Impact of nonalcoholic fatty liver disease on the response to pegylated interferon-α therapy in patients with chronic hepatitis B

Hepatitis B surface antigen (HBsAg) clearance is regarded as the optimal therapeutic endpoint in patients with chronic hepatitis B (CHB). Pegylated interferon-α (PegIFNα) is currently one of the most effective strategies for achieving this goal. However, the impact of concurrent nonalcoholic fatty liver disease (NAFLD) on the PegIFNα treatment response in CHB patients remains controversial. The aim of this study was to investigate the impact of NAFLD on the antiviral efficacy of PegIFNα in patients with CHB and identify baseline predictors of HBsAg clearance. In this retrospective cohort study, 201 CHB patients receiving PegIFNα monotherapy or PegIFNα in combination with nucleos(t)ide analogs were enrolled and stratified into CHB-only ( n = 125) and CHB + NAFLD ( n = 76) groups based on the presence of hepatic steatosis. Baseline clinical, virological (including HBsAg levels), and histological characteristics were collected and compared. Cumulative HBsAg clearance, biochemical response, and virological response rates were assessed. Two Cox proportional hazards regression models were constructed to identify independent predictors of HBsAg clearance through univariable and multivariable analyses. No significant difference was observed in the 48-week cumulative HBsAg clearance rate between the CHB + NAFLD and CHB-only groups (18.42% vs 23.2%, P = 0.41), nor in the virological response rates. However, the biochemical response rate was significantly lower in the CHB + NAFLD group (13.79% vs 22.03%, P = 0.042). Multivariate Cox regression analysis identified baseline HBsAg levels (Model 2: HR = 0.36, 95% CI: 0.26–0.51, P < 0.001) and baseline hepatitis B virus (HBV) DNA levels (Model 2: HR = 0.79, 95% CI: 0.63–1.00, P = 0.049) as independent predictors of HBsAg clearance, while NAFLD comorbidity was not independently associated with HBsAg clearance ( P = 0.58). In CHB patients receiving PegIFNα-based therapy, concurrent NAFLD did not significantly impair HBsAg clearance rates (18.42% vs 23.2% in week 48). However, it was associated with a reduced biochemical response rate. Baseline levels of HBsAg and HBV DNA served as independent predictors of HBsAg clearance. IMPORTANCE Chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD) are two of the most common liver diseases worldwide, and their coexistence is increasingly frequent due to the rising prevalence of metabolic disorders. Achieving hepatitis B surface antigen clearance is a key therapeutic goal, and pegylated interferon-α (PegIFNα) remains one of the most effective treatments to achieve it. However, it remains unclear whether the presence of NAFLD influences the response to PegIFNα therapy. The study found that NAFLD does not impair the clearance or suppression of hepatitis B virus, but it is associated with delayed normalization of biochemical markers. Whether the hepatitis B surface antigen becomes negative depends mainly on baseline viral levels, rather than the presence of NAFLD. These findings provide important clinical insights for the management of patients with both CHB and NAFLD.