Reply
Authors: Hannah S. J. Choi, Willem P. Brouwer, Bettina E. Hansen, Harry L. A. Janssen, Keyur Patel
Journal: Hepatology (2019)

Potential conflict of interest: Dr. Patel consults for, advises for, and received grants from Gilead. Dr. Hansen: has received grants from Intercept, CymaBay, and is a consultant for Intercept, CymaBay, Albireo, Mirum and ChemomAb. Dr. Janssen consults for and received grants from AbbVie, Arbutus, Bristol‐Myers Squibb, Gilead, Janssen, Medimmune, Merck, Roche, and Vir. He consults for Arena, Benitec, Enjoy, GlaxoSmithKline, Myr, Springbank, and Viro. We thank Dr. Huang and Dr. Li for their interest in our study. We agree that antiviral treatment affects outcomes in chronic hepatitis B (CHB) patients. In our study, antiviral therapy use was only significant in univariable analysis, but did not reach significance in the multivariable model for clinical events (P = 0.134). Addition of antiviral treatment to the selected model did not reach significance (P = 0.127) and had no effect on the hazard ratios of other variables. At both tertiary centers, patients were treated with antiviral regimens to ensure effective viral suppression. We were not able to further stratify our analysis based on the types of antiviral drugs to assess their effects on clinical outcomes independently of disease severity or viral suppression. Recent observational studies have attempted to address this with conflicting results, and currently there is no consensus regarding such differences between available therapies.1 We agree with Dr. Li that hepatic steatosis should be separated from non‐alcoholic steatohepatitis (NASH). We have shown that in contrast to NASH, hepatic steatosis was not associated with worse outcomes in our adjusted analysis. Regarding controlling for advanced fibrosis (AF) risk factors, we have clearly shown that NASH was independently and significantly associated with worse outcomes when adjusted for age, sex, hepatitis B e antigen status, presence of AF, and diabetes mellitus. We agree with Dr. Li’s observation that AF alone is a major determinant of adverse outcomes. However, patients with NASH were more likely to have AF, and in cases of AF, superimposed NASH was a detrimental factor associated with worse outcomes, as compared to patients with AF having no‐NASH (adjusted hazard ratio [95% confidence interval], 2.1 [1.2‐3.8]; P = 0.01). We were not able to obtain detailed information on concomitant drugs over the prolonged study timeline. However, even if statin and aspirin were independently associated with improved liver outcomes in CHB, their increased use in patients with metabolic syndrome and/or NAFLD would have been expected to weaken the adverse effect of NASH on outcomes in CHB. We agree that there may be confounding variables related to the tertiary center cohort and study duration. However, we would not be able to include NASH as an important outcome variable without a liver biopsy as the reference standard. Certainly, before the advent of noninvasive methods to assess fibrosis, biopsies were done with less‐stringent selection criteria. Although patients who had been selected for biopsy may have been at higher clinical risk of hepatic injury, our baseline characteristics indicated that 51% of patients had minimal F0‐F1 fibrosis. Furthermore, a long enrollment period and follow‐up were imperative to capture clinical outcomes and assess the long‐term effects of concurrent CHB and NASH.