We read with interest the study by Hsu et al. [1], who evaluated the treatment response in chronic hepatitis B (CHB) patients with mild alanine aminotransferase (ALT) elevation. Favorable histopathological, virological, and biochemical response was achieved in these patients after three years of tenofovir disoproxil fumarate therapy [1]. This study suggested that patients with mild ALT elevation might benefit from antiviral therapy, providing important evidence for the expansion of treatment indications for these patients. However, there is no comparative group of patients with ALT >2 × upper limit of normal (ULN). Moreover, only few patients were hepatitis B e antigen (HBeAg)-positive (18.5%) [1]. Thus, the virological response to nucleos(t)ide analogs (NAs) in patients with mild ALT elevation needs further investigation. We conducted a real-world, multicenter cohort study to validate the treatment response to first-line NAs in CHB patients with mild ALT elevation (1–2×ULN), and compare with patients with ALT >2×ULN.

A total of 724 treatment-naïve non-cirrhosis CHB patients with ALT >1×ULN (40 U/L) and hepatitis B virus (HBV) DNA >2,000 IU/mL were retrospectively included from three hospitals. All patients received antiviral treatment with first-line NAs. Patients were followed up longitudinally at intervals of 6 months or less during antiviral therapy. Virological response was defined as undetectable HBV DNA level (<20 IU/mL), and HBeAg clearance was defined as HBeAg loss regardless of antibody against HBeAg status.

Overall, the median age of patients was 34.0 years and 72.9% of patients were male. The median levels of ALT, HBV DNA, and hepatitis B surface antigen (HBsAg) were 126.3 U/L, 7.0 log₁₀ IU/mL, and 3.8 log₁₀ IU/mL, respectively. 75.1% of patients were HBeAg-positive. The proportion of patients with 1–2×ULN of ALT and ALT >2×ULN were 31.4% and 68.6%, respectively. At baseline, patients with ALT >2×ULN had slightly higher HBV DNA (7.2 log₁₀ IU/mL vs. 6.3 log₁₀ IU/mL, P<0.001) and HBsAg (3.9 log₁₀ IU/mL vs. 3.6 log₁₀ IU/mL, P<0.001) levels, as well as higher proportion of HBeAg positivity (82.1% vs. 59.9%, P<0.001) while were younger (34.0 years vs. 36.0 years, P=0.039) than patients with ALT 1–2×ULN (Supplementary Table 1). The 2-year cumulative incidence of ALT normalization (94.1% vs. 96.0%, P=0.090, Fig. 1A) and virological response (69.7% vs. 67.8%, P=0.357, Fig. 1C) were comparable between ALT 1–2×ULN and ALT >2×ULN groups. Similar results were found in both HBeAg-positive and HBeAg-negative subgroups (Fig. 1D–1G). However, the 2-year cumulative rate of HBeAg clearance was significantly lower in patients with ALT of 1–2×ULN compared to patients with ALT >2×ULN (16.5% vs. 32.9%, P=0.001, Fig. 1B).

The indication for antiviral therapy in CHB patients with mild ALT elevation remains in debate [2-5]. Consistent with the results by Hsu et al. [1], our results confirmed that CHB patients with ALT of 1–2×ULN could achieve similar virological response and biochemical response compared to patients with ALT >2×ULN. However, patients with ALT of 1–2×ULN had lower rate of HBeAg clearance compared to patients with ALT >2×ULN. The long-term treatment response and benefit of antiviral therapy for CHB patients with mild ALT elevation deserves further investigation.