Overview of the Current Standard of Care for Treatment of Chronic Hepatitis C
April 3, 2009
The current standard of care for the treatment of chronic hepatitis C virus
(HCV) infection is combination therapy with pegylated interferon alfa-2a (Pegasys)
or pegylated interferon alfa-2b (PegIntron), both in combination with
At the 13th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD)
last week in Washington, DC, experts in the field of viral hepatitis were
invited to present their views on various issues. Dr. Peter Ferenci of the
Department of Internal Medicine, Gastroenterology and Hepatology at the
Medical University of Vienna, Austria, offered an overview of the use of the
2 pegylated interferons plus ribavirin for chronic hepatitis C. Following is
an edited summary of his remarks.
Current Therapies in Chronic Hepatitis C
Peginterferon-alfa in combination with ribavirin is and will remain for the
next [few] years the current standard for treatment of chronic hepatitis C
The primary goal of treatment for chronic hepatitis C is a sustained
virologic response (SVR). Host factors including age, body weight, race, and
advanced fibrosis influence outcome of treatment (1,2), but are poor
predictors of response. In contrast, viral factors like the genotype and the
on-treatment pattern of viral response can be used to determine the
likelihood of treatment success and guide treatment duration individually
and proved to be very useful in clinical practice.
Stopping Treatment in Likely Nonresponders
The absence of an early virologic response [EVR] at week 12, defined as
undetectable HCV RNA (< 50 IU/mL) by qualitative PCR assay, or greater than
or equal to 2-log decrease relative to the baseline value by a quantitative
PCR assay, has a 98% negative predictive value in a genotype 1 patient (3).
On this basis, treatment may be discontinued in patients who do not achieve
an early virologic response at week 12. Therapy should be stopped in all
patients with a > 2-log decrease in HCV RNA at week 12 who have not become
HCV RNA negative by week 24. Recent studies show that this information can
be used to individualize the duration of therapy.
The HCV RNA status at week 4 also provides useful prognostic information
that can be used to individualize the duration of therapy in genotype 1
patients (4,5). Normalization of ALT on treatment is an indicator of a
therapeutic response but lacks specificity, and, thus cannot be used in
place of serum HCV RNA determinations.
Individualization of Treatment
Genotypes 1 and 4
Loss of HCV RNA by week 4 of treatment documented with a commercial
qualitative HCV RNA assay with a limit of detection of 50 IU/mL is an
excellent predictor of sustained virologic response in patients with
genotype 1 infection (3). When treated for 48 weeks with peginterferon plus
ribavirin 1000 or 1200 mg/day, 87% to 91% of such patients will have a
sustained virologic response (3,6).
Around 24% of European genotype 1 patients achieve an RVR [rapid virological
response] (6).The level of detection of HCV has been improved by the real
time PCR technique to 10 IU/mL. The impact of using more sensitive tests
remains to be studied.
Shortening Treatment Duration:
The retrospective analysis of several randomized controlled trials using
peginterferon-2/ribavirin have shown that the probability of achieving a
sustained virologic response is similar in genotype 1 patients with rapid
virologic response (RVR) treated for 24 or 48 weeks (4).
The concept of treatment shortening was addressed by prospective trials,
showing that > 80% of patients with genotype 1 and 4 achieve a SVR when
treated only for 24 weeks (6). Thus, it is reasonable to consider reducing
the duration of combination therapy to 24 weeks in genotype 1-infected with
RVR when treated with a standard peginterferon plus ribavirin regimen.
Both peginterferons have been approved in the European Union for shortened
treatment duration of 24 weeks in HCV genotype 1 patients with RVR and low
baseline viral load defined as <800.000 IU/ml for peginterferon alfa-2a and
<600.000 IU/ml for peginterferon alfa-2b. Abbreviated therapy may not be
suitable in genotype 1 patients with cirrhosis.
Extending Treatment Duration:
In patients with a slow [or partial] virologic response (pEVR), prolongation
of treatment beyond 48 weeks may reduce relapse rates and thus increase SVR.
Several studies investigated treatment prolongation in slow responders.
Although they substantially differed in design each one has shown that
extending therapy to 72 weeks increases the probability of achieving a
sustained virologic response (5,7,8). There are no data on which to base a
universal recommendation to treat a patient such as this for 72 weeks. In a
recent study it was suggested that patients with detectable HCV at week 8
will benefit from extended treatment (5).
Genotypes 2 and 3
Patients with genotypes 2 and 3 are easier to treat than patients with
genotypes 1 and 4. Peginterferon in combination with [ribavirin] 800 mg/day
is sufficient. A number of studies have demonstrated comparable SVR rates
between shortened (12 to 16 weeks) and 24 weeks of treatment in patients who
achieve a RVR.
However, in a large randomized prospective study, among patients with an RVR,
SVR rates were higher in the 24-week treatment group than in the 16-week
group -- both overall and within each genotype group (9). The difference in
SVR rate reflects a higher relapse rate in the 16-week group (31%) compared
with the 24-week group (18%).
Like in patients with other genotypes, the presence of complete cirrhosis
and a high baseline HCV RNA level are poor prognostic factors for sustained
virologic response (2). Therefore abbreviation of treatment should only be
offered to non-cirrhotic patients with low baseline viral load. Prolongation
of treatment in patients with cirrhosis and in patients without RVR may
improve the overall outcome and is currently [being] investigated by a
prospective randomized trial.
CP Ferenci. Current Therapies in Hepatitis C. 13th International Symposium
on Viral Hepatitis and Liver Disease (ISVHLD). Washington, DC. May 20-24,
2009. Abstract SP-29.
1. Dienstag JL, McHutchison JG. American Gastroenterological Association
technical review on the management of hepatitis C. Gastroenterology
2. Missiha SB, Ostrowski M, Heathcote EJ. Disease progression in chronic
hepatitis C: modifiable and nonmodifiable factors. Gastroenterology 2008;
3. Ferenci P, Fried MW, Shiffman ML et al. Predicting sustained virological
responses in chronic hepatitis C patients treated with peginterferon alfa-2a
(40 KD)/ribavirin. Journal of Hepatology 2005; 43:425-433.
4. Jensen DM, Morgan TR, Marcellin P et al. Early identification of HCV
genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin
therapy. Hepatology 2006; 43:954-960.
5. Sanchez-Tapias JM, Diago M, Escartin P et al. Peginterferon-alfa2a plus
ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C
virus RNA at week 4 of treatment. Gastroenterology 2006;131:451-460
6. Ferenci P, Laferl ,H, Scherzer TM, Gschwantler M, Andreas Maieron A,
Brunner H, et al. Peginterferon alfa-2a and ribavirin for 24 weeks in
hepatitis C type 1 and 4 patients with rapid virological response.
7. Berg T et al. Extended treatment duration for hepatitis C virus type 1:
comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin.
8. Pearlman BL et al. Treatment extension to 72 weeks of peginterferon and
ribavirin in hepatitis C genotype 1-infected slow responders. Hepatology
9. Shiffman ML, Suter F, Bacon BR et al. Peginterferon alfa-2a and ribavirin
for 16 or 24 weeks in HCV genotype 2 or 3. New England Journal of Medicine