http://www.medscape.com/viewarticle/518702

What's New in Hepatitis C: Current State of the Field and Future
Directions  CME
Disclosures

David Bernstein, MD  

Introduction
Our overall understanding of the hepatitis C epidemic continues to
improve with new insights being gleaned regarding its prevalence,
transmission, and treatment. Data presented at this year's meeting of
the American Association for the Study of Liver Diseases (AASLD)
generated much excitement and hope for a better grasp of the issues
relevant to this common and potentially devastating disease. According
to the National Health and Nutrition Examination Survey (NHANES), it is
estimated that approximately 2.7 million individuals in the United
States are currently infected with the hepatitis C virus (HCV).[1] The
latter is believed to be an underestimate of the true scope of the
disease, as this survey excluded several high-risk populations from its
sampling frame. Dr. Brian Edlin from the Weill Medical College of
Cornell University analyzed data from the US Census, the Centers for
Medicare and Medicare Services, the Bureau of Justice Statistics, and
the published medical literature[2]; on the basis of this analysis, he
estimated that the number of persons currently infected with HCV in the
United States is approximately 3.4 million. This higher estimate only
serves to reinforce the growing importance and need for increased
awareness of hepatitis C.

Treatment With Pegylated Interferon and Ribavirin
Fixed-Dose vs Weight-Based Ribavirin Dosing
The current standard of care for the treatment of previously untreated
patients with chronic hepatitis C is a combination of once-weekly
injection of pegylated interferon plus daily oral ribavirin. The
treatment duration is dependent on HCV genotype, with a 48-week course
of therapy recommended for patients infected with genotype 1 or 4, and a
24-week course of therapy recommended for patients infected with HCV
genotypes 2 or 3.

The WIN-R trial (the largest hepatitis C study conducted in US patients)
compared the use of pegylated interferon alfa-2b 1.5 mcg/kg/week plus
either fixed-dose ribavirin 800 mg/day or weight-based dosing of
ribavirin.[3] Weight-based dosing of ribavirin was administered as
follows: Patients weighing < 65 kg received 800 mg/day; patients 65 to <
85 kg received 1000 mg/day; patients 85 to < 105 kg received 1200
mg/day; and patients 105-125 kg received 1400 mg/day. Treatment duration
was 48 weeks for patients with genotype 1 disease, and the use of growth
factors was allowed. The interesting aspect about this trial is that it
included 225 sites, with many being in local communities and not in
large academic centers where most trials are generally performed. The
study enrolled 4913 patients, making it the largest hepatitis C trial to
date. The overall groups were equally matched for sex and viral load.
The sustained viral response rate for patients with genotype 1 disease
with fixed or weight-based dosing of ribavirin was 29% and 34%,
respectively. The sustained viral response rate of genotype 1 patients
with a high viral load was 32% in the weight-based group and 27% in the
fixed-dose group. The study authors reported that both of these
differences in response rate were statistically significant. Perhaps the
most important result to come out of this study was that patients who
weighed > 85 kg had a dramatically better sustained viral response rate
with weight-based dosing of ribavirin than did those receiving
fixed-dose ribavirin. For patients weighing < 85 kg, there was no
difference between the weight-based dosing scheme and a fixed ribavirin
dose of 800 mg/day. The higher dose of 1400 mg ribavirin was also found
to be safe in patients weighing > 105 kg. Although there were more dose
reductions of ribavirin in the weight-based dosing arm, the rate of
treatment discontinuation was the same for both patient groups.*

