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Hepatitis C: Current and Future Treatment
from
Infections
in Medicine ®
Current Treatment
Interferon-a monotherapy and, more recently, combination
interferon-a and ribavirin therapy are the only
treatments for chronic hepatitis C shown to be
effective, although sustained response rates (normal
serum aminotransferase levels and/or undetectable Hepatitis C Virus
RNA 6 months after completion of therapy) still occur in
fewer than half of treated patients. Interferon-a at the
standard dosages of 3 million units, or 9 mg, tiw for 6
months achieves a sustained biochemical and virologic
response with histologic improvement in 7% to 20% of
treated patients.[9-11]
Continuing
interferon-a monotherapy for 12 to 18 months improves
the sustained response rate to 15% to 30%. Results of
the US and European trials with combination interferon
alfa-2b plus ribavirin therapy in previously untreated
patients show a doubling of these biochemical and
virologic sustained response rates to approximately 40%,
making combination interferon/ribavirin the current
treatment of choice for chronic hepatitis C.[12,13]
Candidates for Therapy and Pretreatment
Considerations
The primary goal of antiviral therapy for chronic hepatitis C is
durable viral clearance as evidenced by the absence of
Hepatitis C Virus RNA in serum. A secondary goal is reduction of
damage to the liver as determined by either persistently
normal alanine aminotransferase (ALT) levels or improved
liver biopsy results, with the expectation that this
will delay or prevent cirrhosis, hepatocellular
carcinoma, the need for liver transplantation, and
death. Interferon therapy is indicated in patients with
chronic hepatitis C who are at the greatest risk for
progression to cirrhosis.[2,3]
These patients are characterized by the following:
- Persistently
elevated ALT levels for more than 6 months.
- Detectable
serum Hepatitis C Virus RNA by a qualitative or quantitative
assay.
- Liver
biopsy demonstrating grade 2 or 3 fibrosis (Table
1).
- Moderate
degrees of liver inflammation and necrosis.
While pretreatment liver biopsy has been widely recommended and
is standard in clinical trials evaluating new antiviral
agents,[2,3]
a recent cost-effectiveness analysis showed that routine
liver biopsy increased the cost of managing patients
without improving outcomes.[14]
A potentially acceptable alternative is to offer
antiviral therapy to all patients who have chronic
hepatitis C without contraindications or decompensated
cirrhosis. Liver biopsy would be reserved for the
exclusion of concomitant, alternative liver diseases and
for management decisions -- for example, in patients not
wanting therapy if fibrosis is mild or absent, or in
patients who do not respond to standard therapy and are
considering future, experimental therapies.
Pretreatment
measurement of quantitative Hepatitis C Virus RNA levels and Hepatitis C Virus
genotype are useful in forecasting the success rate of
therapy and determining the length of combination
interferon/ ribavirin treatment -- 6 months for patients
with genotypes 2 or 3, 12 months for patients with
genotype 1.[12,13]
Patients
with histologically mild disease (grade 0 or 1 fibrosis)
have a relatively benign natural history[15] and may not require treatment.[2,3]
Nevertheless, since nonfibrotic liver disease is
associated with a higher likelihood of response to
interferon, with treatment resulting in improved
survival and cost savings, it may be judicious to offer
such patients a trial of antiviral therapy.[12-14]
Several
studies have evaluated the clinical status and response
to treatment of patients with chronic viremia but
persistently normal ALT levels on repeated
determinations.[16] Although advanced histologic changes are seen infrequently and
cirrhosis is rare, abnormal liver histology is found in
the majority of such patients. The results of several
treatment trials indicate that a sustained virologic
response is uncommon, with elevated ALT levels
developing in some patients during treatment and
persisting thereafter.[16]
The current recommendation is not to perform biopsy or
administer treatment in patients with persistently
normal ALT levels.[2,3] Further studies are necessary to determine
whether combination interferon/ribavirin treatment will
result in better outcomes in this subset of Hepatitis C Virus-infected
patients.
Patients
with compensated cirrhosis have a 29% risk of
decompensation and a 21% risk of death over 10 years;
once decompensation occurs, the 5-year survival is only
50%.[17]
Since the efficacy of interferon in patients with
decompensated cirrhosis has not been documented, these
patients should be considered for liver transplantation.
Patients with compensated cirrhosis secondary to chronic
hepatitis C have reduced sustained response rates to
interferon therapy.[2,3] However, data from more recent studies suggest
that interferon therapy improves liver function and may
prevent or delay the onset of decompensation or the
development of hepatocellular carcinoma in patients with
cirrhosis, particularly those who show a complete
response to interferon.[18] Thus, cautious use of interferon with close monitoring for
cytopenias may be warranted in patients with chronic
hepatitis C who have compensated cirrhosis.
