Hepatitis B Virus Is Associated With Low Rejection Rates Following Liver Transplant Independent of Hepatitis B Immunoglobulin Use.

Abstract

Historical data suggests that Hepatitis B virus positive (HBV+) liver transplant (LT) recipients have less acute cellular rejection (ACR) than non-HBV+. It is unclear if this persists in the current era with reduced use of hepatitis B immunoglobulin (HBIG), as it might have immunosuppressive effects akin to pooled immunoglobulin. Thus, we examined the relationship between HBIG use on ACR in both in vitro and clinical studies. We performed a case-control study from the OPTN (2000-2011) comparing ACR rates of primary LT recipients with HBV, Hepatitis C, steatohepatitis (nonalcoholic or alcoholic), and immune-mediated liver disease. ACR was assessed with univariate analysis and multivariate logistic regression. Patient and graft survival was analyzed with the Kaplan-Meier method. The in vitro effect of HBIG on immune and regulatory cell responses was assessed with serial dilutions of HBIG using mixed lymphocyte reaction (MLR) cultures of laboratory volunteers. Of the 40,952 patients identified, 21% had at least one episode of ACR over a median follow up of 3.9 (range: 1.4 to 6.7) years. On univariate analysis, HBV+, Asian race and presence of hepatocellular carcinoma were associated with lower ACR (p<0.001). In multivariate analysis adjusted for age, gender, and immunosuppression, HBV status remained a strong predictor of freedom from ACR (OR 0.58, 95% CI:1.5-2.1). In patients with HBV, there was no effect of HBIG use on ACR status (p=0.09). Overall graft survival (60.8% vs 69.1%) and patient survival (67.7% vs 72.3%) were lower in patients with ACR, except for those with HBV where there was no significant difference in either outcome regardless of ACR status. In vitro, HBIG at all clinically applicable concentrations (e.g. akin to intravenous and intramuscular dosing) did not appear to inhibit immune responses or promote regulatory cell development and expansion. These results suggest that in the current era HBV+ LT recipients are at lower risk for ACR compared to other causes of liver disease independent of HBIG use. Furthermore, HBIG added to MLR cultures did not have direct inhibitory or regulatory effects at clinical concentrations. These findings support reducing immunosuppressive requirements in HBV+ LT recipients without an increase risk of ACR.