Objective

The aim of this systematic review and economic evaluation was to assess the clinical-effectiveness and cost-effectiveness of pegylated interferon-α combined with ribavirin in the treatment of chronic hepatitis C. The comparator was the current standard of treatment, non-pegylated interferon-α combined with ribavirin. Because some patients cannot tolerate ribavirin, treatment with pegylated interferon-α alone was also compared with treatment with non-pegylated interferon-α alone. Additional secondary questions were also addressed, including the effectiveness of retreating non-responders to interferon-α monotherapy, the use of non-invasive tests for gauging the severity of disease (e.g. fibrosis), and the effectiveness of antiviral treatment of patients with mild hepatitis C.

Epidemiology and background

Hepatitis C is a slowly progressive disease of the liver that is caused by infection with the hepatitis C virus (HCV). The virus can be transmitted in a number of ways, but the most common sources of infection are through injected drug use and infected blood products. Although some people infected with hepatitis C spontaneously clear the virus, up to 85% of those exposed develop chronic hepatitis. The rate of progression is slow and variable over 20-50 years. About 20-30% of those initially infected develop cirrhosis within 20 years and a small percentage of these are at high risk of hepatocellular carcinoma. Patients with chronic hepatitis C report diminished health-related quality of life, which can be improved by eradication of the virus. The prevalence of chronic hepatitis C in the UK is uncertain, but is estimated to be between 0.1 and 1%. Prevalence varies across different areas according to risk factors such as injecting drug use. Accurate prevalence rates are difficult to estimate because infection can remain asymptomatic for very long periods. There are several genotypes of the virus, the most common in England and Wales being 1a, 1b and 3a. Genotype 1 is harder to treat than genotypes 2 and 3.

Methods

Several electronic databases were searched including Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Medline and Embase. Other sources searched included the reference lists of retrieved reports, and the industry submissions to the National Institute for Clinical Excellence (NICE). These searches revealed six studies that met the inclusion criteria of being randomised controlled trials (RCTs) involving comparisons between pegylated interferon-α plus ribavirin and non-pegylated interferon plus ribavirin (two trials) or pegylated interferon alone and non-pegylated interferon alone (four trials). The primary outcome in all trials was sustained virological response (SVR) at follow-up. The trials were generally of good quality, although reporting of methodological details could have been more thorough in places.

Results

Economic analysis

A cost-effectiveness model originally developed by the Scottish Health Purchasing Information Centre and used in the previous NICE assessment report of treatment for hepatitis C was updated for the calculation of costs and benefits. The model followed a hypothetical cohort of 1000 individuals with chronic hepatitis C over a 30-year period. Options that were considered included: no treatment (except symptomatically), interferon-α plus ribavirin for 48 weeks, pegylated interferon-α plus ribavirin for 48 weeks, interferon monotherapy for 48 weeks, and pegylated interferon-α monotherapy for 48 weeks. SVRs from the key trials were pooled and entered into the model. The results were presented in terms of costs per quality-adjusted life-years (QALYs) gained.

Conclusions

Well-designed RCTs show that patients treated with pegylated interferon, both as dual therapy and as monotherapy, experience higher sustained viral response rates than those treated with non-pegylated interferon. Patients with genotypes 2 and 3 experience the highest response, with rates in excess of 80%. Patients with the harder to treat genotype 1 nevertheless benefit, with up to 46% of patients experiencing an SVR in one of the trials. Pegylated interferon also appears to be relatively cost-effective in both monotherapy and dual therapy, with cost per QALY estimates remaining generally under £30,000. The most favourable estimates were for patients with genotypes 2 and 3.

Recommendations for further research

Pegylated interferon is a relatively new intervention in the treatment of hepatitis C and therefore there are areas where further research is needed. These are listed below:

• There are no trials in which the efficacies of therapy with PEG-α-2a and PEG-α-2b are compared directly.
• There are no full reports of retreatment of previous non-responders using pegylated interferon (either with or without ribavirin).
• There is very little information on the efficacy of treatments for hepatitis C (particularly using PEG) in patients who have other co-morbidities.
• Other treatment regimens that may prove to be overall more effective than dual therapy with PEG should be evaluated.
• More evidence about the long-term outcomes for such patients would be useful. In addition it would be useful to test prospectively which treatment regimens achieve the best improvements in liver histology and which are most cost-effective.
• Prospective tests of rules governing stopping treatment would be useful, particularly with concurrent collection of cost data.
• Further investigation of treating patients with acute hepatitis C may be merited potentially to avoid the long-term morbidity involved for some patients when they reach the stage of chronic infection.
• Problems that may occur in a minority of patients with hepatitis C, such as cryoglobulinaemia and vasculitis, are not likely to be the subject of clinical trials because of the relatively small number of patients affected. However, clinicians point out that in some patients with vasculitis due to viral/antibody complexes the vasculitis can resolve after long-term treatment. Appropriate treatment of such patients needs to be addressed.
• Additional psychological effects on quality of life due to hepatitis C need to be evaluated.
• Further research is needed on the treatment of children and adolescents with hepatitis C. Previous studies of interferon monotherapy in children have been generally small, uncontrolled trials involving highly selected patients. New therapies, including PEG, should be studied in children. The long-term safety of these medications also needs to be studied in children.

Publication

• Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J. Pegylated interferon α-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation. Health Technol Assess 2004;8(39). [PubMed: 15461877]

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