Association of alanine aminotransferase flares with hepatitis B surface antigen loss and clinical outcomes in treated and untreated patients with chronic hepatitis B virus infection: A US retrospective cohort study.

BACKGROUND: Previous research has demonstrated the clinical significance of alanine aminotransferase (ALT) flares; however, studies have mostly been in Asian countries or populations, and it remains unclear whether ALT flares during treatment are associated with hepatitis B surface antigen (HBsAg) loss and long-term adverse clinical outcomes. OBJECTIVES: To evaluate the association between ALT flares and virologic outcomes (HBsAg and hepatitis B e antigen [HBeAg] loss) as well as adverse clinical outcomes among patients with chronic hepatitis B in the United States, according to treatment status. DESIGN: Retrospective study using the Optum de-identified electronic health record dataset (2012-2019). METHODS: Marginal structural models estimated the associations between ALT flares and outcomes, accounting for time-varying confounding; adjusted odds ratios and 95% confidence intervals were reported. A Cox proportional hazards regression model was used to assess risk factors for flares. RESULTS: 14,328 patients were included in the untreated cohort; of these, 2298 (16.0%) initiated and 1541 (10.7%) subsequently discontinued treatment. At least one ALT flare was experienced by 364 patients (2.5%) in the untreated cohort, 84 (3.7%) in the treatment initiation cohort, and 22 (1.4%) in the discontinuation cohort. Risk factors for ALT flares in the untreated group included male sex, history of flares, metabolic syndrome, liver fibrosis, compensated cirrhosis (CC), and hepatic decompensation. Risk factors after treatment initiation included younger age, White race, history of flares, and evidence of liver damage (liver fibrosis, CC, or hepatic decompensation). Flares in the untreated group were associated with spontaneous HBsAg loss and with an increased risk of hepatic decompensation, hospitalization, and death. Flares after treatment initiation were associated with HBsAg and HBeAg loss but not with adverse clinical outcomes investigated. CONCLUSION: ALT flares in untreated patients were associated with virologic and adverse clinical outcomes; no association with adverse clinical outcomes was observed in patients who initiated treatment.