Hepatology Focus - Update on Hepatitis C Treatment
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Update on Hepatitis C Treatment
Series Editor: Paul Martin, MD, Cedars-Sinai Medical
Center, and UCLA School of Medicine, Los Angeles,
[Medscape Gastroenterology 3(1), 2001. � 2001
Although screening of blood products and other
interventions such as clean-needle exchange programs
have significantly reduced the incidence of acute
hepatitis C in the United States and elsewhere, there
remains a large reservoir of chronically infected
individuals, many of whom are unaware of their
infection. Current estimates suggest a seroprevalence
of 1.8% among Americans, most of whom are viremic.
The clinical burden of chronic hepatitis C virus (HCV)
infection is expected to increase over the next 2-3
decades as a large cohort of patients infected between
the 1960s and 1980s, primarily as a result of
recreational drug use, develops progressive liver
disease. Between 8000 and 10,000 deaths each year in
the United States are believed to be caused by
infection with HCV -- which is now the most frequent
indication for liver transplantation.
Even before identification of HCV, interferon-alfa
(IFN-alfa) had been evaluated as a potential therapy
for what had been called chronic non-A, non-B
Further studies using normalization of serum alanine
aminotransferase (ALT) levels and improvement in liver
histology as endpoints demonstrated the efficacy of
IFN-alfa as therapy for the causative agent of chronic
non-A, non-B hepatitis (HCV).[4,5] Subsequent advances
in molecular diagnosis have now increasingly allowed
establishment of virologic criteria to evaluate
efficacy of treatment in patients with chronic
hepatitis C (see Table).
Definition of Virologic Response in Patients Receiving
Therapy for Chronic Hepatitis C
End-of-treatment response (ETR) refers to absence of
viremia (ie, serum HCV RNA below level of detection)
at completion of therapy. Sustained response (SR)
indicates persistent absence of serum HCV RNA 6 months
or more after cessation of therapy. A study by
Marcellin and coworkers on the long-term clinical
outcome in 80 patients with chronic HCV followed for a
mean of 4 years following therapy highlighted the
clinical implications of a virologic SR. Persistent
absence of HCV RNA from serum was observed in 96% of
patients with a lack of histologic progression on
serial liver biopsy. In addition, ALT levels were
persistently normal in over 90%. The most recent
follow-up biopsy showed normal or near normal
histologic findings in 62% of these patients. Thus,
virologic SR was shown to be associated with both an
absence of detectable serum HCV RNA and marked
Relapsers are defined as patients who have
undetectable serum HCV RNA at completion of therapy
but who subsequently redevelop viremia. Nonresponders
(NRs) are patients who fail to clear HCV RNA from
serum during therapy.
A recent paper by Everson and associates
underscores the importance of HCV RNA testing in
defining treatment response. In patients with marked
fibrosis and cirrhosis, they found a major discrepancy
between biochemical (ALT) and virologic (HCV RNA)
responses to therapy. Two of 7 (29%) patients with
marked fibrosis and 2 of 6 (33%) patients with
cirrhosis cleared HCV RNA without normalizing ALT. In
contrast, only 3 patients (10%) without significant
fibrosis had an HCV RNA response without normalization
of ALT. Thus, clinical trials for chronic HCV are now
typically reported using virologic response rates.
What then are the current goals of antiviral therapy
in patients with chronic hepatitis C? Immediate goals
are eradication of viral replication and improvement
in hepatic inflammation and fibrosis. Long-term
potential goals include prevention of cirrhosis,
hepatocellular carcinoma, and liver failure.
IFN-alfa 2 was the first agent approved for the
treatment of chronic HCV. Since the initial trials
establishing its efficacy, data regarding treatment
duration and dose have evolved. Currently, 2 forms of
IFN-alfa that differ by a single amino acid residue
are approved for treatment of chronic HCV infection:
IFN-alfa 2b (Schering-Plough, Kenilworth, New Jersey)
and IFN-alfa 2a (Hoffmann-La Roche, Basel,
Switzerland). The recommended dose is 3 million units
3 times each week for up to 12 months.
