Optimal Therapy of Hepatitis C
Adrian M. Di Bisceglie, M.D.
Considerable progress
has been made in therapy since the last Consensus Development Conference on
Management of Hepatitis C in 1997. Using the sustained virologic response (SVR)
rate as the standard definition of beneficial outcome of therapy, different
treatments can be compared in various categories of patients. The
combination of interferon alfa-2b and ribavirin resulted in SVR rates of
31–35 percent after a 24-week course and 38–43 percent after a 48-week
course of therapy. (1) The use of pegylated rather than standard interferon
with ribavirin increased the response rate to 54–56 percent. (2,3)
The efficacy of two
different formulations of peginterferon combined with ribavirin were
assessed in two recent pivotal trials. The first of these compared two
different doses of peginterferon alfa-2b plus ribavirin to standard
interferon alfa-2b plus ribavirin for the initial treatment of chronic
hepatitis C. (2) In the trial, 1,530 patients were randomized to receive
either: (1) peginterferon alfa-2b (1.5 mcg weekly: higher dose) plus
ribavirin (800 mg daily), (2) peginterferon alfa-2b (1.5 mcg weekly for 4
weeks followed by 0.5 mcg weekly: lower dose) plus ribavirin (1,000–1,200 mg
daily), or (3) standard interferon alfa-2b (3 million units thrice weekly)
plus ribavirin (1,000–1,200 mg daily). The treatment duration in all groups
was 48 weeks. End-of-treatment virologic responses were achieved in 65
percent of patients treated with higher dose peginterferon, 56 percent
treated with lower dose peginterferon, and 54 percent treated with standard
interferon and ribavirin. Sustained virologic responses occurred in 54
percent of patients in the higher dose peginterferon group, 47 percent in
the lower dose group, and 47 percent in the standard interferon group. Among
patients treated with the higher dose of peginterferon, SVRs were
significantly higher in patients infected with HCV genotype 2 or 3 (82
percent) than in those with genotype 1 (42 percent). The initial level of
HCV RNA in serum also correlated with the SVR rates. Patients with high
initial levels of HCV RNA, defined as greater than 2 million copies/ml, had
significantly lower response rates than those with lower levels of virus
(less than 2 million copies /ml) (42 percent vs. 78 percent). The degree of
hepatic fibrosis had a lesser impact on the outcome of therapy: the SVR rate
was 57 percent in those with no or minimal fibrosis compared to 44 percent
among those with bridging hepatic fibrosis or cirrhosis.
A second recent
large, randomized controlled trial compared peginterferon alfa-2a (180 mcg
weekly) plus ribavirin 1,000 - 1,200mg daily) to the same dose of
peginterferon alfa-2a alone, or standard interferon alfa-2b (3 million units
thrice weekly) plus ribavirin (1,000–1,200 mg daily) in 1,121 patients. (3)
End-of-treatment virologic responses occurred in 69 percent of patients
treated with peginterferon alfa-2a plus ribavirin, 59 percent with
peginterferon alone, and only 52 percent with standard interferon and
ribavirin. Sustained virologic response rates were 56 percent, 30 percent,
and 45 percent, respectively. As in virtually all studies of antiviral
therapy, HCV genotype was a strong predictor of SVR, which occurred in 46
percent of those with genotype 1 compared to 76 percent with genotypes 2 or
3 in the peginterferon plus ribavirin group.
Thus, two large
pivotal trials have shown that the combination of peginterferon and
ribavirin given for 48 weeks yields the highest rate of sustained response.
While this may be the most effective regimen overall, it may not be optimal
for all patients and in all situations. At issue is the optimal dose of
peginterferon, the optimal dose of ribavirin, and the optimal duration of
therapy.
In the large trial of
peginterferon alfa-2b, two doses of peginterferon were compared, both based
upon body weight. (2) While the higher dose yielded a better overall
response rate, SVR rates for patients with genotypes 2 and 3 were similar
with the higher and the lower peginterferon doses (82 percent vs 80
percent). In the trial of peginterferon alfa-2a, a single dose not adjusted
to body weight (180 mcg weekly) was tested, based upon previous studies
which identified this to be the most effective dose when given alone without
ribavirin. (4) Yet, in all of these studies, dose modifications because of
side effects were common, and it is, therefore, possible that lower doses of
peginterferon are just as effective and perhaps better tolerated.
