Four-year Data on Entecavir Resistance in Nucleoside-naïve Patients with Chronic
Hepatitis B  Discovered
at Bristol-Myers Squibb (BMS), entecavir (Baraclude) is a nucleoside
analogue drug that is FDA-approved and indicated for
the treatment of chronic hepatitis B virus (HBV) infection in adults who have
evidence of active HBV replication with either evidence of persistent elevations
in serum aminotransferases (ALT or AST) or histologically active disease.
At the recent 42nd EASL conference in Barcelona, Spain,
BMS announced new results of the entecavir resistance
monitoring program, which found a continued
low incidence of resistance in studies of nucleoside-naïve chronic hepatitis B
patients (n=663) through four years of treatment. Following are excerpts from the BMS statement
on the 4-year data on entecavir resistance presented
at the annual EASL meeting: “In the three nucleoside-naïve studies
analyzed, only two patients (less than 1%), experienced virologic
breakthrough due to entecavir resistance through the
third year, and no additional patients developed resistance in the fourth year.
“In lamivudine-refractory
patients, virologic breakthrough due to entecavir
occurred in 15 percent (n=8/53) of patients during year four. “Drug resistance occurs when a virus mutates
to avoid the effects of the medication. This can make treatment of hepatitis B challenging,
because it can decrease the efficacy of the current medication and may compromise
future treatment options. To date, studies
have shown that multiple mutations are required to develop entecavir resistance. “The low incidence of resistance seen in nucleoside-naïve patients
through four years of treatment reflects entecavir’s
high barrier to resistance in this patient population,” said Richard Colonno, Ph.D., vice president
for virology drug discovery at Bristol-Myers Squibb. About the Analysis “More than 700 patients across six studies initiated therapy on entecavir and were monitored for treatment response
and resistance. “The year four analysis evaluated those patients who received treatment
with entecavir during the fourth year (n=120
for patients in nucleoside-naïve studies and n=53 for patients in lamivudine-refractory studies). “In this comprehensive
analysis, all patients enrolled in Bristol-Myers Squibb clinical trials ETV-014,
-015, -022, -027, -026 and -901 who experienced a virologic
breakthrough (greater than or equal to one log increase in HBV DNA from nadir
as measured by a common
assay - polymerase chain reaction or PCR), or whose virus had not yet reached
undetectable levels – a measurement of the levels of hepatitis B virus in the
blood (HBV DNA levels >300 copies/mL by PCR assay) at weeks 48, 96, 144, 192
or end of dosing were sequenced to determine if any changes occurred in the genetic
code of the virus that would result in resistance or loss of effectiveness of
entecavir. “Viral load reduction in chronic hepatitis B patients treated with
BARACLUDE in nucleoside-naïve and lamivudine-refractory
studies was also evaluated. Data Results “The incidence of BARACLUDE resistance in patients in
nucleoside-naïve studies over time is low, with less than one percent of patients
experiencing virologic breakthrough due to entecavir resistance through four years.
- Virologic breakthrough due to entecavir resistance
(rtS202G) occurred in one patient out of 663 treated during the first year, who
had lamivudine resistance (rtM204I) at the time of study
entry and was initiated on 0.5 mg.
- No
additional virologic breakthroughs due to entecavir resistance were observed during the second
year of treatment. One patient was identified with emerging entecavir resistance without virologic
breakthrough in year two; this patient did not continue into year three.
- Virologic breakthrough due to entecavir resistance
occurred in one additional patient out of 149 treated during the third year of
treatment.
- No additional virologic
breakthroughs due to entecavir resistance were observed
during the fourth year of treatment.
“The
emergence of resistance increased over four years in patients in lamivudine-refractory studies. - Virologic breakthrough due to resistance occurred in one percent (2/187) of
patients during the first year of treatment.
- Virologic breakthrough due to entecavir resistance
occurred in an additional ten percent (14/146) of patients during the second year of
treatment.
- Virologic breakthrough due to entecavir resistance
occurred in an additional 16 percent (13/80) of patients during the third year.
- Virologic breakthrough due to entecavir resistance
occurred in an additional 15 percent (8/53) of patients during the fourth year.
- The results in these patients in years one through four were consistent
with the finding that the pre-existence of lamivudine-resistant
substitutions resulted in an increase in the emergence of entecavir resistance.
References
R J Colonno, R E Rose, K Pokornowski, and others. Four Year Assessment of ETV Resistance in
Nucleoside-naïve and Lamivudine Refractory Patients. 42nd Annual Meeting of the European
Association for the Study of the Liver. April 11 - 15, 2007, Barcelona,
Spain. Bristol Myers Squibb. Four-year Data Demonstrate Continued Low
Incidence of Baraclude (Entecavir)
Resistance in Nucleoside-naïve Chronic Hepatitis B Patients. Press Release. April 14, 2007.
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