We aimed to evaluate the impact of alanine aminotransferase (ALT) normalisation (ALTN) achieved at different time after the start of antiviral treatment on the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB).Methods
We identified a territory-wide cohort of CHB patients who received entecavir and/or tenofovir disoproxil fumarate (TDF) for ≥1 year between 2005 and 2016 in Hong Kong. Serial on-treatment ALT levels were analysed. ALTN referred to ALT level lower than the upper limit of normal (ULN) (30 U/L in males and 19 U/L in females). Early ALTN was defined as ALTN within 12 months. The primary outcome was HCC based on ICD-9-CM diagnosis codes. Patients with cancers previously or during the first year of treatment were excluded.Results
21,182 CHB patients (10 437 with and 10 745 without ALTN at 12 months after antiviral treatment) were identified and followed for a median (interquartile range) of 4.1 (2.4–6.0) years. Patients with or without ALTN at 12 months differed in gender distribution (76.9% vs. 58.4% male), baseline ALT (58 vs. 61 U/L), baseline serum HBV DNA (4.9 vs. 5.1 log10IU/mL), proportion of positive hepatitis B e antigen (31.5% vs. 37.1%), and presence of cirrhosis (8.8% vs. 10.5%) and diabetes mellitus (8.1% vs. 9.1%); 509 (2.4%) patients developed HCC. ALTN at 3, 6, 9 and 12 months were associated with a reduced risk of HCC (Figure 1), with adjusted hazard ratios (aHR) (95% confidence interval [CI]) of 0.55 (0.42,0.71), 0.52 (0.41,0.64), 0.47 (0.38,0.58) and 0.46 (0.37,0.56), respectively (all p<0.001). In contrast, ALT 1 to 2 times the ULN and ALT greater than 2 times the ULN at 12 months were associated with a higher risk of HCC as compared to ALTN at 12 months, with aHR (95% CI) of 2.07 (1.67,2.56) and 3.21 (2.32,4.44), respectively, after adjustment for baseline ALT and important covariates.Conclusions
Early on-treatment ALTN reduces the risk of HCC in CHB patients having entecavir/TDF treatment. On-treatment ALT above 1 and 2 times the ULN at 12 months were associated with higher risk of HCC.