The optimal dose of
ribavirin for use in combination with either form of peginterferon is also
not clear. In the study of peginterferon alfa-2b, two doses were used: 800
mg of ribavirin per day with the higher dose of peginterferon alfa-2b was
compared to the more standard dose of ribavirin of 1,000–1,200 mg daily
(based on body weight) with the lower dose of peginterferon. Post-hoc
analyses suggested that the 800 mg dose of ribavirin was suboptimal, in that
response rates correlated with body weight, so that SVR rates increased as
the ribavirin dose per kg body weight increased up to the highest rates,
which were achieved at 13 mg/kg. Only the standard dose of ribavirin was
used in the studies of peginterferon alfa-2a. (3) Clearly, the effects of
these small differences in ribavirin doses need to be properly assessed in
prospective controlled trials.
In both of the
pivotal trials of peginterferon, therapy was given for 48 weeks. Thus, the
relative efficacies of shorter or longer courses are not known. A full 48
weeks of therapy is clearly not needed to achieve SVR in all patients.
Evidence from earlier studies of standard interferon with ribavirin
suggested that 24 weeks of therapy was sufficient for patients with
genotypes 2 or 3 and in patients with genotype 1 and low levels of HCV RNA.
(1) Furthermore, sequential testing for HCV RNA levels suggests that
patients who do not respond can be identified as early as 24 or even 12
weeks of therapy; (2,3) if so, their therapy could be curtailed early, thus
minimizing side effects and cost. Future studies are needed to assess the
optimal duration of therapy in different categories of patients as well as
to assess the possible role of sequential measurements of HCV RNA levels as
a means of determining the optimal duration of treatment.
References
-
McHutchison JG, Poynard T. Combination therapy with interferon plus
ribavirin for the initial treatment of chronic hepatitis C. Semin Liver
Dis 1999;19:57–65.
- Manns MP,
McHutchison JG, Gordon SC, et al.
Peginterferon alfa-2b plus
ribavirin compared with interferon alfa-2b plus ribavirin for initial
treatment of chronic hepatitis C: a randomized trial. Lancet
2001;358:958–65.
- Fried MW,
Shiffman ML, Reddy K, et al. Pegylated (40 kDa) interferon alfa-2a
(PEGASYS) in combination with ribavirin: Efficacy and safety results from
a phase II, randomized, actively-controlled, multicenter study.
Gastroenterology 2001;120:A-55 (abstract).
- Zeuzem S,
Feinman SV, Rasenack J, et al.
Peginterferon alfa-2a in
patients with chronic
hepatitis C. N Engl J Med 2000;343:1666–72.
Retreatment of Patients
With Chronic Hepatitis C
Mitchell L. Shiffman, M.D.
A large number of
patients with chronic hepatitis C have been treated with alpha interferon
with or without ribavirin since the 1997 Consensus Development Conference.
Unfortunately, a majority of these patients probably did not achieve a
sustained virologic response (SVR). As new therapies are developed for
hepatitis C, the issue of retreatment of these non-responders will continue
to arise. Recommendations regarding retreatment should be based upon several
factors: (1) the previous type of response, (2) the previous therapy and the
difference in potency of the new therapy, (3) the severity of the underlying
liver disease, (4) viral genotype and other predictive factors for response,
and finally (5) tolerance of previous therapy and compliance. (1)
Types of Non-Response
Patients who fail to
achieve SVR can be categorized as either relapsers or non responders. In
general, relapsers are more likely to achieve SVR during retreatment with a
more potent regimen than are non-responders. Yet among patients referred to
as non-responders, there is the subset who have a marked reduction without
disappearance of HCV RNA (1–2 log units or more) during therapy. These
partial responders may also be good candidates for retreatment, if a more
potent regimen of therapy is being applied, such as the currently
recommended combination of peginterferon and ribavirin. In at least one
study of retreatment, only non-responders who had a decline in HCV RNA to an
absolute titer <100,000 copies/ml during previous treatment with interferon
alone achieved SVR when retreated with interferon and ribavirin. (2)
Retreatment of Non-Responders
The likelihood that
non-responder patients will respond to retreatment depends in large part
upon the previous therapy. Retreatment of non-responders with the same
therapy will not result in viral clearance, whereas retreatment with a more
potent regimen can result in SVR in a proportion of patients. Thus,
preliminary results suggest that up to 30 percent of non-responders to the
standard interferon/ribavirin combination became HCV RNA negative on
retreatment using the peginterferon/ribavirin combination. (3,4) Higher
rates occurred in patients with HCV genotypes 2 or 3 compared to genotype 1.
