CTLA-4 haplotype predicts HBsAg and HBcrAg levels and HBeAg seroconversion age in children with chronic HBV infection

Jia-Feng Wu; Chi-San Tai; Kai-Chi Chang; Ting-Wei Chen; Huey-Ling Chen; Yen-Hsuan Ni; Hong-Yuan Hsu; Mei-Hwei Chang

doi:10.1016/j.jhepr.2024.101061

CTLA-4 haplotype predicts HBsAg and HBcrAg levels and HBeAg seroconversion age in children with chronic HBV infection

JHEP Rep. 2024 Mar 8;6(5):101061. doi: 10.1016/j.jhepr.2024.101061. eCollection 2024 May.

Authors

Jia-Feng Wu¹, Chi-San Tai¹, Kai-Chi Chang¹, Ting-Wei Chen¹, Huey-Ling Chen^{1

2}, Yen-Hsuan Ni^{1

2}, Hong-Yuan Hsu¹, Mei-Hwei Chang^{1

2}

Affiliations

¹ Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
² Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.

Abstract

Background & aim: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) attenuates cytotoxic T lymphocyte (CTL) activation. This study was performed to examine the relationships between CTLA-4 genotypes/haplotypes, hepatitis B surface antigen (HBsAg), and hepatitis B core-related antigen (HBcrAg) levels, and their potential impact on the clinical course of chronic HBV infection.

Methods: We recruited 145 treatment-naïve patients with genotype B or C chronic HBV infection who were initially hepatitis B e-antigen (HBeAg)-positive and had been followed from a mean age of 7.08 years for a total of 4,787 person-years in the study cohort. We also recruited another 69 treatment-naïve adults with genotype B or C chronic HBV infection as a validation cohort. We assessed the CTLA-4 gene single nucleotide polymorphisms rs4553808 (-A1661G)/rs5742909 (-C318T) in both cohorts, and the serum HBsAg and HBcrAg levels in the study cohort.

Results: CTLA-4 promoter haplotypes were associated with HBsAg and HBcrAg levels at 10 and 15 years of age in the study cohort. Patients with the CTLA-4 AA/CC haplotype showed earlier spontaneous HBeAg seroconversion (hazard ratio = 1.58; p = 0.02), and a more rapid annual decline in the serum HBsAg level than other patients (0.09 vs. 0.03 log₁₀ IU/ml/year, p = 0.02). The CTLA-4 AA/CC haplotype was also predictive of HBeAg seroconversion in the validation cohort (p = 0.01).

Conclusions: Chronic HBV-infected patients with a CTLA-4 AA/CC haplotype had lower serum HBsAg and HBcrAg levels in childhood and earlier spontaneous HBeAg seroconversion.

Impact and implications: The role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in chronic HBV-infected children has not been studied previously. In a very long-term cohort followed from childhood to adulthood, we showed that CTLA-4 haplotypes are associated with HBV biomarker levels in childhood and are correlated with the clinical course of chronic HBV infection. CTLA-4 pathway may serve as a future target for the development of therapeutic agents against HBV infection.

Keywords: covalently closed circular DNA; hepatitis B core-related antigen; hepatitis B surface antigen; liver stiffness measurement; transient elastography.