Several
presentations at the recent 57th Annual Meeting of the American Association for
the Study of Liver Diseases (AASLD) in Boston concerned use of the nucleoside
analog entecavir (Baraclude)
for the treatment of chronic hepatitis B.
Hepatitis
B therapy is limited by the development of drug resistant virus. Resistance to
lamivudine (Epivir-HBV) emerges
relatively rapidly when lamivudine is used as monotherapy. Many hepatitis B studies
have looked at substituting or adding other antiviral agents in previously treated
patients who have already developed YMDD mutations conferring resistance to lamivudine.
Study
1
In
a departure from prior studies, N. Leung and an international team of colleagues
reported results from the E.A.R.L.Y. trial comparing entecavir
vs adefovir (Hepsera) in individuals
who had not received prior antiviral therapy with lamivudine. This was the first
study to directly compare entecavir vs adefovir in treatment-naive patients.
In
this study, 69 antiviral-naive HBeAg positive chronic hepatitis B patients were
randomly assigned to receive either entecavir (0.5 mg) or adefovir (10 mg) once
daily for a minimum of 52 weeks and up to 96 weeks. Measurements of serum HBV
DNA by PCR assay were obtained through Week 12 for assessment of viral load reduction
and viral kinetics. Additional serum samples were obtained at Week 24 for determination
of HBV DNA by PCR.
Results
The mean baseline HBV DNA levels were 10.26 log copies/mL in the entecavir arm
and 9.88 log copies/mL in the adefovir arm.
Entecavir demonstrated superior early antiviral activity and viral kinetic profiles
compared with adefovir as early as Day 10.
Viral load reduction was more variable with adefovir than with entecavir.
Entecavir produced superior reduction in HBV DNA at Week 12 (6.23 vs 4.42 log
copies/mL; P < 0.0001).
At Week 24, the mean HBV DNA decrease from baseline was 6.97 log copies/mL in
the entecavir arm vs 4.84 log copies/mL in the adefovir arm (difference 1.86;
95% CI 2.51-1.20).
At Week 24, 75% of entecavir-treated patients achieved HBV DNA < 104 copies/mL
compared with 32% of adefovir-treated patients.
At that time, just 3% of patients receiving entecavir had viral loads > 105
copies/mL, compared with 50% of adefovir-treated patients.
45% of patients receiving entecavir achieved undetectable HBV DNA (< 300 copies/mL)
by Week 24 compared with 13% in the adefovir arm.
A trend test showed that HBV viral load at Day 10 was predictive of Week 24 virological
response.
Among those patients achieving HBV DNA < 106 copies/mL by Day 10, 91% in the
entecavir arm and 50% in the adefovir arm subsequently achieved undetectable viral
load at Week 24.
Both entecavir and adefovir had similar overall safety profiles throughout the
study period.
In
conclusion, the researchers wrote:
"At Week
24, entecavir-treated patients achieved a mean 1.86 log10 (72-fold) greater reduction
in HBV DNA, with a higher proportion of patients achieving undetectable viral
load compared to adefovir."
"The extent
of HBV DNA reduction at Day 10 was predictive of achieving undetectable HBV DNA
at Week 24."
"Both antivirals
were generally well tolerated."
Study
2
G.
Yao and colleagues presented 2-year results from a study of previously treatment-naive
patients starting therapy with entecavir or lamivudine in a Phase III study in
China (ETV-023).
Prior
data showed that entecavir demonstrated superior virological and biochemical efficacy
compared to lamivudine after 48 weeks in nucleoside-naive chronic hepatitis B
patients. The present analysis updated those results through a second year.
The study included 519 HBeAg positive or HBeAg negative patients with chronic
hepatitis C and compensated liver disease who were randomly assigned to receive
0.5 mg entecavir (n=258) or 100 mg lamivudine (n=261) once daily for at least
52 weeks. At Week 52 a decision was made about further therapy:
Patients who had a response to therapy at Week 48 (defined as HBV DNA < 0.7
MEq/mL by bDNA assay, HBeAg negative for at least 6 months, and ALT < 1.25
x ULN) stopped therapy.
Those who achieved HBV DNA < 0.7 MEq/mL but did not yet achieve a consolidated
response (i.e., undetectable HBV DNA, HBeAg clearance, and ALT normalization)
continued blinded therapy with entecavir or lamivudine.
Those with persistent HBV DNA ? 0.7 MEq/mL stopped therapy.
Results
At the end of dosing through Year 2, the mean decrease in HBV DNA from baseline
was significantly greater in the entecavir arm compared with the lamivudine arm
(5.89 vs 3.55 log10 copies/mL; P < 0.0001).
The total proportions of patients achieving a consolidated response at Week 48
or at the end of dosing in Year 2 were 30% and 24%, respectively.
Response was sustained after 24 weeks of off-treatment follow-up for 70% of patients
receiving entecavir and 48% receiving lamivudine.
Among patients who continued to the second year of therapy (193 receiving entecavir,
145 receiving lamivudine), 74% and 41%, respectively, had HBV DNA levels <
300 copies/mL at the end of dosing.
96% and 82%, respectively, had ALT levels ? 1 x ULN at the end of dosing.
About one-quarter of subjects in both arms experienced HBeAg loss.
The proportions of patients with any adverse events while on therapy were 64%
for entecavir and 60% for lamivudine.
ALT flares were observed in a low proportion of patients in both treatment groups
during therapy (4% vs 7%, respectively).
This study supports the use of entecavir 0.5 mg once daily as first line therapy
for the treatment of chronic hepatitis B in nucleoside-naive patients," the
researchers concluded. "Treatment with entecavir for up to 2 years proved
significant clinical benefit compared to lamivudine. Entecavir was well-tolerated
with a safety profile comparable to that of lamivudine."
11/10/06
References
N
Leung, C Peng, J Sollano, and others. Entecavir Results in Higher HBV DNA Reduction
vs Adefovir in Chronically-Infected HBeAg(+) Antiviral-Naive Adults: 24 WK Results
(E.A.R.L.Y. Study). 57th AASLD. October 27-31, 2006. Boston, MA. Abstract 982.
G
Yao, C Chen, W Lu, and others. Entecavir Achieves Superior Virologic Response
Compared to Lamivudine for the Treatment of Chronic Hepatitis B: 2-year Results
from a Phase 3 Study in Nucleoside-naive Patients in China (ETV-023). 57th AASLD.
Abstract 997.
The mean baseline HBV DNA levels were 10.26 log copies/mL in the entecavir arm
and 9.88 log copies/mL in the adefovir arm. 
