Editorial: HBeAg-Positive Chronic Hepatitis B With Low HBsAg Levels—Exploring Clinical Significance of preS2 Deletion Mutations

Abstract

Chronic hepatitis B virus (HBV) infection typically follows a natural history that includes phases of ‘immune tolerance’ and hepatitis B e antigen (HBeAg) clearance [1]. HBeAg positivity usually indicates active replication and is associated with high viral load and elevated hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B (CHB) [2]. However, the conventional phases cannot characterise all HBeAg-positive patients. A subset of these HBeAg-positive patients exhibit low HBsAg levels, accompanied by complex virological and immunological profiles, and tends to develop aggressive liver fibrosis and cirrhosis [3, 4]. Additionally, different HBV genes and mutations are linked to diverse serological and clinical characteristics, including antigen seroconversion, response to antiviral treatment, vaccine escape, liver fibrosis status and the development of hepatocellular carcinoma (HCC) [5]. The mechanisms underlying the clinical presentation of HBeAg-positive CHB with low HBsAg levels remain unclear.

In a recent study published in the journal, Chen et al. enrolled 171 treatment-naïve HBeAg-positive CHB patients with HBsAg concentrations below 1000 IU/mL, to investigate potential explanations by analysing their virological and immunological characteristics [6]. Liver fibrosis severity was measured using non-invasive fibrosis indices. The results revealed that these patients had lower HBV DNA concentrations, higher rates of anti-HBs and anti-HBe positivity, elevated fibrosis scores and a predominance of genotype C. Moreover, there was a higher prevalence of viral quasispecies variants associated with the preS2 deletion. Notably, patients with preS2 deletion mutations exhibited higher fibrosis scores compared to both those infected with the wild-type virus, and HBeAg-positive CHB patients with high HBsAg concentration. They concluded that preS2 deletion mutants might enable HBV to evade host immunity and contribute to liver disease progression. These findings suggest that these patients warrant greater medical attention.

Extrapolating findings from this retrospective study should be approached cautiously. Potential confounding factors, such as host genetics or environmental influences, [7, 8] may contribute to fibrosis or immune modulation and were not fully accounted for in this study. It remains unclear whether preS2 deletion mutations arise as a result of liver disease progression, or alternatively, causally contribute to it. Moreover, in vitro experiments may not fully replicate the intricate host immune interactions occurring in vivo and disease progression. To further clarify the role of preS2 deletions in the natural history of CHB, prospective cohort studies that longitudinally track the emergence of preS2 deletions are needed to establish a clear temporal association with clinical outcomes such as fibrosis progression or HCC. Additionally, causal inference techniques, such as directed acyclic graphs and mediation analyses, may help to better disentangle the complex effects of specific viral variants [9]. Furthermore, animal models, such as humanised mouse models expressing wild-type or preS2-deleted HBV, could directly test the impact of viral variants on liver inflammation, fibrosis and immune responses under controlled conditions [10].

In summary, this study demonstrating that HBeAg-positive patients with low HBsAg concentrations exhibited more aggressive liver fibrosis and cirrhosis reveal an atypical serological and clinical pattern in CHB. The findings suggest that preS2 deletion mutants may enhance viral immune evasion and contribute to poorer clinical outcomes. However, prospective studies with longitudinal follow-up and/or animal models are needed to confirm a causal relationship.

Ying-Nan Tsai: conceptualization, investigation, writing – original draft. Yao-Chun Hsu: conceptualization, writing – review and editing, supervision.

Ying-Nan Tsai reported no conflicts of interest. Yao-Chun Hsu has received research grants from Gilead Sciences, lecture fees from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Grifols and Roche, and has served as an advisory committee member for Gilead Sciences and Sysmex.

This article is linked to Chen et al papers. To view these articles, visit https://doi.org/10.1111/apt.18448 and https://doi.org/10.1111/apt.18504.