Heavy
drinkers with chronic hepatitis C are at risk for more
advanced histologic disease secondary to Hepatitis C Virus infection
and should be encouraged to abstain from alcohol.[2,3] Recently published retrospective and prospective studies
have demonstrated that the occurrence of acute hepatitis
A in patients with chronic hepatitis C and other chronic
liver diseases is associated with increased morbidity
and mortality.[19,20]
Although
not directly studied, there is also probably a worse
outcome of acute hepatitis B in patients with
preexisting chronic liver diseases, including chronic
hepatitis C. The safety and efficacy of hepatitis A
vaccine in patients with chronic liver disease was
recently demonstrated[21];
hepatitis B vaccine also has effectiveness in chronic
liver disease, although higher doses of the vaccine may
be required.[22]
These
observations led to the recommendation by the CDC that
all patients with chronic liver disease receive
hepatitis A vaccine.[23]
The NIH Consensus Development Conference recommended
that all patients with hepatitis C be screened for prior
immunity and undergo vaccination for both hepatitis A
and B if susceptible.[2]
Interferon Monotherapy
Three types of interferon-a have been studied and are approved
for the treatment of chronic hepatitis C (Table 2):
- Interferon
alfa-2b.
- Interferon
alfa-2a.
- Alfacon-1
(consensus interferon).
Although these interferons have demonstrated some differences in
efficacy in subgroup analyses, the NIH Consensus
Development Conference panel concluded that all 3
interferons have generally comparable safety and
efficacy in the treatment of chronic hepatitis C when
given at the standard dosages of 3 million units, or 9
µg, tiw for 12 months or longer.[2]
Response
rates to interferon therapy vary according to dosage and
duration of therapy and baseline characteristics of
treated patients. Duration of treatment appears to be
more important than the dosage of interferon in
achieving a sustained response. Only 7% to 20% of
patients have a long-term sustained response after 6
months of therapy; treatment for 12 to 24 months is
associated with a sustained virologic response of 15% to
30% and a significantly greater decrease in hepatic
inflammation.[2,3,11]
The efficacy of higher interferon doses and daily
induction therapy is currently under evaluation.
Pretreatment
factors associated with a greater likelihood of response
to interferon include[24]:
- Low
serum Hepatitis C Virus RNA level (less than 1 to 2 x 106
copies/mL).
- Hepatitis C Virus
genotype 2 or 3.
- Absence
of advanced fibrosis or cirrhosis on biopsy.
A remarkable and unexplained poor response to interferon has been
shown in African Americans when compared with white
patients, with end-of-treatment and sustained virologic
responses of only 5% and 2% versus 33% and 12%,
respectively.[25]
Responses
to antiviral therapy for chronic hepatitis C are defined
by convention on the basis of various outcomes.[26] A biochemical response is defined on the basis
of a normal ALT level and a virologic response by an
undetectable level of serum Hepatitis C Virus RNA. The time of these
findings is expressed either as an end-of-treatment
response or as a long-term post-treatment sustained
response. Persistence of a biochemical and/or virologic
response for 6 months or more after cessation of therapy
is the operational definition of a sustained response.
Evidence
is now accumulating that a sustained virologic response
6 months after completion of interferon therapy predicts
a long-term clinical response over 4 to 10 years.[27,28]
In studies by Marcellin and coauthors[27] and Lau and associates,[28]
there was permanent loss of serum Hepatitis C Virus RNA in more than
95% of patients and improvement of liver histology,
including evidence of regression of hepatic fibrosis, in
noncirrhotic patients. These studies suggest that some
patients may indeed be cleared of chronic Hepatitis C Virus infection
and that a reduction in mortality should be expected if
cirrhosis, with its risk of progression to
hepatocellular carcinoma, can be prevented.
Nonresponse
is defined as persistently elevated ALT levels and/or
detectable serum Hepatitis C Virus RNA. A variant of nonresponse
called "breakthrough" is defined as an initial
decrease of ALT levels into the normal range or the
disappearance of detectable Hepatitis C Virus RNA with subsequent
elevation of ALT levels or presence of detectable Hepatitis C Virus
RNA while the patient is still receiving treatment.
Failure to clear Hepatitis C Virus RNA after 12 weeks of interferon
monotherapy or 24 weeks of combination therapy predicts
the lack of a sustained virologic response and has been
considered reason to stop therapy.[2,3,12,13]
However, histologic improvement may still occur in
nonresponders at the end of a complete course of
therapy, and thus continuation of therapy may be
beneficial.[18]
A large NIH 5-year study of the potential benefit of
long-term interferon therapy in nonresponders with
advanced fibrosis is currently under way.
