Hepatitis C Virus Infection: An Update
- American Association for the Study of Liver Diseases
52nd Annual Meeting
[Medscape, 2001. � 2001 Medscape, Inc.]
Hepatitis C Virus Infection: An Update
David Bernstein, MD
Hepatitis C virus (HCV) infection continues to be a
major focus of interest for researchers, as evidenced
by sessions presented during the 52nd Annual Meeting
of the American Association for the Study of Liver
Diseases. Since the identification of the first
antibody to HCV in 1989, significant progress has been
made in our understanding of the natural history and
treatment of this common infection.
This review highlights some of the important new
information regarding hepatitis C that was presented
during this meeting, with a view toward implications
for clinical practice.
Acute Hepatitis C
Although chronic hepatitis C is common, acute
hepatitis C is uncommon in clinical practice. Due to
the lack of large, well-controlled studies, the
natural history and treatment of acute disease remains
Gerlach and colleagues reported on 56 patients with
acute hepatitis C. The majority of these patients had
some constitutional complaints, whereas 9 of 56 were
completely asymptomatic. Twenty-four percent developed
jaundice; 6 patients received immediate antiviral
therapy and were not included in the analysis. Of the
remaining 50 patients, 23 were HCV RNA-negative at the
end of follow-up vs 27 who were HCV RNA-positive.
Female sex, the development of jaundice, and
constitutional symptoms were strong predictors of
spontaneous viral clearance. The majority of patients
(86%) who spontaneously cleared virus did so by week
12 postexposure. Therefore, antiviral therapy was
initiated at week 12. Twenty-four patients were
started on therapy at week 12. As of the time of this
presentation, there have been 15 sustained responders,
1 relapser, and 3 nonresponders. Five patients remain
This study is helpful in guiding development of a
strategy for the treatment of acute hepatitis C.
According to these findings, many symptomatic patients
may spontaneously clear virus by week 12. Therefore,
it seems reasonable to delay treatment in the
symptomatic patient until the determination of a
12-week serum HCV RNA. If this study is positive, an
antiviral regimen should be initiated. In the case of
asymptomatic acute hepatitis C, treatment should start
as soon as the disease is identified.
Durability of Response
One of the most important questions asked by hepatitis
C patients and treating physicians alike concerns the
durability of the sustained viral response. By
convention, the medical community has defined a
sustained viral response to interferon or combination
interferon plus ribavirin therapy as a negative serum
HCV RNA 6 months after stopping antiviral therapy.
What is the likelihood of the recurrence of viremia in
patients who achieved a sustained viral response,
according to the definition indicated above? John
McHutchison, MD, from the Scripps Clinic in La Jolla,
California, reported on the 4-year follow-up of
patients treated in several crucial trials of both
previously untreated hepatitis C patients or naive
patients and patients who relapsed following cessation
of interferon alfa-2b monotherapy.
In these trials, 455 patients treated with interferon
alfa-2b plus ribavirin and 103 patients treated with
interferon alfa-2b monotherapy were sustained
responders. Three hundred twenty-two sustained viral
responders to combination therapy and 73 sustained
viral responders to interferon monotherapy
participated in the follow-up. Of the group that
responded to combination therapy, 112 were naive
patients treated for 24 weeks, 151 were naive patients
treated for 48 weeks, and 59 were relapse patients
treated for 24 weeks. Of the group that responded to
monotherapy, 4 were naive patients treated for 24
weeks, 61 were naive patients treated for 48 weeks,
and 8 were relapse patients treated for 24 weeks.
Overall, 10 patients had a virologic relapse during
the follow-up phase. Seven of these relapse patients
had received combination therapy, whereas 3 had
received interferon monotherapy. All patients relapsed
within 2 years of stopping therapy. There has been no
further recurrence of viremia in the last 2 years of
follow-up. The overall likelihood of achieving a viral
response 4 years after stopping therapy was reported
by treatment group and is as follows: (1) previously
untreated patients given interferon monotherapy for 24
weeks, 75% � 22%; (2) previously untreated patients
given combination therapy for 24 weeks, 97% � 1.6%;
(3) previously untreated patients given combination
therapy for 48 weeks, 99%� 1%; and (4) relapse
patients given combination therapy for 24 weeks, 96% �
Based on these data, it appears that late relapse
following a sustained viral response to either
interferon alfa-2b monotherapy or in combination with
ribavirin is uncommon, and the responses seen are
highly durable over a 4-year period. However, the use
of the term "cure" after a sustained viral response
may be premature, as evidenced by the single sustained
responder with cirrhosis who developed hepatocellular
carcinoma in the follow-up period.
