High Intrahepatic cccDNA in Resolved HBV Infection: Insights From Living Donor Liver Transplantation With...

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.

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.

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.

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.