Re-treatment
with Entecavir Results in Undetectable HBV by Week 48 A
major concern for patients with chronic hepatitis B virus (HBV) infection is the
development of resistance to the available anti-HBV drugs, which are most often
used as sequential monotherapy. Researchers are testing new HBV treatment strategies,
including dual combinations of anti-HBV agents, and -- in the present study --
re-treatment with the same agent in HBeAg-negative chronic hepatitis B patients.
Entecavir
(Baraclude) is an oral nucleoside analog drug that has selective anti- HBV activity.
The U.S. Food and Drug Administration (FDA) approved entecavir on March 30, 2005
for the treatment of chronic hepatitis B in adults. The recommended dosage is
a single 0.5 mg tablet once-daily for patients beginning treatment for the first
time (nucleoside-naive), and a single 1 mg tablet once-daily for patients who
have developed resistance to lamivudine.
In the current study, presented
at the 42nd Annual Meeting of the European Association for the Study of the Liver last week in Barcelona, Spain, researchers reported data from a cohort
of 99 nucleoside-naive, HBeAg-negative chronic hepatitis B patients (study ETV-027/901).
These data showed that patients who had detectable levels of HBV in their blood
following interruption of treatment with entecavir achieved viral suppression
and liver enzyme (ALT) normalization when re-treated with entecavir for 48 weeks.
Overall, 93% of patients re-treated with entecavir achieved undetectable
HBV viral load (HBV DNA < 300 copies/mL, measured by PCR) and 83% achieved
liver enzyme normalization (ALT) 1 times the upper limit of normal [x ULN]) after
48 weeks of therapy.
"This study showed that when treated again with
Baraclude [entecavir] for 48 weeks, patients achieved responses similar to those
seen prior to treatment interruption, with safety results consistent with previously
reported experience," said Hakan Senturk, MD, of the Ist.Univ.Cerrahpasa
Tip Fak in Istanbul, Turkey.
No deaths or treatment discontinuations due
to adverse events were reported in this cohort. The most common adverse events,
occurring in more than 10% of patients, were abdominal pain, fatigue, upper respiratory
tract infections, nasopharyngitis, increased ALT, arthralgia, and headache.
The
Nucleoside-naive, HBeAg-negative Entecavir Re-treatment Cohort
This
analysis evaluated entecavir in nucleoside-naive chronic HBeAg-negative patients
who discontinued study therapy in ETV-027, and subsequently restarted treatment
in rollover study ETV-901, with a greater than 60-day gap between the end of treatment
in ETV-027 and start of treatment in ETV-901. •
Study ETV-027
compared 0.5 mg entecavir vs 100 mg lamivudine in nucleoside-naive HBeAg-negative
chronic hepatitis B patients.
•
Rollover
study ETV-901 was established as an open-label, follow-up protocol for patients
in Phase II and III studies of entecavir.
•
Due
to ongoing blinding of study ETV-027, most patients retreated in ETV-901 initially
received a combination of 1 mg entecavir plus 100 mg lamivudine, and were subsequently
switched to 1 mg entecavir monotherapy. The
analysis cohort was defined regardless of treatment response at the end of dosing
in ETV-027, and independent of virological or ALT measurements at the start of
dosing in ETV-901. During off-treatment follow-up, the majority of patients had
recurring HBV viremia (virus in the blood) and increases in ALT.
Summary
of Results
At
the end of dosing for study ETV-027:
•
94%
(93 of 99) of the re-treatment cohort had undetectable HBV viral load.
•
78%
(77 of 99) experienced ALT normalization.
At
entry into ETV-901:
•
4%
(4 of 99) had undetectable HBV viral load.
•
8%
(8 of 97) had ALT normalization.
Following re-treatment in study ETV-901:
•
93%
(82 of 88) had undetectable viral load (HBV DNA < 300 copies/mL) by week 48
of re-treatment with entecavir.
•
83%
(79 of 95) had ALT normalization (ALT ? 1 x ULN by week 48 of re-treatment entecavir.
Adverse events in study ETV-027/901 re-treatment cohort:
•
67%
(66 of 99) experienced an adverse event.
•
The
most common adverse events occurring in more than 10% of patients were abdominal
pain, fatigue, upper respiratory tract infections, nasopharyngitis, increased
ALT, arthralgia, and headache.
•
There
were no deaths or treatment discontinuations due to adverse events.
•
9%
(9 of 99) experienced a serious adverse event.
•
Serious
adverse events included ALT elevation or hepatitis exacerbation (4), bilirubin
elevation (1), inguinal hernia (1), sialoadenitis (1), thrombocytopenic purpura
(1), groin pain (1), macular edema (1), urinary incontinence (1), and cholelithiasis
(1).
•
The
investigators considered 2 of these events -- hepatitis exacerbation (1) and thrombocytopenia
(1) -- possibly related to treatment.
5% (5 of 99) experienced ALT flares
on treatment (ALT > 2 x baseline and > 10 x ULN)
Conclusion
In
conclusion, the study investigators wrote, "Entecavir re-treatment of nucleoside-naive,
HBeAg-negative [patients] who had discontinued therapy results in undetectable
HBV DNA and ALT normalization in most patients. The safety profile of entecavir
remains consistent with previously reported experience."
Cerrahpasa
Medical Faculty, Istanbul, Asksaray, Turkey; Tel-Aviv Sourasky Medical Center,
Tel-Aviv, Israel; Hospital Italiano, Buenos Aires, Argentina; Department Of Gastroenterology,
Singapore General Hospital, Singapore; Cedars Sinai Hospital, Los Angeles, CA;
Taipei Veterans General Hospital, Taipei, Taiwan-ROC; University Of Hawaii, Honolulu,
HI; Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil; Bristol-Myers
Squibb Pharmaceutical Research Institute, Wallingford, CT and Princeton, NJ.
04/17/07
Sources
H Senturk, Y Lurie, A Gadano, and others. ETV Re-treatment
of Nucleoside-Naive HBeAg(-) Patients. 42nd Annual Meeting of the European Association
for the Study of the Liver. April
11 - 15, 2007, Barcelona,
Spain.
Bristol-Myers
Squibb. Baraclude (Entecavir) Therapy Resulted in Undetectable Levels of Hepatitis
B Virus in a Cohort of Patients Who Re-started Treatment Press Release.
April 13, 2007.
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