Effects on Natural History
Hepatitis C infection is known to progress to
cirrhosis and its complications. The development of
advanced disease is associated with an increased
mortality rate when compared with the general
population. Several studies have shown that interferon
therapy may reduce the risk of developing
Imai and colleagues studied the effect of
interferon therapy on the development of
hepatocellular carcinoma and mortality in 3296
patients with chronic hepatitis C. These investigators
found that sustained and transient viral responders to
interferon therapy had a significantly lower risk of
developing hepatocellular carcinoma than did untreated
patients. Nonresponders to interferon therapy
developed hepatocellular carcinoma at a rate similar
to untreated patients. Overall, survival rates were
better in the interferon-treated group than in the
untreated group, especially in those patients
achieving either a sustained or transient viral
response. Age at time of diagnosis, male sex, and
higher histologic stage (P = .0001) were independent
risk factors for cirrhosis and death.
Pegylated interferon. Pegylated interferon in
combination with ribavirin has become the new regimen
of choice for treatment of hepatitis C. Studies with
both pegylated interferon alfa-2a and pegylated
interferon alfa-2b have shown improved efficacy over
standard interferon alfa-2b plus ribavirin in
In a study reported by Poynard and colleagues, the
effect of pegylated interferon alfa-2b plus ribavirin
on underlying hepatitis fibrosis was examined. This
study involved 3010 patients with pre- and
posttreatment liver biopsies who underwent antiviral
therapy with interferon alfa-2b monotherapy,
interferon alfa-2b plus ribavirin, or pegylated
interferon alfa-2b plus ribavirin. Necrosis and
inflammatory scores improved in 73% of patients
receiving pegylated interferon plus ribavirin and in
39% receiving standard interferon therapy. All
regimens significantly reduced fibrosis progression
rates in comparison to rates before treatment. This
effect is likely related to the antifibrotic
properties of interferon.
Interesting to note is that these study authors
reported on the reversal of cirrhosis in 75 of the 153
patients with cirrhosis at baseline entry into the
study. The well-known high rate of sampling error with
percutaneous liver biopsy may play a role in these
findings. The results of this study are very
encouraging, and additional investigations need to
corroborate these important histologic findings.
As a group, hemophilia patients are known to have one
of the highest prevalence rates of chronic hepatitis C
infection. Despite this fact, few studies have
evaluated the treatment of patients with inherited
coagulation disorders with antiviral therapy, and all
of the major registration trials have excluded
patients with hemophilia.
Michael Fried, MD, from the University of North
Carolina, presented data on use of thrice-weekly
interferon alfa-2b plus ribavirin in 113 patients with
inherited coagulation defects and HCV infection.
In this study, 93% of patients had either hemophilia A
or B. The mean age was 28 years; 67% of subjects had
genotype 1. Patients were randomized to receive either
interferon alfa-2b (n = 57) or combination interferon
alfa-2b plus ribavirin (n = 56). Subjects were treated
for 1 year, with a 24-week follow-up period. Liver
biopsies were not routinely performed. The sustained
viral responses in the groups receiving combination
therapy vs monotherapy were 29% and 7%, respectively.
Among patients younger than 18 years of age treated
with combination therapy, the sustained viral response
was 59%. The sustained viral response of adult
patients was 15%. Overall, 19% of patients in this
study had to have treatment prematurely discontinued.
Ten patients had therapy stopped secondary to adverse
Although overall response rates to combination therapy
were lower than those seen in the general hepatitis C
population, the findings in this high-risk group are
encouraging. The lack of baseline liver histology, the
high degree of dose reduction, and the high rate of
early treatment discontinuation may have contributed
to the lower than expected sustained response rate in
this intention-to-treat analysis.
Relapsers and Nonresponders
Relapsers and nonresponders to conventional antiviral
therapy pose a difficult clinical challenge for
practitioners and patients with hepatitis C infection.
With the availability of pegylated interferon alone
and in combination with other antiviral agents, many
investigators have shown interest in the use of these
drugs for this difficult-to-treat patient group.
