It remains unknown whether antiviral treatment for HBeAg‐negative chronic hepatitis B (CHB) patients having high viral loads without significant elevation of alanine aminotransferase (ALT) levels would reduce the risks of clinical events.

To compare clinical outcomes of high viral load CHB patients untreated for normal or mildly elevated ALT vs those treated for ALT ≥ 2 upper limit of normal (ULN).

This historical cohort study included 5414 HBeAg‐negative CHB patients without cirrhosis at a tertiary hospital in Korea from 2000 to 2013. Inactive phase was defined as serum hepatitis B virus [HBV] DNA < 2000 IU/mL and persistently normal ALT (n = 3572). High viral load (HBV DNA ≥ 2000 IU/mL) patients were classified into three phases by ALT levels: Replicative (persistently normal ALT, n = 900); Mildly active (ALT 1‐2ULN, n = 396); and Active (ALT ≥ 2ULN, n = 546) phases. All Active phase patients were treated with nucleos(t)ide analogues.

The mean age of the patients was 47 years without a significant difference among the groups. Compared with the treated Active phase group, the untreated Replicative phase group showed a significantly higher risk of hepatocellular carcinoma (HCC; HR 1.76; 95% CI 1.00 ‐ 3.10, P = 0.05) and death/transplantation (HR 2.14; 5% CI 1.09 ‐ 4.21, P = 0.03) by propensity score‐matched analysis. The untreated mildly active phase patients had further increase in risk of HCC and death/transplantation compared with the treated Active phase group by unadjusted, PS‐matched, competing risks, and multivariable‐adjusted analyses.

Untreated high viral load HBeAg‐negative CHB patients without significant ALT elevation had higher risks of clinical events than treated Active phase patients with elevated ALT.