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Chronic hepatitis C is a major global health challenge with an estimated 3% of the world population exposed to the hepatitis C virus (HCV).1 The current standard treatment is pegylated interferon (peginterferon) and ribavirin which leads to a sustained virological response (SVR) in 40–50% of genotype 1 patients and approximately 70–80% of genotype 2 and 3 patients. Two formulations of peginterferon (α2a and α2b) are available and both have been evaluated in large clinical trials involving hundreds of patients. However, there is still debate as to the optimal dosing regimen which would ideally minimise side effects and maximise sustained virological response rates and use of the health dollar.

One aspect of the debate on optimising therapy is weight-based dosing of peginterferon α2b (peginterferon α2a is flat dosed). An initial dose ranging study2 with peginterferon α2b monotherapy for 48 weeks reported that patients treated with doses of 1.0 µg/kg and 1.5 µg/kg achieved similar SVR rates (25% and 23%, respectively). Approximately 70% of patients in this study were infected with HCV genotype 1. Due to a higher end of treatment response in the 1.5 µg/kg group, this dose was chosen for subsequent studies of combination treatment with ribavirin.3,4 Subgroup analysis highlighted that genotype 2- and 3-infected patients with less than 2 million copies/ml of virus achieved high SVR rates with both 1.5 µg/kg (68%) and 1.0 µg/kg (62%) peginterferon doses.

In the era of combination therapy, Meyer et al.5 directly compared peginterferon α2b 1.0 µg/kg to 1.5 µg /kg with flat dosing of ribavirin (800 mg daily) for 24 weeks in 227 patients. Again, there was a predominance of genotype 1-infected patients. There was no difference in SVR between the two doses for either genotype 1 patients (38% vs 39%) or genotype 2/3-infected patients (71% vs 81%). More recently, the IDEAL study was conducted as a post-approval commitment to the US Food and Drug Administration to compare the two peginterferon α2b doses. Over 3000 HCV genotype 1 patients were randomised. The recently reported findings showed that the 1.0 and 1.5 µg/kg doses with weight-based ribavirin achieved similar SVR rates (38% and 39.8%, respectively).6

Thus the study of Kawaoka et al.7 reported in this edition of the Journal is of particular interest. This randomised clinical trial compared 24 weeks of peginterferon α2b 1.0 µg/kg to 1.5 µg/kg dose plus weight-based ribavirin in treatment-naïve Japanese patients with HCV genotype 2 infection. The investigators found that, while end-of-treatment response (ETR) rates were similar (89% vs 93%), treatment with peginterferon 1.0 ug/kg was associated with a significantly lower SVR rate than that seen with 1.5 µg/kg (39% vs 74%, respectively). This is the first study to show a difference in SVR achieved with 1.0 ug/kg versus 1.5 µg/kg of peginterferon α2b in genotype 2 patients. In fact the SVR achieved in the patients receiving the lower peginterferon α2b dose is much lower than that seen in other studies, and much lower than would be expected in a genotype 2 HCV-infected population. The authors suggest reasons for this finding, including race, older patient age and the dose of ribavirin.

Could the lower SVR rates in the peginterferon 1.0 µg group be explained entirely by inadequate interferon exposure compared to the 1.5 µg group? As noted above, most studies have identified equivalent SVR rates between the two peginterferon doses. In an Italian study addressing shortened treatment duration in 283 HCV patients (213 with genotype 2) receiving peginterferon 1.0 µg, the overall SVR rate was 80% and relapse rates were under 10%. Achieving a SVR is highly associated with undetectable HCV RNA at treatment week 4 (a rapid virological response or RVR). As a predictor of SVR, RVR appears to be independent of genotype, type of interferon and ribavirin exposure.8,9 In the Kawaoka study, fewer patients in the lower dose peginterferon group achieved a RVR (58% with 1.0 µg/kg; 78% with 1.5 µg/kg), but the difference was not statistically significant. As a result, somewhat paradoxically, achieving an RVR did not translate into a sustained virological response for the lower dose group. The authors suggest that the duration of HCV RNA non-detectability in this context is a more important factor than peginterferon dose.

