Impact of PC/BCP Mutations on Seroconversion and Relapse in HBeAg-Positive Chronic Hepatitis B Patients Treated with Nucleoside Analogues.

Background: Precore/Basal core promotor (PC/BCP) mutations are critical mechanisms by which hepatitis B virus (HBV) evades host immunity and antiviral therapy. These mutations are prevalent in HBeAg-positive chronic hepatitis B (CHB) patients, potentially leading to suboptimal responses to nucleos(t)ide analogues (NAs) and high relapse risk after treatment discontinuation. Objective: This study aimed to investigate the impact of PC/BCP mutations on seroconversion and relapse rates and analyze their association with drug resistance mechanisms. The study also evaluated the significance of mutation count (one, two, or three mutations) and specific types of mutations (A1762T, G1764A, G1896A) in relation to the seroconversion and relapse processes. Methods: From 2016 to 2019, 48 HBeAg-positive CHB patients were collected and divided into mutation (n=37) and non-mutation (n=11) groups based on PC/BCP status. Seroconversion rates after 144 weeks of NA therapy and relapse rates after 48 weeks of treatment discontinuation were analyzed. Baseline viral load (HBV DNA), liver function (ALT), and Precore/ Basal Core Promoter (PC/BCP) mutation status were analyzed for their correlation with clinical outcomes. Results: Among the 37 patients in the mutation group, 9 exhibited G1896A mutation, 15 exhibited A1762T/G1764A double mutations, 13 exhibited A1762T/G1764A/G1896A triple mutations. The mutation group showed significantly lower seroconversion rates than the non-mutation group (37.8% vs 81.8%, P=0.016). The seroconversion rate was inversely correlated with the number of mutations, with triple mutations (A1762T, G1764A, G1896A) associated with the lowest seroconversion rate. The mutation group exhibited a 100% relapse rate (14/14 cases) with HBeAg reactivation, while no relapses occurred in the non-mutation group (0/9 cases, P=0.0001). PC/BCP mutations (eg, A1762T/G1764A) likely reduce NA sensitivity by enhancing viral replication (upregulating pgRNA transcription) and immune evasion (HBeAg epitope variation), leading to delayed treatment response and viral rebound after discontinuation of therapy. Conclusion: PC/BCP mutations are independent risk factors for poor NA response and high relapse rates in HBeAg-positive CHB patients. Patients with these mutations should be managed as "occult HBeAg-negative CHB" to avoid premature treatment discontinuation. Routine PC/BCP mutation testing is recommended to guide individualized treatment duration in HBeAg-positive CHB patients.