Gilead Sciences, Inc. (Nasdaq:GILD) today announced new
five-year data from the open-label phase of two pivotal Phase 3
clinical trials (Studies 102 and 103) evaluating the efficacy of
Viread® (tenofovir disoproxil fumarate) for the treatment of
chronic hepatitis B virus (HBV) infection among primarily
treatment-naïve patients. Results show that Viread maintains
long-term viral suppression of HBV and is associated with a
reduction in liver fibrosis and a reversal of cirrhosis. Among
patients in both studies, the majority (88 percent) experienced an
improvement in overall liver histology. Together, these two studies
represent one of the largest datasets evaluating the impact of an
oral antiviral therapy on histologic changes and showing a
reduction in liver fibrosis. These findings are being presented
Monday, November 7 at the 62nd annual meeting of the American
Association for the Study of Liver Diseases (The Liver Meeting
2011) in San Francisco.
“We have long theorized that long-term antiviral therapy can not
only help chronic hepatitis B patients achieve and maintain
virologic suppression, but also help to improve clinical outcomes,
including a reduction in the risk of fibrosis or cirrhosis,” said
Patrick Marcellin, MD, of Hôpital Beaujon in Clichy, France, INSERM
CRB3 and University of Paris Denis Diderot, and the principal
investigator of Study 102. “These results represent an important
advance in HBV therapy because they elucidate Viread’s potential to
reduce or reverse signs of liver damage in patients with chronic
hepatitis B.”
Studies 102 and 103 were designed to compare Viread to Hepsera®
(adefovir dipivoxil) in a blinded manner over 48 weeks, among both
HBeAg-negative (Study 102) and HBeAg-positive (Study 103) patients
with compensated liver disease. Patients originally randomized to
Hepsera in both studies were switched to open-label Viread at 48
weeks and patients randomized to Viread continued on open-label
Viread.
The data show that the majority of patients who received Viread
continuously for 240 weeks experienced sustained suppression of HBV
DNA (viral load) levels in the blood below 400 copies/mL (83
percent and 64 percent for Studies 102 and 103, respectively).
Patients who were randomized to Hepsera and rolled over to Viread
at week 48 and received Viread for a subsequent 192 weeks also
maintained viral suppression (84 percent and 66 percent for Studies
102 and 103, respectively).
Notably, among the 331 patients who had paired biopsies at both
baseline and week 240, 292 (88 percent) experienced an improvement
in overall liver histology, as measured by an improvement of at
least two points in Knodell necroinflammatory score without
worsening in Knodell fibrosis score. Of the 94 patients who had
cirrhosis (Ishak fibrosis score ≥ 5) at the start of therapy, 69
(73 percent) experienced regression of cirrhosis and 68 (72
percent) had at least a two-point reduction in Ishak fibrosis
score.
Among HBeAg-positive patients receiving Viread through 240 weeks
(Study 103), the cumulative probability (estimated by Two-State
Markov model) of “s” antigen loss and seroconversion was 9 percent
and 7 percent, respectively. Additionally, no resistance to Viread
emerged over 240 weeks of treatment.
“Viral resistance is a significant challenge for physicians
treating patients with chronic hepatitis B,” said Jenny Heathcote,
MD, of the University of Toronto, Canada, and the principal
investigator for Study 103. “These five-year results are important
in that they demonstrate Viread’s high genetic barrier to
resistance, which is essential for the long-term success of HBV
therapy.”
Viread for HBV was approved by the U.S. Food and Drug
Administration (FDA) in 2008 and has since become the
most-prescribed medicine for chronic HBV in the United States.
These five-year data have been submitted to the FDA and to the
European Medicines Agency for review and potential inclusion in the
Viread label.
About Studies 102 and
103
Studies 102 and 103 were both multi-center, randomized,
double-blind Phase 3 clinical trials comparing Viread to Hepsera
among HBeAg-negative (Study 102; n=375) and HBeAg-positive (Study
103; n=266) chronic hepatitis B patients with compensated liver
disease. Patients had HBV DNA above 100,000 copies/mL and elevated
levels of alanine aminotransferase (ALT, an enzyme that serves as a
measure of liver inflammation) upon study initiation. The majority
of patients were treatment-naïve.
