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

Abstract

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%]; I2 = 55.0%). Higher rates of reactivation were observed in recipients with negative anti-HBs (34/421; 7.8%; 95% CI [5.2%, 10.9%]; I2 = 36.0%) by pooling 6 studies, experiencing acute rejection (13/266; 5.8%; 95% CI [2.3%, 14.5%]; I2 = 63.2%) by pooling 3 studies, receiving ABO blood type-incompatible transplantation (8/111; 7.0%; 95% CI [2.9%, 12.7%]; I2 = 0%) by pooling 3 studies, receiving rituximab (10/133; 7.3%; 95% CI [3.4%, 12.6%]; I2 = 0%) by pooling 3 studies, and receiving anti-thymocyte immunoglobulin (ATG, 25/504; 4.9%; 95% CI [2.5%, 8.1%]; I2 = 49.0%) by pooling 4 studies. Among recipients with post-transplant HBV reactivation, 11.0% (7/52; 95% CI [4.0%, 20.8%]; I2 = 0.3%) developed HBV-related hepatic failure, and 11.0% (7/52; 95% CI [4.0%, 20.8%]; I2 = 0.3%) had HBV-related death. Negative anti-HBs (crude odds ratio [OR] 5.05; 95% CI [2.83, 9.00]; p < 0.001; I2 = 0%), ABO blood type-incompatible transplantation (crude OR 2.62; 95% CI [1.05, 6.04]; p = 0.040; I2 = 0%), history of acute rejection (crude OR 2.37; 95% CI [1.13, 4.97]; p = 0.022; I2 = 0%), ATG use (crude OR 3.19; 95% CI [1.48, 6.87]; p = 0.003; I2 = 0%), and rituximab use (crude OR 3.16; 95% CI [1.24, 8.06]; p = 0.016; I2 = 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.

Hepatitis B Virus Reactivation in Non‐Liver Solid Organ Transplantation: Incidence and Risk Analysis

“…A metaanalysis of nonliver SOT recipients with past HBV infection showed that the incidence of HBVr was much lower compared to our study (3% vs. 12%) [14]. Furthermore, in the subgroup analysis of that meta-analysis, the incidence of HBVr was below 10% in all subgroups: induction with ATG (5%), history of acute rejection (6%), negative HBsAb (8%), and use of rituximab (8%) [14]. Our study might have a higher HBVr rate for several reasons compared to previous studies.…”

“…Antiviral prophylaxis is recommended when the risk of HBVr is >10%, but not when the risk is <1% [12]. A metaanalysis of nonliver SOT recipients with past HBV infection showed that the incidence of HBVr was much lower compared to our study (3% vs. 12%) [14]. Furthermore, in the subgroup analysis of that meta-analysis, the incidence of HBVr was below 10% in all subgroups: induction with ATG (5%), history of acute rejection (6%), negative HBsAb (8%), and use of rituximab (8%) [14].…”

“…Our study might have a higher HBVr rate for several reasons compared to previous studies. First, the study subjects in the meta-analysis were primarily kidney transplant recipients, in contrast to our study (2840/2913 [97%] vs. 56/97 [58%]) [14]. Additionally, we observed that HBVr rates in patients with past HBV infection were higher in the kidney (16%) and heart (15%) compared to lung (5%) transplant recipients.…”

“…Patients who received rituximab are recommended to receive universal 1-year antiviral prophylaxis for both past HBV and chronic HBV infection [13]. Interestingly, in patients with past HBV infection, the incidence of HBVr in those who received rituximab is much lower in nonliver SOT recipients compared to oncology populations (8% [data from meta-analysis] vs. >20%) [14,16]. The reason for this difference has not yet been explained.…”

Risk of HBV Reactivation During Therapies for Hcc: A Systematic Review

“…In solid organ transplant (SOT) recipients, immunosuppression can result in HBV reactivation with ccc DNA serving as the replication template, which may further cause progressive hepatitis, hepatic failure, and even death. 11 HBV reactivation can occur in hepatocellular carcinoma (HCC) treatment such as transarterial chemoemblization (TACE), resection, and radiofrequency ablation (RFA). HBV reactivation after TACE in HCC treatment has been wellstudied.…”