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Recent trends in the treatment of chronic hepatitis C

Pegylated interferon and ribavirin combination therapy is accepted as the standard antiviral treatment for chronic hepatitis C regardless of HCV genotype. This combination therapy achieves higher response rates than previous therapy, but, nevertheless, a large proportion of patients suffer from treatment failure or adverse events. Recent clinical studies of viral kinetics during antiviral treatment have led to the introduction of response-guided therapy, the concept of 'customized therapy depending on viral response', which focuses on modulation of the treatment period depending on the viral response to create a sustained viral response without unnecessary medication and costs. New upcoming direct-acting antivirals (DAAs) maximize response rate, and triple therapy including DAAs along with pegylated interferon and ribavirin combination therapy could soon be the standard therapy. In this article, we reviewed the factors affecting treatment, response guided treatment, retreatment after failure of standard treatment, management of adverse events during treatment, and new treatment options.


INTRODUCTION
Chronic hepatitis C affects an estimated 1-2% of the Korean population and is one of the leading causes of liver cirrhosis and hepatocellular carcinoma in Korea. 1 Over the past decade, pegylated interferon (peginterferon) and ribavirin combination therapy has become the standard antiviral treatment for chronic hepatitis C regardless of hepatitis C virus (HCV) genotype. Although standard peginterferon and ribavirin combination therapy achieves better response rates than previous interferon and ribavirin combination therapy or peginterferon monotherapy, a high proportion of patients still suffer from treatment failure or adverse effects of the therapy.
The recent results of clinical trials show that there has been much progress in the treatment of chronic hepatitis C.
Viral kinetics during antiviral treatment has emerged as an important predictor of treatment response and is used to guide treatment: the more rapidly HCV RNA disappears during treatment, the higher the response rate to treatment is.
This suggested that the viral response to treatment could be used to modify treatment duration. Response-guided therapy, the concept of 'customized therapy depending on viral response', which modifies the treatment period depending on the viral response, is a newly emerging 'proof of concept'. Shorter treatments would not only improve overall tolerability, but also reduce unnecessary medication and expense.
In this article, we reviewed recently updated American Association for the Study of Liver Disease (AASLD) and However, the SVR rates did increase significantly but only to 16% when 72 week extended treatment was performed in the REPEAT trial. 30 Interestingly, treatment success rates were relatively high in both the EPIC-3 and REPEAT trials when EVR was obtained after retreatment.
Two retrospective studies regarding the retreatment of Korean patients have been published as abstracts. The results in summary are as follows. Among patients who had used peginterferon and ribavirin, SVR rate was 0% (n=1) in the non-responders and 70% (n=10) in the relapsed patients.
Among patients who had used non-pegylated interferon and ribavirin, SVR rate was 17.6% (n=17) in non-responders and 81.3% (n=16) in relapsed patients. 31,32 In conclusion, retreatment with peginterferon and ribavirin should be considered in patients who received nonpegylated interferon or peginterferon monotherapy. 2 However, when SVR is not attained despite an adequate period of treatment with peginterferon and ribavirin, careful consideration should precede retreatment with the same drugs. In Europe, retreatment is not recommended for nonresponders to standard therapy that includes peginterferon.
In such cases, triple combination therapy including a protease inhibitor which is expected to be released onto the market soon may be considered.

Management of adverse effects during treatment
Adverse effects associated with combination therapy with interferon and ribavirin are relatively frequent. It has been reported that 10-14% of patients discontinued treatment because of adverse effects. Neutropenia is defined as <1,500 neutrophils/mm 3

(ANC)
and severe neutropenia is defined as ANC <500/mm 3 in  20,33,34 Granulocyte colony stimulating factor (G-CSF) is often used in severe neutropenic patients with fever after anti-cancer therapy, and has been shown to reduce mortality associated with infections. While a number of clinicians have tried using G-CSF in the antiviral therapy of chronic hepatitis C, cases other than hepatic cirrhosis patients requiring G-CSF are rare as severe infections are not common during the therapy even in cases of neutropenia. 35 In the studies that used 150-300 μg of G-CSF weekly, increase in ANC, not in SVR was demonstrated. 36,37 As for platelets, it is recommended to halve the dose of peginterferon if they decline to <50,000/mm 3  respectively, which were significantly higher than the 40% in the standard therapy. The addition of BOC to peginterferonribavirin also resulted in significantly higher SVR rate than that of peginterferon-ribavirin alone in previously treated genotype 1 chronic hepatitis C patients (66% vs. 21%, respectively).
The use of BOC or TVR in combination with peginterferon alfa and ribavirin is accepted as the optimal therapy for genotype 1 in recently updated AASLD guideline.