Pegylated interferon alpha-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation

J Shepherd, H Brodin, C Cave, N Waugh, A Price, J Gabbay
Health Technology Assessment: HTA 2004, 8 (39): iii-iv, 1-125

OBJECTIVES: To assess the clinical-effectiveness and cost-effectiveness of pegylated interferon-alpha combined with ribavirin in the treatment of chronic hepatitis C.

DATA SOURCES: Electronic databases, reference lists of retrieved reports, and the industry submissions to the National Institute for Clinical Excellence.

REVIEW METHODS: Sources were rigorously searched and studies were selected that met the inclusion criteria of being randomised controlled trials (RCTs) involving comparisons between pegylated interferon-alpha 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. A cost-effectiveness model followed a hypothetical cohort of 1000 individuals with chronic hepatitis C over a 30-year period.

RESULTS: In the two trials that tested pegylated interferon plus ribavirin against non-pegylated interferon plus ribavirin the combined percentage of sustained virological response was 55%. The relative risk (RR) for remaining infected was reduced by 17% for pegylated interferon plus ribavirin compared with non-pegylated interferon plus ribavirin. Response to therapy varied according to viral genotype. Patients with genotype 1 had the lowest levels of sustained virological response and patients with genotype 2 or 3 had the highest. In the four trials that evaluated pegylated interferon monotherapy against non-pegylated interferon the combined sustained virological response rates were 31% for pegylated interferon and 14% for non-pegylated interferon. The RR for remaining infected with hepatitis C was reduced by 20% with the use of pegylated interferon. Patients with genotype 1 had the lowest levels of sustained virological response. There were also variations in sustained virological response according to other prognostic variables such as baseline viral load. Regimens involving pegylated interferon appear to be fairly well tolerated. Adverse events were been reported, but they did not differ substantially from levels of adverse events in regimens involving non-pegylated interferon. The incremental discounted cost per QALY for comparing no active treatment to 48 weeks of dual therapy with pegylated interferon and ribavirin (PEG + RBV) was 6045 pounds sterling. When moving from 48 weeks of dual therapy with non-pegylated interferon and ribavirin (IFN + RBV) to 48 weeks of dual therapy with PEG + RBV the figure was 12,123 pounds sterling. Subgroup analyses for dual PEG + RBV therapy demonstrated that the most favourable incremental discounted cost per QALY estimates were for patients infected with genotypes 2 and 3, and with low baseline viral load (3921 pounds sterling) compared with no active treatment. Results of one-way sensitivity analyses showed that the estimates varied according to differences in SVRs, drug costs and discount rates. In general estimates remained under 30,000 pounds sterling per QALY. The incremental discounted cost per QALY when moving from no active treatment to 48 weeks of monotherapy with pegylated interferon was 6484 pounds sterling. When moving from 48 weeks of monotherapy with IFN to 48 weeks of monotherapy with PEG the figure was 8404 pounds sterling. As with dual therapy, the lowest incremental cost per QALY was for patients with genotypes 2 and 3 and low baseline viral load, in the range 2641-4194 pounds sterling. The highest estimates were for patients with genotype 1 and high baseline viral load, around 30,000 pounds sterling.

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 pounds sterling. The most favourable estimates were for patients with genotypes 2 and 3. Pegylated interferon is a relatively new intervention in the treatment of hepatitis C and therefore there are areas where further research is needed. These include: efficacies of therapy with PEG-alpha-2a vs PEG-alpha-2b; retreatment of previous non-responders using pegylated interferon; efficacy of treatments and long-term outcomes in patients who have other co-morbidities; prospective tests of rules governing stopping treatment; treating patients with acute hepatitis C; problems that may occur in a minority of patients with hepatitis C, such as cryoglobulinaemia and vasculitis; additional psychological effects on quality of life due to hepatitis C and also on the treatment of children and adolescents with hepatitis C.

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