Gilead Sciences Inc. announced that it has submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for the approval of once-daily Truvada (emtricitabine/tenofovir disoproxil fumarate) for pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection among uninfected adults. Truvada was approved by the FDA in 2004 for the treatment of HIV-1 infection and is currently the most-prescribed antiretroviral treatment in the United States.

If the sNDA is approved, Truvada would be the first agent indicated for uninfected individuals to reduce the risk of acquiring HIV through sex, a prevention approach called PrEP. The sNDA is based on the results of two large placebo-controlled trials of Truvada as PrEP, sponsored by the U.S. National Institutes of Health (NIH) and the University of Washington. Several other clinical studies support the use of Truvada for HIV risk reduction.

"The data from these large-scale clinical trials suggest that Truvada may have a role to play in meeting the urgent public health need to reduce new HIV infections," said John C. Martin, PhD, Chairman and Chief Executive Officer of Gilead Sciences. "Gilead is proud to have played a part in helping to define the use of Truvada as a potential new prevention tool and we commend the many institutions, investigators and study volunteers for their commitment to advancing this important area of research."

According to current Centers for Disease Control and Prevention (CDC) data, each year some 50,000 people are newly infected with HIV in the United States. Despite extensive efforts to prevent infections using existing interventions, the HIV incidence rate has remained steady for many years. More than half of new infections (61%) occur among men who have sex with men, and nearly a quarter (23%) occur among women.

Truvada is not currently indicated to reduce the risk of HIV infection.

The first trial providing data to support the Truvada sNDA is a Phase 3 randomized, double-blind, placebo-controlled trial known as the Pre-Exposure Prophylaxis Initiative (iPrEx), which was sponsored by the NIH and conducted among 2,499 high-risk HIV-negative adult men who have sex with men in the United States and countries in Africa, Asia and South America. Results from the trial, published in The New England Journal of Medicine in November 2010, showed that once-daily use of Truvada for PrEP reduced the risk of acquiring HIV overall by 44% compared with placebo and by up to 73% among men who reported taking the drug consistently (defined as at least 90% of days). Among men who took the drug consistently enough to have detectable drug in their body, the risk was reduced by more than 90%.

"It is clear that new prevention strategies are urgently needed to tackle the unacceptably high number of new HIV infections in the United States," said Robert M. Grant, MD, MPH, Betty Jean and Hiro Ogawa Endowed Investigator, Gladstone Institute of Virology and Immunology, University of California, San Francisco and lead investigator of the iPrEx trial. "It is exciting to consider the prospect of a new intervention that, when offered with condoms and other preventative measures, can help to further reduce the individual risk of HIV acquisition and the community impact of the disease."

The Truvada sNDA submission is also supported by data from Partners PrEP, a Phase 3 randomized, double-blind, placebo-controlled trial conducted among 4,758 heterosexual couples in Kenya and Uganda in which one partner was infected with HIV and the other was not. Partners PrEP, sponsored by the University of Washington, released initial results in advance of the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, held in July 2011. Once-daily use of oral Truvada by the HIV-negative participants reduced their risk of acquiring HIV by 73% compared with placebo.

"This year marked the 30-year milestone of the AIDS pandemic and the loss of an estimated 30 million lives, but it has also been a year of hope with several significant new advances in antiretroviral-based HIV prevention," said Connie Celum, MD, MPH, Professor of Global Health and Medicine at the University of Washington and lead investigator of the Partners PrEP trial. "To turn the tide in this epidemic, we need to use the prevention strategies that work, including the effective treatment of people already infected with HIV, and pre-exposure prophylaxis for persons at high risk of acquiring HIV. The efficacy results observed in the Partners PrEP trial indicate that PrEP may be an important new tool for HIV prevention among heterosexuals in serodiscordant relationships, who account for a large proportion of new HIV cases worldwide."

Additional supportive data come from two studies sponsored by CDC. The first trial, known as TDF2, was a Phase 3 randomized, double-blind, placebo-controlled trial conducted in Botswana among 1,200 HIV-negative heterosexual men and women. Participants taking once-daily oral Truvada for PrEP had 63% fewer HIV infections compared with those receiving placebo. The second trial, known as CDC 4323, was a Phase 2 randomized, placebo-controlled, double-blind study of men who have sex with men in the United States designed primarily to assess the safety, adherence and acceptability of PrEP.

Although full details are not yet available, another separate Phase 3 study of Truvada for PrEP known as FEM-PrEP was stopped in April 2011 based on a recommendation by the study's Independent Data Monitoring Committee that the trial would not be able to establish the efficacy of Truvada among HIV-negative women in sub-Saharan Africa. The reason for this outcome is not yet understood and a complete detailed analysis of the data is currently underway.

In all studies, side effects included nausea, weight loss and serum creatinine elevations. The incidence of side effects was consistent with Truvada's safety and tolerability profile when used as HIV treatment, which is supported by more than 1.8 million years of patient use. Overall, there have been more than 4.4 million patient years of experience with tenofovir-containing regimens. Three cases of resistance to emtricitabine were reported in the iPrEx trial among participants who tested negative for HIV infection by serology at enrollment, but were later found to have been infected with HIV prior to enrollment using a different assay. Two of these cases occurred in the active drug arm, and one case occurred in the placebo arm.

Based on the iPrEx trial results, in January 2011 CDC issued interim guidance on Truvada as PrEP among high-risk adult men who have sex with men. Both study investigators and CDC have emphasized the need for HIV testing and clinical screening before initiation of PrEP to ensure that anyone starting PrEP is not already HIV infected; close monitoring for viral-like symptoms among PrEP patients that could be an indication of acute HIV infection; and discontinuation of PrEP if HIV infection does occur.

CDC guidance also stresses that effectiveness is highly dependent on medication adherence; the importance of confirming that patients who take Truvada for PrEP are at substantial ongoing risk for HIV infection; the need to provide counseling on the importance of adhering closely to the prescribed regimen and using other HIV prevention methods; and the importance of regularly testing for HIV infection.

CDC is currently developing formal U.S. Public Health Service guidelines for the use of PrEP. Among the topics that will be addressed by the formal guidelines are procedures for initial HIV testing and health screening, as well as ongoing monitoring for side effects, clinical toxicities, HIV infection and possible drug resistance among those who become infected despite taking PrEP.

Date: December 15, 2011
Source: Gilead Sciences Inc.