In a series of votes by the U.S. Food and Drug Administration’s Antiviral Drugs Advisory Committee, Truvada (tenofovir plus emtricitabine) has been recommended for approval as the first prescription drug—to be used daily and in conjunction with condoms and other safer-sex measures—to prevent HIV among those at risk for the infection.

At a May 10 meeting on the FDA’s White Oak Campus in Silver Spring, MD, which lasted more than 12 hours, the strongest vote—19 in favor and three against—was to recommend approval for men who have sex with men (MSM) at risk for HIV. A similar vote—19-2, with one abstention—resulted in Truvada being recommended as as pre-exposure prophylaxis (PrEP) for HIV-negative partners in serodiscordant relationships. The closest vote—12 in favor and eight against, with two abstentions—was for other individuals at risk for acquiring HIV through sexual activity.

Though the FDA is not required to follow the approval recommendations of its independent advisory committees, it usually does so. The agency is expected to announce its decision on or before June 15, which will likely reflect other key discussion points at the May 10 meeting, including the frequency of HIV testing and safety assessments for individuals using Truvada as PrEP, Gilead’s proposed strategies to minimize risks associated with Truvada as PrEP and any post-approval study requirements.

During a contentious public comment period, in which roughly 50 activists and health care professionals testified, the majority argued against the approval of Truvada as PrEP, based on efficacy and safety concerns.

Michael Weintstein, who founded and currently heads the Los Angeles-based AIDS Healthcare Foundation, an organization that has waged a long-standing campaign against GIlead’s PrEP approval request, likened the situation to the U.S. government’s Tuskegee syphilis experiment—designed to study the progression of untreated syphilis in poor, rural black men—and said that FDA approval “would be a reckless act.”

Several people did testify in favor of approval, based on safety and efficacy data reported previously and fully summarized at the May 10 meeting. “We need additional tools in our prevention toolbox,” explained Richard Elion, MD, of the Whitman Walker Clinic in Washington, DC. ”We are not winning the battle. We’re asking for a modality that’s still being developed to be added to our toolbox."

“The only way we are going to end the epidemic is through a combination approach,” said Susan Buchbinder, MD, of the San Francisco Department of Health, in a scheduled overview of existing HIV prevention strategies at the start of the meeting. Noting that condoms are not 100 percent effective—in part because of improper use and breakage—and that behavioral intervention strategies aren’t universally successful, she explained that what’s needed “are new treatments and prevention strategies to have a major impact on the US epidemic.”

Specific concerns raised by those offering public testimony, by those for and against approval, and the advisory committee panel—which included HIV-treating clinicians, researchers and three consumer representatives—included the need for daily adherence, which was a problem in many of the clinical trials conducted to date. Other worries included the risk of drug resistance emerging in those who become infected while using the drug and the known side effects of Truvada, notably kidney damage and bone loss.

Whether Truvada as PrEP is associated with significant safety issues has not been fully determined. Though several placebo-controlled clinical trials have been conducted, HIV infections and serious side effects while receiving Truvada have been rare. Additional research, including well-designed feasibility studies, are needed to allow for a more complete assessment of Truvada’s risks and benefits as an HIV prevention strategy.

Numerous data sets from the clinical trials were reviewed by the advisory committee, including results from the National Institutes of Health (NIH)-funded international iPrEx study; the University of Washington’s Partners PrEP study conducted in Kenya and Uganda; the U.S. Centers for Disease Control’s TDF2 safety study conducted in Botswana; Family Health International’s FEM-PrEP study conducted in Kenya, South Africa and Tanzania; and the NIH VOICE study conducted in Uganda, South Africa and Zimbabwe.

Results from iPrEx were used to support the approval recommendation for MSM. In that study, involving roughly 2,500 MSM at risk of HIV, Truvada PrEP was associated with an average 44 percent reduction in the risk of HIV infection, compared with those who took placebo. Among the 10 percent of study participants who used the drug at least 90 percent of the time, the risk reduction was 73 percent.

Data supporting the approval of Truvada PrEP for HIV-negative individuals partnered with people living with HIV comes from the Partners PrEP trial. In that study, involving more than 4,500 individuals, daily Truvada was associated with a 75 percent reduction in the HIV transmission risk.

The advisory committee’s more divided vote ultimately in favor of Truvada’s approval for other individuals at risk for acquiring HIV through sexual activity is based on the mixed results of TDF 2, FEM-PreP and VOICE. FEM-PrEP, for example, originally planned to enroll 4,000 adult at-risk women before it was discontinued prematurely due to the lack of an efficacy difference between those receiving daily Truvada and those receiving placebo. Conversely, while TDF2 demonstrated a 62 percent risk reduction among adult heterosexual men and women at risk for HIV, the study was not specifically designed to determine the efficacy of Truvada as PrEP.

Truvada PrEP was generally safe and well tolerated. As noted by the FDA, both in its pre-advisory committee briefing document and in oral comments to the panel, “[Truvada] appeared to be well tolerated overall amongst HIV-uninfected individuals in these clinical trials. No new safety issues were identified. In general, adverse events appeared to be balanced between active and control arms. In iPrEx, unintended weight loss, nausea, vomiting, flatulence, and abdominal pain were reported more often in subjects receiving [Truvada]. In Partners PrEP, moderate to severe neutropenia was observed more frequently in subjects receiving [Truvada] or tenofovir as compared with placebo.”

The FDA noted some kidney-related laboratory abnormalities that could potentially be linked to Truvada use in iPrEx, but not in FEM-PrEP. As for bone mineral density (BMD) changes, mild but statistically significant decreases were more likely to occur among men using Truvada in iPrEx, compared with placebo.   

As for the risk of drug resistance among those who become infected with HIV while receiving Truvada, the FDA noted that uncertainties remain. “Analysis of HIV isolates from individuals [in clinical trials] who became infected while taking PrEP have failed to identify resistance mutations that developed following seroconversion, consistent with the finding that study subjects who seroconverted were generally not adherent to medication. Selection of resistance among trial participants may have been minimized due to monthly monitoring for seroconversion.

“The impact of PrEP on resistance beyond a clinical trial setting is difficult to predict,” the FDA briefing document adds, “but resistance is expected among infected individuals using PrEP. The frequency of resistance might be minimized by limiting the duration of drug exposure after infection occurs with frequent monitoring for HIV seroconversion.”

To mitigate risks of Truvada PrEP, Andrew Cheng, MD, of Gilead described the company’s risk evaluation and mitigation strategies (REMS), which were reviewed and discussed by the advisory committee members.

Gilead’s plans are primarily educational in nature and are intended “to inform and education prescribers, health care professional and individuals at high risk for acquiring HIV infection.”

First, the company has proposed dispensing a Truvada medication guide with each Truvada PrEP prescription. Second, Gilead will implement voluntary training and education through a Truvada for PrEP educational program for health care providers. Both initiatives will address two identified risks associated with Truvada as PrEP—HIV acquisition and the development of drug resistance—and a potential, but very serious, risk: the need for careful prescribing, adherence and follow-up practices for individuals with chronic hepatitis B virus (HBV) infection, who can experience acute liver disease exacerbations if tenofovir and emtricitabine (both are effective against HBV) are not taken correctly or are stopped abruptly.

Gilead said it is also committed to providing vouchers for free HIV testing, HBV testing and condoms. The company will also provide assistance for drug-resistance testing for individuals who become infected with HIV while using Truvada, an opt-in testing reminder service and has established a PrEP registry project to assess adherence over time.