Chronic HCV Infection
interferon (PEG-IFN) combined with ribavirin is the best
currently available therapy for HCV infection.
predictors of treatment response have been identified, including
absence of serum HCV RNA 6 months after discontinuation
of therapy predicts durable viral eradication.
of patients with chronic HCV infection is associated with
significant side effects, although most of these are not
serious or life-threatening.
use of hematopoietic growth factors shows promise for managing
the anemia and neutropenia associated with anti-HCV therapy,
but further studies are warranted.
It has been estimated
that approximately 3% of the world's population is infected with HCV.59
This represents nearly 170 million persons worldwide.59
In the United States, the prevalence of anti-HCV is 1.8%; 74% of these
patients exhibit HCV RNA positivity. This corresponds to 2.7 million
chronically infected persons in the United States alone.1
morbidity, mortality, and economic burden associated with HCV infection
are responsible for the striking worldwide public health impact
of this condition. Currently, HCV infection is responsible for an
estimated 8,000 to 10,000 deaths annually in the United States,
and that number is predicted to triple in the next 10 to 20 years.
HCV-related disease is the leading indication for liver transplantation
in the United States. The decision to treat patients with chronic
HCV infection should be made after many factors have been considered
and each case has been individualized (see "The
Team Approach to Hepatitis C Management").
(PEG-IFNs)which are produced by the conjugation of IFN and a
polyethylene glycol moleculerepresent a recent therapeutic advance
in the treatment of HCV infection. This modified formulation of IFN
has resulted in improved therapeutic effectiveness over unmodified
IFN, likely because its sustained action is the result of a long half-life.
Trials of PEG-IFN in combination with ribavirin have established its
safety and efficacy.
Combination therapy with nonpegylated IFN alfa and ribavirinuntil
recently considered to be the treatment of choice for chronic hepatitis
Cis less convenient and probably less effective. Fewer than
40% of patients achieve a durable benefit, ie, a sustained virologic
response, defined as the absence of serum HCV RNA 6 months after the
end of treatment, as measured by a sensitive assay with a lower limit
of detection of at least 50 IU/mL.
been slower in the development of non-IFN-based therapies for HCV
infection, including protease inhibitors, helicase inhibitors, ribozymes,
antisense therapies, cytokine-based therapies, and T-cell-based
therapeutic vaccines. Overall, advances in the development of therapies
for HCV infection have been hindered by the lack of dependable cell
culture systems and an adequate animal model. Furthermore, variations
in the response to IFN treatment by different viral genotypes and
differences in the type or vigor of immune responses may represent
other obstacles to the development of a uniformly effective therapy
OF A TYPICAL PATIENT
The typical HCV-infected
patient for whom therapy is well established is an adult who has chronic
infection (ie, evidence of infection for at least 6 months). The typical
patient has elevated serum transaminase levels, detectable serum HCV
RNA, and histologic evidence of liver injury in the absence of decompensated
cirrhosis. In addition, other liver diseases or confounding comorbid
conditions have been excluded. For the typical HCV-infected patient,
IFN-based therapeutic regimens have been found to be safe and often
In the 1980s, even
before HCV was identified, therapy with IFN alfa was shown to be associated
with normalization of transaminase levels in patients with non-A non-B
hepatitis.60 In 1989,
the results of two controlled clinical trials that evaluated the efficacy
of IFN treatment in chronic HCV infection were published.61,62
In both trials, patients received 1 to 3 million IU of IFN alfa-2b
three times weekly for 6 months. Complete biochemical remission was
achieved in half of these patients. However, in almost 50% of the
responders, serum transaminase levels returned to pretreatment levels
6 to 12 months after IFN therapy was discontinued.
In 1997, Carithers
and Emerson published a meta-analysis of randomized trials in which
IFN alfa-2bin regimens of at least 2 million IU three times
weekly for a minimum of 24 weekswas given to IFN-naive patients.63 They concluded that IFN alfa is effective in treating chronic HCV
infection. A biochemical sustained responsethat is, normalization
of ALT levels by 6 months following discontinuation of therapywas
achieved in 23% of the treated group, compared with only 2% of the
untreated group (p < 0.001).
