Statins associated with better clinical outcomes in patients achieving HBsAg seroclearance: a long-term follow-up study

Abstract

Introduction: Hepatitis B surface antigen (HBsAg) seroclearance is a clinical event that occurs either spontaneously or during treatment with nucleos(t)ide analogue (NA) therapy or interferon. We aimed to describe the long-term clinical course after HBsAg seroclearance, and to identify factors that modify disease outcomes, as clinical studies on these aspects are lacking. Methods: Chronic hepatitis B patients with HBsAg seroclearance occurring between 1986 and 2017 were recruited. Primary outcome was cirrhosis/hepatocellular carcinoma (HCC), and secondary outcomes were hepatic decompensation, liver-related death/transplantation, and all-cause mortality. Multivariable Cox model included demographics, prior antivirals, comorbidities, drugs (statins, metformin, proton-pump inhibitors, nonselective beta-blockers), and laboratory parameters (anti-HBs, platelet, liver function test, prothrombin time, and alpha-fetoprotein [AFP]). Statin users were propensity score matched (PSM) with non-users (1:2 ratio) for survival analysis of all outcomes. Results: Of 913 patients with HBsAg seroclearance (613 male [67.1%]; median age 53.4 years [range, 18.5-87.0]), 129 (14.1%) were statin users. During median follow-up of 7.7 years (up to 29.1 years), 64/833 (7.7%) developed cirrhosis, 25/905 (2.8%) developed HCC, 3/913 (0.3%) underwent transplantation, and 76/913 (8.3%) died. Statins were associated with lower cirrhosis/HCC risk (adjusted hazard ratio [aHR]=0.44; 95% confidence interval [CI]=0.20-0.96; aHR for every 1-year increase in use: 0.85; 95% CI=0.75-0.97). Statin users had no hepatic decompensation or liver-related death/transplantation (vs 18/778 [2.3%] and 18/784 [2.3%] cases in statin nonusers, respectively). Statins also associated with lower all-cause mortality risk (aHR=0.21; 95% CI=0.08-0.53). PSM yields consistent results for beneficial effects of statins (log-rank P<0.05 for all outcomes). Other factors for cirrhosis/HCC included increasing age (aHR=1.06), diabetes (aHR=2.03), higher creatinine (aHR=1.008), gammaglutamyl transferase >50 U/L (aHR=3.25) and AFP >9 ng/mL (aHR=10.14). Conclusion: Long-term survival in patients with HBsAg seroclearance is good. However, liver-related adverse outcomes still develop, necessitating further investigations on beneficial effects of statins.