Hepatitis B Immunoglobulins Withdrawal in Hepatitis B Virus Mono-Infected Liver Transplant Recipients: An Italian Multicentre Prospective Study

Background & Aims: Despite recommendations from scientific societies that hepatitis B immunoglobulin (HBIG) can be safely discontinued, centres across Europe continue to use the combination nucleoside analogues (NAs) plus HBIG for long-term prophylaxis against hepatitis B virus (HBV) recurrence after liver transplant (LT). The aim of this study was to evaluate the safety of HBIG withdrawal in a cohort of LT recipients on long-term HBIG+NAs. Methods: All patients under third-generation NAs + HBIG and who adhered to the INSIGHT-B protocol were followed up after HBIG withdrawal, in a multicentre, prospective, Italian cohort study, to evaluate the risk of HBV reactivation. The probability of HBsAg reappearance after HBIG withdrawal, stratified by presence of HCC at LT, was estimated through Kaplan–Meier curves and Log-rank tests. Results: Between February 2021 and January 2024, 222 liver transplant (LT) recipients withdrew HBIG 11.6 (IQR 6.7–17.0) years after LT and were followed up for a median time of 24 months. After HBIG withdrawal, Hepatitis B surface antigen (HBsAg) reappearance was observed in 12 patients (5.4%) with a cumulative 1-, 2- and 3-year recurrence rate of 4.08%, 5.36% and 6.89% respectively. HBsAg serum levels remained very low over the entire period of observation (median 9 months, range 3–20), and in four cases fluctuated around the detectability threshold. In all cases, HBV-DNA persisted undetectable, liver function tests (LFTs) remained within the normal range, and neither HBV-related hepatitis nor HCC were observed. No baseline patients' features were found to be significantly associated with the likelihood of HBsAg reappearance after HBIG withdrawal, including the presence of HCC at transplantation. Conclusions: HBIG could be safely withdrawn in HBV mono-infected LT recipients on long-term combination HBIG plus third generation NAs.