Duration of Therapy
Many investigators are now looking at the duration of therapy to
determine whether current recommendations are applicable for all
patients or whether tailored, individualized therapy is a better option
for certain patient groups. During this year's AASLD meeting, Ferenci
and colleagues[4] presented data on HCV-infected patients who were
treated for 24 weeks. In this study, patients with HCV genotype 1 and 4
were treated with pegylated interferon alfa-2a 180 mcg/week plus
ribavirin 1000-1200 mg/day. HCV-RNA levels were measured at week 4 on
therapy. Patients with undetectable HCV-RNA at week 4 were assigned to
complete a total course of 24 weeks of therapy. The overall sustained
viral response rate in this group labeled as "super-responders"
(genotype 1 and 4 patients who were HCV-RNA-undetectable after 4 weeks
of antiviral therapy) was 75%. The sustained viral response rate in the
genotype 4 patients in this group was 100%. Viral kinetics appear to be
very important in predicting response to therapy. We currently evaluate
patients after 12 weeks of therapy to determine virologic response and
use this information to determine whether patients should be continued
on therapy. These current study findings support the notion that early
virologic response at week 4 may help determine duration of therapy.
This concept needs to be further addressed as the implications on
patient quality of life and overall economic costs related to a shorter
duration of therapy are positively influenced by these results.*

Is There a Role for Epoetin Alfa in Reducing the Frequency of Anemia?
Effective treatment of chronic hepatitis C with pegylated interferon
plus ribavirin-based therapy is complicated by the associated side
effects, and this can limit the ability to achieve a sustained viral
response. One of the most common side effects of combination therapy is
the development of anemia, which often requires that the ribavirin dose
be reduced or discontinued early. Many clinicians advocate the use of
growth factors to help improve the anemia to allow patients to complete
the therapeutic course without ribavirin dose reduction. Although this
strategy is widely employed, there have been no data to show that this
strategy leads to an improved sustained viral response rate.

Shiffman and colleagues[5] presented their findings regarding the use of
both high-dose ribavirin and supplemental epoetin alfa in patients
infected with HCV genotype 1. One hundred and fifty patients were
randomized into 3 treatment groups. All groups were treated for 48
weeks. Group 1 received pegylated interferon alfa-2b (1.5 mcg/kg/week)
plus weight-based ribavirin 13.3 mg/kg/day (800-1400 mg/day). Group 2
received pegylated interferon alfa-2b (1.5 mcg/kg/week) plus
weight-based ribavirin 13.3 mg/kg/day (800-1400 mg/day) plus epoetin
alfa 40,000 units per week. Group 3 received pegylated interferon
alfa-2b (1.5 mcg/kg/week) plus weight-based ribavirin 15.2 mg/kg/day
(1000-1600 mg/day) plus epoetin alfa 40,000 units per week. Thirty-four
percent of patients were black and the mean body weight was 82.4 kg. The
sustained viral response rates for groups 1, 2, and 3 were 27%, 24%, and
45%, respectively. The improved sustained viral response rate seen in
group 3 appeared to be secondary to a decreased relapse rate after
stopping therapy. The study authors concluded that a significant
increase in sustained viral response rates can be achieved in hepatitis
C genotype 1 patients if treated with higher doses of ribavirin along
with epoetin alfa to limit ribavirin dose reduction.*

Nonresponders to Interferon and Ribavirin-Based Therapy
The choice of therapy for patients who fail to respond to a previous
course of antiviral therapy with either thrice-weekly interferon or
pegylated interferon plus ribavirin-based treatment is unclear. Given
that the overall nonresponse rate remains at about 50% in all treated
patients, the total number of nonresponder patients is growing.

Gaglio and colleagues[6] looked at the efficacy of re-treatment with
pegylated interferon alfa-2b 1.5 mcg/kg/week and either fixed-dose
ribavirin 800 mg/day or weight-based ribavirin at 800-1400 mg/day for a
period of 48 weeks in patients who either did not respond to standard
thrice-weekly interferon monotherapy, did not respond to standard
thrice-weekly interferon plus ribavirin, or who relapsed following
previous therapy.* They found an overall sustained response rate of
about 20% for re-treatment. The response rate was not improved with
higher-dose ribavirin. However, response rates were higher in patients
with genotype non-1 disease, in patients who had never been previously
treated with ribavirin (ie, who had received interferon monotherapy),
and in relapsers.

