Treatment for Decompensated Cirrhotics
Individuals with decompensated cirrhosis need treatment urgently, as their five-year survival is 50% (Fattovich 1997). The safety of interferon and ribavirin in decompensated cirrhotics is a significant concern. Individuals with decompensated cirrhosis are at greater risk of life-threatening complications during therapy, such as deteriorating liver function, bone marrow suppression, and infections. Because of these concerns, individuals with decompensated cirrhosis have been excluded from pivotal clinical trials. Data on treatment of decompensated cirrhotics are very limited; there have been no randomized, controlled treatment trials in this population.

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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Treatment for Compensated Cirrhotics
Cirrhotics may remain stable for several years. During this window, initiation of HCV treatment may delay progression to hepatic decompensation or hepatocellular carcinoma. In a retrospective follow-up of 384 compensated cirrhotics with hepatitis C, the five-year survival probability was 91%, decreasing to 79% at ten years, suggesting that this interval presents a valuable opportunity for HCV treatment (Fattovich 1997).

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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