recognizable for anyone working in the area--but hopefully of interest to a wide audience in medicine in public health:

http://jama.jamanetwork.com/article.aspx?articleid=1262682

PrEP News: FDA Approves First Drug for HIV Prevention

[Reposted from the O'Neill Institute Blog]

The Food and Drug Administration announced today its approval of tenofovir-emtricitabine (aka Truvada) for HIV prevention.  Truvada, which has been approved since 2004 for use in HIV treatment, is now approved for use as preexposure prophylaxis (“PrEP”)–a strategy in which an HIV-negative person uses an antiretroviral drug (in this case a daily pill) to reduce the risk of acquiring HIV from behaviors such as unprotected sex.  [More info on this strategy from CDC and AVAC.]

Although the approval had been anticipated–an advisory committee recommended approval in May–there had remained questions about the parameters of the approval:

(1) Populations: clinical trials have demonstrated clear (albeit partial) efficacy of Truvada among men who have sex with men and heterosexual couples in which one partner is HIV positive and the other is negative, leading the advisory committee to vote overwhelmingly to approve for these populations.  However, the data among heterosexual women are more mixed.  As a result, the advisory committee’s vote on whether to approve for “other individuals at risk for acquiring HIV through sexual activity” was a close call at 12-8.  Today, FDA announced that Truvada would be approved for anyone “at high risk of HIV infection and who may engage in sexual activity with HIV-infected partners”–a win for women’s health advocates who supported broader access, citing the vulnerability of many women to HIV exposure from male partners who refuse to use condoms.

(2) Risk mitigation: the FDA‘s decision was originally fast-tracked with a target date of June 15, but pushed back with the announcement that the FDA would be considering new materials on the Risk Evaluation Management Strategy (REMS) from the drug’s manufacturer.  This topic had received extensive discussion among the advisory committee, and for those skeptical of PrEP as a public health intervention, it was key: concerns about the drug’s safety (risks of kidney damage and bone density loss) and drug resistance (among those who become HIV infected and continue taking Truvada instead of full-on ARV therapy) had led some to suggest strict limitations to control access, e.g. only to patients who could show a negative HIV test.  Instead, the FDA‘s announcement described a REMS based on education for providers and patients, explaining that stricter limits would have added “unnecessary burdens to health care professionals and patients.”

Less strict requirements may be important for patients with less consistent access to health systems, many of whom may face elevated HIV risk.  The CDC is expected to issue new clinical practice guidelines for PrEP, and the debate over how best to roll out this intervention–safely, effectively, and equitably–will certainly continue.

"Question 1(c)"

When FDA's Antiviral Advisory Committee finally voted last night whether to recommend an HIV prevention indication for Truvada (see previous posts), it turned out that some of the suspense was unwarranted: for men who have sex with men and HIV negative people in serodiscordant relationships (i.e., their stable partner is HIV positive), the group voted 19-3 and 19-2, respectively, to recommend approval. 

The vote on "Question 1(c)," however (the panel voted on each proposed indication one at a time), was much closer.  The question was whether to recommend approval for indication in "Other individuals at risk for acquiring HIV through sexual activity."  As a committee member noted before the vote, this question was primarily about heterosexual women, many of whom face a high risk of HIV acquisition in the U.S. (not to mention globally), but in whom the clinical trials data have been less conclusive.  It has been widely noted that the FEM-PrEP trial, testing Truvada in heterosexual women, was stopped when an interim review showed that it would not demonstrate efficacy.  It has emerged subsequently, however, that adherence in FEM-PrEP was too low for the trial to have demonstrated an effect, regardless of the pill's actual efficacy.  Women have been included in other studies of oral tenofovir-based products (including Truvada), but neither of those studies was powered to draw conclusions by gender.  At the same time, it is biologically plausible that the products would not work in women, based on relatively low drug concentration in vaginal tissue associated with Truvada (compared to levels found effective in CAPRISA 004 from a topical tenofovir product, or compared to levels found in rectal tissue in men).  Thus, the shortage of efficacy data in women was a curveball for the panel, deciding how broadly to approve the indication for Truvada.

The committee voted 12-8 to approve the wider indication.  This close vote signals that the most interesting question, in advance of the FDA's anticipated June 15 decision on labeling, may be the "1(c)" population.  FDA appears likely to approve for MSM and serodiscordant couples, perhaps dampening the public debate on these questions--but focusing the debate on the wider indication? 

PrEP: does risk compensation matter?

