Reply
Authors: Jacinta A. Holmes, Gail V. Matthews, Alexander J. Thompson
Journal: Hepatology (2014)

We thank Dai et al. for their interest in our work. We found in the CHARIOT cohort that inosine triphosphatase (ITPase) deficiency protects against ribavirin (RBV)-induced anemia, but is not associated with sustained virological response (SVR).1 They ask whether rapid virological response (RVR), achieved in 32.8%, had any effect on the result of the association between SVR and the hemoglobin (Hb) decline or upon RBV pharmacokinetics. Patients in the CHARIOT study were randomized to standard (180 μg weekly) versus induction (360 μg weekly) dosing of pegylated interferon (IFN) for the first 12 weeks of the 48-week treatment course.2 In the substudy analyzed in our article, RVR rates were higher in those who were randomized to the induction-dosing arm (37.9% vs. 27.5%; P = 0.011), although this did not translate into higher week 12 response or SVR rates. RVR was strongly associated with SVR on univariable analysis (P < 0.0001). RBV levels at weeks 4 and 8 were not associated with RVR, and ITPA genotype did not predict RVR. We then added RVR into the two multivariable models presented in the original analyses. The first model included fibrosis stage, nadir Hb, and baseline predictors of SVR. Although nadir Hb was still an independent predictor of SVR, RVR was the strongest predictor of SVR (odds ratio: 9.85; P < 0.001). When week 8 RBV levels were added into the model together with RVR, the relationship between nadir Hb and SVR was attenuated, similar to that observed in the original model (data not shown). When the analysis was stratified according to week 4 viral response, nadir Hb was only associated with SVR in patients who attained an RVR, but not in those who did not achieve an RVR (109 vs. 115 for SVR and no SVR, respectively, in RVR patients [P = 0.0142] and 114 vs. 113 for SVR and no SVR, respectively, in non-RVR patients [P = 0.1094]). This suggested that there may be an interaction between RVR and nadir Hb. We formally tested this using interaction testing in the models. However, when the interaction term for RVR and nadir Hb was included, either with or without RBV levels, this was not statistically significant. Therefore, the data are inconclusive; although this is a small substudy, it raises the interesting question of whether RBV-induced anemia/pharmacokinetics might preferentially benefit patients with greater IFN responsiveness, perhaps by modulation of intrahepatic IFN-stimulated genes, as previously suggested.3 Analysis of IL28B genotype would indeed be relevant, and this analysis is ongoing. Jacinta A. Holmes, MBBS, FRACP1,2 Gail V. Matthews, M.B.Ch.B., MRCP (UK), FRACP, Ph.D.3 Alexander J. Thompson, MBBS, FRACP, Ph.D.1,2,4,5 on behalf of the CHARIOT Study Group 1St Vincent's Hospital University of Melbourne Melbourne, VIC, Australia 2Department of Medicine University of Melbourne Melbourne, VIC, Australia 3Kirby Institute for Infection and Immunity in Society University of New South Wales Sydney, NSW, Australia 4Victorian Infectious Diseases Reference Laboratory North Melbourne, VIC, Australia 5Duke University Medical Center Durham, NC