Chronic hepatitis B virus (HBV) infection is a global health crisis, affecting millions worldwide. Despite advancements in antiviral treatments, achieving long-term suppression of HBV replication remains a significant challenge for many patients. The role of specific mutations in the precore (PC) and basal core promoter (BCP) regions of the HBV genome has emerged as a critical factor in treatment outcomes and relapse risks. These mutations, particularly G1896A in the PC region and the A1762T/G1764A double mutation in the BCP region, disrupt the typical correlation between HBeAg status and disease activity, leading to ambiguous serological profiles.
Patients with PC/BCP mutations often exhibit lower HBeAg titers, reduced seroconversion rates, and significantly higher relapse rates after discontinuing nucleos(t)ide analog (NA) therapy. Studies have shown that the cumulative recurrence rate after NA withdrawal in patients with HBeAg seroconversion can reach an alarming 80%, rendering current withdrawal criteria unreliable for a substantial number of patients. Furthermore, for HBeAg-negative CHB patients driven by PC/BCP mutations, there is currently no validated endpoint for NA discontinuation, highlighting a critical gap in clinical management.
The clinical significance of PC/BCP mutations extends beyond serological ambiguity. These mutations impact HBV replication efficiency and modulate host immune responses, influencing treatment efficacy and resistance patterns. Despite their known prevalence in both HBeAg-positive and -negative CHB patients, routine genotypic testing for these mutations is not yet standard practice in many regions, even though such testing could provide crucial prognostic information and guide individualized treatment duration, especially in high-prevalence settings.
One of the major challenges is the inability to accurately distinguish between wild-type and PC/BCP-mutant infections among HBeAg-positive patients before or during antiviral therapy. This leads to two clinically indistinguishable scenarios: patients initially infected with wild-type HBV who may achieve genuine immune control during therapy, and patients with mixed infections or mutant-dominant strains, where HBeAg negativity is not due to immune control but mutation-induced suppression of HBeAg expression. In the latter case, patients may be mistakenly considered eligible for treatment discontinuation, exposing them to high risks of relapse and liver disease progression.
To address this critical knowledge gap, a retrospective analysis of historical data was proposed to investigate the prevalence and clinical impact of PC/BCP mutations among HBeAg-positive patients undergoing NA therapy. The study aimed to delineate the serological and virological characteristics associated with mutant strains, clarify their implications for treatment endpoints, and guide the development of more precise, mutation-informed antiviral management strategies.
The study, conducted at the People's Hospital of Taixing between July 2016 and July 2019, included 48 patients with confirmed chronic hepatitis B. Patients were stratified into two groups based on the presence or absence of PC/BCP mutations. The mutation group, consisting of 37 patients, had one or more mutations in the PC/BCP regions, while the non-mutation group, with 11 patients, had wild-type sequences at both loci.
The study found that patients in the mutation group had significantly lower seroconversion rates compared to the non-mutation group, with a clear negative correlation between the number of mutations and seroconversion success. Patients carrying the triple mutation A1762T/G1764A/G1896A had the lowest seroconversion rate, suggesting that these mutations significantly inhibit the host immune response and hinder sustained viral suppression.
Furthermore, the study highlighted the significant impact of PC/BCP mutations on the relapse rate after discontinuation of nucleotide analog treatment. The relapse rate in the mutation group reached 100% at 48 weeks after discontinuation, while the non-mutation group had a relapse rate of 0%. This stark contrast emphasizes the crucial role of these mutations in predicting relapse risk.
The findings also revealed a negative correlation between seroconversion rate and ALT levels in the mutation group, challenging the traditional view that elevated ALT levels typically reflect better treatment outcomes. In the context of PC/BCP mutations, elevated ALT levels may indicate a stronger immune response against the virus, paradoxically undermining the efficacy of NA therapy.
The study's implications are significant. There is currently no curative treatment for chronic HBV infection, and long-term use of NAs is crucial for suppressing viral replication and reducing the incidence of liver complications. However, HBsAg clearance remains a challenging goal, and the high relapse rate after discontinuation of NA treatment underscores the need for improved standards for HBV treatment cessation. Future research should focus on developing more precise and personalized cessation guidelines, considering factors such as PC/BCP mutations, baseline viral load, and host immune response.
In conclusion, PC/BCP mutations are key predictors of treatment failure and relapse in HBeAg-positive chronic hepatitis B patients. Routine mutation testing in HBeAg-positive patients is essential for guiding treatment decisions and improving clinical outcomes. By incorporating mutation monitoring into clinical practice, clinicians can tailor personalized treatment plans, reduce the risk of relapse, and prevent disease progression. Further research is needed to elucidate the mechanisms by which these mutations alter viral replication, immune responses, and treatment outcomes, ultimately leading to more effective and personalized CHB treatment strategies.
