Association between deletions in the preS1/2 region of the hepatitis B virus genome and persistently abnormal ALT levels in patients with chronic hepatitis B treated with nucleos(t)ide analogs

Patients with chronic hepatitis B (CHB) are at risk of developing hepatocellular carcinoma (HCC) during treatment with nucleos(t)ide analogs (NAs). Several factors, including abnormal ALT levels during NA treatment, are associated with HCC risk; however, the mechanisms of ALT abnormalities remain unknown. Here, deletions in the preS1/2 region of the hepatitis B virus (HBV) genome were evaluated in the context of persistent ALT abnormalities after NA treatment. Out of the 198 patients with CHB who had been treated with NAs, 40 who had been treated with entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide fumarate as the first-line therapy and from whom serum samples had been collected before NA treatment were selected for analysis of the infecting virus. Total DNA was extracted from the samples and subjected to nested PCR to detect deletions in the preS1/2 region of the HBV genome. Patients for whom deletions were found in ≥ 40% of the amplicons were classified as the "high-del" group, and the others were the "low-del" group. The preS1/2 region was amplified from 39 (97.5%) of the 40 samples, and a deletion was found in 19 of these patients (48.7%). The cumulative incidence of HCC was found to be significantly higher in the high-del group than in the low-del group (25% vs. 7% at 2 years, P = 0.021). The high-del group also had significantly higher ALT levels than the low-del group after 1 year of NA treatment (35 vs. 26 U/L, P = 0.020). In summary, patients with CHB with frequent preS1/2 deletions showed higher ALT levels after NA treatment and a higher risk of developing HCC.