Re-treatment With Interferon Monotherapy
Re-treatment studies have been performed on patients with chronic
hepatitis C who were nonresponders or relapsers after a
course of interferon monotherapy. Re-treatment response
rates have been highly variable and depend on the
response to the initial course of treatment. The only
treatment strategies that have shown some favorable
results with interferon monotherapy are using a higher
dose for a longer period[29]
or using a different interferon.[30] In general, response rates are much higher in patients who
previously responded and relapsed than in patients who
did not respond to an initial course of therapy.
Re-treatment
of relapsers with interferon alfacon-1 at a higher
dosage of 15 mg tiw for 12 months achieved a 58%
sustained virologic response,[30]
similar to the re-treatment response rate of combination
interferon alfa-2b and ribavirin.[31]
The substantially higher tolerability of interferon
monotherapy compared with combination therapy -- rates
of discontinuation of approximately 5% to 10% versus 15%
to 20%, respectively -- makes monotherapy an excellent
re-treatment option for those who relapsed following
prior therapy.
In
contrast to the reasonably good results with
re-treatment of relapsers, the cumulative data indicate
that nonresponders to interferon therapy achieve only
modest responses with re-treatment, as shown by a 13%
sustained virologic response to interferon alfacon-1 at
a dosage of 15 mg tiw for 12 months.[30]
However, approximately 30% of nonresponders have the
breakthrough subtype of nonresponse. With re-treatment
with interferon alfacon-1 at 15 mg tiw for 12 months,
27% of those with a viral breakthrough had a virologic
sustained response, compared with 8% of nonresponders
without breakthrough.[32]
Therefore, prior nonresponders with breakthroughs have a
better chance of responding to re-treatment.
Combination Interferon With Ribavirin
Since therapy for chronic hepatitis C with interferon-a is less
than ideal, numerous other approaches have been studied.
Results of recently concluded trials comparing standard
interferon-a monotherapy with interferon alfa-2b/ribavirin
combination therapy have shown an approximate doubling
in response rate for all measures of efficacy.[12,13]
Although the rate of drug-induced adverse effects is
higher, the overall safety profile of combination
therapy is acceptable.[12,13]
Ribavirin
is a nucleoside analogue typically given orally, 1000 to
1200 mg/d. Combination therapy with ribavirin and
interferon-a initially showed promise in uncontrolled
pilot studies, with later confirmation in randomized
trials. Results of the recently concluded US and
European trials comparing standard interferon-a
monotherapy with interferon alfa-2b plus ribavirin have
shown significant improvement in response rates for all
measures of efficacy in treatment-naive patients with
chronic Hepatitis C Virus infection,[12,13]
including:
- Clearance
of Hepatitis C Virus RNA.
- Normalization
of ALT levels.
- Improved
histology.
These studies have also shown important differences in outcome
based on genotype. Patients with genotype 1 had
increased rates of sustained virologic response with 48
weeks versus 24 weeks of combination therapy, while
patients with other genotypes derived no added benefit
after the additional 24 weeks of combination therapy
(Table 3).
In
patients who relapse after an end-of-treatment response
with interferon-a alone, combination treatment with
interferon/ribavirin for 24 weeks has achieved a 49%
response rate compared with 4% with interferon alone at
standard dosage.[31]
However, nonresponders to interferon-a alone rarely
achieve a sustained response with combination treatment.
The
chief side effect of ribavirin therapy is a
dose-dependent hemolytic anemia, which is reversible and
usually stabilizes after 4 to 8 weeks of treatment. Most
patients experience a drop in hemoglobin level of 2 g/dL,
and some patients may become severely anemic,
necessitating discontinuation of therapy. Other common
side effects associated with ribavirin treatment are
respiratory symptoms (cough, dyspnea); skin disorders (pruritus,
rash, dry skin); neuropsychiatric symptoms (insomnia,
depression, anxiety); and GI disorders (anorexia,
dyspepsia). Ribavirin is potentially teratogenic, and
contraception is mandatory during treatment and for 6
months after therapy.
In
the US multicenter study of combination therapy,
discontinuation of therapy was necessary in 8% to 21% of
patients in the 4 treatment groups and more common in
the combination groups. In the 2 combination-treatment
groups, dose reduction was required in 7% to 9% of
patients because of anemia and 13% to 17% for other
reasons.[13] The most frequent reason for discontinuation of therapy in
all groups in the US trial was the development of
psychiatric symptoms, primarily depression.
Contraindications
to combination therapy with interferon and ribavirin are
listed in Table 4. Some of these contraindications
relate primarily to ribavirin therapy. For example,
patients with preexisting anemia usually cannot tolerate
the degree of hemolysis that occurs with ribavirin.
Patients with significant cardiovascular disease are
also at risk if severe anemia develops during therapy.
Patients with chronic hepatitis C and the above baseline
conditions should be treated with interferon monotherapy
rather than combination therapy.[11]
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