The respected British medical journal The Lancet analyzes the FDA’s recent decision to push back its deadline evaluating Gilead’s application for use of its AIDS treatment Truvada as a form of Pre-exposure Prophylaxis (PrEP).
What is increasingly clear is that FDA approval, when it comes, will be far from the end of the story.
The immediate prospects of antiretroviral pre-exposure prophylaxis (PrEP) suffered an unexpected setback this week, just days before the US Food and Drug Administration (FDA) was due to issue its ruling on a once-daily combination pill of tenofovir and emtricitabine (TDF—FTC, marketed as Truvada by Gilead Sciences, Foster City, CA, USA) to reduce the risk of sexually acquired HIV infection in high-risk, seronegative individuals. As the journal was going to press, the FDA pushed back the deadline for a decision from June 15 until mid-September, to give itself more time to assess Gilead’s revised risk-management plan for the drug combination—the first to be assessed by the FDA for use as PrEP.
The unusual move by the FDA follows a meeting early in May during which PrEP took a huge step towards becoming a clinical reality, when the FDA’s Antiviral Drugs Advisory Committee voted to recommend that the agency approve the use of TDF—FTC for HIV prevention. The antiretroviral drugs are already used as part of a cocktail to treat diagnosed cases of HIV.
The FDA panel was tasked with ruling on the suitability of TDF—FTC as PrEP in three populations, with votes of 19 to three in favour of approving the drug combination as PrEP for HIV-seronegative men who have sex with men (MSM); 19 to two with one abstention in favour for HIV-uninfected partners of HIV-infected individuals (serodiscordant couples); and a much closer vote of 12 in favour versus eight against with two abstentions for “other individuals at risk for acquiring HIV through sexual activity”.
The narrow margin in favour of approval in the ill-defined “other individuals at risk” population might have played a part in the FDA’s decision to delay approval, but it is more likely that several concerns about safety voiced during the meeting of the advisory committee steered the agency towards a more cautious approach.
That TDF—FTC for PrEP is effective when taken correctly is now widely accepted—the IPrEx trial in men and transgender women who have sex with men, for example, showed that TDF—FTC led to a 44% reduction in HIV transmission in the treatment group compared with the placebo group, but this climbed to a 70% reduction in HIV infections when participants stuck to their PrEP treatment regimen on 90% or more study days. Similarly, the Partners PrEP trial in serodiscordant couples in Kenya and Uganda showed that daily TDF—FTC reduced HIV infections by 73%. Instead, the main point of contention at the May meeting focused on whether or not an HIV-negative test result should be required before an individual can be prescribed TDF—FTC: a safeguard that some who presented evidence to the FDA panel argue is necessary to prevent drug-resistant strains of HIV emerging if infected individuals were given the drug.
Michael Weinstein is President of the AIDS Healthcare Foundation (Los Angeles, CA, USA), which ran a high-profile campaign against PrEP and petitioned the FDA extensively before the May meeting. Weinstein told TLID that approving TDF—FTC would amount to “a dangerous experiment”, but that “if the FDA ultimately goes forward with an approval of the drug for prevention use, at minimum they should require HIV testing as part of the protocol”. Gilead has offered to provide free HIV testing as part of its risk-mitigation strategy, but the details of how this will be administered are still to be ironed out with the FDA.
Another concern focuses on treatment adherence. The CAPRISA 004 trial , which showed that 1% tenofovir gel used before and after sex significantly reduced a woman’s risk of being infected with HIV, caused a sensation when it was presented at the AIDS 2010 Conference in Vienna, Austria, and reinvigorated the search for an effective mode of PrEP. But speaking to The Lancet at the time, co-principal investigator on the study Salim Abdool Karim described adherence as the “Achilles’ heel of the trial”. In the 2 years since CAPRISA 004, trial data have come thick and fast, with the IPrEx trial in November, 2010, followed by Partners’ PrEP and TDF2 in July, 2011. But problems with maintaining and measuring drug adherence have persisted.
