Virologic Response at 12 Months Predicts Lower Hepatocellular Carcinoma Risk in Genotype D Chronic Hepatitis B Patients Treated with Nucleos(t)ide Analogues

<b>Background/Objectives:</b> Hepatitis B virus (HBV) is a virus that can cause chronic hepatitis B (CHB) in humans, leading to cirrhosis and hepatocellular carcinoma (HCC). In this study, we aimed to investigate the relationships between early ALT normalization (at 12 months), the virologic response in CHB patients, and the risk of HCC development. <b>Methods:</b> Data from a retrospective cohort study involving 616 chronic hepatitis B patients were used. The effects of ALT normalization and virologic response on the risk of developing HCC at 12 months of treatment were analyzed. <b>Results:</b> During a median treatment duration of 70.9 months, 36 (5.8%) HCC cases were detected in the total patient population. ALT normalization was detected in 68.83% of patients at 12 months of treatment. The rate of HCC in the group with early ALT normalization was lower than that in the group without ALT normalization, but this difference was not statistically significant (5% vs. 7.8%, <i>p</i> = 0.161). At the end of 12 months of treatment, virologic response was detected in 80.68% of the patients. The rate of patients developing HCC was significantly lower in the virologic response group (4.8% vs. 10.1%, <i>p</i> = 0.028). However, the risk of developing HCC was also significantly higher in the virologically unresponsive group, according to the virologic response at 12 months (<i>p</i> = 0.034). <b>Conclusions:</b> According to the results of this study, achieving virologic response at the end of 12 months in genotype D CHB patients treated with nucleos(t)ide analogs (NAs) reduces the risk of developing HCC.