Unfortunately, relapse was common once therapy was discontinued, so that the
rate of SVR was only 15–20 percent overall.
Retreatment of Relapsers
Several studies have
shown that patients with prior relapse have a high rate of SVR when
retreated with more effective therapy. Thus, 50 percent of patients who
relapsed following treatment with interferon alone achieved SVR when
retreated with interferon/ribavirin combination. (5) The ability to achieve
SVR following retreatment with peginterferon/ribavirin in patients who
relapsed following interferon monotherapy or standard interferon/ribavirin
therapy is currently being evaluated. The majority of relapsers become HCV
RNA negative during retreatment, even when the regimen is the same. When the
same regimen is used, however, virtually all patients relapse again after
treatment is stopped. Extending the duration of retreatment without changing
the dose or regimen may reduce relapse, but this has not been prospectively
proven.
Severity of Liver Disease and Retreatment
Knowledge of the
severity of the underlying liver disease is important in recommending
retreatment of chronic hepatitis C. Patients with no or minimal fibrosis
probably have an excellent long-term prognosis and low risk for developing
cirrhosis or complications of chronic hepatitis C. These patients,
therefore, could forgo retreatment and await further advances in therapy. On
the other hand, patients with advanced fibrosis or cirrhosis are at
increased risk for developing hepatic decompensation and should be
considered for retreatment, especially if the previous treatment was
interferon alone. For patients with intermediate degrees of fibrosis and
disease activity, recommendations for retreatment should weigh the type of
initial response, the improvement in treatment regimen, factors such viral
genotype, initial titer of HCV RNA, as well as tolerance of therapy.
Non-Responders to Combination Therapy with Peginterferon and Ribavirin
Patients who fail to
respond even to the current optimal therapy with peginterferon/ ribavirin
are a great challenge for management, particularly those with advanced
fibrosis or cirrhosis. In several studies of standard interferon, up to 40
percent of non-responders developed evidence of a histological response
despite persistence of HCV RNA. (6,7) These histological responses occurred
largely among patients with a partial virological response as shown by a
significant reduction in HCV RNA titer. In a prospective, randomized
controlled trial, these histological improvements were shown to be
maintained by continuation of interferon monotherapy. (8) The possible role
of maintenance therapy with peginterferon alone in preventing further
progression of cirrhosis, clinical decompensation, or development of
hepatocellular carcinoma is currently the focus of a large-scale,
multi-center U.S. trial, referred to as HALT-C. Until the results of that
study or similar studies are available, the role of long-term, continuous
therapy with peginterferon (or ribavirin or both) for non-responder patients
must be considered experimental.
Tolerance and Compliance
An important reason
for relapse and non-response to interferon therapy of hepatitis C is
non-compliance. Non-compliance can be the result of severe side effects or
lack of commitment by the patient, but also can be due to poor counseling
regarding side effects and inadequate management. If the causes of
non-compliance can be corrected or lessened, retreatment can be successful.
In contrast, if side effects are intolerable despite adequate counseling and
management, retreatment is unlikely to be successful and should not be
encouraged.
References
- Shiffman
ML. Management of interferon therapy non-responders. Clin Liver Dis
2001;5:1025–43.
- Shiffman ML,
Hofmann CM, Gabbay J, et al.
Treatment of chronic hepatitis
C in patients who failed interferon monotherapy: Effects of higher doses
of interferon and ribavirin combination therapy. Am J Gastroenterol
2000;95:2928–35.
- Minuk GY,
Reddy KR, Lee SS, et al. Enhanced virologic response to treatment with
40KDA peginterferon-alpha-2a (Pegasys) in patients previously unresponsive
to treatment with interferon-alpha-2a. Hepatology 2001;34:330A.
- Shiffman
ML, for the HALT-C trial investigators. Retreatment of interferon and
interferon-ribavirin non-responders with peginterferon-alpha-2a and
ribavirin: Initial results from the lead-in phase of the HALT-C trial.
Hepatology 2001;34:243A.
- Davis GL,
Esteban-Mur R, Rustgi V, et al.
Interferon alfa-2b alone or in
combination with ribavirin for the treatment of relapse of chronic
hepatitis C. N Eng J Med 1998;339:1493–9.
- Shiffman ML,
Hofmann CM, Thompson EB, et al.
Relationship between
biochemical, virologic and histologic response during interferon treatment
of chronic hepatitis C. Hepatology 1997;26:780–5.
- Shiffman
ML. Histologic improvement in response to interferon therapy in chronic
hepatitis C. Viral Hepatitis Reviews. 1999;5:27–43.
