"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?

HPTN 052 results and Partners PrEP (part II)

...is Partners PrEP unethical?

If HIV prevention research requires maximal risk reduction for all participants, then it appears unethical based on the 052 data. Maximal risk reduction would involve treating all of the HIV+ partners in the study, even if doing so were inconsistent with answering the study question.

For those who do not take a hard line on maximal risk reduction in HIV prevention, a study offering submaximal risk reduction might be justified by the value of the study question (and its methodological incompatibility with providing maximal risk reduction). Arguably, HPTN 052 undermines the value of Partners PrEP data: why would we pursue a PrEP strategy--giving ARVs to the HIV- partner for prevention--when giving the ARVs to the HIV+ partner virtually eliminates transmission? Is PrEP a viable strategy in serodiscordant couples?

Some arguments for why it might still be:
1. in some couples, the HIV+ partner will decline therapy or will not take ARVs regularly. In these couples, a method controlled by the HIV- partner has value.
2. the HIV- partner may have risk factors other than sexual contact with the stable romantic partner (e.g. concurrent relationships). PrEP could be a viable strategy for protecting these individuals.
3. outside of stable serodiscordant couples, there are high-risk individuals (e.g. sex workers) who would be candidates for a PrEP strategy. Partners PrEP could provide scientific support for this strategy outside of serodiscordant couples.

Here's one thing we can say about these arguments: for some couples in Partners PrEP, none of the arguments will offer a reason why that couple is better off. Whenever this is true, then potential benefit to the study participant is being traded in favor of scientific knowledge and/or public health benefit. So we are accepting that some couples are probably left worse off by the Partners regimen (especially in the control group) than they would be on the 052 regimen.

Another important (?) factor: Partners PrEP meets or exceeds local standards of care in the communities where it is being conducted. If maximal risk reduction represents one end of the spectrum, the opposite end of the spectrum is the view that local standards of care represent the baseline or minimal standard for research. For those who are sympathetic to this view, the 052 data would not disturb the assumption that Partners PrEP should continue as designed, unless it suddenly appeared that Partners PrEP had no value from a public health standpoint.

So perhaps the question is where the default lies. If the maximal risk reduction is the default, then the ongoing value of Partners PrEP is probably not compelling enough to justify the deviation (assuming that we're willing to allow any deviations). If local standards are the default, then the ongoing value of Partners PrEP is probably sufficient to justify continuation as designed. If we are disposed towards a moderate view--somewhere between the two extremes--it will be tougher to determine whether Partners PrEP should continue as designed.

Implications of HPTN 052 for standards of prevention in serodiscordant couples (part I)

HPTN 052 recently found that, in stable relationships consisting of an HIV positive partner and an HIV negative partner ("serodiscordant couples"), early antiretroviral treatment of the HIV+ partner dramatically reduces transmission of the virus. These study data support the idea that "test and treat"--identifying and treating HIV+ individuals as early as possible, post-infection--will reduce HIV transmission rates on a community level. Of course, an important question is whether the will and resources exist even to implement this strategy in the U.S., let alone in lower-resource settings where HIV incidence is higher.

While the public health implications of this research raise numerous ethical issues (which may be considered later on this blog), here's a research ethics question: among serodiscordant couples, does early treatment of the HIV+ partner now represent the correct standard of care? This question could affect other studies among serodiscordant couples, especially the Gates Foundation's Partners PrEP study. In Partners PrEP, SD couples are randomized such that in two thirds of the couples, the HIV- partner receives oral PrEP--that is, taking antiretroviral pills for prophylaxis. In the control group, the HIV- partner receives a placebo. In all of these couples, the HIV+ partner was enrolled at a CD4 count where he/she was not eligible for ART under national guidelines (although the couple stays on-study if the HIV+ partner becomes eligible for ART and begins taking it).

Therefore, many Partners PrEP participants, whose CD4 counts are in the range where 052 found a 96% reduction in transmission from treating the HIV+ partner, are not receiving ARVs. In the experimental groups of the study, the HIV- partner is receiving an intervention which has shown effectiveness in preventing incidence among men who have sex with men (the iPrEx study) but not among heterosexual women (FHI stopped the FEM-PrEP study in April due to futility). The placebo group will be receiving no intervention.

This issue represents a twist on the "standards of prevention" problem that is vexing HIV prevention researchers: once a new modality is known to be effective for HIV prevention, is it ethically acceptable to conduct a study which withholds that modality from any study participants? The Declaration of Helsinki seems to prohibit this practice, and recent HIV prevention trials have provided a comprehensive "background package" of all known effective interventions (condoms, risk reduction counseling, etc.). So, suppose WHO issues a strong recommendation based on the 052 data, recommending that serodiscordant couples should start early treatment of the HIV+ partner whenever possible. Is Partners PrEP unethical?