Everson and colleagues studied safety, efficacy, and tolerability of a gradually accelerated dosing regimen. This strategy resulted in SVR among 22% (20/91), with 40% (8/20) of those who achieved SVR remaining HCV-RNA-undetectable after liver transplantation. The regimen started with low doses of interferon (1.5 MIU thrice weekly), plus ribavirin (600 mg/day). Doses of each drug were gradually increased every two weeks, as tolerated. Growth factors were used to maintain blood cell counts when needed (Everson 2000). Information on changes in hepatic function, Child-Pugh scoring after treatment (see Chapter IV, Diagnostics), and serious adverse events was not available.

Crippin and colleagues conducted a pilot study of the safety, tolerability and efficacy of interferon with or without ribavirin in individuals with decompensated cirrhosis. Fifteen participants awaiting liver transplantation were randomized to:

• Interferon alfa-2b, 1 MIU/day;
• Interferon alfa-2b, 3 MIU/thrice weekly; or
• Interferon alfa-2b, 1 MIU/day, plus ribavirin 800 mg/day.

At the end of treatment, 33% had undetectable HCV RNA, and 55% had reduced viral loads. During the study, two individuals had liver transplants; both had recurrent hepatitis C. Adverse events were frequent and serious; 20 of the 23 adverse events were serious (severe thrombocytopenia and neutropenia, hepatic encephalopathy, and serious infections). One person died from infectious complications (Crippin 2003). The study was ended because of the frequency of severe adverse events.

Garcia-Retortillo and colleagues treated 30 individuals (13 cirrhotics and 17 with hepatocellular carcinoma) awaiting liver transplantation. Treatment was initiated when the anticipated interval before transplantation was less than five months and continued until transplantation. At the time of transplantation, 9/30 had undetectable HCV-RNA levels and 6/9 remained undetectable after transplantation (median follow-up of 26 weeks; range: 5-60 weeks).

The original regimen was standard interferon alfa-2b (3 MIU daily) plus ribavirin (400 mg every 12 hours). The dose of interferon was reduced in 60% (18/30); the ribavirin dose was reduced in 20% (6/30). Growth factors were given when necessary (G-CSF to 10/30; epoetin-alfa to 8/30). Treatment was discontinued permanently by four individuals and temporarily by two. There were three serious adverse events: two cases of sepsis and one case of hepatitis. Leukopenia was reported in 18/30, thrombocytopenia in 13/30, and anemia in 5/30 (Garcia-Retortillo 2002b).

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A retrospective analysis of data from 637 cirrhotics, treated and untreated, found that treatment with interferon—regardless of the outcome—seems to affect the oncogenic mechanisms of HCV. Interferon alfa is active against a number of cancers, including AIDS-associated Kaposi's sarcoma (KS). The International Interferon-a Hepatocellular Carcinoma Study Group identified predictors of progression from compensated cirrhosis to hepatocellular carcinoma (male sex, older age, and signs of portal hypertension) and time from diagnosis of cirrhosis to development of hepatocellular carcinoma. The study compared outcomes of two matched groups, one of 356 untreated cirrhotics and one of 281 cirrhotics treated with interferon. The median duration of therapy was 7 months (range: 3-30 months). Participants were followed for at least three years. The overall risk of progression to HCC was 1.99 for untreated individuals (95% CI, 1.09-3.6; P=0.027), with 66 untreated individuals and 29 treated individuals developing HCC during an interval of 36-250 months. Among cirrhotics with HCV infection, the relative risk of progression to hepatocellular carcinoma among untreated individuals was 3.14 times that of those treated with interferon (95% CI, 1.46-6.80; P=0.004). In a subgroup of cirrhotics who were HCV-antibody-positive and anti-HBV-negative, the risk of progression to hepatocellular carcinoma for untreated individuals was 6.28 times greater (95% CI, 1.65-23.97; P<0.007) (The International Interferon-a Hepatocellular Carcinoma Study Group 1998).

The effect of interferon on the clinical outcomes of 189 cirrhotics was retrospectively assessed by Benvegnù and colleagues during a mean follow-up of 71.5 ± 23.6 months; 7.9% of those who received treatment (88/189) and 21.8% of untreated individuals (101/189) had progressive liver disease (by Child's staging; see Chapter IV, Diagnostics). Hepatocellular carcinoma developed in 5.6% of treated persons vs. 26% of untreated individuals (P<0.001) (Benvegnù 1998).