When used alone in monotherapy, the alfa interferons
have similar efficacies, with SRs of only 10% to 20%,
with the modestly higher response rates associated
with more prolonged therapy. Higher-dose IFN-alfa (ie,
> 9 million units per week) results in SRs between 8%and 20% in treatment-naive patients. High-dose
IFN-alfa has also been studied in NRs and relapsers,
but with mixed results. With prior NR, SRs achieved
with higher doses are only between 0% and 4%. In
relapsers, SRs range from 20% to 40%. However, side
effects are more troublesome with higher doses.
Because of the low overall response rate to standard
IFN-alfa, more recent studies have focused on newer
regimens, including synthetic IFN (IFN alfacon-1),
"combination" therapy (IFN-alfa 2b + ribavirin), and
longer-acting IFNs (pegylated IFNs). A number of major
pretherapy predictors of NR have been identified,
notably HCV genotype 1, the presence of cirrhosis, and
higher viral load. In addition, patient's race
appears to affect response to IFN, with African
Americans having an overall low SR to therapy.
A significant improvement in SR resulted from the
addition of ribavirin to standard IFN-alfa. Ribavirin,
a guanosine analogue, was initially evaluated as
monotherapy for chronic HCV because of its antiviral
activity against other RNA viruses.[11-13] Although as
monotherapy it reduces ALT levels, it does not appear
to have a direct antiviral effect and fails to lower
serum HCV RNA levels. Moreover, results of most
studies with ribavirin have found no improvement in
hepatic histology, although a longer 2-year treatment
regimen was shown to reduce necroinflammatory
However, in combination with IFN-alfa 2b, ribavirin
leads to a significant increase in SR in
treatment-naive patients. SRs of 31% with 24 weeks
and 38% with 48 weeks of combination therapy were
achieved vs 6% with 24 weeks and 13% with 48 weeks of
IFN monotherapy. In relapsers, enhanced SR rates
also occur on retreatment using combination therapy,
from 30% to 49%; in prior NRs, SR of 14% has been
reported with 6 months of combination therapy.[15,16]
Histologic improvement was more common among
treatment-naive patients treated with combination
therapy. Similar improvement was found in a
randomized controlled trial of treatment-relapse
However, the improved SR rates observed with
combination therapy are also associated with more
expense and an increased frequency of adverse effects
compared with IFN-alfa monotherapy. Dose-related
hemolytic anemia is a particular concern with
ribavirin[11,13] as is teratogenicity, based on animal
studies. The mean drop in hemoglobin in patients
treated with combination therapy is between 2 and 3
g/dL, although a fall of more than 4 g/dL has been
observed in about 10% of patients. The anemia may be
poorly tolerated in patients with ischemic heart
disease in particular as treatment is extended to
older patients. Accumulation of ribavirin
metabolites that are not cleared by dialysis occurs in
end-stage renal disease.(18)
Consensus IFN (CIFN; IFN alfacon-1, Amgen, Thousand
Oaks, California) is a genetically engineered compound
synthesized by combining the most common amino acid
sequences from naturally occurring IFNs.[19,20] CIFN
shares 88% homology with IFN-alfa and 30% with
IFN-beta. Although it has greater cytokine induction,
antiviral, antiproliferative, natural killer cell, and
gene-induction activities than both IFN-alfa 2a and
IFN-alfa 2b on an equal mass basis, initial studies
with the recommended CIFN dose of 9 mcg in IFN-naive
patients with chronic hepatitis C resulted in viral
response rates similar to those achieved with standard
More recently, higher-dosage CIFN regimens of 15 mcg
thrice weekly were reported to result in virologic SRs
of 13% in prior NRs and 58% in relapsers treated for
Pharmacokinetic studies have provided a rationale for
enhanced IFN dosing. The initial decline in serum HCV
RNA levels seen after a single dose of IFN therapy is
believed to reflect a direct antiviral effect, whereas
the subsequent and more delayed decline in HCV RNA
levels is due to destruction of infected
hepatocytes. An important limitation of the
antiviral effect of standard IFN dosing is the rapid
decline in circulating drug level with thrice-weekly
administration. The short half-life of the drug and
the rapid production of HCV virions diminish the
efficacy of standard IFN therapy. In an effort to
achieve more stable and efficacious IFN activity,
pegylated formulations have been developed.