IFN AND RIBAVIRIN
Ribavirin is an
oral nucleoside analog with activity against a broad spectrum of DNA
and RNA viruses. When used alone, it has little or no activity against
HCV. Both direct antiviral and immune modulatory effects have been
proposed as mechanisms of action.64
Placebo-controlled studies of ribavirin monotherapy in patients with
chronic HCV infection found that although 20% to 40% of patients had
a biochemical response at the end of therapy, none had a virologic
In the mid-1990s,
small pilot studies suggested that treatment with IFN and ribavirin
for 6 months was more effective than treatment with IFN alone. A
meta-analysis of individual patient data from four European centers
found that the efficacy of IFN and ribavirin combination therapy
was two- to three-fold greater than the efficacy of IFN alone.66
Also, two randomized controlled trials published in 1998 showed
that the combination of IFN alfa-2b and ribavirin produced better
rates of sustained virologic and biochemical response in patients
with HCV infection who were given it as initial treatment (IFN-naive
patients) and in those who had experienced a virologic relapse after
a previous course of IFN monotherapy.67 68
Sustained virologic response rates ranged from 31% to 38% when combination
therapy was given as the initial treatment, and the sustained virologic
response rate was 49% when it was given for relapse. These rates
are three to five times as high as those achieved with monotherapy.
WITH AND WITHOUT RIBAVIRIN
PEG-IFNs were recently
approved in the United States and Europe for the treatment of chronic
HCV infection. The rationale for developing anti-HCV agents that have
a longer half-life (which PEG-IFN does) is based on the dynamics of
the viral response to IFN. A substantial decrease in viral load occurs
during the first 24 hours following a single injection of IFN alfa-2b.
However, viral counts begin to rebound at 48 hours, suggesting that
longer-acting medications may be more appropriate for these patients.52 Because pegylation prolongs the half-life of IFN, only one dose per
week is required to maintain effective levels in the blood (vs.
three doses per week with standard IFN).52
of three large trials of PEG-IFN alfa-2a and alfa-2b therapy in
patients with chronic HCV infection established its superiority
over conventional IFN alfa.45 69 70.
Overall, sustained viral eradication was achieved in 25% to 39%
of patients who were treated with PEG-IFN (alfa-2a or alfa-2b) monotherapy,
compared with only 7% to 19% of those who received standard IFN.
In all trials, the incidence of adverse effects among patients who
received PEG-IFN was similar to that among patients who received
In one of these
trials, Zeuzem et al randomly assigned 531 HCV RNA-positive patients
with chronic HCV infection without cirrhosis to receive either PEG-IFN
alfa-2a (180 µg weekly for 48 weeks) or IFN alfa-2a (6 million
IU three times weekly for 12 weeks, followed by 3 million IU three
times weekly for 36 weeks).69
PEG-IFN alfa-2a was associated with a significantly greater virologic
response than standard IFN. Sustained virologic and biochemical
responses were achieved in 38% of the patients treated with PEG-IFN
(compared with only 17% of those treated with standard IFN), which
was similar to the results seen in patients who were given the combination
of standard IFN and ribavirin.
In the second
trial, Heathcote et al randomly assigned patients with chronic HCV
infection who had cirrhosis to receive either 90 or 180 µg
of PEG-IFN alfa-2a weekly or standard IFN alfa-2a (3 million IU
three times weekly) for 48 weeks.45 They found that a sustained virologic response was achieved by 30%
of the patients who received PEG-IFN at 180 µg weekly.
The third trial
of PEG-IFN included 1,219 patients with chronic HCV infection who
were assigned to receive standard IFN alfa-2b (3 million IU three
times weekly) or PEG-IFN alfa-2b given in one of three doses (0.5,
1.0, or 1.5 µg/kg body weight once weekly).70 Sustained virologic response was substantially greater with PEG-IFN
alfa-2b at the doses of 1.0 or 1.5 µg/kg compared with standard
IFN alfa-2b (23% to 25% vs. 12%).
large trials of PEG-IFN and ribavirin combination therapy established
its role in treating patients with chronic HCV infection.49 50 71
Sustained viral eradication rates in patients who received PEG-IFN
and ribavirin ranged between 48% and 56%, compared with rates of
29% to 47% among those who received standard IFN and ribavirin.
all patients with chronic HCV infection are candidates for antiviral
therapy. However, only a subgroup of patients has a clear indication
for treatment. The restriction of treatment is justified because of
the naturally slow course of the infection, the expense of the treatment,
the occurrence of adverse effects, and the relative ineffectiveness
of treatment. Previously untreated patients with detectable levels
of HCV RNA who have persistently elevated aminotransferase levels
and whose liver biopsy specimens show fibrosis (or at least moderate
necrosis and inflammation) are at high risk for disease progression.