- Shiffman
ML, Hofmann CM, Contos MJ, et al. A randomized, controlled trial of
maintenance interferon for treatment of chronic hepatitis C
non-responders. Gastroenterology 1999;117:1164–72.
Treatment
for Hepatitis C: A Systematic Review
Geetanjali Chander, Mark S. Sulkowski, Mollie
W. Jenckes, Kelly A. Gebo, Khalil G. Ghanem, H. Franklin Herlong,
Michael Torbenson, Kirk A. Harris,
Samer El-Kamary, and Eric B. Bass
Introduction
Hepatitis C is a
spherical enveloped RNA virus of the Flaviviridae family, which has
been recognized as a major cause of chronic hepatitis and hepatic fibrosis
that progresses in some patients to cirrhosis and hepatocellular carcinoma (HCC).
In the United States, approximately 4 million people have been infected with
hepatitis C (HCV) and 10,000 HCV-related deaths occur each year. Effective
treatment strategies are needed to prevent hepatitis C-related morbidity and
mortality.
Objective
We conducted a
systematic review of the literature to determine: (1) the extent to which
randomized controlled trials have shown the efficacy and safety of current
treatment options for chronic hepatitis C in treatment-naive patients,
including: pegylated interferon plus ribavirin; pegylated interferon alone;
interferon plus ribavirin; and interferon plus amantadine; (2) the extent to
which randomized controlled trials have shown the efficacy and safety of
current interferon based treatment options (including interferon alone) for
chronic hepatitis C in selected subgroups of patients, especially those
defined by the following characteristics: age less than or equal to 18
years, race/ethnicity, HCV genotype, presence or absence of cirrhosis,
minimal vs. decompensated liver disease, concurrent hepatitis B or HIV
infection, non-response to initial interferon based therapy, and relapse
after initial interferon based therapy; and (3) the long-term outcomes of
current treatment options for chronic hepatitis C infection.
Methods
Literature Sources
Seven electronic
databases were searched through DIALOG for the period from January 1996 to
March 2002. Additional articles were identified by searching references in
pertinent articles, hand searching relevant journals, and querying technical
experts.
Eligibility
Criteria
Exclusion criteria
for review included: non-English language, articles limited to basic science
or non-human data, previously reported data, and meeting abstracts.
Inclusion criteria for review were: study designed to address our key
question, information pertinent to management of hepatitis C, and 30 or more
study subjects with hepatitis C. In addition, treatment articles reviewed
were limited to randomized controlled trials. To explore modern treatment
options, we limited eligible studies to those evaluating interferon alone or
in combination with other treatment options, e.g., ribavirin, amantadine,
etc., and where outcomes were assessed by virologic and/or histologic
measures of outcomes. Studies of interferon alone were only included when
the study participants were subgroups of interest, e.g., renal disease, HIV
co-infection. Studies evaluating long-term followup could be either
randomized controlled trials or cohorts but required at least 60 months of
observation.
Assessment of
Study Quality
Each eligible article
was reviewed by a pair of reviewers, including at least one team member with
relevant clinical training and/or one with training in epidemiology and
research methods. Paired reviewers independently rated the quality of each
study in terms of the following categories: representativeness of study
subjects (5 items); bias and confounding (4 items); description of therapy
(4 items); outcomes and follow-up (5 items); statistical quality and
interpretation (4 items). Reviewers assigned each response level a score of
0 (criterion not met), 1 (criterion partially met), or 2 (criterion fully
met) to each relevant item on the quality form. The score for each category
of study quality was the percentage of the total points available in each
category and therefore could range from 0–100 percent. The overall quality
score was the average of the five categorical scores. We also documented
source of funding.
Extraction of Data
The paired reviewers
also abstracted data on type of study and geographical location; study
groups; specific aims; inclusion and exclusion criteria, screening regimen;
demographic, social and clinical characteristics of subjects, and results.
Differences between the two reviewers in either quality or content
abstraction were resolved by consensus.
Synthesis
Results of
Literature Search
We identified 3,104
potentially relevant citations and 1,731 of these were deemed eligible for
abstract review. Through the abstract review process, we identified 486
articles that could have been related to one of our key questions regarding
treatment. After reviewing these 486 articles, we found 231 studies
including 165 randomized controlled trials reporting on current treatment
and 66 reporting on long-term outcomes. Data from these eligible studies
will be presented in a series of evidence tables and figures highlighting
their distinguishing characteristics, methodological strengths and
limitations, and key findings.