Chronic Hepatitis B: The Hidden Impact of PC/BCP Mutations on Treatment Outcomes
Chronic hepatitis B virus (HBV) infection remains a significant global health challenge, affecting approximately 300 million people worldwide and causing over 800,000 deaths annually due to complications like cirrhosis and hepatocellular carcinoma (HCC). While nucleos(t)ide analogues (NAs) such as entecavir and tenofovir have revolutionized treatment, reducing the risk of end-stage liver disease, a critical therapeutic milestone in HBeAg-positive chronic hepatitis B (CHB) is HBeAg seroconversion. This seroconversion, from HBeAg to anti-HBe, is a marker of durable immune control and favorable long-term outcomes. Patients achieving this typically exhibit improved liver histology and reduced risks of cirrhosis and HCC. However, here's where it gets controversial: emerging evidence suggests that HBV genomic mutations, particularly in the precore (PC) and basal core promoter (BCP) regions, significantly impact both virological and serological responses, challenging conventional treatment endpoints.
Among the most well-characterized mutations are G1896A in the PC region, which introduces a premature stop codon abolishing HBeAg expression, and the A1762T/G1764A double mutation in the BCP region, which suppresses HBeAg production while enhancing viral replication. These mutations disrupt the typical correlation between HBeAg status and disease activity, often leading to discordant serological profiles. Clinically, patients with these mutations are frequently misclassified as having achieved immune control based solely on serologic markers. They often exhibit lower HBeAg titers, reduced seroconversion rates, and markedly higher relapse rates after NA cessation, despite achieving virological suppression during therapy. And this is the part most people miss: studies show that the cumulative recurrence rate after NA withdrawal in patients with HBeAg seroconversion can reach up to 80%, rendering current withdrawal criteria unreliable for many.
The clinical significance of PC/BCP mutations extends beyond serological ambiguity. These mutations alter HBV replication efficiency and modulate host immune responses, influencing treatment efficacy and resistance patterns. Despite their prevalence in both HBeAg-positive and -negative CHB patients, routine genotypic testing for these mutations is not standard practice in many regions, even though it could provide crucial prognostic information and guide individualized treatment duration. One major challenge is the inadequate discrimination between wild-type and PC/BCP-mutant infections among HBeAg-positive patients before or during antiviral therapy. There are two common but clinically indistinguishable scenarios: (1) patients initially infected with wild-type HBV who undergo genuine HBeAg seroconversion, potentially achieving immune control; and (2) patients with mixed infections or mutant-dominant strains, where HBeAg negativity results from mutation-induced suppression rather than immune control. In the latter case, although seroconversion is observed, the underlying infection resembles HBeAg-negative CHB, which lacks validated endpoints for NA cessation. These patients may be inadvertently considered eligible for treatment discontinuation, exposing them to high risks of relapse and disease progression.
To address this critical knowledge gap, we conducted a retrospective analysis of historical data from 48 HBeAg-positive patients undergoing NA therapy at the People’s Hospital of Taixing. Patients were stratified into mutation (n = 37) and non-mutation (n = 11) groups based on the presence of PC/BCP mutations detected via Sanger sequencing. Baseline characteristics were comparable between groups, ensuring homogeneity for analysis. Seroconversion rates were significantly lower in the mutation group at all time points, with the most pronounced difference at 96 weeks (37.8% vs. 81.8%, P = 0.016). Relapse rates after 48 weeks of drug withdrawal were starkly different: 100% in the mutation group versus 0% in the non-mutation group (P = 0.0001). These findings highlight the profound impact of PC/BCP mutations on treatment outcomes and the urgent need for mutation-informed management strategies.
Controversially, our study also revealed a negative correlation between ALT levels and seroconversion rates in the mutation group, challenging the traditional view that elevated ALT levels indicate active viral replication and better treatment outcomes. In the context of PC/BCP mutations, elevated ALT levels may reflect exacerbated liver inflammation, undermining NA therapy efficacy. This finding underscores the complex interplay between viral mutations, immune responses, and liver inflammation, suggesting that ALT may not be a reliable biomarker for disease progression in these patients.
In conclusion, PC/BCP mutations are key predictors of treatment failure and relapse in HBeAg-positive CHB patients. Routine mutation testing should be integrated into clinical practice to guide personalized treatment plans, reduce relapse rates, and improve long-term outcomes. But here's the thought-provoking question: as we move toward more precise, mutation-informed antiviral management, should we reconsider the current criteria for NA cessation, especially in high-prevalence settings? The answer may lie in future research exploring the immune escape and resistance mechanisms induced by these mutations, ultimately paving the way for more effective CHB treatment strategies.