From today's meeting of the Antiviral Drugs Advisory Committee, which will advise FDA on whether to approve a new prevention indication for Truvada: Susan Buchbinder from the SF Dept of Public Health discusses the potential role of risk compensation in PrEP implementation.  (Risk compensation would occur if patients, perceiving PrEP to reduce their risk of HIV acquisition, start to engage in riskier behaviors and/or reduce their use of other protection methods such as condoms.  Clinical trials on PrEP have not found significant evidence of risk compensation, but can't rule out the possibility in real-world practice.)

Buchbinder notes that in terms of overall risk reduction, even partial PrEP efficacy would offset a fair amount of risk compensation--that is, it would take a lot more unprotected sex to eliminate the benefit of an intervention that reduces risk by, say, 60%.  She also draws an analogy to statins, a partially effective drug intervention used to reduce risk of cardiovascular diseases.  Whereas risk compensation is continually debated in the context of partially effective HIV risk reduction methods such male circumcision and PrEP, she notes, it is rarely discussed in the context of statins: doctors don't withhold statins based on the worry that patients will end up eating more cheeseburgers.

This analogy raises the question of whether the focus on risk compensation in HIV prevention has something to do with social norms: whereas eating an unhealthy diet is common in most groups, are the activities that increase HIV risk--unprotected sex, especially anal sex, and IV drug use--regarded in a way that makes the possibility of their increase seem disproportionately problematic?  Is the concern amplified by cultural taboos? 

FDA Review of Truvada on Biocentury This Week

A pill to prevent HIV?

The FDA is currently reviewing an application from Gilead Sciences to expand the labeling indication of Truvada, a combination antiretroviral drug, for HIV prevention.  While the drug is currently used in many regimens for HIV therapy, clinical trials have demonstrated its ability to prevent HIV acquisition among HIV negative people, when taken correctly.  (If you take the pill every day, your risk of acquiring HIV appears to be greatly reduced: in the iPrEx study, participants who took the drug regularly (as confirmed by blood samples, not the less reliable self-reports) had 90% fewer infections than a control group.) 

Despite its clear potential, there remain concerns about the drug's cost (at least $10k/yr for daily use), safety (associated with kidney injury and bone mineral density loss), appropriateness for different populations (especially heterosexual women, among whom the efficacy data are mixed), drug resistance (if a person who's already HIV positive uses Truvada instead of a full 3- or 4- drug combination regimen) and patients' ability to take it regularly (adherence was found to be so low in the FEM-PrEP trial that it was impossible to draw any conclusions about the drug's efficacy).

Most researchers, clinicians and HIV advocates seem to be taking a cautious but optimistic stance towards incorporating this intervention into clinical practice.  CDC has issued interim guidance and a limited number of providers have already been prescribing Truvada off-label.  One group opposing FDA approval of the new indication, however, is the AIDS Healthcare Foundation.  Here, you can see me discuss this topic on the TV show Biocentury This Week along with Tom Myers of AHF and Owen Ryan of amfAR:

 


More content on this topic to come.  For now, enjoy the video!

Re: HIV Ethics Blog

Thanks to everyone who checked out last year's test run of this blog!  A new phase will launch soon, either here or via the soon-to-be-revamped blog at the O'Neill Institute for National and Global Health Law.  Keep an eye out for new content on HIV ethics, law and policy.

Jon

Cash incentives for HIV prevention (part I)

Conditional cash transfer programs are gaining steam as an intervention to prevent HIV infection. Under these programs, health authorities offer people money to increase incentives for healthy behaviors. For instance, in Malawi, the World Bank recently tested a program for HIV prevention among young women. In this program, if you were a girl randomized to the intervention arm, your parents received $4-10/month and, if you attended school regularly, you received $1-5. In the study, the intervention cut HIV incidence by more than half. Additional studies testing similar interventions are underway.

These interventions are being considered for large-scale rollout. They're also pretty controversial: USAID considered the topic as part of its debate series on emerging issues in HIV response. In particular, opponents object to the conditioning of the cash transfer. Inevitably somebody will use the word "bribe" to describe what happens: some people will alter their behavior in order to obtain the incentive. (If the incentive is unconditional, then the mechanism of action seems a little different: perhaps access to greater resources reduces young women's dependence on men, a likely reason that some of them engage in risky sexual behaviors.) But suppose that the program is cost-effective (or even cost-saving)--what's wrong with using money to get people to do what you want them to?

Well, we can start by looking at a program that looks pretty bad to most people: the attempt by a U.S.-based nonprofit to increase contraceptive use in Kenya by offering HIV-positive women $40 to have an intrauterine device implanted. The founder of the program, Barbara Harris--who gained notoriety in the '90s for offering $300 to drug-using California women to be sterilized--says the goal of the program is to reduce the transmission of HIV to newborns. An observer says this program is "coercive and discriminatory." Can we distinguish it from other conditional cash transfer programs?