High Intrahepatic cccDNA in Resolved HBV Infection: Insights From Living Donor Liver Transplantation With Anti-HBc-Positive Grafts.

AIM: In hepatitis B surface antigen (HBsAg)-negative recipients with antibody to hepatitis B core antigen (anti-HBc)-positive liver grafts, hepatitis B virus (HBV) can be reactivated under post-transplant immunosuppression. We recently reported a median intrahepatic covalently closed circular DNA (cccDNA) level of 238 copies/μg in HBsAg-positive patients. Meanwhile, the potential levels of intrahepatic cccDNA in anti-HBc-positive grafts have never been focused on as a factor for HBV recurrence.

METHODS: Among 168 patients who underwent living donor liver transplantation (LDLT) between 2018 and 2022, 4 HBsAg-negative recipients with anti-HBc-positive grafts were consecutively enrolled in this prospective study. Intrahepatic cccDNA levels in donor grafts were measured based on an intraoperative liver biopsy and digital droplet polymerase chain reaction.

RESULTS: In all four donor grafts, intrahepatic cccDNA levels ranged from 5.2 to 408 copies/μg, and all were negative for the high-sensitivity hepatitis B core-related antigen. Three of four recipients experienced HBV reactivation 14-24 months after LDLT. Two patients developed hepatitis with high HBV DNA and HBsAg levels, escape mutations (G145R ± K141R) with genotype B or C were detected. Entecavir therapy achieved serological and virological clearance within 2-9 months. The fourth patient remained recurrence-free during 36 months of follow-up.

CONCLUSIONS: Even among patients with resolved HBV infection, there are cases possessing intrahepatic cccDNA levels as high as or even higher than those in HBsAg-positive patients. To resolve this critical pitfall in immunosuppressed patients, the development of serum markers that precisely reflect intrahepatic cccDNA levels will be essential for improving HBV prophylaxis strategies.