Afdhal and colleagues reported on the use of
once-weekly 40-kilodalton pegylated interferon alfa-2a
in combination with ribavirin, mycophenolate mofetil,
and amantadine, for the treatment of patients who
either relapsed or did not respond to standard
thrice-weekly combination interferon alfa-2b plus
One hundred twenty relapse and 120 nonresponder
patients were included in the study. End-of-treatment
(48 weeks) viral response data were reported for all
groups. The 48-week viral response data in the relapse
patient groups were as follows: (1) pegylated
interferon alfa-2a plus ribavirin, 61%; (2) pegylated
interferon alfa-2a plus mycophenolate mofetil, 72%;
(3)pegylated interferon alfa-2a plus amantadine, 42%;
and (4) pegylated interferon alfa-2a plus amantadine
plus ribavirin, 71%. The 48-week viral response data
in the nonresponder patient groups were as follows:
(1) pegylated interferon alfa-2a plus ribavirin, 25%;
(2) pegylated interferon alfa-2a plus mycophenolate
mofetil, 28%; (3) pegylated interferon alfa-2a plus
amantadine, 11%; and (4) pegylated interferon alfa-2a
plus amantadine plus ribavirin, 40%. No significant
adverse events have been noted.
This preliminary report is encouraging but cannot be
fully analyzed until all patients have completed a
follow-up phase and until sustained viral response
numbers are available.
Despite numerous studies on interferon and ribavirin
use in adults, few large investigations employing this
combination are available in children.
Kelly and colleagues presented data on the
treatment of 61 children with a mean age of 11 years.
The sustained viral response with interferon alfa-2b
thrice weekly plus ribavirin 8 mg/kg/day, 12
mg/kg/day, and 15 mg/kg/day were 33%, 35%, and 45%,
respectively. Children were able to tolerate the
hemolytic and neutropenic effects of combination
therapy better than described in adult populations.
Efficacies of these regimens are similar to those seen
The sustained viral response of African Americans to
standard interferon plus ribavirin combination therapy
has been disappointing and poorly characterized.
Jeffers and associates reported on the use of
pegylated interferon alfa-2a plus ribavirin in
previously untreated African Americans with chronic
hepatitis C and HCV genotype 1 infection. All patients
participating in this study are scheduled to be
treated with pegylated interferon alfa-2a plus
ribavirin for 48 weeks. The study authors reported on
preliminary 24-week data.
African American and white patients underwent a
virologic assessment of response at week 24.
Seventy-three percent of whites and 56.9% of African
Americans had a 2-log drop in HCV RNA level. Loss of
viremia at week 24 was seen in 65.2% of whites and 49%
of African Americans. Late virologic clearance was
more common in African Americans.
These preliminary findings support the continued study
of pegylated interferon alfa-2a plus ribavirin in
African American patients infected with HCV genotype
The hepatitis C antiviral long-term treatment against
cirrhosis (HALT-C) trial was designed and sponsored by
the National Institutes of Health to determine if
long-term interferon therapy could prevent the
progression of baseline histology, reduce the
development of hepatocellular carcinoma, and prevent
the need for liver transplantation in patients with
chronic hepatitis C and cirrhosis.
Patients enrolled in this trial had to have a positive
serum HCV RNA, baseline liver biopsy showing advanced
fibrosis or cirrhosis, and previous nonresponse to
interferon monotherapy or combination
interferon-plus-ribavirin therapy. All patients
enrolled in the study were treated with 24 weeks of
pegylated interferon alfa-2a 180 mcg/week plus
ribavirin 1000 or 1200 mg per day, depending on body
weight. Patients found to have a negative HCV RNA at
20 weeks continued therapy for a total of 48 weeks.
Patients found to be serum HCV RNA-positive at 20
weeks were eligible to enter the HALT-C trial.
Upon entering the HALT-C trial, patients were
randomized to either pegylated interferon alfa-2a or
placebo for a 4-year treatment course. Liver biopsies
are scheduled to be performed every 2 years during
this ongoing trial. Adrian Di Bisceglie, MD, presented
preliminary data from this study. To date, 268
patients have completed 20 weeks of therapy -- 88% of
these are white, 84% are HCV genotype 1, and 41% had
underlying cirrhosis at baseline. At week 20, 15
patients had therapy discontinued due to adverse
events. Of the remaining 253 patients, 107 (42%) had
undetectable virus. Fifty-three percent of patients
who received prior interferon monotherapy and 31% of
those who previously received combination interferon
and ribavirin therapy were HCV-negative at week 20.
