OBJECTIVES: Serum hepatitis B virus (HBV)-DNA > 2,000 IU/mL is associated with higher risk of disease progression. However, without hepatocellular carcinoma (HCC) or cirrhosis, nucleos(t)ide analogs (NUCs) are recommended only for patients with elevated serum HBV-DNA and alanine aminotransferase ≥2 × upper normal limit. METHODS: We evaluated prognosis of untreated minimally active (MA) hepatitis patients (defined as HBV-DNA > 2,000 IU/mL, but never fulfilling current criteria for NUCs during follow-up) (untreated MA group), compared to virological responders by NUCs (NUC-VR group). Eligible patients undergoing transient elastography were consecutively enrolled. Patients with an immune-tolerant or inactive phase and with cirrhosis or HCC at enrollment were excluded. Cumulative risks of disease progression were assessed using the Kaplan-Meier method. RESULTS: The untreated MA group (n = 152) had higher HBV-DNA, alanine aminotransferase, and total bilirubin levels, and lower proportions of male and positive hepatitis B e antigen, compared to the NUC-VR group (n = 641). The untreated MA group had higher risks of HCC (adjusted hazard ratio [HR] 3.485, 95% confidence interval [CI] 1.234-9.846; P = 0.018), but similar risks of cirrhotic complications (adjusted HR 0.649, 95% CI 0.227-1.854; P = 0.420), compared to the NUC-VR group. Inverse probability of treatment weighting analysis using propensity score showed that the untreated MA group had higher risks of HCC (HR 4.464, 95% CI 2.008-9.901; P < 0.001), but similar risks of cirrhotic complications (HR 1.171, 95% CI 0.594-2.309; P = 0.649), compared to the NUC-VR group. DISCUSSION: Through appropriate adjustment of potential prognostic factors, the untreated MA group consistently showed higher risks of HCC, but similar risks of cirrhotic complications, compared to the NUC-VR group. HCC risk might be reduced through earlier NUCs for the untreated MA group.
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