Reply:
Authors: Lisa I. Backus, Derek B. Boothroyd, Barbara R. Phillips, Larry A. Mole
Journal: Hepatology (2007)

We thank Dr. Riley for his interest and critical reading of our article and for the opportunity to respond. As Dr. Riley points out, there may be differences among those individuals who were initiated on pegylated interferon (PEG-INF) 2A versus 2B, such as racial make-up or baseline genotype, that explain the difference in sustained virologic response (SVR) rates. We ran and presented separate multivariate models that allowed for differences between PEG-INF forms to depend on a key baseline characteristic, namely genotype, in addition to 17 other baseline covariates, including race, that reached a P < 0.1 in univariate analyses for either the entire cohort or a genotype subgroup. The genotype-specific models allowed for the effect (if any) of interactions between genotype and other characteristics. (We had no a priori reason to search for other interactions.) In unpublished data, we did compare the characteristics of those treated with PEG-INF 2A versus 2B. There were only a few statistically significant differences at baseline between these 2 groups. The magnitudes of these differences were small, and they did not consistently favor PEG-INF 2A or 2B. For example, the PEG-INF 2A group had slightly higher rates of black race (29% versus 24%, P = 0.05) whereas the PEG-INF 2B group had more patients with body mass index ≥ 30 kg/m2 (36% versus 39%, P = 0.05). Nonetheless, we fully acknowledge that this study is based on observational data, that patients were not randomized to PEG-INF form, and that the observed difference in SVR rates for patients treated with PEG-INF 2A and 2B could be due to a factor not controlled for in our multivariate models. Dr. Riley also points out the apparent difference in the dosing of PEG-INF 2A versus 2B relative to U.S. Food and Drug Administration (FDA) recommendations. In our cohort, 98% of PEG-INF 2A patients started on the FDA recommended dose whereas 70% of PEG-INF 2B patients started on at least 1.4 μg/kg/week, 20% started on 1.2-1.3 μg/kg/week, and another 9% started on 0.9-1.1 μg/kg/week. In our study, the SVR rates did not differ across these 3 PEG-INF 2B dosing groups. Our results, and other studies, suggest that the acceptable dose range for PEG-INF 2B may be much broader than the FDA recommended 1.5 μg/kg/week and includes 1.2 μg/kg/week and probably 0.9 μg/kg/week.1, 2 Thus, 99% of all PEG-INF 2B initiations in our population likely received an equally effective dose. To determine definitively whether one PEG-INF form in combination with ribavirin is superior for specific genotypes would require a large, randomized, head-to-head trial. We point out in the publication that the ongoing IDEAL trial, which has both PEG-INF 2A and 2B treatment arms, may provide critical information on this issue. At the same time, our findings of substantially lower SVR rates in routine medical practice compared to those from the preferentially selected populations of randomized trials serves as a reminder that the results from such trials may not always apply to routine medical practice. Clinicians and patients must frequently make treatment decisions in the absence of results from randomized clinical trials, and in such situations, results from well-constructed analyses of large retrospective observational cohorts can inform their decisions. Lisa I. Backus*, Derek B. Boothroyd*, Barbara R. Phillips*, Larry A. Mole*, * Center for Quality Management in Public Health, Veterans Health Administration, Palo Alto, CA.