Reply: Hepatitis C virus genotype 2/3 patients who can receive an abbreviated course of peginterferon/ribavirin: The important role of initial ribavirin doses
Authors: Moises Diago
Journal: Hepatology (2010)

We appreciate the interest in our article1 expressed by Dai and colleagues.2 Dai et al.2 present the hypothesis that the use of a fixed dose of ribavirin in genotype 2 or 3 patients is suboptimal and that weight-based dosing should be preferred. Unfortunately, the studies that they cite in support of their hypothesis were primarily designed to examine the duration of treatment rather than the dose of ribavirin and thus do not necessarily support their argument. Retrospective calculation of ribavirin dosages on a milligram per kilogram basis can be problematic. In fact, analyses based on such calculations may actually be confounded by the patient's weight. Increased weight is a well-established negative predictor of sustained virological response in patients with chronic hepatitis C treated with peginterferon plus ribavirin.3 The reason for the negative impact of body weight on sustained virological response is complex and may involve insulin resistance or hepatic steatosis.3 The question of whether higher initial dosages of ribavirin increase sustained virological response rates in genotype 2 or 3 patients regardless of baseline viral load strata can be answered only with the results of trials that have randomized patients to different dosage regimens. This is the only way to avoid confounding by body weight. Three such studies are available, none of which has reported a statistically significant differences in sustained virological response rates between genotype 2 or 3 patients randomized to two different dosage regimens of ribavirin.4-6 Hadziyannis et al.4 reported sustained virological response rates of 79% to 84% in genotype 2 and 3 patients randomized to peginterferon alfa-2a (40 kDa) plus ribavirin at either a fixed dosage (800 mg/day) or a weight-based dosage (1000/1200 mg/day) for either 24 or 48 weeks. Importantly, sustained virological response rates were similar in patients treated for a longer duration (48 weeks) with a fixed dose of ribavirin (800 mg/day) and in those treated for a shorter duration (24 weeks) with a weight-based dose (1000/1200 mg/day; 79% versus 81%, respectively), but relapse rates were higher with the shorter treatment duration.4 Jacobsen et al.5 reported similar sustained virological response rates in patients randomized to peginterferon alfa-2b (12 kDa) plus ribavirin at a fixed dose (800 mg/day; 62%) or a weight-based dosage (800-1400 mg/day; 60%) for 24 or 48 weeks. More recently, Ferenci et al.6 reported no statistically significant difference between sustained virological response rates in genotype 2 or 3 patients randomized to a fixed ribavirin dosage of 400 or 800 mg/day. Secondary analyses of data from the trials by Hadziyannis et al. (reported by Rizzetto et al.7) and Ferenci et al. confirmed the overall finding of no statistically significant differences between ribavirin dosage regimens in the smaller subgroups of genotype 2 and genotype 3 patients. The best evidence shows clearly that weight-based ribavirin dosing does not significantly increase sustained virological response rates in genotype 2 or 3 patients. The most important drawback to the use of abbreviated treatment for genotype 2 or 3 patients is relapse.8 Patients assigned to abbreviated 12- to 16-week treatment regimens generally have 2- to 3-fold higher relapse rates in comparison with those treated for the standard 24-week duration.9-13 This trend includes patients treated with higher weight-based ribavirin dosages,9, 11, 13 patients with a rapid virological response,9-11 and Taiwanese patients enrolled in the trial by Yu et al.13 Sustained virological response rates generally decrease as the baseline viral load increases. Shiffman and colleagues12 showed that this trend is accentuated in genotype 2 or 3 patients treated with an abbreviated 16-week regimen in comparison with the standard 24-week regimen. Patients enrolled in the trial by Yu et al.13 had a low mean baseline viral load (4.8-log), and other studies have not reported outcomes stratified by viral load. Thus, there are no data to show whether increasing the dose of ribavirin compensates for the negative effect of increasing the baseline viral load. Dai et al.2 point to the higher rates of rapid virological response and sustained virological response in Taiwanese patients versus Western patients. This phenomenon, which has been noted by others,14 may be due in part to the lower mean body weight of patients in their trial in comparison with some of the other studies that they cite.9, 10, 12 However, it is more likely that this difference is due to a recently identified genetic polymorphism that is a highly significant predictor of sustained virological response.15 In their analysis of data from genotype 1-infected individuals, Ge and colleagues15 found that Asian patients had the highest frequency of the advantageous allele. To our knowledge, the impact of this polymorphism in the gene for interleukin 28B on sustained virological response rates has not yet been reported in patients infected with hepatitis C virus genotype 2 or 3. It will be interesting to determine the impact of this polymorphism not only on sustained virological response rates in genotype 2 or 3 patients but also on the rate of relapse in patients with a rapid virological response assigned to abbreviated treatment regimens. Perhaps the frequency of interleukin 28B genotypes will ultimately explain the differences in virological response rates described by Dai and colleagues and direct us toward improved use of ribavirin in different patient populations. Moises Diago*, * Hepatology Section, Hospital General de Valencia, Valencia, Spain.