Other investigators have evaluated the use of both higher-dose pegylated
interferon and weight-based ribavirin in patients who were previously
treated with interferon plus ribavirin-based therapy but failed to clear
virus from the blood. The RENEW trial[7] randomized patients who had
failed previous interferon and ribavirin-based therapy to 48 weeks of
therapy with pegylated interferon alfa-2b at either 0.5, 1.5, or 3.0
mcg/kg/week plus daily weight-based ribavirin at a dose of 800-1400
mg/day.* Use of growth factors to prevent ribavirin dose reduction was
not allowed. More than 800 patients were initiated on therapy in this
study. Primary endpoint was absence of HCV RNA 24 weeks after treatment.
The sustained viral response in the pegylated interferon alfa-2b 3.0
mcg/kg/week arm was 17%, whereas the sustained viral response in the
pegylated interferon alfa-2b 1.5 mcg/kg/week arm was 12%. Further
analyses showed that patients with bridging fibrosis or cirrhosis, as
well as black patients, were less likely to have a sustained viral
response. Sustained viral response was not related to baseline body
weight. Due to the lack of use of growth factors in this study, rates of
dose reduction were quite high, with 45% of patients requiring
reduced-dose ribavirin in the high-dose pegylated interferon group. This
is an intriguing study and raises the question of whether response rates
would have been higher if growth factors were used to prevent dose
reduction. On the basis of these findings, it seems that a similar study
with the allowance of growth factors to prevent ribavirin dose reduction
is warranted, as demonstrated by Shiffman and colleagues.[5]

Impact of Treatment of Cirrhotic Patients on the Development of
Hepatocellular Carcinoma
The goal of treatment for hepatitis C is viral eradication. In patients
without underlying cirrhosis, we assume that viral eradication will
prevent the progression of hepatitis C-related liver disease and
therefore prevent the development of hepatocellular carcinoma. Thus, the
impact of sustained virologic response on the development of
hepatocellular carcinoma in patients with cirrhosis warrants study.

Bruno and colleagues[8] reviewed the databases of 23 Italian hospitals
and identified a total of 1214 patients with hepatitis C and cirrhosis
who were treated with interferon monotherapy. Sixteen percent (n = 199)
of patients had a sustained viral response (based on HCV RNA
undetectability 24 weeks after stopping interferon) to antiviral
therapy. During the follow-up period of approximately 9 years, 183
patients developed hepatocellular carcinoma. Of these 183 patients, only
12 had demonstrated a sustained viral response to interferon. Overall,
the patients who had a sustained viral response were found to have a
significant increase in life expectancy when compared with
nonresponders.

These findings indicate that achievement of a sustained viral response
in patients with underlying cirrhosis is associated with a decreased
likelihood of developing hepatocellular carcinoma (but the risk is not
eliminated). Therefore, continued screening for hepatocellular carcinoma
in this population is warranted.

New Treatments for Hepatitis C
Due to potential limitations associated with current pegylated
interferon plus ribavirin-based therapy for chronic hepatitis C, the
development of novel oral medications has offered great excitement in
the field. During this year's AASLD meeting, preliminary results with
new, small molecules were discussed. It is important to keep in mind
that the information discussed below regarding these new antiviral
agents represents only the early stages in their evaluation. These novel
molecules will not become commercially available for several years, if
at all, as future large-scale trials must still be performed.

Results of 2 small studies evaluating the use of an oral hepatitis C
protease inhibitor, SCH 503034,* in the treatment of nonresponders to
pegylated interferon were presented during this meeting. In the first of
these studies, Zeuzem and colleagues[9] reported on the utility of SCH
503034 in patients infected with HCV genotype 1 who had failed to
respond to previous pegylated interferon-based therapy. Patients were
treated with either SCH 503034 100 mg twice daily, SCH 503034 200 mg
twice daily, SCH 503034 400 mg twice daily, or SCH 503034 400 mg thrice
daily for a total treatment course of 14 days. SCH 503034 was found to
decrease HCV-RNA viral load and this decrease in viral load was
dose-dependent. This novel protease inhibitor was well tolerated. In the
second study, Zeuzem and colleagues[10] examined the efficacy of SCH
503034 used in combination with pegylated interferon alfa-2b for the
treatment of patients who did not respond to previous treatment with
either pegylated interferon alone or in combination with ribavirin.*
Four of 10 patients treated with the combination regimen became HCV
RNA-negative during therapy. The side-effect profile for combination
treatment was comparable to that of pegylated interferon alone, with
more headaches reported in the group receiving SCH 503034. The results
of these 2 small trials are promising in that SCH 503034 has
demonstrated potent antiviral activity in HCV genotype 1 pegylated
interferon nonresponders. However, larger studies must be performed to
evaluate sustained viral response rates with this novel protease
inhibitor, and the authors report that these studies are currently being
planned.

