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Gut. 2006 September; 55(9): 1362–1363.
PMCID: PMC1860018

Disappointing results of combination therapy for HCV?

Hepatitis C virus (HCV) infection is a common cause of liver disease in the UK. HCV can cause liver failure and liver cancer, and is a frequent indication for liver transplantation. HCV infection can be cured by antiviral therapy. Standard therapy includes the combination of pegylated interferon and ribavirin (PEG‐IFN/RIBA) for 24 or 48 weeks, according to HCV genotype.1,2,3 A sustained virological response (SVR), defined as undetectable serum HCV RNA six months after cessation of therapy, indicates successful treatment, almost certainly cure. Published registration trials reported encouraging SVR rates of 42–52% for genotype 1 and 77–88% for genotypes 2/3.1,2,3

However, analysis of the combined experience of six European and US centres reported significantly worse results.4 In that report, the response rate to treatment of genotype 1 infection with pegylated IFN alpha 2a and ribavirin was only 36%. Also, a large US based prospective randomised study reported response rates of 29–34%, depending on the dose of ribavirin used.5 In contrast, a Canadian study that prospectively tracked patients receiving HCV treatment reported SVR rates of 47.1% for patients with genotype 1 infection.6 Pretreatment counselling requires discussion with the patient of the likely response to treatment. Most physicians probably quote to their patients the success rates from the registration studies. It is important to be able to discuss the chance of cure as it stands before embarking on treatment, and also the chance of cure if the patient is able to tolerate and complete the proposed course of treatment.

We undertook a casenote and database review of consecutive patients at our centre treated with PEG‐IFN/RIBA therapy between 2000 and 2005. We report an intention to treat (ITT) analysis of the results of treatment for this cohort. We also examined baseline clinical and laboratory characteristics of our treated cohort to identify those patients who would have been eligible for treatment according to the inclusion and exclusion criteria for one of those studies.1 In practice, these criteria identify patients with more advanced liver disease, a difficult to treat (DTT) population. The results of treatment for the proportion of our cohort that would have been suitable for treatment in that registration study were examined. Finally, we examined the incidence and reasons for treatment intolerance or non‐compliance.

A total of 243 patients were treated and had six months of follow up; 70% of patients were male and median age was 44 years (range 17–68). The genotype distribution was genotype 1–38%, genotype 2–10%, and genotype 3–49%. Ten patients were genotype 4, 5, or 6, or of mixed genotypes. Of 190/243 patients for whom fibrosis stage was known before treatment, 64 (26%) had established cirrhosis.

In our study 186/243 (77%) patients completed the proposed treatment duration. Outcome is known for 183 patients (table 11).). On ITT analysis, SVR rates of 28% were observed for genotype 1, 78% for genotype 2, 59% for genotype 3, and 90% for other genotypes. For patients who completed the proposed duration of treatment, response rates were 36% for genotype 1, 88% for genotype 2, 72% for genotype 3, and 88% for other genotypes. Of particular interest were the 57 (23%) patients who were unable to complete the duration of treatment that was proposed at baseline. This is a higher rate of attrition than in published clinical trials (for example, 14% in Manns and colleagues1). The most frequent reasons for withdrawal were depression or an inability to tolerate side effects. Treatment cessation for neutropenia, anaemia, or thrombocytopenia was infrequent, although many patients required dose reduction during treatment. Inclusion/exclusion criteria adopted by Manns and colleagues1 identified 88/243 (36%) patients as DTT. When DTT patients were excluded from the analysis, the SVR achieved was superior to the ITT SVR results—33% for genotype 1, 85% for genotype 2, and 68% for genotype 3.

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Table 1 Outcome of patients in the study

On ITT analysis, the results of HCV treatment at our centre appear significantly worse than those in the published literature. This appears to be true for patients with genotype 1 infection in particular. In part, we believe that inferior results reflect inclusion in our cohort of patients with more DTT disease. These patients have more advanced liver disease, with more imminent serious clinical events, and a more urgent need for viral eradication. Despite predictably inferior response rates, they are worthy recipients of antiviral treatment. However, they are more often intolerant of treatment, need more frequent dose adjustment, and are less likely to complete the course of treatment. Analysis of SVR after exclusion of patients with DTT infection showed improved response rates for all genotypes.

A relatively high proportion of our cohort failed to complete the planned course of treatment. Patients with genotype 2/3 infection were more likely to complete the planned duration of therapy than patients with genotype 1. This probably reflects greater difficulty in tolerating the demands of 12 months of treatment for genotype 1 infection compared with six months for genotypes 2/3. Psychological intolerance, mainly depression, appeared quite frequent. A more intensive pretreatment evaluation of psychological status may help to identify individuals whose ability to cope with treatment would be enhanced by antidepressant therapy and/or psychological support. Finally, it is essential that treatment centres know their own results which should be shared with patients at the time of pretreatment counselling.

Conflict of interest declared (the declaration can be viewed on the Gut web site at


Conflict of interest: None declared.

Conflict of interest declared (the declaration can be viewed on the Gut web site at


1. Manns M P, McHutchinson J G, Gordon S C. et al Peginterferon alfa‐2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001. 358958–965.965 [PubMed]
2. Fried M W, Shiffman M L, Reddy K R. et al Peginterferon alfa‐2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002. 347975–982.982 [PubMed]
3. Hadziyannis S J, Sette H, Jr, Morgan T R. et al Peginterferon‐alfa2a and ribavirin combination therapy in chronic hepatitis C: a randomised study of treatment duration and ribavirin dose. Ann Intern Med 2004. 5346–355.355 [PubMed]
4. Almasio P L, Cavalletto L, Chemello L. et al Efficacy of PEG‐IFN alfa‐2b vs. PEG‐IFN alfa‐2a+ribavirin regimens in treatment‐naïve chronic HCV patients: a cumulative meta‐analysis of retrospective data from 6 clinical sites. Hepatology 2005. 42(suppl 1)671A
5. Jacobson I M, Brown R S, Freilich B. et al Weight‐based ribavirin dosing (WBD) increases sustained virological response (SVR) in patients with chronic hepatitis C (CHC): final results of the WIN‐R study, a US community based trial. Hepatology 2005. 42(suppl 1)749A
6. Abadir N, Marotta P, Feinman S V. et al Pegetron prospective optimal weight‐based dosing response program (POWER): preliminary results. Hepatology 2005. 42(suppl 1)693A

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