Summary and Introduction
Summary
Background: The benefits of prolonging peginterferon and ribavirin after 48 weeks of treatment to maximize sustained virological responses (SVR) in hepatitis C virus (HCV) genotype 1-infected patients remain to be understood.
Aim: To investigate whether extended treatment longer than 72 weeks may be superior to 72-week treatment.
Methods: A total of 120 treatment-naïve or retreated patients with HCV genotype 1 were treated with peginterferon-alpha-2b (1.5 μg/kg/week) plus weight-based ribavirin. We had 34 late responders, in whom HCV RNA first became undetectable at week 12-48, and randomized them into three groups receiving standard-dose peginterferon-alpha-2b plus low-dose ribavirin (200 mg/day) for extended 24 weeks (group A), receiving low-dose peginterferon-alpha-2b (0.75 μg/kg/week) plus low-dose ribavirin for extended 48 weeks (group B) or no extended treatment (group C), and evaluated the outcome according to their virological response.
Results: Multivariate analysis showed that the treatment for 96 weeks was identified as a significant, independent factor associated with SVR in HCV genotype 1-infected late responders in comparison with group A [odds ratio (OR), 10.002; P = 0.080] and group C (OR, 17.748; P = 0.025).
Conclusion: Extending the treatment duration from 48 weeks to 96 weeks improves SVR rates in genotype 1-infected patients with late virological response to peginterferon-alpha-2b and ribavirin.
Introduction
The hepatitis C virus (HCV) is a common cause of cirrhosis and hepatocellular carcinoma. For the management of HCV genotype 1 infection, 48 weeks of therapy with pegylated interferon plus ribavirin is recommended. Although the introduction of pegylated interferon in combination with ribavirin in recent years greatly improved the treatment outcome of HCV infection, the treatment outcome of HCV type 1-infected patients remains unsatisfactory and sustained virological responses (SVR) can be obtained in only approximately 45%.
Hepatitis C virus kinetics during the early phase of treatment is recognized as a predictor of the final therapeutic outcome. Assessment of early virological response (EVR) correlates closely with the likelihood of the ultimate eradication of HCV in patients treated with ribavirin in combination with interferon or pegylated interferon. After 48 weeks of treatment, the likelihood of SVR was approximately 90% in patients who achieved undetectable serum HCV RNA at week 4 of treatment in subjects infected with HCV genotype 1, whereas patients with less than 2-log decrease in HCV RNA levels by week 12 of treatment had virtually no chance of developing SVR. On the basis of these findings, discontinuation of treatment in nonresponders at this time was recommended to avoid unnecessary therapy. However, high relapse rates in slow responders may indicate that treatment was not administered for a sufficient duration in patients with slow virological response.
An analysis based on a mathematic model from a phase III randomized trial of peginterferon-alpha-2a and ribavirin, Drusano and Preston suggested that the rate of SVR in patients infected with HCV genotype 1 directly correlates with the duration of treatment once HCV RNA has been cleared from serum. As the average time to clear serum HCV RNA was over 30 weeks, the authors concluded that 48-week duration of therapy was inadequate for most patients with genotype 1. Indiscriminate extension of treatment in patients with HCV genotype 1 is not beneficial. It has been currently reported that there is a subgroup of genotype 1-infected patients, the so-called 'slow responders', who benefit from extending the treatment duration from 48 weeks to 72 weeks that significantly improves SVR rates. Therefore, prolonged treatment has the potential to improve cure rates, although it will increase the cost of treatment and may increase the probability that a patient will experience adverse events. However, prolonged duration and optimal doses of pegylated interferon or ribavirin after 48 weeks of treatment to maximize SVR still remain to be understood. We aimed to investigate whether extended treatment longer than 72 weeks using the dose reduction of pegylated interferon after 48 weeks of treatment may be superior to the 72-week treatment using the standard dose of pegylated interferon. To tolerate such a long treatment, we tapered doses of pegylated interferon and/or ribavirin substantially after 48 weeks of treatment.
In hepatitis C genotype 1 patients, a slow virological responder was commonly defined as a patient with at least a 2-log decrement in baseline serum HCV RNA, albeit detectable viraemia at 12 weeks and undetectable serum HCV RNA at 24 weeks. However, Mangia et al. reported that SVR rates of HCV genotype 1 patients who first achieved undetectable HCV RNA at week 12 were 38.1% and 63.4% in 48 weeks and 72 weeks treatment respectively. In a multicentre study in Japan, SVR rate of HCV genotype 1b patients in whom HCV RNA became negative for the first time at week 12 was 41.2% in 48 weeks treatment, although SVR rate of patients in whom HCV RNA became negative within 8 weeks was over 80% (personal communication to Dr Kuboki). These studies indicate that extended treatment duration is recommended in patients with undetectable HCV RNA at week 12 to improve cure rates.
Following these concepts, we randomized HCV genotype 1-infected late responders, in whom HCV RNA was positive at 8 weeks of treatment and negative for the first time during 12-48 weeks of treatment, into groups receiving standard-dose peginterferon-alpha-2b (1.5 μg/kg/week) plus low-dose ribavirin (200 mg/day) for additional 24 weeks (total 72 weeks) or receiving low-dose peginterferon-alpha-2b (0.75 μg/kg/week) plus low-dose ribavirin (200 mg/day) for additional 48 weeks (total 96 weeks) and evaluated the outcome according to their virological response.