Entecavir for Slow Responders
Treatment-naive hepatitis B patients who stay on entecavir
(Baraclude) monotherapy despite suboptimal response at
48 weeks are likely to go on to achieve undetectable viral
FDA-approved nucleotide/nucleoside analogs demonstrate good activity
against hepatitis B virus (HBV), but drug resistance can emerge
over time and compromise the effectiveness of long-term therapy,
especially if the virus continues to replicate.
is among the more potent nucleoside analogs approved to treat chronic
hepatitis B. Current European Association for the Study of the
Liver (EASL) treatment guidelines recommend that patients who do
not experience compete virological response, or undetectable HBV
DNA, by 48 weeks should modify therapy by switching or adding additional
As described in the May
11, 2011, advance online edition of Hepatology, Roeland
Zoutendijk from Erasmus University Medical Center in Rotterdam and
colleagues investigated the long-term safety and efficacy of entecavir
in chronic hepatitis B patients who still had detectable HBV DNA
after 48 weeks on treatment.
This cohort study included 333 participants treated with entecavir
monotherapy between 2005 and 2010 at 10 large hepatitis referral
centers in Europe. Of these, 243 were nucleoside/nucleotide-naive
at the start of therapy, while 90 had previously used this class
of drugs. All participants included in the analysis took entecavir
for at least 3 months.
Three-quarters of participants were men, about half were white,
about 30% were Asian, and the average age was 43 years. The mean
baseline HBV viral load was 6.2 log IU/ml, 43% were hepatitis B
"e" antigen (HBeAg) positive, and 27% had liver cirrhosis.
People with HIV and hepatitis C coinfection were excluded.
48 weeks, 48% of HBeAg positive and 89% of HBeAg negative nucleoside/nucleotide-naive
participants achieved virological response (HBV DNA < 80
response rates for nucleoside/nucleotide-naive patients continued
to increase with further time on entecavir monotherapy:
weeks: 76% of HBeAg positive and 98% of HBeAg negative
weeks: 90% of HBeAg positive and 99% of HBeAg negative
nucleoside/nucleotide-naive patients with at least 48 weeks
of follow-up, 21% had partial virological response, or continued
detectable HBV viral load.
of people with partial response achieved compete virological
response during prolonged entecavir monotherapy.
participants developed entecavir resistance despite ongoing
viral replication after week 48.
22 patients with viral load < 1000 IU/mL at 48 weeks, all
but 1 (95%) achieved complete virological response with longer
treatment, compared to 57% of participants with >1000
IU/mL at week 48.
HBV DNA decline was observed among most participants without
complete virological response during follow-up.
7 patients with partial response -- including 3 with suboptimal
adherence according to treating physicians -- never achieved
full viral suppression with longer therapy.
entecavir monotherapy was safe and well-tolerated, and did not
lead to kidney-related adverse events or cause lactic acidosis
(a sign of mitochondrial toxicity).
on these findings, the study authors concluded, "Entecavir
monotherapy can be continued in [nucleoside/nucleotide analog]-naive
patients with a detectable HBV DNA at week 48, particularly in those
with a low viral load at week 48, as long-term entecavir leads to
a virological response in the vast majority of patients."
"The current multicenter study showed that entecavir is effective
up to 3 years in [nucleoside/nucleotide analog]-naive patients,
irrespective of having a virological response at week 48,"
they elaborated in their discussion.
added that most people with partial virological response went on
to achieve undetectable HBV DNA with prolonged entecavir monotherapy
therapy without treatment modification, suggesting they should be
considered slow responders rather than non-responders.
-- including 2 with viral breakthrough -- developed entecavir resistance,
the researchers noted. In contrast, previous studies of adefovir
(Hepsera) and telbivudine (Tyzeka)
plus lamivudine (Epivir-HBV) found
that persistent viral replication at weeks 24 and 48 predicted emergence
conclusion, in contrast to what is suggested in recently published
EASL guidelines on the management of chronic hepatitis B, adjustment
of entecavir monotherapy in [nucleoside/nucleotide analog]-naive
patients with a partial virological response at week 48 is not necessary,"
highlights that treatment paradigms based on data from studies investigating
agents with a low barrier to resistance cannot be translated to
newer and more potent drugs [such] as entecavir and [tenofovir (Viread)],"
Investigator affiliations: Department of Gastroenterology and
Hepatology, Erasmus MC University Medical Center Rotterdam, Netherlands;
Department of Hepatology and Gastroenterology, Imperial College
London, UK; Department of Hepatology, Hotel Dieu Hospital Lyon,
France; Department of Hepatology and Gastroenterology, Queen Elizabeth
Hospital, Birmingham, UK; Department of Gastroenterology, Hepatology,
and Endocrinology, Medical School Hannover, Germany; Liver Unit,
IFI Institute, Asklepios Klinik St. Georg, Hamburg, Germany; Medizinische
Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität,
Frankfurt am Main, Germany; Department of Hepatology, Hospital Vall
de Hebron, Barcelona, Spain; Clinic of Infectious Diseases, University
of Foggia, Italy; Klinik und Poliklinik für Gastroenterologie
und Rheumatologie, Leipzig, Germany; Department for Internal Medicine,
University Medical Center, Hamburg-Eppendorf, Germany.
Zoutendijk, JG Reijnders, A Brown, et al. Entecavir treatment for
chronic hepatitis B: Adaptation is not needed for the majority of
naive patients with a partial virological response. Hepatology
May 11, 2011 (Epub ahead of print).