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Chronic hepatitis C genotype 2 and 3: Are we ready for personalized medicine? (12-16 weeks therapy??)
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Journal of Hepatology
Maya Gambarin-Gelwan, Ira M. Jacobson
Division of Gastroenterology and Hepatology, Center for the Study of Hepatitis C, Weill Cornell Medical College, NY, USA
Articles in Press
published online 18 April 2011.
Uncorrected Proof
Over the last several years, efforts have been made in patients with genotypes 2 and 3 chronic hepatitis C (CHC) to assess whether shortening the duration of therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) might preserve the efficacy of the standard 24week treatment duration while decreasing side-effects and improving tolerability. Data on viral kinetics have shown that both the effectiveness of IFN in blocking production of the virus in the first phase of viral decline (rapid decline) and the rate of decline in the second phase (slower decline) differ in patients with hepatitis C virus (HCV) genotype 1 and in those with genotypes 2 or 3 [1], [2]. This led several investigators to the hypothesis that in patients with CHC genotype 2 or 3 and rapid virologic response (RVR, i.e. HCV RNA undetectable after 4weeks of therapy), 12-16weeks of treatment with PEG-IFN and RBV may be as effective as a course of 24weeks [3], [4], which induces sustained virologic response (SVR) in about 80% of patients [5], [6].
While several European studies [3], [7], [8], [9] and a study from Taiwan [10] appeared to support this hypothesis, the results were somewhat different in the ACCELERATE [11] and NORTH-C [12] trials. The conflicting results may have been due to differences in the study design, prevalence of advanced fibrosis and cirrhosis, baseline viral counts, predominant genotype, ethnic background of the study population, and different RBV dosing schedules. The earlier trials by Dalgard et al. [7] and VonWagner et al. [8] included a relatively young HCV population with mostly early-stage fibrosis, while almost 25% of patients in ACCELERATE (a large prospective randomized, multinational non-inferiority trial) had bridging fibrosis or cirrhosis [11]. The absence of bridging fibrosis/cirrhosis was shown to be an independent predictor of SVR among genotype 2 and 3 patients by both Dalgard et al. [7] and Shiffman et al. [11], although this has not been reported by others [3], [8], [13].
Unlike most prior studies which evaluated truncation of treatment duration to less than 24weeks in genotype 2 and 3 patients, ACCELERATE used a fixed dose RBV (800mg/d). Since the mean body weight of ACCELERATE patients with genotype 2, for example, was about 84kg [11], that resulted in a mean daily dose of RBV of 9.52mg/kg, in contrast to 15.3mg/kg in the study of genotype 2 patients by Yu et al. (mean body weight about 66kg) [10]. Although Hadziyannis et al. [14] previously showed that a combination of PEG-IFN alfa-2a and RBV 800mg/d was as effective as a combination of PEG-IFN alfa-2a and RBV 1000-1200mg/d in patients with genotypes 2 and 3 using a 24-week treatment regimen, the prevailing literature as of the publication of the ACCELERATE study left open the question of whether a higher weight-based dose of RBV might still permit a shorter-duration of treatment of genotype 2 and 3 patients with RVR without increasing the risk of relapse.
The notion that the impairment in SVR with truncated therapy in RVR patients in ACCELERATE was due to the low, flat RBV dose (800mg daily) used in that study was challenged by results of the NORTH-C trial [12]. Using PEG-IFN alfa-2b 1.5ug/kg/wk and RBV 800-1400mg daily in patients (n=298) with genotype 2 and 3, the authors were unable to show non-inferiority of the 14-week regimen (as compared to a 24-week regimen) in patients with RVR, with lower SVR (81% vs. 91%) and higher relapse rates (11% vs. 5%) in those treated for 14weeks. Despite the inferiority of the 14-week regimen, Dalgard et al. suggested that a 26-32% reduction of drug exposure and cost with 14weeks of treatment in patients with RVR - recognizing that this would entail a 24-week course of retreatment for the minority with relapse - justified truncation of therapy in such patients (as long as the relapse rate is less than 35%) [12].