Patients originally randomized to Hepsera in both studies rolled
over to open-label Viread treatment (n=196) at week 48, while
patients originally randomized to Viread continued open-label
Viread (n=389). All patients were asked to undergo liver biopsy at
48 weeks of treatment and again at five years of treatment, and a
total of 331 patients were evaluated in the histology analysis.
Seventy-two percent of patients in Study 102 and 50 percent of
patients in Study 103 achieved normalized ALT at week 240. Viread
was well-tolerated in both studies. The most commonly observed
adverse events were abdominal pain, nasopharyngitis, headache,
influenza, back pain and hypertension. Across both studies, 2.1
percent of patients who received Viread for five years discontinued
treatment due to an adverse event and 0.9 percent of patients
experienced a confirmed increase in serum creatinine of at least
0.5 mg/dL or calculated creatinine clearance less than 50
mL/min.
Important Information About Viread for
Chronic Hepatitis B
Viread (tenofovir disoproxil fumarate) is indicated for the
treatment of chronic hepatitis B in adults. The following points
should be considered when initiating therapy with Viread for the
treatment of HBV infection: This indication is based primarily on
data from the treatment of nucleoside-treatment-naïve patients, and
a smaller number of patients who had previously received lamivudine
or adefovir. Patients were adults with HBeAg-positive and
HBeAg-negative chronic hepatitis B with compensated liver disease.
Viread was evaluated in a limited number of subjects with chronic
hepatitis B and decompensated liver disease. The number of patients
in clinical trials who had lamivudine- or adefovir-associated
substitutions at baseline was too small to reach conclusions of
efficacy.
Lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with the use of
nucleos(t)ide analogs, including Viread, in combination with other
antiretrovirals.
Severe acute exacerbations of hepatitis have
been reported in HBV-infected patients who have discontinued
anti-hepatitis B therapy, including Viread. Hepatic function should
be monitored closely with both clinical and laboratory follow-up
for at least several months in patients who discontinue
anti-hepatitis B therapy, including Viread. If appropriate,
resumption of anti-hepatitis B therapy may be warranted.
New onset or worsening of renal impairment including cases of
acute renal failure and Fanconi syndrome has been reported with the
use of Viread. It is recommended to assess creatinine clearance
(CrCl) before initiating treatment with Viread and monitor CrCl and
serum phosphorus in patients at risk, including those who have
previously experienced renal events while receiving Hepsera.
Administering Viread with concurrent or recent use of nephrotoxic
drugs should be avoided.
Viread should not be used with other tenofovir-containing
products (e.g., Atripla®, Complera®, Truvada®). Viread should not
be administered in combination with Hepsera.
Due to the risk of development of HIV-1 resistance, Viread
should only be used as part of an appropriate antiretroviral
combination regimen in HIV-infected patients with or without HBV
coinfection. HIV antibody testing should be offered to all
HBV-infected patients before initiating therapy with Viread.
Decreases in bone mineral density (BMD) have been observed in
HIV-infected patients. It is recommended that BMD monitoring be
considered for patients with a history of pathologic fracture or
who are at risk for osteopenia. The bone effects of Viread have not
been studied in patients with chronic HBV infection. Cases of
osteomalacia (associated with proximal renal tubulopathy and which
may contribute to fractures) have been reported in association with
the use of Viread.
In controlled clinical trials in patients with chronic hepatitis
B with compensated liver disease, the most common adverse reaction
(all grades) was nausea, observed in 9 percent of patients taking
Viread at week 48. Other adverse reactions observed at week 48 in
greater than 5 percent of patients treated with Viread include
abdominal pain, diarrhea, headache, dizziness, fatigue,
nasopharyngitis, back pain and skin rash.
In HBV-infected patients with decompensated liver disease, the
most common adverse reactions (all grades) reported in greater-than
or equal to 10 percent of patients treated with Viread were
abdominal pain (22 percent), nausea (20 percent), insomnia (18
percent), pruritus (16 percent), vomiting (13 percent), dizziness
(13 percent), and pyrexia (11 percent).
Coadministration of Viread with didanosine increases didanosine
concentrations. Use with caution and monitor for evidence of
didanosine toxicity (eg, pancreatitis, neuropathy). Didanosine
should be discontinued in patients who develop
didanosine-associated adverse reactions. In adults weighing >60
kg, the didanosine dose should be reduced to 250 mg when it is
coadministered with Viread. Data are not available to recommend a
dose adjustment of didanosine for patients weighing
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