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

[Guest guest]

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

Directions

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.