“The dose—response relationship seen in these trials underscores the importance of adherence—if you don’t use PrEP, ie have drug on board when you are exposed to HIV, then PrEP can’t protect you”, says Catherine Hankins, Deputy Director of Science at the Amsterdam Institute for Global Health and Development. “The FemPrEP trial was stopped for futility when no difference in the HIV infection rates was seen in the two arms of the trial, and initial findings on drug concentrations suggest that adherence was very low”, Hankins explains. “The VOICE trial, also in women, stopped both the tenofovir gel and oral tenofovir arms for futility—and we are awaiting data on adherence levels.”
As with worries about the veracity of HIV status in individuals prescribed PrEP, anxieties over low rates of adherence are driven by a fear of the emergence of antiretroviral-resistant strains of HIV. “What we find really concerning is that a widespread use without proper control outside high-risk situations might coincide with the outbreak of resistant strains of HIV, with a negative impact on the availability of therapeutic tools for the whole population”, say Giuseppe Pimpinella and Renato Bertini Malgarini, of the Italian Medicines Agency, Rome, Italy, who argue that the use of antiretrovirals for PrEP “should be restricted to selected groups of high-risk patients”. Hankins agrees. “At both the individual and population level there needs to be tailoring to those people and those populations who need additional prevention approaches and would be most likely to benefit from PrEP programmes”, she argues, adding that mathematical modelling to predict the results of prioritising PrEP for certain populations including men and transgender women who have sex with men, sex workers, and people who inject drugs, has shown that in most epidemic settings the PrEP programmes that are most cost effective are those for key populations.
Although the cost of a course of TDF—FTC for PrEP will rank low on the FDA’s criteria for approval, the cost-effectiveness of any PrEP intervention is an especially important consideration in the low-income and middle-income settings in which HIV is most prevalent. Many of the individuals at highest risk of HIV infection are socially disadvantaged, Pimpinella and Malgarini note, and the price of the drugs—estimates vary between US$6000 and $14000—is only one factor to take into account when budgeting for PrEP. “An optimal PrEP package includes not only prescriptions, but also components such as testing, long-term monitoring, and supportive behavioral interventions”, explains Kristin Underhill, a member of the Center for Interdisciplinary Research on AIDS at Yale University in the USA.
The economic case for PrEP is further complicated by the potential conflict of priorities that arises because the same drugs are used for treatment and prevention. “Clearly, there are trade-offs when the same drugs are used in PrEP as in treatment programmes”, notes Hankins. She argues that “from an ethical standpoint, first priority for drugs has to go to those most in need, those living with HIV who are symptomatic, in clinical decline, and facing significant illness and the risk of death in the not so distant future”. Addressing current treatment bottlenecks should be the programmatic priority for most countries, she asserts.
What is increasingly clear is that FDA approval, when it comes, will be far from the end of the story. “Because PrEP use is currently limited, it is difficult to predict exactly what all the impacts of PrEP will be in real-world settings”, says Underhill. “Participants in clinical trials are unsure whether they are receiving placebo or an active drug, and they are also unsure whether the active drug is efficacious. Real-world users will have different expectations of PrEP’s effectiveness, and follow-up studies are needed to understand how PrEP will fit into their daily lives.” Some studies, such as the iPrEx Open-Label Extension trial, are already being done to try to address some of these questions, while Underhill points to the important role of continuing research into the most effective ways to educate and support PrEP users “in order to maximise PrEP’s safety and effectiveness in real-world settings”.
Last year WHO delayed the release of its guidance document outlining recommendations for a public health approach to the treatment of HIV serodiscordant couples, so that it could include new recommendations based on the new evidence that was coming to light at the time from clinical trials of PrEP. A more comprehensive review of the evidence on PrEP in the form of Rapid Advice from WHO is due before July this year, and will pave the way for countries to “conduct demonstration projects to determine whether PrEP can be delivered in a cost-effective and culturally-appropriate manner”, says Hankins. Weinstein, meanwhile, has vowed that “the battle against PrEP has just begun”