Back grey_arrow_rt.gif
FDA Committee Recommends HIV PrEP, Concerns Persist
  PrEP FDA & Gilead Briefing Documents:

Download the PDF here

Download the PDF here by Seth Kandel

The FDA Antiviral Drugs Advisory Committee (ADAC) has recommended the approval of a combination antiretroviral drug for HIV preexposure prophylaxis (PrEP) in seronegative individuals.

The panel voted 19-3 in favor of once-daily Truvada (emtricitabine and tenofovir disoproxil fumarate; Gilead Sciences) for use in uninfected men who have sex with men (MSM) and 19-2 (one abstention) in favor of its use in uninfected heterosexual individuals. Truvada currently is approved for use in combination treatment regimens for HIV.

The ADAC discussion did include concerns about the potential for patients who use this modality to develop a false sense of security regarding risky sexual behaviors. Additionally, treatment adherence issues with a daily regimen and the development of drug-resistant strains of HIV also were discussed.

"People living with HIV have to live with both the side effects and the realities of adherence to these medications-it can be a struggle and challenge for them. In my experience, it is not rational to expect that people who are otherwise healthy will adhere to this chemotherapy," said Jessie Gruttadauria, director of public health and domestic advocacy, AIDS Healthcare Foundation in Los Angeles, California, during the panel discussion.

To this end, the FDA asked Gilead to submit a risk evaluation and management strategy (REMS) proposal for PrEP with Truvada. The REMS would include awareness about strict medication adherence for both health care providers and individuals at high-risk for acquiring HIV; information about the monitoring of HIV serostatus and steps to take upon seroconversion; and a comprehensive HIV prevention strategy that discusses modalities in addition to Truvada. But the proposed REMS program currently does not require a negative HIV test for patients to receive a prescription for PrEP with Truvada.

The ADAC was convened to discuss the supplemental new drug application submitted by Gilead. They conducted a risk-benefit analysis for PrEP with Truvada based on the results of two comprehensive investigations: the iPrEx (Preexposure Prophylaxis Initiative) and the Partners PrEP studies.

Weighing the Evidence

iPrEx was a double-blind, placebo-controlled study that included 2,499 MSM across 11 sites in six countries. Participants had negative HIV tests at enrollment and received either Truvada or placebo. They also received counseling on HIV awareness and condoms and were tested for sexually transmitted diseases throughout the study. Median follow-up was 1.2 years.

The use of Truvada led to a 44% reduction in HIV transmission in the treatment group. The incidence of HIV infections in the Truvada arm was 2.88% (36 of 1,251 participants) compared with 5.13% in the placebo group (64 of 1,248 participants). Although this rate was lower than researchers initially had hoped for, when patients adhered to their PrEP regimen on 90% or more of the study days, Truvada offered a 70% rate of protection against HIV. The rates of moderate or serious adverse events (AEs) were similar across both treatment arms.

Partners PrEP was a randomized, placebo-controlled study that enrolled 4,758 heterosexual, serodiscordant couples in Kenya and Uganda for 36 months. The seronegative partners were assigned to once-daily tenofovir, Truvada or placebo. Participants also received risk reduction counseling and condoms.

The study found that Truvada reduced the risk for HIV transmission by 75% compared with 67% for tenofovir. There were 82 new HIV infections overall during the study: Seventeen occurred in the tenofovir group, 13 occurred in the Truvada group and 52 occurred in the placebo group. The authors reported a 97% rate of medication adherence throughout the study, as measured by monthly pill counts.

There were no significant differences in the protective rates provided by either study drug between men and women. The rate of serious AEs was similar across both treatment arms.

Next Steps

The panel's majority support for Truvada PrEP in both populations does not ensure that the FDA will approve this new indication, however. In addition to concerns over false bravado toward the need for condoms and increased rates of drug-resistant virus, there are cost issues to consider. Estimates of the cost for PrEP with once-daily Truvada range from $6,154 to $14,000 per year.

Members of the review committee also expressed displeasure with the passive REMS program because it does not require patients to test negative for HIV prior to receiving the drug, thus increasing the risk for HIV mutations. In response to this, Judith Feinberg, MD, acting chair of the ADAC, noted that it would be difficult to have two systems in place for dispensing the same drug and patients easily could circumvent one system for another.

"Prevention is a key goal in the efforts to stem the HIV epidemic," Dr. Feinberg said during the panel discussion. "Patients who are infected with HIV need to be able to access Truvada without restriction, as do those requiring PrEP."

The FDA is expected to make a final decision on the new indication for Truvada by June 15.


Updated: FDA committee recommends Truvada's approval as PrEP

By Meredith Mazzotta May 11, 2012

The U.S. Food and Drug Administration (FDA) Antiviral Drugs Advisory Committee recommended Thursday that the supplemental application for Gilead Sciences' HIV drug Truvada (a combination of emtricitabine plus tenofovir, or TDF-FTC) as pre-exposure prophylaxis (PrEP) be approved for high-risk, HIV-negative individuals to reduce the risk of sexually acquired HIV infection.


A slide showing the results from various Truvada PrEP Phase 2B/3 HIV prevention trials.

