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

January 25, 2006

Medscape coverage of: 56th Annual Meeting of the American Association for

the Study of Liver Diseases | Viral Hepatitis

CME

Disclosures

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. 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.

References <cut>

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

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January 25, 2006