Imazeki and colleagues retrospectively analyzed the effect of interferon on survival rates of people with hepatitis C. Of the 459 individuals in this study, 104 were untreated. Among cirrhotics, those who achieved SVR had a reduced rate of mortality during the eight-year follow-up. Hepatocellular carcinoma accounted for 25 deaths overall; only one was a sustained virological responder (Imazeki 2003).

There are particular safety concerns for cirrhotics; many are more vulnerable to side effects and adverse events, especially the hematologic toxicities of pegylated interferons. As a result, dose reductions may be more frequent, and the efficacy of treatment may be diminished. For example, there were dose reductions among 83% (44/53) of those participating in an ongoing study of the viral kinetics of pegylated interferon alfa-2a plus ribavirin in cirrhotics (Gane 2002).

Interim data from an HCV treatment trial in people with advanced liver disease (bridging fibrosis or cirrhosis) suggests that full-dose pegylated interferon and weight-based dosing of ribavirin, especially in non-1 genotypes, may increase the likelihood of sustained virological responses. Participants were randomized to receive 48 weeks of treatment with either full-dose (1.5 µg/kg once weekly) or half-dose (0.75 µg/kg once weekly) pegylated interferon alfa-2b, plus 800 mg/day of ribavirin. Sustained virological response data are available from 165 of 210 participants who have completed follow-up (Abergel 2003). No information on adverse events, dose reductions, or discontinuations was provided.

Table 25. Sustained Virological Response by Regimen and Genotype

A subset of individuals with bridging fibrosis and cirrhosis have participated in large HCV treatment trials. The treatment regimens and study populations differ, so it is difficult to draw conclusions from pooled data.

Table 26. Sustained Virological Response Rate Among Persons With Bridging Fibrosis and Cirrhosis: Subgroup Data From Four Trials

The goals of therapy may be different for those with advanced liver disease. Averting liver transplantation, slowing disease progression, and improvement in liver histology may be relevant outcomes in the absence of achieving SVR, although histological response often correlates with virological response. Without long-term follow-up, it is impossible to know if histological improvement and/or viral eradication translate into increased quality of life and survival. Long-term studies of interferon maintenance therapy for non-responders with advanced liver disease are underway.

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Prognostic factors—genotype, baseline HCV RNA—and ability to tolerate HCV treatment influence the likelihood of successful re-treatment. The type of response to the initial course of treatment may also contribute to the success of re-treatment. Relapsers (who become HCV RNA undetectable but do not remain aviremic after completion of treatment) are more likely to achieve an SVR after re-treatment than non-responders (Shiffman 2002a). There are two patterns of non-response to HCV therapy. A partial response indicates a decrease in HCV RNA of >2.0 log and persistently detectable HCV RNA during treatment; a flat response is characterized by a decrease of <2.0 log in HCV RNA while on treatment, which may be an indication of interferon resistance.

Strategies for effective re-treatment have included higher-dose interferon monotherapy, different types of interferon, a longer duration of therapy and re-treatment with a combination of interferon plus ribavirin or pegylated interferon plus ribavirin. Data from two meta-analyses of re-treatment for non-responders to interferon monotherapy report low overall SVR rates (ranging from 13% to 20%). Individuals were re-treated with inteferon plus ribavirin. Reponse rates depended on duration of re-treatment therapy and individual prognostic factors (Cheng 2001; Cummings 2001).

Pegylated Interferon in Relapsers and Non-Responders
End-of-treatment results are available from a study examining responses to re-treatment with 48 weeks of pegylated interferon alfa-2a plus ribavirin in 64 individuals who relapsed after 24 weeks of treatment with the same regimen. The maximum allowable dose for pegylated interferon was 180 µg once weekly; the maximum dose for ribavirin was 1,000-1,200 mg/day. Some individuals received lower doses of one or both drugs based on their experience with each drug during the previous regimen. End-of-treatment results are available from 59 participants who completed 48 weeks of treatment (Goncales 2002). Since all participants achieved undetectable HCV RNA after their initial course of treatment (with the exception of one person, who was withdrawn from this study) the efficacy of re-treatment with the same regimen for a longer interval can be determined only at week 72.