The panel of medical experts, people living with HIV/AIDS and community advocates voted to decide if the current application supports a favorable risk-benefit assessment adequate to approve Truvada for a PrEP indication in three populations. For HIV uninfected men who have sex with men (MSM) the panel voted 19-3 in favor; for HIV uninfected partners in serodiscordant couples (where one partner is HIV infected and the other is not) the panel voted 19-2 in favor with one abstention; and for other individuals at risk for acquiring HIV through sexual activity 12 voted in favor, eight against with two abstentions.

"The third vote for 'others at-risk' was kind of close, but I'm ok with that. We don't yet have a specific trial that addresses Truvada's use among people outside of discordant couples or high-risk MSM," said Dr. Veronica Miler, director of the Forum for Collaborative HIV Research. "Although, in the end, if it's approved for the first two populations, it will be prescribed for people outside of a discordant relationship, too."

Miller said there was also some contention on the panel about requiring an HIV-negative test when getting the prescription filled. "The prescriber should make sure the patient has an HIV-negative test. That's the level where it needs to be done. It can't be policed. The FDA can't require that level of control at the point of distribution of the drug," Miller said.

An impressive group of HIV experts gathered at the FDA White Oak campus in Maryland to review data from various studies that showed the protective benefit of daily oral administration of Truvada for the committee. Gilead applied for a six-month priority review of its application, which it was granted due to the drug's potential for providing significant improvement in the protection of HIV infection and that there is no other drug product on the market with an indication for HIV prevention.

"Those of us who were involved in the trials and who interact with people at risk for HIV do not think that TDF-FTC is a panacea, but we do believe that culturally-tailored programs that combine chemoprophylaxis with behavioral and/or social-structural interventions can make a difference," said Kenneth Mayer, MD, principal investigator of the Fenway Health trail site of the iPrEx study. Discussed in depth at Thursday's committee meeting, iPrEx found that daily oral dosing of Truvada among high-risk MSM indicated a 44 percent reduction in the incidence of HIV. Detectable levels of the study drug in participants' blood strongly correlated with the prophylactic effect, with high adherence boosting protection up to 92 percent. In 2011 the Centers for Disease Control and Prevention (CDC) posted interim guidelines for the use of Truvada as PrEP for high-risk MSM in response to the iPrEx results.

"Advocates can challenge pharma and funders about costs, but the science suggests that the judicious use of the medication can decrease HIV incidence. For some people, that additional help may keep them uninfected during a vulnerable period. It is time to reflect and to think about how to ensure that PrEP can assist the momentum to curb the epidemic," Mayer said.

The committee's recommendation to the FDA is not binding, but often followed. During the open public hearing portion of the meeting, more than 40 people gave their opinion to the committee - a substantial number of whom spoke on behalf of the AIDS Healthcare Foundation (AHF). Robert D. Elliott, RN Care Manager at AHF, argued that risk compensation was too real and too risky to make PrEP available at a population level. A final FDA decision is expected by June 15.

"Our challenge now is to understand how to use PrEP effectively to tackle HIV incidence worldwide," said Chris Collins, amfAR's vice president and director of public policy, in a press release. "PrEP is certainly not for everyone, but delivered in a targeted way and as part of a comprehensive approach that includes other evidence-based interventions like AIDS treatment, condoms, education, syringe exchange, and male circumcision, PrEP may play an important role in beginning to end the AIDS epidemic."

AIDS advocacy group AVAC issued a press release Friday urging the FDA to follow the committee's recommendation, and giving four recommendations for moving forward:

· Create public health guidance via the CDC, the World Health Organization (WHO), and other agencies on the appropriate use of Truvada as PrEP in different populations and settings.

· Continued research to answer urgent questions such as how best to implement PrEP, how to provide PrEP safely and efficiently, how to integrate PrEP with other essential prevention interventions such as condoms, and how to ensure high levels of adherence.

· Donor and government support of investment in PrEP research and initiatives.

· Additional research to test PrEP in other populations, such as injection drug users, and to evaluate new drugs and less frequent PrEP dosing schedules.

The Risk Evaluation and Mitigation Strategy (REMS)

The main arguments against providing Truvada as PrEP include fears of risk compensation - where an individual engages in risky sexual behavior once on the prophylactic - and development of resistance to the drug if the patient does not take the pill as indicated. Side effects from Truvada, including liver toxicity, are also of concern. Truvada is already FDA approved for HIV treatment, so doctors can prescribe the drug for "off-label use" for HIV prevention. But, advocates argue, expanding the approval to include prevention for HIV-negatives might ensure the drug is used more safely and effectively.

Gilead Sciences agreed to provide various materials to providers and patients as part of the Risk Evaluation Mitigation Strategy (REMS), which included a notification letter to health care providers (HCPs) on the details of PrEP, full prescribing information, a medication guide with every bottle of Truvada, a training guide for HCPs, a prescriber safety brochure, an individual safety brochure, and a Truvada wallet card (all available online and hardcopy). Gilead also offered free HIV and HBV testing, free condoms, subsidized HIV-1 resistance testing to individuals who seroconvert, and a Medication Assistance Program for Truvada for a PrEP indication for individuals who lack prescription coverage. Safety data on Truvada for PrEP also will be collected as part of the existing routine vigilance program.

  icon paper stack View Older Articles   Back to Top