Earlier serum alanine aminotransferase (ALT) normalization in patients with chronic hepatitis B was independently associated with lower hepatocellular carcinoma (HCC) risk, regardless of fatty liver or cirrhosis at baseline and on-treatment virologic response. These study results were published in the American Journal of Gastroenterology.

Investigators analyzed data from 4639 patients with chronic hepatitis B who initiated treatment with entecavir or tenofovir. Normal ALT was defined as ≤35 U/L for men and ≤25 U/L for women, and virologic response as serum hepatitis B virus DNA <15 IU/mL.

During a median of 5.6 years of treatment, 11.0% of patients developed HCC. Normalization of ALT occurred at year 1 for 65.6% of patients and at year 2 for 81.9%; it was associated with a significantly lower HCC risk in both landmark (P <.001) and time-dependent Cox analyses (adjusted hazard ratio [aHR], 0.57; P <.001). Delayed ALT normalization at 6 to 12 months, 12 to 24 months, and >24 months was associated with incrementally increasing HCC risk (aHR 1.40, 1.74, and 2.45, respectively; P <.001) compared with normalization within 6 months.

Continue Reading

Related Articles

Results demonstrated that these results were independent of fatty liver or cirrhosis at baseline and virologic response during treatment. Investigators also found that neither earlier virologic response (aHR 0.93; P =.53) nor earlier hepatitis B e antigen seroclearance (aHR, 0.91; P =.31) was associated with a significantly lower HCC risk.

It must be noted that due to this being a historic cohort study, unavoidable biases may exist. The investigators attempted to not overestimate the effect of surrogate endpoints resulting from immortal time bias, because surrogate endpoints occurring at different times were evaluated. The results also need to be validated in patients other than the study population here, which was limited to those of Korean ethnicity, who are mostly infected by HBV genotype C. Also, the prevalence of cirrhosis or fatty liver may have been underestimated by the use of ultrasonographic criteria for the diagnosis. The investigators further reported that they may have missed intermittent elevations of ALT levels during treatment. Finally, they report that liver biopsy was not conducted in most patients, and advances in imaging techniques for diagnosis of HCC and assessment of hepatic fibrosis and fatty liver were not applicable to the study.

This study remains, however, a comprehensive assessment of a large number of patients, and the results did show that earlier ALT normalization was independently associated with significantly lower risks for HCC and death or transplantation, after the adjustment of fatty liver at baseline and achievement of virologic response during treatment. Investigators recommend that the biologic mechanism of this association should be the focus of future work. In the meantime, they concluded that efforts should be made to achieve ALT normalization as early as possible during treatment, as this may minimize the risk for HCC and mortality.


Choi J, Kim GA, Han S, Lim YS. Earlier alanine aminotransferase normalization during antiviral treatment is independently associated with lower risk of hepatocellular carcinoma in chronic Hepatitis B [published online January 2, 2020]. Am J Gastroenterol. doi:10.14309/ajg.0000000000000490