- VCU Researcher Advances New Treatment for Hepatitis C
Study by Lead U.S. Investigator is Detailed in New England Journal of
RICHMOND, Va., Dec. 7 /PRNewswire/ -- A Virginia Commonwealth University
researcher is part of a study that shows the drug peginterferon alfa-2a,
also referred to as Pegasys, is superior to other forms of interferon in
the treatment of patients with chronic hepatitis C virus infection.
Interferon, alone or in combination with an anti-viral drug, is the only
effective therapy for hepatitis C.
Published in the Dec. 7 issue of the New England Journal of Medicine,
study involved 271 patients and 22 U.S., Canadian and Australian medical
centers, including VCU's Medical College of Virginia Hospitals.
to many previous studies of patients with chronic hepatitis C., this
was unique in that only patients with advanced liver disease, those with
advanced fibrosis and cirrhosis, were treated.
"Hepatitis C patients -- both in the early stages of the disease and
with cirrhosis -- are in dire need of more effective treatments," said
Mitchell L. Shiffman, M.D., medical director of VCU's Hepatology-Liver
Transplant Program and the study's lead U.S. investigator. "This study
clearly demonstrates that Pegasys is superior to standard forms of
interferon in the treatment of chronic hepatitis C."
Pegasys was developed by attaching a non-toxic compound called PEG to
interferon. This alters the interferon drug so that it lasts longer in
the body, has less side effects and at the same time is more effective
against the hepatitis C virus. Standard interferon is administered
times weekly. Pegasys needs to be administered only once weekly.
In this study, 30 percent of patients with advanced liver disease
with Pegasys lost all evidence of hepatitis C virus, compared to 6
of patients treated with standard interferon alfa-2a. Patients are
considered to be virus-free or have a sustained viral clearance when the
virus doesn't return after drug treatments stop. In this study, patients
were treated for 48 weeks with Pegasys and followed for an additional 24
weeks after the treatment ended.
"The first priority is to eradicate the virus. However, the findings in
this study are also demonstrate that Pegasys is also beneficial to a
number of patients in whom sustained viral clearance was not attained,"
Shiffman said. "What we've learned is that it may possible for patients
to show an improvement in the liver disease following treatment with
Pegasys even if this treatment did not get rid of the virus."
In this study, patients randomly received either Pegasys weekly or
interferon alfa-2a three times weekly. Researchers conducted liver
biopsies on participants both before and after the treatment. The
showed that even when they were not virus-free, 54 percent of patients
treated with Pegasys showed improvement in underlying liver damage,
compared to 31 percent of patients treated with standard interferon.
Hepatitis C is a blood-borne infectious disease of the liver and a
cause of cirrhosis and liver cancer. It is also the primary reason for
liver transplantation in the United States. An estimated 2.7 million
Americans are chronically infected with the virus, with about 35,000 new
infections reported each year.
The virus is transmitted through body fluids, primarily blood or blood
products, and by sharing needles. In many patients, the mode of
transmission is unknown. Unfortunately, most people infected with
hepatitis C are unaware of it because it may take years for symptoms to
According to the Centers for Disease Control and Prevention estimates,
hepatitis C is responsible for up to 10,000 deaths per year in the
States. The CDC projects that annual rate could increase to 38,000 by
year 2010, surpassing the number of deaths attributed annually to
The study was funded by a research grant from F. Hoffmann-La Roche,
of Basel, Switzerland, the manufacturer of Pegasys. An application for
Pegasys was filed with the Food and Drug Administration on May 22.
VCU is a Carnegie Research-Extensive University -- the top category for
U.S. research universities. VCU ranks among the nation's top 100
universities in sponsored research, with nearly $120 million in annual
funding. With more than 23,500 students, VCU is the largest public urban
doctoral-granting university in Virginia. The university offers 156
degree and certificate programs in 11 schools and one college.
SOURCE Virginia Commonwealth University
CO: Virginia Commonwealth University; F. Hoffmann-La Roche, Ltd.; New
England Journal of Medicine
- Hepatology Focus
Update on Hepatitis C Treatment
Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA
Medicine, Los Angeles, California
Sammy Saab, MD, Clinical Instructor, UCLA School of Medicine, Los
Angeles, California, and
Paul Martin, MD, Medical Director, Liver Transplantation, Cedars-Sinai
Associate Professor of Medicine, UCLA School of Medicine, Los Angeles,
[Medscape Gastroenterology 3(1), 2001. © 2001 Medscape, Inc.]
Although screening of blood products and other interventions such as
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
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 hepatitis.
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
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 histologic improvement.
Relapsers are defined as patients who have undetectable serum HCV RNA at
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
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
(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
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
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
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
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
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
Histologic improvement was more common among treatment-naive patients
combination therapy. Similar improvement was found in a randomized
controlled trial of
However, the improved SR rates observed with combination therapy are
also associated with
more expense and an increased frequency of adverse effects compared with
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
Consensus IFN (CIFN; IFN alfacon-1, Amgen, Thousand Oaks, California) is
engineered compound synthesized by combining the most common amino acid
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 48
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,
Pegylation is already used in the delivery of other drugs. Its
attachment to IFN-alfa permits
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
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 virus.*
* Abbreviations: IFN = interferon; CSN = consensus interferon;
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
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 benefit.
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,
strategies are also likely to become a reality in the future, although
therapy will remain
interferon-based the next several years.
Table. Response (HCV RNA/ALT*) to Antiviral Therapy
Type of Response
6 Months After
* 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
abnormal alanine aminotransferase values. Negative denotes no serum
HCV RNA by
polymerase chain reaction and normal alanine aminotransferase
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