In another study, O'Brien and colleagues[11] presented data on the use
of the HCV-RNA polymerase inhibitor valopicitabine (NM283)* in hepatitis
C patients with genotype 1 disease who were nonresponders to previous
pegylated interferon plus ribavirin-based therapy. This trial was
conducted as a randomized, open-label, phase 2b study comparing 5
different treatment regimens:

Valopicitabine monotherapy;

Valopicitabine 400 mg/day plus pegylated interferon alfa-2a 180 mcg
weekly;

Valopicitabine 800 mg/day plus pegylated interferon alfa-2a 180 mcg
weekly;

Valopicitabine 400 mg/day increased to 800 mg/day, plus pegylated
interferon alfa-2a 180 mcg weekly; or

Combination pegylated interferon alfa-2a plus ribavirin 1000-1200
mg/day.
Twelve-week on-therapy data were reported. Pegylated interferon plus
valopicitabine at a dose of either 800 mg/day or 400 mg/day increased to
800 mg/day showed a significant reduction in HCV-RNA levels when
compared with re-treatment with pegylated interferon plus ribavirin.
Although these data are encouraging, final assessments cannot be made
until the trial is complete and sustained viral response data are made
available.

Reesink and colleagues[12] presented results from a phase 1b trial
involving the NS3-4A protease inhibitor VX-950.* The study authors
assessed the safety and tolerability of this new agent in the treatment
of both healthy controls and patients with hepatitis C genotype 1
disease for a total of 14 days. .Mean serum alanine aminotransferase
levels normalized in all hepatitis C patients receiving VX-950. All
patients treated with VX-950 had at least a 2-log drop in HCV-RNA level,
with 26 of 28 demonstrating at least a 3-log decline in viral load.
VX-950 was well tolerated by both healthy controls and patients with
hepatitis C. The most common side effects associated with VX-950 were
headache and diarrhea. This very preliminary study offers the hope of
potential efficacy of this new agent in the treatment of hepatitis C.
However, additional investigations are warranted before any assessments
can be made regarding the efficacy of VX-950, as the aim of this phase
1b study was evaluation of safety and tolerability.

Concluding Remarks
It is hoped that the above discussion demonstrates the prominent focus
on chronic hepatitis C infection and its potential treatments provided
during this year's AASLD meeting. On the basis of data presented during
these meeting proceedings, we learned that the prevalence of hepatitis C
in the United States is higher than previously estimated, and that the
current therapies, although effective, can perhaps be made even more
effective. Additionally, findings showed that tailored, individualized
therapy may be the most appropriate strategy for assessing patients with
chronic hepatitis C infection, and weight-based dosing of ribavirin
increases sustained viral response rates in patients weighing > 85 kg.
Much excitement revolved around the new therapies in development for
hepatitis C. Data were presented for several novel and promising
antiviral agents. It must be stressed, however, that these data are only
preliminary, and that there have thus far been no phase 3 studies
performed with any of these agents. Although we remain optimistic about
the potential of these new treatment options, clinicians must view these
data with caution until larger, well-designed, randomized controlled
trials are completed and more information is made available. It may take
several years before these additional data are available. Until that
time, the standard of care for the treatment of hepatitis C remains the
combination of once-weekly injections of pegylated interferon plus daily
oral ribavirin.

*This section mentions off-label uses for some medications. These may
describe clinical uses for medications that have not been approved by
the FDA.

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