Therefore, combination therapy is recommended for this group if there
are no contraindications to either IFN or ribavirin.22 72
standard recommended therapy is a weekly dose of PEG-IFN alfa-2a
or PEG-IFN alfa-2b and ribavirin at 1,000 to 1,200 mg daily for
6 to 12 months. For other groups of patients, indications for treatment
are less clear, and decisions should be made on a case-by-case basis.
special groups of patientsfor example, children, liver transplant
recipients, and patients who have persistently normal aminotransferase
levels, cirrhosis, coinfection with HIV or HBV, or extrahepatic
manifestations of hepatitis Cis discussed later in this monograph.
In principle, patients
with genotype 1, 4, or 6 virus should be given at least 12 weeks of
treatment and then checked for early virologic response. Early virologic
responsedefined as the lack of detectable HCV RNA or a greater
than 2-log drop (99% reduction) in the level of HCV RNAis believed
to be the most reliable factor in predicting sustained virologic response.22
If there has been less than a 2-log drop in HCV RNA after 12 weeks
of therapy in patients with genotype 1 HCV, therapy should be discontinued.
Because of the random fluctuation of viral levels, a decision to discontinue
therapy when a nearly 2-log drop is encountered needs to be individualized.
For genotype 1 patients who have a 2-log drop in viral load after
12 weeks of therapy, treatment should be continued for a year. For
those with genotype 2 or 3 HCV, no interim viral load testing is needed,
and a total of 24 weeks of therapy is given.
of a favorable response to combination therapy have been determined
from an analysis of the combined data from three major trials.49 50 70 The most consistent factors were non-1 genotype, lower levels of HCV
RNA (<800,000 IU/mL), and lower body mass index. Among patients
with genotype 2 or 3, sustained virologic response rates with standard
IFN and ribavirin were similar to those seen with PEG-IFN and ribavirin.
Furthermore, a 24-week course of PEG-IFN and ribavirin was found to
be as effective as a 48-week course in patients with genotype 2 or
3, but not in patients with genotype 1. Finally, a lower dose of ribavirin
(800 mg/d) appeared to be adequate for patients with genotype 2 or
3, but a higher dose yielded better results in patients with genotype
Because of the
potential adverse effects of IFN treatment, careful screening and
monitoring of the patient's condition is needed. Monitoring should
include a complete blood count, serum chemistry panel, and liver function
tests performed monthly. The level of thyroid-stimulating hormone
should be checked periodically. For women of childbearing age, a serum
pregnancy test should be performed while the patient is receiving
ribavirin. If pregnancy occurs at any time during treatment, as demonstrated
by a positive pregnancy test, treatment should be discontinued immediately.
The patient should be counseled about the risks to the fetus posed
by ribavirin. An assessment of neuropsychiatric side effects, especially
depression, should be undertaken at each visit during therapy. Psychiatric
complications of HCV infection are discussed later in this monograph.
With the improved
efficacy of treatment for HCV infection, patients who failed to achieve
viral eradication after previous therapy with IFN with or without
ribavirin are being considered for retreatment with PEG-IFN. In general,
patients who failed to achieve viral eradication with previous therapy
can be classified into two broad categories: nonresponders and relapsers.
Nonresponders are those who are not HCV RNA-negative at the end of
therapy; these include several subcategories, as outlined in Table
9. In contrast, relapsers are patients who become HCV RNA-negative
by the end of therapy only to redevelop HCV RNA after stopping therapy.
Approximately 20% of patients with undetectable viral levels at the
end of therapy will relapse after treatment discontinuation.73
of nonresponse to anti-HCV therapy
who are not HCV RNA-negative at the end of therapy
with no significant decline in HCV RNA
with a first-phase viral response but a poor
with temporary disappearance of circulating virus followed by
reemergence of virus while still on therapy
who become HCV RNA-negative by the end of therapy only to redevelop
HCV RNA after stopping therapy
The first step
when considering retreatment in a patient without sustained response
to prior therapy is to determine whether the patient experienced
true nonresponse or relapse after an adequate course of therapy.
