Incidence, risk factors, and clinical outcomes of HBV reactivation in non-liver solid organ transplant recipients with resolved HBV infection: A systematic review and meta-analysis

BACKGROUND: Current guidelines do not recommend routine antiviral prophylaxis to prevent hepatitis B virus (HBV) reactivation in non-liver solid organ transplant (SOT) recipients with resolved HBV infection, even in anti-hepatitis B surface antigen (anti-HBs)-negative recipients and those receiving intense immunosuppression. This systematic review and meta-analysis aimed to determine the incidence, risk factors, and clinical outcomes of HBV reactivation in non-liver SOT recipients. METHODS AND FINDINGS: Three databases (PubMed, Embase, and Cochrane Library) were systematically searched up to December 31, 2022. Clinical studies reporting HBV reactivation in non-liver SOT recipients were included. Case reports, case series, and cohort studies with a sample size of less than 10 patients were excluded. Random-effects analysis was used for all meta-analyses. We included 2,913 non-liver SOT recipients with resolved HBV infection from 16 retrospective cohort studies in the analysis. The overall HBV reactivation rate was 2.5% (76/2,913; 95% confidence interval [95% CI 1.6%, 3.6%]; I(2) = 55.0%). Higher rates of reactivation were observed in recipients with negative anti-HBs (34/421; 7.8%; 95% CI [5.2%, 10.9%]; I(2) = 36.0%) by pooling 6 studies, experiencing acute rejection (13/266; 5.8%; 95% CI [2.3%, 14.5%]; I(2) = 63.2%) by pooling 3 studies, receiving ABO blood type-incompatible transplantation (8/111; 7.0%; 95% CI [2.9%, 12.7%]; I(2) = 0%) by pooling 3 studies, receiving rituximab (10/133; 7.3%; 95% CI [3.4%, 12.6%]; I(2) = 0%) by pooling 3 studies, and receiving anti-thymocyte immunoglobulin (ATG, 25/504; 4.9%; 95% CI [2.5%, 8.1%]; I(2) = 49.0%) by pooling 4 studies. Among recipients with post-transplant HBV reactivation, 11.0% (7/52; 95% CI [4.0%, 20.8%]; I(2) = 0.3%) developed HBV-related hepatic failure, and 11.0% (7/52; 95% CI [4.0%, 20.8%]; I(2) = 0.3%) had HBV-related death. Negative anti-HBs (crude odds ratio [OR] 5.05; 95% CI [2.83, 9.00]; p < 0.001; I(2) = 0%), ABO blood type-incompatible transplantation (crude OR 2.62; 95% CI [1.05, 6.04]; p = 0.040; I(2) = 0%), history of acute rejection (crude OR 2.37; 95% CI [1.13, 4.97]; p = 0.022; I(2) = 0%), ATG use (crude OR 3.19; 95% CI [1.48, 6.87]; p = 0.003; I(2) = 0%), and rituximab use (crude OR 3.16; 95% CI [1.24, 8.06]; p = 0.016; I(2) = 0%) increased the risk of reactivation. Adjusted analyses reported similar results. Limitations include moderate heterogeneity in the meta-analyses and that most studies were conducted in kidney transplant recipients. CONCLUSIONS: Non-liver SOT recipients with resolved HBV infection have a high risk of HBV-related hepatic failure and HBV-related death if HBV reactivation occurs. Potential risk factors for HBV reactivation include rituximab use, anti-thymocyte immunoglobulin use, anti-HBs negative status, acute rejection history, and ABO blood type-incompatible transplantation. Further research on monitoring and routine antiviral prophylaxis of non-liver SOT recipients at higher risk of HBV reactivation is required.