Standard therapies for chronic hepatitis B include a number
of direct-acting oral antiviral drugs including lamivudine
(Baraclude), and tenofovir
(Viread), as well as pegylated
interferon alfa-2a (Pegasys). The oral drugs are better
tolerated and generally suppress HBV viral load better than
pegylated interferon, but are less likely to produce serological
response (loss of HBeAg or hepatitis surface B antigen [HBsAg])
and must be taken for a longer time. Although treatment
for chronic hepatitis C virus requires combination therapy
with pegylated interferon plus ribavirin, the latter drug
is not typically used for hepatitis B.
Vincent Rijckborst and fellow investigators with the PARC
Study Group designed a trial to assess whether adding ribavirin
might reduce the high rate of relapse among HBeAg negative
chronic hepatitis B patients treated with pegylated interferon.
The analysis included 138 participants who were randomly
assigned to receive either 180?mcg/week pegylated interferon
alfa-2a monotherapy with placebo, or else combination therapy
with the same dose of pegylated interferon plus 1000-1200
mg/day weight-adjusted ribavirin for 48 weeks -- the same
regimen used for genotype 1 or 4 chronic hepatitis C. About
80% of participants had HBV genotype D, which some studies
have shown does
not responds as well to interferon as other genotypes.
Participants were followed for 24 weeks after completion
of therapy to see if they achieved a combined sustained
response, defined as HBV DNA < 10,000?copies/mL (or <
1714?IU/mL) and normalized alanine aminotransferase (ALT).
The modified intention-to-treat population included 133
patients after 5 were excluded from the analysis.
the end of treatment, combined response rates were 36%
in the pegylated interferon monotherapy group and 41%
in the pegylated interferon/ribavirin combination therapy
group, not a significant difference (P = 0.60).
relapse was common in both treatment groups.
the end of follow-up, combined sustained response rates
were 20% in the pegylated interferon monotherapy group
and 16% in the combination therapy group, again not
a significant difference (P = 0.49).
at HBV viral load alone, only about 8% of participants
overall achieved sustained undetectable HBV DNA (<
groups experienced decreases in HBV DNA (mean change
-3.9 vs -2.66 log copies/mL, respectively) and a small
reduction in HBsAg (-0.56 vs -0.34 log IU/mL, respectively).
DNA rebounded after treatment ended, but HBsAg remained
at end-of-treatment levels.
patients experienced HBsAg loss, indicating clearance
interferon/ribavirin combination therapy was generally
well-tolerated, but was associated with a higher rate
of anemia and neutropenia compared with pegylated interferon
with peginterferon alfa-2a resulted in a limited sustained
response rate in HBeAg negative chronic hepatitis B patients,"
the study authors concluded. "Addition of ribavirin
did not improve response to therapy."
"Pegylated interferon...has been recommended as a first-line
therapy for [HBeAg] negative chronic hepatitis B; however,
data supporting this recommendation are derived from a single
randomized controlled trial," wrote Jules Dienstag
from Harvard Medical School in an accompanying editorial.
"This study challenges the value and limits the appeal
of pegylated interferon therapy for HBeAg negative chronic
"Ultimately, this important trial...in HBeAg negative
chronic hepatitis B not only shows a lack of efficacy for
the addition of ribavirin to pegylated interferon, but also
challenges the entire premise that pegylated interferon
should remain a first-line treatment for this category of
chronic hepatitis B," he continued. "For both
HBeAg reactive and negative chronic hepatitis B, the limited
added efficacy of pegylated interferon over oral agents,
its higher cost and resource consumption, and its substantially
poorer tolerability all together reduce its appeal as treatment,
let alone as a first-line choice."
Investigator Affiliations: Department f Gastroenterology
and Hepatology, Erasmus MC, University Medical Center, Rotterdam,
Netherlands; Department of Gastroenterohepatology, Istanbul
University Medical School, Istanbul, Turkey; Department
of Internal Medicine 3, Gastroenterology and Hepatology,
Medical University of Vienna, Vienna, Austria; Department
of Infectious Diseases, Istanbul University Cerrahpasa Medical
School, Istanbul, Turkey; Department of Gastroenterology,
Turkiye Yuksek lhtisas Hospital, Ankara, Turkey; Department
and Clinic of Infectious Diseases, Hepatology and Acquired
Immune Deficiences, Medical University Wroclaw, Wroclaw,
Poland; Second Medical Department, Aristototle University
of Thessaloniki, Thessaloniki, Greece; Department of Gastroenterology,
Ankara University School of Medicine, Ankara, Turkey; Department
of Pathology, Erasmus MC, University Medical Center, Rotterdam,
Netherlands; Department of Epidemiology and Biostatistics,
Erasmus MC, University Medical Center, Rotterdam, Netherlands.
V Rijckborst, MJ ter Borg, Y Cakaloglu, and others (PARC
Study Group). A Randomized Trial of Peginterferon ?-2a With
or Without Ribavirin for HBeAg-Negative Chronic Hepatitis
B. American Journal of Gastroenterology 105(8): 1762-1769
J Dienstag. Peginterferon Therapy for HBeAg-Negative Chronic
Hepatitis B: Less Than Meets the Eye (Editorial). American
Journal of Gastroenterology 105(8): 1770-1772 (Free
full text). August 2010.