Gilead requests HIV PrEP approval

South San Francisco-based Gilead Sciences announced this month that it has submitted a supplemental new drug application to the federal Food and Drug Administration seeking approval of its Truvada combination pill for HIV pre-exposure prophylaxis, or PrEP.

The company, which made the announcement December 15, has asked for priority review, meaning a decision could come as early as June. Clinicians can currently prescribe drugs "off label" as they see fit, but official approval of Truvada PrEP would have implications for public health programs and insurance coverage.

"The data from clinical trials clearly show that taking Truvada every day and using condoms can be very effective in preventing HIV for people at highest risk for infection," said Project Inform Executive Director Dana Van Gorder. "We believe in the right of HIV-negative people to choose the evidence-based prevention methods that best support their efforts to remain negative, and we urge quick FDA approval of Truvada for prevention."

PrEP trial results

Gilead's request is based on findings from a series of large international trials of oral PrEP using Truvada or the medications it contains, tenofovir (sold separately as Viread) and emtricitabine (Emtriva). Overall, results have been promising but several questions remain unanswered.

The large iPrEX trial, which enrolled nearly 2,500 gay and bisexual men and transgender women in six countries (including San Francisco and Boston in the U.S.), found that daily Truvada reduced the risk of acquiring HIV by 44 percent overall, with 36 new infections among men receiving PrEP compared with 64 among men taking a placebo pill.

Further data presented at the International AIDS Society conference this summer in Rome showed that risk reduction exceeded 90 percent for participants who had detectable drug levels in their blood, indicating good adherence.

"With 2.6 million new HIV infections occurring each year, and fewer than half of people with HIV receiving treatment, the world needs new and effective HIV prevention strategies," said iPrEx protocol chair Dr. Robert Grant from the Gladstone Institutes and UCSF. "Men who have sex with men have borne an enormous burden in this epidemic, and have also been consistently at the head of efforts to help reverse it."

Two other trials discussed in Rome - Partners PrEP and TDF2 - showed that the drugs in Truvada reduced the risk of HIV infection among heterosexual men and women in Africa by 60 percent to 75 percent.

In contrast, however, two studies of heterosexual African women have not seen a similar effect. The Fem-PrEP study of daily Truvada was halted earlier this year due to lack of effectiveness, as was an arm of the VOICE trial testing oral tenofovir alone (the tenofovir/emtricitabine combination is still being evaluated.)

Unanswered questions

While Truvada PrEP appears highly effective when used appropriately by well-selected, high-risk populations, advocates and public health officials have raised concerns about practical effectiveness, long-term side effects, drug resistance, and cost and access.

PrEP trials have administered antiretroviral drugs as part of a comprehensive prevention package that also includes condoms and risk-reduction counseling. Some experts suspect PrEP would not fare as well under "real world" conditions without such support; others worry that people using the drugs might think they are adequately protected and forego safer sex practices.

While Truvada is among the most widely used medications for HIV treatment and is generally safe and well-tolerated, the risk-benefit calculation is different when considering routine use by healthy HIV-negative people.

Studies have shown that the tenofovir component of Truvada can cause kidney problems and bone loss in susceptible patients, and its longer-term effects beyond 10 years are not yet known.

Furthermore, it is important for people considering PrEP to be tested for HIV before starting and regularly thereafter, since using tenofovir/emtricitabine alone if the virus is present can lead to drug resistance that could limit future treatment options.

The AIDS Healthcare Foundation issued a statement opposing Gilead's bid for expanded approval, and questioned the "lack of transparency" of the FDA's application process.

"We are disappointed that Gilead has irresponsibly decided to proceed with their application for an indication for PrEP despite the failed results from numerous trials," said AHF president Michael Weinstein. "This is yet another example of a drug company putting profit before ethical conduct."

AHF and others have expressed concerns about who would have access to PrEP and how it would be funded for HIV-negative people, especially given that many HIV-positive people in the U.S. and worldwide are unable to obtain antiretroviral drugs for treatment.

There have also been rumblings from both within and outside the AIDS community about the wisdom of offering expensive drugs to enable people to continue having unprotected sex.

But this type of intervention is common in public health, for example providing statin medications to reduce the risk of heart attacks among people who continue to smoke or eat fatty food.

"We would remind policy makers and the public that people at risk for HIV infection are hardly the only people who know what health behaviors are best for them but nevertheless struggle to maintain them," Van Gorder told the Bay Area Reporter. "Some will moralize about this prevention strategy, but we believe it is more important to end the HIV epidemic than to sit in judgment of people's behaviors."