Ten percent of blacks were virus-negative at week 20.
Virologic response was influenced by genotype, with
HCV genotypes 2 and 3 patients having a significantly
greater viral response rate. Body mass index did not
appear to influence response. The sustained viral
response rates and the results of the remainder of the
HALT-C trial remain to be determined.
Quality of Life
Quality-of-life analysis has emerged as an important
component in our evaluation of hepatitis C infection
and its treatments. The overall quality of life of
hepatitis C patients has been reported to be lower
than that of the general population. Hepatitis C
therapy has also been shown to lower the quality of
life while the patient is on therapy and, therefore,
limits patient adherence to these therapies. Sustained
viral response to antiviral therapy improves quality
of life following therapy. Thus, the evaluation of
quality of life on antiviral therapy has assumed a
more important role because adherence to therapy has
been positively correlated with sustained viral
Hassanein and colleagues reported on the quality
of life in patients treated with combination pegylated
interferon alfa-2a plus ribavirin, pegylated
interferon alfa-2a monotherapy, and standard
interferon alfa-2b plus ribavirin. The instruments
used to assess quality of life were the Short Form-36
and the fatigue severity scale. During the 48 weeks of
therapy, patients receiving pegylated interferon
alfa-2a plus ribavirin reported better quality of life
and less fatigue than those receiving interferon
alfa-2b plus ribavirin. The most significant
differences seen were better vitality scores, less
body pain, improved social functioning, and less
fatigue with pegylated interferon alfa-2a plus
ribavirin. At the end of follow-up, those patients who
achieved a sustained viral response reported
significant improvements in quality of life and
fatigue scores, regardless of the therapy received.
The greatest improvements in quality of life were
reported in the role-physical, role-emotional, general
health, and vitality scores.
This study emphasizes the importance of quality of
life on therapy as it relates to adherence and
improved sustained viral response. Because adherence
is associated with an improved viral response, the
quality of life on therapy has assumed greater
importance in the physician's choice of therapies.
Those therapies with less of a side-effect profile may
aid in achieving a better compliance rate and
therefore improve sustained viral response rates by
allowing patients to take the prescribed dosages of
antiviral therapy for the prescribed period of time.
The results of trials using several new agents for the
treatment of chronic hepatitis C infection were
presented during this meeting as well.
ISIS 14803 is an antisense oligodeoxynucleotide that
inhibits HCV RNA and protein expression in cell
culture and mouse models.
McHutchison and coworkers reported on the use of
this agent in a small number of patients who were
nonresponsive to combination interferon and ribavirin
therapy. This pilot trial of 11 patients found that
use of this novel compound at a dose of 2 mg/kg
resulted in less than a 2-log drop in viral levels in
2 patients. The antiviral activity was dose-dependent
and did not result in loss of viremia in any patient.
Additional studies are planned with this compound.
Lurie and colleagues reported on the utility of
combination histamine dihydrochloride and interferon
alfa-2b in previously untreated patients with chronic
hepatitis C infection.
One hundred twenty-nine patients were entered into the
study and 108 were available at the end of follow-up
for evaluation. The overall sustained response rate
for the combination of these 2 agents was 40%. The HCV
genotype 1 response was 38% and the nongenotype 1
response was 45%. Patients with a high viral load had
a sustained viral response of 29%, whereas those with
low viral load had responses of 54%.
The addition of histamine dihydrochloride to standard
interferon therapy appears to improve the sustained
viral response of standard interferon alfa-2b
monotherapy. These sustained viral response rates,
however, are all lower than that seen with combination
pegylated interferon plus ribavirin.
Pockros and colleagues reported on the use of
recombinant human interleukin-12 in a population of
patients previously unresponsive to antiviral therapy.
Approximately 1% of patients showed a sustained
virologic response, whereas 3% developed severe
adverse events, resulting in early termination of the
Discussion of hepatitis C and its treatment comprised
a significant portion of these meeting proceedings.
