The effect of universal infant vaccination on the prevalence of hepatitis B immunity in adult solid organ transplant candidates

Abstract Background Hepatitis B virus (HBV) immunity is recommended to optimize outcomes after solid organ transplantation (SOT). This study assessed the prevalence and predictors of HBV immunity at the time patients were placed on transplant waiting list over a period from 1997 to 2019 in a low HBV endemic region. Methods Data were obtained from the University Hospitals Leuven transplant database. Minors and patients with past/current HBV infection were excluded. From 1986, Belgian patients are covered by the universal infant vaccination; therefore, birth cohort was stratified in those born ≥1986 vs <1986. Results The study population consisted of 3297 SOT candidates. HBV immunity rate was superior in renal transplant candidates (55.3%), and this number was 21.5%, 15.4% and 16.8% for liver, cardiac and pulmonary transplant candidates, respectively, P < .001. Among liver transplant candidates, HBV immunity rate was 14.8% in decompensated cirrhotic patients and 27.9% in those without advanced cirrhosis (P < .001). The overall immunity rate increased from 19.3% in period 1997‐2008 to 32.8% in 2009‐2019, P < .001. In multivariable analyses, younger age (odds ratio (OR) 95% confidence interval (CI): 0.97‐0.98, P < .001) and birth cohort ≥ 1986 (OR 95% CI: 1.18‐2.66, P = .006) were associated with increased HBV immunity. Conclusion An increase in HBV immunity was observed over a 20‐year period related to the introduction of universal infant HBV vaccination. Nevertheless, this study highlights the low overall HBV immunity at the time of listing for organ transplantation and points out the need of an increased awareness and vaccination strategy at an early disease stage.

This study provides information on the prevalence of HBV immunity at the time SOT candidates were placed on the transplant waiting list over the period 1997-2019 in Belgium, a low endemic region for HBV. The current study also assessed the impact of universal HBV vaccination on HBV immunity at the time of transplant listing. In Belgium, universal infant HBV vaccination began in 1999 with catch-up vaccination for 10-to 13-year-olds (birth cohort born in 1986 or after). 28,29 2 | PATIENTS AND ME THODS

| Study design
We conducted a retrospective study at the University Hospitals Leuven, an academic hospital in Leuven with a capacity of 1995 beds. The hospital is involved in transplant care with active programmes of liver, kidney, heart, lung, pancreas, bowel, bone marrow and composite tissue grafts.

| Outcome measures
The primary study end point was the overall trend in HBV immunity rates among SOT candidates at the time of listing. We also assessed the independent predictors for HBV immunity among our study population of SOT candidates. HBV immunity was defined as an anti-HBs level ≥ 10 mIU/mL in line with the recommendations of the Advisory Committee on Immunization Practices. 6
Conclusion: An increase in HBV immunity was observed over a 20-year period related to the introduction of universal infant HBV vaccination. Nevertheless, this study highlights the low overall HBV immunity at the time of listing for organ transplantation and points out the need of an increased awareness and vaccination strategy at an early disease stage.

| Statistical analysis
According to the European Association for the Study of the Liver, primary diseases leading to liver transplantation were classified in decompensated cirrhosis, liver cancer, cholestatic diseases, acute hepatic failure, metabolic diseases and other. 30

| Hepatitis B virus immunity: age and sex
The HBV immunity rates for age groups 18-to 24-year-olds (young  Table 2 shows the odds ratios (95% confidence interval) for HBV immunity by different risk factors. Male sex was significantly associated with lower immunity rates in multivariable analysis (P < .001).

| Factors Associated with hepatitis B virus immunity
Increasing year on waiting list (P < .001), younger age (P < .001) and birth cohort ≥ 1986 (P < .001) indicated a higher rate of HBV immunity.

| DISCUSS ION
In our study, only 29% of SOT candidates were HBV immune at the time of listing, leaving 71% at risk of acquiring HBV during or after transplantation and subsequently the risk of developing chronic hepatitis or even fibrotic cholestatic hepatitis. This is of particular importance in case of liver transplantation when anti-HBc-positive liver donors are used. In such a situation, HBV immunity in the acceptor remains essential to lower the risk of de novo HBV infection in recipients of anti-HBc-positive donors. 33,34 Without the use of antiviral prophylaxis, the TA B L E 1 Baseline characteristics among liver, renal, cardiac and pulmonary transplant candidates (n = 3297)

Characteristics
Total (n = 3297) F I G U R E 2 Hepatitis B virus immunity rates, 1997-2019 (n = 3297) and proportion of patients born in 1986 or later. Abbreviation: HBV: hepatitis B virus. †Immunity was defined as hepatitis B surface antibody levels > 10 mIU/mL. ‡Patients born in 1986 or later are covered by the universal infant HBV vaccination programme in Belgium with catch-up in 10-to 13-y-olds risk of de novo HBV infection is previously estimated at 47.8% over 35 months in hepatitis B naïve individuals and 9.7% over 40 months in individuals with vaccine immunity. 34 For non-liver organs, the risk of de novo HBV infection from HBsAg-negative/anti-HBc-positive donors is negligible in recipients with HBV immunity, but the risk is up to 5% in those without HBV immunity. 33,35 The growing organ shortage favours the use of grafts from HBsAg-negative/anti-HBc-positive donors as it is estimated that approximately 2 billion people have been exposed to HBV, and excluding all these donors would significantly reduce the global number of available grafts. 36 An important finding of our study was the increasing HBV immunity rate from 19% in 1997-2008 to 33% in 2009-2019. This increase could be explained by the effect of universal vaccination at a young age and in the absence of underlying disease. 6,10,27,28 Considering the rigorous immunization programme in dialysis patients, the highest HBV immunity rate was observed in renal transplant candidates. Nevertheless, the response rate was still suboptimal in this condition. The management of HBV infection within the haemodialysis unit focuses on identifying the virology status of all patients starting haemodialysis, offering a hepatitis B immunization schedule if indicated and monitoring anti-HBs levels with repeat immunization in those without protective antibody levels. 37 However, a concern is that seroprotection rates in these SOT candidates are still suboptimal even with the double-dose (40 µg) hepatitis B immunization schedule. [12][13][14][15][16][17][18][19][20][21][22][23][24][25] The expectation of low effectiveness of currently licensed HBV vaccines in renal transplant recipients was shown to be the most important barrier to guideline adherence among Dutch nephrologists. 38 Similarly for liver transplant candidates, HBV immunity rate was significantly lower in patients with more advanced liver dis-

ACK N OWLED G EM ENTS
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