Hepatitis delta virus (hdv) replication through hbv integrants in hcc recurrence after liver transplantation.

A PWID man, HCV/HBV-HDV/HIV-infected, underwent liver transplantation (LT) for HCC in 2012 at the age of 52 years. HCC tissue showed high HDV-RNA (88,400 copies/cell), low total HBV-DNA (0.00001 c/c), and HBVcccDNA0.00008 c/c), without detectable HBV-RNA. High-throughput HBV integration sequencing (HBIS) identified 657 HBV integration sites.HBV integrants were predominantly represented by HBx gene sequences. After LT, Tacrolimus, Bictegravir/Emtricitabine/TAF, and anti-HBs immunoglobulin were administered, yielding HBsAg, HDV-RNA, and HCV-RNA negativity. In 2018, HBsAg reversion was observed with undetectable HBV-DNA and HDV-RNA >19,000 c/ml. In 2019, HDV-related hepatitis occurred. Intrahepatic HBcAg, HBsAgHBV DNA, HBVcccDNA, and HBV-RNA were undetectable. HDV RNA concentrations were very high in the liver (3,920,000 c/c) but low in the serum (214 IU/mL). CT scan (CTs) suspected an isolated HCC recurrence in the left adrenal gland, confirmed by adrenalectomy. Real-time PCR in the tumor from the adrenal gland revealed high levels of HDV RNA (5.5 c/c) but low levels of HBV DNA (0.00009 c/c) and HBVcccDNA (0.00001 c/c). HBV RNA was undetectable. HBIS identified 3497 HBV integrations, most of which included HBs gene sequences. After adrenalectomy, HBsAg and HDV-RNA became undetectable. Anti-HBs immunoglobulin was continued with Everolimus. In 2021, CTs showed two HCC nodules in the liver and one in the right adrenal gland. TACE was performed, and TKI therapy was started. In 2023, new HDV hepatitis occurred, with HDV-RNA>3,631,360 UI/ml and HBV-DNA <10UI/ml. For the progression of HCC, RFA on the right adrenal gland was performed, and Bulevirtide was started. After 3 months, HDV-RNA was 48,638 c/ml, and transaminases were normal. This case demonstrates HDV replication in extrahepatic HCC recurrence, despite low levels of HBVcccDNA. The decreased HDV RNA levels after RFA and BLV therapy suggest that HCC metastases may serve as HBsAg production sites following HBV integration. [ABSTRACT FROM AUTHOR]