Gilead Sciences, Inc. (Nasdaq: GILD) announced today 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 percent) occur among men who have sex with men, and nearly a
quarter (23 percent) 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 percent compared with placebo
and by up to 73 percent among men who reported taking the drug
consistently (defined as at least 90 percent 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 percent.
“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 percent 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 percent 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.
Gilead donated drug and placebo tablets for iPrEx, Partners
PrEP, TDF2 and CDC 4323, as well as for other ongoing trials of
PrEP for HIV prevention being conducted worldwide among multiple
high-risk populations.
Important Safety Product Information
About Truvada, Including Boxed Warnings
Truvada, a combination of Emtriva® (emtricitabine) and Viread®
(tenofovir disoproxil fumarate [DF]), is indicated in combination
with other antiretroviral agents (such as non-nucleoside reverse
transcriptase inhibitors or protease inhibitors) for the treatment
of HIV-1 infection.
The following points should be considered when initiating
therapy with Truvada for the treatment of HIV-1 infection:
- It is not recommended that Truvada be
used as a component of a triple nucleoside regimen.
- Truvada should not be coadministered
with Atripla® (efavirenz/emtricitabine/tenofovir DF), Emtriva,
Viread, or lamivudine-containing products.
- In treatment-experienced patients, the
use of Truvada should be guided by laboratory testing and treatment
history.
WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS
and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
Lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with the use of
nucleoside analogs, including Viread, a component of Truvada, in
combination with other antiretrovirals.
Truvada is not approved for the treatment of chronic
hepatitis B virus (HBV) infection, and the safety and efficacy of
Truvada have not been established in patients coinfected with HBV
and HIV-1. Severe acute exacerbations of hepatitis B have been
reported in patients who are coinfected with HBV and HIV-1 and have
discontinued Truvada. Hepatic function should be monitored closely
with both clinical and laboratory follow-up for at least several
months in patients who are coinfected with HIV-1 and HBV and
discontinue Truvada. If appropriate, initiation of anti-hepatitis B
therapy may be warranted.
WARNINGS AND PRECAUTIONS
New Onset or Worsening Renal Impairment
- Emtricitabine and tenofovir are
principally eliminated by the kidney. Renal impairment, including
acute renal failure and Fanconi syndrome (renal tubular injury with
severe hypophosphatemia), has been reported with the use of
tenofovir DF.
- Assess CrCl before initiating treatment
with Truvada. Routinely monitor CrCl and serum phosphorus in
patients at risk for renal impairment, including patients who have
previously experienced renal events while receiving Hepsera®
(adefovir dipivoxil).
- Dosing interval adjustment of Truvada
and close monitoring of renal function are recommended in all
patients with CrCl 30–49 mL/min. No safety or efficacy data are
available in patients with renal impairment who received Truvada
using these dosing guidelines, so the potential benefit of Truvada
therapy should be assessed against the potential risk of renal
toxicity. Truvada should not be administered in patients with CrCl
60 kg. Data are not available to recommend a dose adjustment of ddI
for patients weighing
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