OBJECTIVES:

It was suggested that normalization of serum alanine aminotransferase (ALT) levels at 1 year of antiviral treatment is associated with a lower risk of hepatic events in patients with chronic hepatitis B (CHB). However, it remains unclear whether earlier ALT normalization is associated with lower hepatocellular carcinoma (HCC) risk, independent of fatty liver or cirrhosis and on-treatment virological response (VR), in patients with CHB.

METHODS:

We analyzed 4,639 patients with CHB who initiated treatment with entecavir or tenofovir using landmark analysis and time-dependent Cox analysis. We defined normal ALT as≤ 35 U/L (men) and≤ 25 U/L (women) and VR as serum hepatitis B virus DNA< 15 IU/mL.

RESULTS:

During a median 5.6 years of treatment, 509 (11.0%) patients developed HCC. ALT normalization occurred in 65.6% at 1 year and 81.9% at 2 years and was associated with a significantly lower HCC risk in landmark (P< 0.001) and time-dependent Cox analyses (adjusted hazard ratio [AHR] 0.57; P< 0.001). Compared with ALT normalization within 6 months, delayed ALT normalization at 6–12, 12–24, and> 24 months was associated with incrementally increasing HCC risk (AHR 1.40, 1.74, and 2.45, respectively; P< 0.001), regardless of fatty liver or cirrhosis at baseline and VR during treatment. By contrast, neither earlier VR (AHR 0.93; P= 0.53) nor earlier hepatitis B e antigen seroclearance (AHR 0.91; P= 0.31) was associated with a significantly lower HCC risk.

DISCUSSION:

In patients with CHB treated with entecavir or tenofovir, earlier ALT normalization was independently associated with proportionally lower HCC risk, regardless of fatty liver or cirrhosis at baseline and on-treatment VR.