The failure to achieve a SVR in the Kawaoka study was closely linked to a greater relapse rate in the low dose peginterferon group (50%) compared to the high dose peginterferon group (19%) following equivalent end-of-treatment responses. There is emerging evidence that ribavirin is important in preventing relapse following an ETR.10 A post hoc analysis from the landmark registration trial by Manns et al.4 showed that patients who received greater than 10.6 mg/kg of ribavirin in combination with peginterferon had higher SVR rates than patients receiving lower ribavirin doses. Two recent studies have re-examined optimal ribavirin dosing. A community-based study of over 5000 patients addressed the impact of flat ribavirin dosing (800 mg/day) versus weight-based dosing (800–1400 mg/day) on SVR.11 Across all genotypes, SVR was achieved by significantly more patients on weight-based dosing than fixed ribavirin dosing, although no difference was found between the two ribavirin dosing regimens for genotype 2/3-infected patients. A smaller study of 100 HCV genotype 2 and 3 patients receiving a relatively lower dose of peginterferon α2a (135 µg/week) plus weight-based ribavirin resulted in an overall SVR rate of 85%12 for genotype 2 patients. While weight-based ribavirin dosing was utilised in the Kawaoka study, the actual ribavirin dose was lower than that which is often used in Western clinical practice (600 mg/day for ≤ 60 kg, 800 mg/day for > 60 kg to ≤ 80 kg and 1000 mg/day for > 80 kg). It is noteworthy that a greater proportion of patients receiving peginterferon 1.0 µg underwent ribavirin dose reduction compared to the high dose group (58% vs 37%, respectively). While the difference in ribavirin dose reduction between the groups was not statistically significant, it would be important to determine the difference in average ribavirin dose during treatment since less ribavirin exposure, especially early in treatment, may contribute to higher relapse rates and thus lower sustained responses.

Host factors such as hepatic fibrosis, steatosis, obesity, insulin resistance, age and race also affect treatment outcomes. In the current study steatosis and insulin resistance were not examined and liver fibrosis was not advanced in the majority of patients. While many studies have found that younger patients are more likely to respond than older patients,13,14 a more intriguing question is whether Asian race was a factor in the different SVR rates seen by Kawaoka, et al. The impact of race on HCV treatment outcome is well recognized but inadequately understood. The most comprehensive data exist in relation to the lower SVR rates seen in African American patients compared to Caucasians. Aside from the higher prevalence of genotype 1 in the African American population compared to Caucasians,15 there also appear to be differences in viral kinetics in response to interferon-based regimens. Compared with Caucasians, African American patients show impairment of both first and second phase decline in viral load in response to interferon-based therapy; the reasons underlying this observation remain uncertain.16 Data on the impact of Asian race on SVR are mixed and mechanisms poorly understood. Retrospective analysis of a large multicentre study of combination therapy with peginterferon α2a17 showed that Asian race was an independent predictor of SVR as was viral genotype, body mass index, degree of fibrosis and compliance with ribavirin treatment. Yu et al.12 found that the combination of weight-based ribavirin and peginterferon α2a resulted in SVR rates over 90% in Taiwanese patients with genotype 2 HCV. In contrast, a retrospective study of genotype 3-infected patients treated with combination therapy showed a trend toward lower rates of SVR in Asian patients compared with Caucasians (42% and 62%, respectively; P = 0.063) primarily due to a higher post-treatment relapse rate.18 In that study, Asians had a significantly higher histological fibrosis stage prior to treatment, and this could explain the difference in SVR rates between the two groups.

We previously studied a group of Asian and Caucasian patients with a novel genotype mix that included HCV genotype 6 and its subtypes (previously denoted as genotypes 7, 8 and 9). Both genotype and Asian race were independent predictors of SVR, with Asian patients significantly more likely than Caucasians to clear HCV infection.19 Another study also suggested that race was an independent predictor of SVR as the investigators found that Chinese patients were more likely to respond to beta interferon than Caucasians in a group of interferon non-responders.20 It seems logical to propose that racial differences in HCV treatment outcome may arise from divergence in host genomic responses to peginterferon and ribavirin (pharmacokinetics or immunogenetics), or even to regional variability in viral populations. However these interesting hypotheses remain to be tested and explored.

Given the high level of interest in individualising antiviral treatment duration, especially developing truncated regimens for patients with genotypes 2 and 3, and longer duration treatment courses for genotype 1 and 2/3 cases associated with slow initial response, the Kawaoka study reminds us to bear in mind specific population characteristics. In our region, race, age, severity of liver disease and metabolic risk factors may be particularly important when investigating low-dose interferon and ribavirin regimens. The results from this new Japanese study and the above considerations challenge our ability to generalise findings from selected groups of patients in the initial registration studies, mostly performed in Europe and North America, to the larger community of HCV-infected individuals in the Asia-Pacific region.

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