Prevention of HBV Recurrence after Liver Transplant: A Review

Abstract

Globally, hepatitis B virus (HBV) infection is recognized as a major risk factor for the development of hepatocellular carcinoma, and HBV-induced liver failure is one of the leading indications for liver transplantation. Until about two decades ago, liver transplantation in patients with chronic HBV infection was a relative contraindication, due to high risk of viral replication with the use of immunosuppressants which could result in graft infection. In the 1990s, hepatitis B immunoglobulin (HBIg) use significantly reduced the risk of graft infection, improving outcomes of liver transplant in patients with chronic HBV infection. However, very high costs, especially with the need for long-term use, became a major concern. With the advent of nucleos(t)ide analogs (NAs), there was less need for high-dose, long-term HBIg use to prevent HBV recurrence. Lamivudine was initially used but resistance soon became a major issue. This was followed by more potent NAs, such as entecavir and tenofovir, emerging as the more preferred agents. Additionally, the use of these antiviral agents (HBIg and/or NAs) have made it possible to use the grafts from donors with positivity for hepatitis B core antibody, allowing for expansion of the donor pool. Nevertheless, there is no consensus on management protocols, which vary significantly amongst centers. In this review, we appraise studies on management strategies used and the role of active vaccination in the prevention of HBV recurrence in post-liver transplant patients.

Keywords: Hepatitis B; Liver transplant; Recurrence; Vaccination.

Fig. 1.. Simplified illustration of HBV cell cycle.

The viral envelope proteins, such as HBsAg, bind to host cell surface receptors, resulting in endocytosis of the hepatitis B virion into the host cell. The nucleocapsid releases relaxed circular HBV DNA (rcDNA) into the nucleus,2 which is converted into covalently closed circular double stranded DNA (cccDNA). The cccDNA is a template for transcription of viral RNA. The transcribed pregenomic RNA (pgRNA) undergoes reverse transcription, forming rcDNA. At the endoplasmic reticulum, virions assemble (not shown in diagram) and the mature virions are excreted from the host cell via budding. Occasionally (10%), double-stranded linear DNA (dslDNA) is produced, which can be integrated into the host genome.

Fig. 2.. Selected proposed mechanisms involved in occult HBV infection.^,

Methylation of covalently closed circular DNA (cccDNA) correlates with decreased HBV replication. Chronic HBV infection can upregulate the production of APOBEC genes, which is associated with hyperedited HBV genome and decreased HBV replication. MicroRNAs are small, non-coding molecules found in viruses that function in RNA silencing and post-transcriptional mechanisms which may be involved in decreasing viral replication. These mechanisms do not result in complete viral suppression and low-level replication may persist. These mechanisms may be reversible, resulting in overt infection.

Fig. 3.. An algorithm for suggested approach towards prevention and management of HBV recurrence in post-liver transplant patients.

Serial blood tests include those for hepatitis s antigen (HBsAg) and HBV DNA. + refers to positive test result or detectable markers. – refers to negative test result or undetectable markers. Abbreviations: DNA, deoxyribonucleic acid; ETV, entecavir; HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NA, nucleoside analog; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.