It is important to identify the reasons for the previous lack of
response. These may involve patient issues, such as poor treatment
adherence or poor timing of therapy in the context of other life
events (eg, a new job, a change in insurance status). They also
may involve provider issues, particularly poor side effect management
during initial therapy, which may have resulted in dose reductions
or early withdrawal from treatment. These considerations should
be aimed at identifying interventionssuch as use of growth
factors to avoid dose reductions or prophylactic antidepressant
therapy if severe depression was a problem during prior therapythat
might increase the chance of success with retreatment.
It is also important
to identify the patient's HCV genotype, since retreatment is more
likely to yield a sustained virologic response in nonresponders
with genotypes 2 or 3 than in those with genotype 1.
for retreatment are limited to PEG-IFN plus ribavirin, or the use
of consensus IFN. Available data suggest that approximately 25%
to 40% of nonresponders to IFN monotherapy will achieve a sustained
virologic response with PEG-IFN and ribavirin combination therapy,
while only 10% to 12% of nonresponders to combination IFN and ribavirin
therapy will achieve a response with PEG-IFN and ribavirin.74 75
These modest results suggest that physicians should be selective
when deciding which patients should be retreated, at least to the
extent that sustained virologic response is the treatment goal.
Fewer data are
available on the effectiveness of combined PEG-IFN and ribavirin
for the treatment of patients who relapsed following IFN or IFN-ribavirin
therapy. Preliminary data suggest that sustained viral eradication
in this group of patients is as high as 60%.74
to the patient's prior therapy and the nature of response to that
therapy, the factors that are predictive of sustained virologic
response with retreatment are similar to the predictors of response
in treatment-naïve patients (Table
that should influence retreatment decisions*
response to therapy
or partial response
HCV RNA level
(if reversible factors are identified)
retreatment decisions should be individualized.
Adapted from Shiffman.76
data have indicated that the combination of consensus IFN and ribavirin
may yield impressive sustained virologic response rates of approximately
40% in nonresponders to previous IFN-ribavirin therapy,77
but these findings must be validated in large, well-controlled trials,
which are currently under way.
role of maintenance therapy with PEG-IFN alone in preventing further
progression of liver diseaseincluding hepatic decompensation
and hepatocellular carcinomais currently under investigation.
OF SIDE EFFECTS
In addition to
its suboptimal efficacy, IFN-based therapy has other shortcomings.
It is expensive, it must be administered subcutaneously, and it is
associated with numerous side effects (Table 11). The most
common IFN-related side effects are symptoms consistent with a flu-like
illness. This flu-like syndrome usually disappears after 2 to 4 weeks
of therapy. These symptoms can be ameliorated by acetaminophen given
before IFN is injected. Long-term side effects include fatigue, weight
loss, reversible alopecia, hematologic abnormalities, and neuropsychiatric
symptoms. Autoimmune phenomena may develop, especially in patients
who have an underlying autoimmune disorder. Antithyroid antibodies
and autoimmune thyroiditis may develop in some cases and may not be
reversible after treatment is stopped.
of side effects in patients with
chronic hepatitis C treated
syndrome: fever, headache, chills, myalgia, fatigue
disorders: nausea, anorexia, diarrhea
disorders: depression, irritability
disorders: alopecia, pruritus, rash, dry skin
marrow hypoplasia requiring dose modification, anemia, neutropenia
disorders: arrhythmia, cardiomyopathy, congestive heart failure,
disorders: exacerbation of diabetes mellitus, hypothyroidism,
and biliary diseases: liver failure/encephalopathy, jaundice
disorders: arthritis, leg cramps, muscle weakness
system disorders: amenorrhea, impotence, uterine bleeding
respiratory, urinary, vision disturbances, hearing loss
from data in references 67
and 68 and the package inserts
of IFN alfa-2b and PEG-IFN alfa-2a and -2b.
spectrum of side effects associated with PEG-IFN appears to be similar
to that seen with standard IFN therapy.78
Ribavirin treatment is universally associated with varying degrees
of hemolytic anemia, which may increase fatigue and decrease quality
of life during therapy; as a result, dose adjustment may be necessary.