Given the intense motivation among most physicians and patients to optimize the chance of success with the initial course of therapy for CHC, the non-uniformity of the data on truncation of therapy in patients with genotypes 2 and 3 who attain RVR has led many clinicians to continue to treat these patients for 24weeks. The study by Manns et al. [15], as reported in the current issue of the Journal, provides the opportunity to glean further insights into this question, along with other aspects of therapy for patients with genotypes 2 and 3, within the context of a large study evaluating both a lower dose of PEG-IFN alfa-2b and a reduced treatment duration. In this study, treatment-naïve patients with CHC genotype 2 and 3 infection were derived from two cohorts: the Hep-Net cohort enrolled in Germany and an international cohort enrolled throughout Europe and Asia. Patients were randomized to receive PEG-IFN alfa-2b (1.5μg/kg/wk) for 24weeks (group A), PEG-IFN alfa-2b (1.0μg/kg/wk) for 24weeks (group B) or PEG-IFN alfa-2b (1.5μg/kg/wk) for 16weeks (group C); all in combination with weight-based RBV (800-1200mg/day). Treatment duration in group C, as well as in groups A and B, was independent of RVR; patients were not randomized to 16 vs. 24weeks of therapy based on RVR. Moreover, data on week 4 HCV RNA were assessed only in the International cohort.
Of the 682 patients enrolled in the study 80% were of genotype 3, which potentially constrains the ability to draw comparably robust conclusions about both of the evaluated genotypes. SVR rates were 66.5%, 64.3%, and 56.6% for groups A, B, and C, respectively, with groups B and C failing to show non-inferiority relative to group A. Relapse rates were 17.8%, 16.3%, and 29.3%, respectively. Among those who achieved an RVR in the International cohort, SVR rates were consistently high across all treatment arms: 75.3%, 75.9%, and 72.4%, respectively. The relapse rates in the RVR patients were not provided. Among genotype 3 patients, SVR was similar in groups A and B but lower in group C. While in group A SVR rates were highest in patients with genotype 2 infection and low baseline viral load, even among genotype 2 patients with low baseline viral load, SVR rates were lower in group C compared with group A. Treatment-related serious adverse events were highest in group A and predictably, lowest in group C. However, adverse events leading to discontinuation of therapy were similar across the arms.
The current study by Manns et al. [15] adds support to the growing body of literature including two recent meta-analyses [16], [17], suggesting that 24weeks of therapy should be considered the standard of care for genotype 2 and 3 patients. It does demonstrate, however, that the dose of Peg-IFN alfa-2b can be reduced to 1.0μg/kg/wk in those with safety concerns without marked decline in efficacy. It reaffirms that genotype 3 patients should not be treated routinely for less than 24weeks, as well as those patients with either genotype 2 and 3 without RVR. It again brings up the question whether, based on the low SVR rate of about 50% in these non-RVR populations, treatment of over 24weeks duration might be indicated and randomized controlled trials, such as one currently in progress, are needed to address that issue.
The current study by Manns et al. lends support to the concept of truncation of therapy among patients with genotype 2 or 3 who achieve an RVR with weight-based ribavirin. The data in the overall literature, however, remain inconclusive as to whether this can be done routinely without jeopardizing the chance of SVR to any significant extent even among "favorable" patient populations with characteristics such as younger age [7], [10], [11], [18], no or minimal fibrosis [7], [9], [11], [19], BMI≤30kg/m2 [11], [19], [20], low viral load [7], [8], [9], [11], [19], genotype 2 [8], [11], or platelet count >140,000 [20]. Despite the potential merit of a cost-effectiveness argument in support of shorter treatment, or a modest improvement in tolerability, many clinicians would find it problematic to routinely administer a regimen that had failed to demonstrate non-inferiority to patients who wish to maximize their prospects of success during the initial treatment course without incurring any incremental chance of having to undergo a repeat therapy. Based on the available data, truncated therapy with PEG-IFN and RBV should be reserved - after individualized discussion about benefit-risk considerations - for genotype 2 or 3 patients with favorable treatment characteristics who have attained RVR if they have significant tolerability issues after 12-16weeks of therapy.
References
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