was the first oral drug approved to treat chronic
hepatitis B virus (HBV) infection, and it has proved to
be effective in slowing disease progression and reducing the
risk of liver decompensation and liver
taking lamivudine over the long term results in high rates
of drug resistance -- up to 76% after 8 years of treatment.
In contrast, the newer drug entecavir
has a very low resistance rate -- only about 1% after 5 years
of monotherapy. This makes lamivudine less than ideal as a
treatment for chronic hepatitis B.
that early suppression of HBV predicts a positive outcome
over time, including fewer drug-resistance mutations, James
Fung and colleagues from the University of Hong Kong hypothesized
that people with sustained undetectable HBV viral load while
on entecavir might continue to do well if they switch to lamivudine,
a weaker but less expensive drug. The lower cost of lamivudine
-- especially in countries with large numbers of people with
hepatitis B -- may have been a primary rationale for this
described in the April
2011 issue of Hepatology, the researchers designed
a 2-arm study to evaluate whether switching to lamivudine
might provide optimal HBV suppression after patients took
entecavir for 6 or more months. One half of the study participants
remained on 0.5 mg/day entecavir for 96 weeks while the other
half (with a few exceptions) switched to 100 mg/day lamivudine
monotherapy for the duration of the study.
were 50 participants in the study, largely men (72%). About
20% were hepatitis B "e" antigen (HBeAg) positive.
All had been treated with 0.5 mg/day entecavir for 6 to 25
months prior to study entry and had normal alanine aminotransferase
(ALT) and undetectable HBV DNA (< 60 copies/mL). There
were 6 participants with compensated liver cirrhosis at study
entry. Patients with elevated ALT or detectable HBV viral
load were excluded from the trial. Other exclusion criteria
included evidence of liver cancer and a history of decompensated
who were randomly assigned to take lamivudine switched back
to entecavir for the remainder of the study if they showed
was evidence of HBV virological rebound. If they developed
lamivudine resistance, they were treated with a combination
of lamivudine and adefovir (Hepsera).
96 weeks, all 25 (100%) of participants in the entecavir
arm still had undetectable HBV viral load.
in the lamivudine arm did not fare as well: 6 out of 25
(24%) experienced HBV viral rebound.
were no significant differences in the time on entecavir
or pre-treatment viral load between patients with and
without virological rebound after switching to lamivudine.
ALT elevation was seen in any participants in either arm
of the trial through 96 weeks.
the participants taking lamivudine who experienced HBV
rebound, 3 achieved undetectable viral load again after
switching back to entecavir.
new symptoms or serious adverse events occurred throughout
participants (12%) in the lamivudine arm developed lamivudine
resistance, while none of the participants in the entecavir
arm developed resistance mutations.
researchers discussed several limitations of their study:
1) The length of treatment with entecavir was not controlled,
since patients had been taking entecavir for at least 6 months
-- but often much longer -- before joining the study; 2) Most
of the study participants were HBeAg negative, and the results
might vary if they had been HBeAg positive; and 3) Neither
hepatitis B genotype nor rates of achieving undetectable HBV
viral load were determined, so their effects on virological
rebound could not be assessed.
on their findings, the researchers concluded, "Prior
optimal viral suppression with entecavir did not confer any
significant advantage in patients who switched to lamivudine."
In fact, they continued, switching from entecavir to lamivudine
"resulted in a virological rebound rate of 24% and a
resistance rate of 12% after 96 weeks [2 years]."
affiliations: Hepatitis and Liver Clinic and State Key Laboratory
for Liver Research, Queen Mary Hospital, Hong Kong.
Fung, Ching-Lung Lai, John Yuen, et al. Randomized trial of
lamivudine versus entecavir in entecavir-treated patients
with undetectable hepatitis B virus DNA: Outcome at 2 Years.
Hepatology 63(4): 1148-1153 (abstract).