Many, but not
all, of these side effects are dose-dependent and reversible, but
they can lead to nonadherence by some patients and decrease the
likelihood of a response. The rate of nonadherence has been estimated
to range between 5% and 10%.79
Based on results from a large phase III clinical trial of PEG-IFN
alfa-2a and ribavirin,50
the rate of premature withdrawal of therapy due to laboratory abnormalities
or adverse events was 10%, while dose reduction occurred in 32%
of patients. Hematologic abnormalities including anemia, neutropenia,
and thrombocytopenia were the most frequent indication for dose
reduction. Emerging strategies for the management of these hematologic
abnormalities are discussed in the following subsection.
agent modafinil is increasingly being used for the management of
IFN-associated fatigue, at a dosage of 50 to 100 mg daily. Its potential
benefits must be weighed, however, against any potential addictive
tendencies and the fact that modafinil may reduce the effectiveness
of steroidal contraceptives. Further study of the safety and potential
benefits of modafinil in this patient population is encouraged.
OF GROWTH FACTORS AS AN
ADJUNCT TO ANTI-HCV THERAPY
No uniform approach
has been proposed for managing the hematologic adverse effects of
IFN and ribavirin therapy in patients with hepatitis C, which continues
Anemia related to anti-HCV therapy is attributed largely to ribavirin,
although IFN (and, to a lesser extent, PEG-IFN) also is believed
to play a role. Research on the management of anemia related to
anti-HCV therapy has focused on erythropoietic growth factors. Two
randomized trials have shown that epoetin alfa therapy (40,000 IU
weekly) was associated with increased hemoglobin values and maintenance
of ribavirin dose levels in HCV-infected patients whose hemoglobin
level fell below 12 g/dL during combination therapy with IFN or
PEG-IFN plus ribavirin.80 81 In the first trial, hemoglobin levels rose by 2.8 g/dL in the epoetin
alfa group compared with 0.4 g/dL in the control group, which received
"standard of care" (ribavirin dose reduction).80
More patients in the epoetin alfa group were able to maintain a
ribavirin dose greater than 800 mg/d (83% vs. 54%). In the second
trial, the ribavirin dose was maintained at a level equal to or
greater than the dose at randomization in 88% of patients who received
epoetin alfa for 8 weeks compared with 60% of patients who received
placebo for 8 weeks.81
Quality-of-life scores also improved significantly over the course
of therapy in the epoetin alfa group.
promising findings, no published prospective studies have yet demonstrated
a direct relationship between the use of erythropoietic growth factors
in HCV-infected patients and an increase in sustained virologic
response rates. Additionally, no cost-effectiveness analyses of
growth factors in this patient population have yet been published
that take into account sustained virologic response. Finally, because
erythropoietic growth factors are not currently approved by the
FDA for use in patients with HCV infection, insurance coverage of
these therapies may be a challenge. This panel recommends that erythropoietic
growth factors be considered on an individualized basis for patients
with symptomatic anemia during antiviral therapy for HCV
Neutropenia is attributed to the IFN component of anti-HCV therapy
and appears to occur at higher rates with PEG-IFN than with standard
IFN. Reduction of the dose of PEG-IFN has been recommended for patients
with neutrophil counts of less than 750 cells/mm3 based
on data from cancer patients undergoing chemotherapy. Neutropenia
induced by anti-HCV therapy may be particularly pronounced in liver
transplant recipients and patients with cirrhosis or HIV coinfection.
However, neutropenia in the HCV-infected population has not been
associated with sepsis.
the management of neutropenia in HCV-infected patients has centered
on granulocyte colony-stimulating factor (GCSF) and granulocyte-macrophage
colony-stimulating factor (GMCSF), although data are rather limited.
Several small studies suggest that these therapies can safely maintain
neutrophil counts above 750 cells/mm3 in HCV-infected
patients during IFN-based therapy.82-84 Given these limited data and the generally benign outcome of neutropenia
in HCV-infected patients during therapy, it is difficult to recommend
the routine use of GCSF or GMCSF at this time. However, GCSF may
be considered, at a dosage of 300 µg subcutaneously one to
three times weekly, in selected patients with neutrophil counts
less than 500 cells/mm3. Notably, the response to GCSF
is immediate and does not require discontinuation of IFN or PEG-IFN
A reduction in platelet count may be observed in patients receiving
IFN or PEG-IFN, although it is rarely a cause of dose reduction
or treatment discontinuation. Recombinant human interleukin-11,
or oprelvekin, has been studied for efficacy against thrombocytopenia
in a small number of HCV-infected patients but appears to be limited
by safety concerns and is generally not recommended.85