The production of a pegylated IFN involves the
addition of a nontoxic long-acting formulation of
interferon using the drug delivery system of
pegylation. Polyethylene glycol molecules are added to
IFN-alfa 2a (Pegasys, Hoffmann-La Roche) and IFN-alfa
2b (PEG-Intron, Schering-Plough). Pegylation is
already used in the delivery of other drugs. Its
attachment to IFN-alfa permits once-weekly dosing.
In a recent report, Zeuzem and colleagues indicate
that at week 72, the SR was 39% after 48 weeks of
therapy at a dose of 180 mcg with pegylated IFN
alfa-2a compared with a 19% SR in control patients.
Drug discontinuation in these treatment-naive patients
and frequency of dose reduction were similar in the 2
treatment arms. Heathcote and colleagues have also
reported on the use of pegylated IFN alfa-2a in a
controlled trial in cirrhotic patients. SR was 30%
following 48 weeks of therapy with 180 mcg, compared
with 8% for patients treated with standard alfa IFN,
again without a significant increase in side effects
with the pegylated product.
Trepo and colleagues have also reported, in
abstract form, initial studies with pegylated IFN-alfa
2b. Virologic SR for the unmodified IFN-alfa 2b (3
million units, thrice weekly for 48 weeks) was 12%,
whereas the SR for the pegylated IFN-alfa 2b was 18%,
25%, and 23% with 0.5 mcg/kg, 1.0 mcg/kg, and 1.5
mcg/kg, respectively, administered weekly in
As with standard IFN-alfa monotherapy, ribavirin may
augment response rates when combined with the
pegylated IFNs.[26,27] Recent trials will help
evaluate further the role of ribavirin in augmenting
the efficacy of pegylated IFN (see Figure).
Figure. Initial antiviral therapy against hepatitis C
* Abbreviations: IFN = interferon; CSN = consensus
interferon; IFN/RIB = interferon + ribavirin; PEG =
pegylated interferon; PEG/RIB = pegylated interferon +
There has been continued interest in developing
non-IFN-based therapies for HCV despite the promise of
the pegylated IFNs. A recent study examined the role
of human interleukin-10 in treating prior NRs with
chronic HCV. Although, HCV RNA remained detectable
in all patients at the end of treatment, 5 (23%)
of the 22 treated patients had persistent ALT
normalization at the end of follow-up. Future studies
should determine whether combining interleukin-10 with
other antiviral agents will increase efficacy in this
setting. Interleukin-12 has also been evaluated as
monotherapy, again without clear antiviral
There is also increasing enthusiasm for targeting HCV
molecular products. For example, ribozyme gene therapy
has the potential to accurately degrade HCV RNA.
Human studies are anticipated.
Treatment options for HCV infection continue to
expand. Whereas SRs of 10% were achieved with IFN
monotherapy only several years ago, it may soon be
possible to achieve SR rates greater than 50% with
combination pegylated IFN and ribavirin.
Molecular-based, specific therapeutic strategies are
also likely to become a reality in the future,
although therapy will remain interferon-based the next
Sammy Saab, MD, Clinical Instructor, UCLA School of
Medicine, Los Angeles, California, and Paul Martin,
MD, Medical Director, Liver Transplantation,
Cedars-Sinai Medical Center, Associate Professor of
Medicine, UCLA School of Medicine, Los Angeles,
Table. Response (HCV RNA/ALT*) to Antiviral Therapy
Type of Response� During Treatment End of Treatment 6
Months After Treatment Completed
End-of-Treatment Negative Negative
Sustained Negative Negative Negative
Relapse Negative Negative Positive
Nonresponder Positive Positive Positive
* HCV RNA measured by polymerase chain reaction; ALT =
alanine aminotransferase; HCV = hepatitis C virus.
� Positive denotes HCV RNA present in the serum by
polymerase chain reaction and abnormal alanine
aminotransferase values. Negative denotes no serum HCV
RNA by polymerase chain reaction and normal alanine
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