Reply

Abstract

We thank Professors Aghemo and Colombo for their comprehensive review and discussion of the IDEAL trial and appreciate the opportunity provided by the editors of gastroenterology to provide additional discussion.First, the IDEAL study is one of the largest randomized controlled trials of HCV genotype 1 infected patients treated with PegIFN alfa2b or 2a, enrolling substantially more patients than the registration trials of either agents. Further, unlike the registration trials that enrolled heterogeneous, multinational populations, the IDEAL study was performed in 1 country, the United States. Second, in light of the recently recognized importance of an interleukin-28B genetic polymorphism and the distinct regional prevalence of these polymorphisms (East Asia > Europe > Africa), the comparison across study populations to other clinical trials is particularly problematic, because the genetics of the enrolled patients will clearly impact virologic response (Nature 2009;461:399–401; Nature 2009;461:798–801). Thus, comparisons of the results of this large, homogeneous, randomized, controlled trial to other smaller, heterogeneous, and, in some cases, nonrandomized studies has the potential to be misleading, introduce bias, and underscore the reasons why such a large, randomized, controlled trial was performed on a uniform patient population. For these reasons, we specifically avoid comparison of the IDEAL data with other studies, such as the retrospective, nonrandomized United States Veterans Affairs study with respect to comparative SVR rates or the smaller studies conducted in multinational settings (including East Asia and Europe) with respect to the relapse rate.We agree that the issue of ribavirin dosing and dose reduction has been difficult for HCV treating clinicians to digest. Nonetheless, these data clearly demonstrate that persons with RBV dose reduction did not experience lower rates of viral response or higher rates of viral relapse regardless of initial RBV dosing or dose reduction strategy (Table 2; N Engl J Med 2009;361:580–593). Based on this fact and space limitations in the New England Journal of Medicine, we did not provide detailed RBV exposure data. We believe that the confusion related to these data is based on the critical clinical distinction between RBV dose reduction and discontinuation. Importantly, the higher rate of viral relapse observed in the study by Bronowicki et al (Gastroenterology 2006;131:1040–1048) occurred after discontinuation of RBV. Further, in other studies, the definition of RBV exposure as the proportion of intended doses included both RBV discontinuation and reduction resulting in the inability to distinguish the impact of dose reduction and discontinuation. We interpret these data to reflect the observation that anemia is a marker of the pharmacodynamic effect of RBV, and its development is the result of adequate (or high) intracellular RBV exposure. We recommend that studies that examine the effect of RBV exposure carefully distinguish dose discontinuation from dose reduction.Finally, our conclusion is that the SVR rate and tolerability did not differ significantly between the 2 available peginterferon–ribavirin regimens. We agree that the ideal treatment for patients with difficult to cure genotype 1 hepatitis C will likely include direct-acting viral therapies because many of these patients are likely to harbor genetic factors that are associated with PegIFN/RBV nonresponsiveness, which is independent of the type of peginterferon. We thank Professors Aghemo and Colombo for their comprehensive review and discussion of the IDEAL trial and appreciate the opportunity provided by the editors of gastroenterology to provide additional discussion. First, the IDEAL study is one of the largest randomized controlled trials of HCV genotype 1 infected patients treated with PegIFN alfa2b or 2a, enrolling substantially more patients than the registration trials of either agents. Further, unlike the registration trials that enrolled heterogeneous, multinational populations, the IDEAL study was performed in 1 country, the United States. Second, in light of the recently recognized importance of an interleukin-28B genetic polymorphism and the distinct regional prevalence of these polymorphisms (East Asia > Europe > Africa), the comparison across study populations to other clinical trials is particularly problematic, because the genetics of the enrolled patients will clearly impact virologic response (Nature 2009;461:399–401; Nature 2009;461:798–801). Thus, comparisons of the results of this large, homogeneous, randomized, controlled trial to other smaller, heterogeneous, and, in some cases, nonrandomized studies has the potential to be misleading, introduce bias, and underscore the reasons why such a large, randomized, controlled trial was performed on a uniform patient population. For these reasons, we specifically avoid comparison of the IDEAL data with other studies, such as the retrospective, nonrandomized United States Veterans Affairs study with respect to comparative SVR rates or the smaller studies conducted in multinational settings (including East Asia and Europe) with respect to the relapse rate. We agree that the issue of ribavirin dosing and dose reduction has been difficult for HCV treating clinicians to digest. Nonetheless, these data clearly demonstrate that persons with RBV dose reduction did not experience lower rates of viral response or higher rates of viral relapse regardless of initial RBV dosing or dose reduction strategy (Table 2; N Engl J Med 2009;361:580–593). Based on this fact and space limitations in the New England Journal of Medicine, we did not provide detailed RBV exposure data. We believe that the confusion related to these data is based on the critical clinical distinction between RBV dose reduction and discontinuation. Importantly, the higher rate of viral relapse observed in the study by Bronowicki et al (Gastroenterology 2006;131:1040–1048) occurred after discontinuation of RBV. Further, in other studies, the definition of RBV exposure as the proportion of intended doses included both RBV discontinuation and reduction resulting in the inability to distinguish the impact of dose reduction and discontinuation. We interpret these data to reflect the observation that anemia is a marker of the pharmacodynamic effect of RBV, and its development is the result of adequate (or high) intracellular RBV exposure. We recommend that studies that examine the effect of RBV exposure carefully distinguish dose discontinuation from dose reduction. Finally, our conclusion is that the SVR rate and tolerability did not differ significantly between the 2 available peginterferon–ribavirin regimens. We agree that the ideal treatment for patients with difficult to cure genotype 1 hepatitis C will likely include direct-acting viral therapies because many of these patients are likely to harbor genetic factors that are associated with PegIFN/RBV nonresponsiveness, which is independent of the type of peginterferon. Peginterferon Alfa-2B Versus Peginterferon Alfa-2A With Ribavirin for the Treatment of Chronic Hepatitis C: The Pursuit of an IdealGastroenterologyVol. 138Issue 1PreviewMcHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580–593. Full-Text PDF