Table 24. HCV-RNA Levels at Week 48 of Re-treatment

HALT-C: Treatment in Non-Responders with Advanced Liver Disease
The Hepatitis C Antiviral Long-Term Treatment Trial Against Cirrhosis (HALT-C) is assessing tolerability and rate of SVR in individuals with advanced fibrosis or cirrhosis (Ishak score 3 by liver biopsy; see Chapter IV, Diagnostics) who were non-responders to prior therapy with standard interferon, with or without ribavirin. During the lead-in phase of HALT-C, all participants received 24 weeks of pegylated interferon alfa-2a 180 µg once weekly plus ribavirin (1,000-1,200 mg/day, based on weight). Individuals with detectable HCV RNA after 20 weeks of treatment were rolled into HALT-C. Those with undetectable HCV RNA at week 20 were treated for an additional 28 weeks, then followed for 24 more weeks.

So far, SVR data is available from 604/863 who have completed treatment and follow-up. Overall, 18% (109/604) achieved SVR. Prior interferon monotherapy, genotype 2 or 3, a lower AST:ALT ratio and no cirrhosis were associated with achievment of a sustained virological response. SVR was more likely among those who received ≥60% of the ribavirin dose (21% vs. 11%; P=0.05) (Shiffman 2004).

In a sub-group of 212 HALT-C participants who completed therapy by late 2002, the likelihood of SVR was significantly greater in non-African Americans, non-1 genotypes, those with a 2.0 log decrease in HCV RNA at week 12, and persons less than 50 years old (P<0.005 for all). More than half of these the participants had dose reductions of pegylated interferon and/or ribavirin. Week 24 discontinuations for fatigue, depression, or hematologic abnormalities were reported in 5% (Shiffman 2002b).

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Late-Evening Snacks Containing Branched-Chain Amino Acids Benefit
Hepatitis-Caused Cirrhosis
By Maria Bishop

BOSTON, MA -- November 8, 2004 -- Long-term consumption of a late-evening
snack that is rich in branched-chain amino acids (BCAAs) may help improve
cirrhosis caused by hepatitis virus -- including reducing muscle cramps and
stopping progression of the cirrhosis.

These findings were presented on November 1st by Japanese researchers here
at the 55th Annual Meeting of the American Society for Liver Diseases.

Recent studies have shown that protein-energy malnutrition has a great
impact on both quality of life and survival in a cirrhotic patient.
Yoshitaka Fukuzawa, MD, PhD, professor, Division of Gastroenterology, School
of Medicine, Aichi Medical University, Nagoya, led a prospective study on
the effects in outpatients with cirrhosis caused by hepatitis C. The
subjects were 70% male, and the average age was 60 years old.

Subjects with poor nutrition (90%) were identified and grouped using the
Maastricht Index, and were then prescribed a late-evening snack product with
6.1 g BCAAs and 13.7 g of protein (Aminoleban® EN (Otsuka Pharmaceutical
Co., Ltd., Tokyo, Japan). The product was given in divided doses, 1 hour
before bedtime for 3 months. The researchers conducted a statistical
comparison of classic dietetic, immunological and biochemical parameters, as
well as Short Form 36 quality of life questionnaire (SF-36) scales before
and after treatment.

Patients who took the late-evening snacks had a significant increase in each
parameter, which resulted in a significant decrease in Maastricht Index
score (P <.001) 3 months after treatment compared to the pre-treatment
baseline. In addition, arm circumference and arm-muscle circumference
increased significantly (P <.001) in these patients, while the triceps
skin-fold thickness decreased significantly (P <.001). For the
non-poor-nutrition group, changes in the various parameters were not
significant during the treatment period.

Virtually no adverse reactions were noted in the treated group. Muscle
cramps were reported by 20% of patients before treatment and by 10% at the
3-month mark. Three parameters improved significantly (P <.05) in the
quality-of-life assessment based on SF-36 -- role functioning (physical),
vitality, and mental health.

The researchers found the nutritional assessment based on the Maastricht
Index to be convenient and useful for screening patients with poor
nutrition, allowing them to conduct appropriate nutritional assessments at
an early stage of cirrhosis.

Aminoleban® EN is marketed by Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan.


[Study title: "Nutrition Assessment and Management in Outpatients With Liver
Cirrhosis Caused by HCV (LC-C) - Usefulness of a Branched Chain Amino Acid
(BCAA)-Rich Product As Late-Evening Snacks (LES)." Abstract 798]

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