Important data were addressed regarding the treatment
of special patient groups, such as children, blacks,
and hemophiliacs. Many of the papers presented
concerned the use of pegylated interferon plus
ribavirin for the treatment of previously untreated
hepatitis C patients as well as patients unresponsive
to previous antiviral regimens. Several new agents for
the treatment of hepatitis C were also discussed,
although based on reported data, none appears to
suggest immediately that it would have greater
efficacy than current therapies.
Perhaps the most important points made during this
meeting concerned the high durability of a sustained
viral response given its current definition, as well
as the increased importance that quality-of-life
assessments play in the ongoing evaluation of
patients. As we move into the 21st century, we are
realizing yet again that patient concerns and
well-being are first and foremost on the agenda of
physicians treating for hepatitis C.
1. Gerlach TJ, Zachoval R, Gruener N, et al. Acute
hepatitis C: natural course and response to anti-viral
treatment. Hepatology. 2001;341A. [Abstract 676]
2. McHutchison J, Davis G, Esteban-Mur R, et al.
Durability of sustained virological responses in
patients with chronic hepatitis C after treatment with
interferon alfa-2b alone or on combination with
ribavirin. Hepatology. 2001;34:244A. [Abstract 281]
3. Imai Y, Kasahara A, Okanoue T, et al. Effect of
interferon therapy on the risk of hepatocellular
carcinoma and mortality in patients with chronic
hepatitis C: a large retrospective cohort study of
3296 patients. Hepatology. 2001;34:216A. [Abstract
4. Poynard T, McHutchison J, Manns M, et al. Impact of
pegylated interferon alfa-2b and ribavirin on the
progression of liver fibrosis in patients with chronic
hepatitis C. Hepatology. 2001;34:244A. [Abstract 282]
5. Fried M, Peter J, Hoots K, et al. Hepatitis C in
adults and adolescents with inherited coagulation
disorders in the United States: results of a
randomized, multi-center trial of combination therapy.
Hepatology. 2001;34:243A. [Abstract 278]
6. Afdhal N, Flamm S, Imperial J, et al. Analysis of
40 KDA peginterferon alfa-2a (Pegasys[R]) in
combination with ribavirin, mycophenolate mofetil,
amantadine or amantadine plus ribavirin in patients
that did not respond to Rebetron[tm] therapy: a report
of two randomized, multicenter, efficacy and safety
trials. Hepatology. 2001;34:243A. [Abstract 277]
7. Kelly DA, Bunn SK, Apelian D, et al. Safety,
efficacy and pharmacokinetics of interferon alfa-2b
plus ribavirin in children with chronic hepatitis C.
Hepatology. 2001; 342A. [Abstract 680]
8. Jeffers LJ, Cassidy W, Howell C, et al. 40 KDA
Peginterferon alfa-2a in combination with ribavirin in
African American and Caucasian patients with HCV
genotype 1: a preliminary report of a comparative,
multicenter, efficacy and safety study. Hepatology.
2001;326A. [Abstract 617]
9. Shiffman ML, HALT-C Trial Investigators.
Retreatment of interferon and interferon-ribavirin
non-responders with peginterferon-alfa 2a and
ribavirin: initial results from the lead in phase of
the HALT-C trial. Hepatology. 2001;34:243A. [Abstract
10. Hassanein TI, Cooksley G, Sulkowski M, et al.
Treatment with 40 KDA Peg-interferon (Pegasys[R]) in
combination with ribavirin significantly enhances
quality of life compared with interferon alfa-2b plus
ribavirin. Hepatology. 2001;34: 243A.[Abstract 280]
11. McHutchison JG, Pockros P, Nyberg L, et al. A dose
escalation study of ISIS 14803, an anti-sense
inhibitor of HCV, in chronic hepatitis C patients.
Hepatology. 2001;350A. [Abstract 712]
12. Lurie Y, Pakula R, Malnick S, et al. Efficacy and
safety of the combination of histamine dihydrochloride
and interferon alfa-2b in a phase 2 trial in naive
patients with chronic hepatitis C. Hepatology.
2001;350A. [Abstract 713]
13. Pockros PJ, McHutchison JG, O'Brien C, et al. A
phase 2 randomize, double blind, placebo controlled,
multicenter trial of recombinant human interleukin-12
for the treatment of chronic hepatitis C virus
infection in patients non-responsive to previous
treatment with or without ribavirin. Hepatology.
2001;350A. [Abstract 714]
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