Hepatitis B immunoglobulins withdrawal in Hepatitis B Virus mono-infected liver transplant recipients: an Italian multicenter prospective study

Abstract

Background & Aims

Despite recommendations from scientific societies that Hepatitis B Immunoglobulin (HBIG) can be safely discontinued, centers 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). 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. Patients transplanted between January 1st, 1991 and December 31st, 2022 were considered for HBIG withdrawal on occasion of the scheduled follow-up visit in the clinic at each site. (Milano-Niguarda, Milano-Policlinico, Bergamo-ASST Papa San Giovanni XXXIII; Pisa-Cisanello; Roma-Umberto I; Torino-Molinette; and Palermo-ISMETT). Informed consent was obtained from all patients before HBIG discontinuation. 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(fig 1) At LT, 43 (19%) patients were HBV DNA positive. 22% of donors were anti-HBc positive. HBIG were stopped after a median time from LT of 11.6 years (range 1-31 years). 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 (fig. 2). The median time of HBsAg reappearance from HBIG discontinuation was 9 (IQR 4.5–15) months and HBsAg serum levels remained very low over the entire period of observation (median 9 months, range 3-20), and in 4 cases fluctuated around the detectability threshold (tab 1). 10 out of 12 patients experiencing HBsAg reappearance, were continued on hgbNA alone, while 2 were restarted on HBIG (in 1 case for patient preference, in the other on clinician advise). Both patients were restarted on the same HBIG dose they were taking before withdrawal, and both became HBsAg negativeIn all cases HBV-DNA persisted undetectable, liver function tests (LFTs) remained within the normal range and neither HBV-related hepatitis or HCC were observed. 77 patients (27 %) were on LAM at the time of HBIG withdrawal and were switched either to ETV (49%) or to TDF/TAF (51%). 24/77 patients with eGFR < 60ml/min/1.73m2 at the time of HBIG discontinuation were switched to TAF. No significant worsening in renal function was observed during the follow-upNo 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 (tab.2).

Conclusions

In patients receiving high genetic barrier-NA monoprophylaxis, reappearance of HBsAg is not associated with hepatitis when serum HBV-DNA is not detectable. HBIG could be safely withdrawn in HBV mono-infected LT recipients on long-term combination HBIG plus third-generation NAs.