What is the clinical significance of the high prevalence of occult hepatitis B in US liver transplant patients with chronic hepatitis C?

Abstract

Occult hepatitis B virus (HBV) infection is currently defined as persistent HBV-DNA sequences in liver tissue in hepatitis B surface antigen (HBsAg)–negative individuals (with or without evidence for circulating viral DNA in serum).1 Frequently, but not exclusively, such patients are hepatitis B core antibody (anti-HBc)–positive without detectable HBsAg or hepatitis B surface antibody (anti-HBs) by conventional assays. However, the presence of a serologic profile of anti-HBc+/anti-HBs+ does not exclude occult HBV infection, and detectable HBV-DNA has also been reported in individuals who are HBsAg−/anti-HBc−/anti-HBs−. anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; OLT, orthotopic liver transplantation. The prevalence of occult HBV infection worldwide varies significantly between geographic regions as well as patient populations tested.1 Thus, occult HBV has been reported in 18% of anti-HBc–positive and 8% of HBV-seronegative healthy individuals in North America, in 45%-50% of intravenous drug users or patients with hemophilia, in up to 36% of patients on dialysis, and in approximately 30% of HBsAg-negative hepatitis C virus (HCV) carriers. However, data regarding the true prevalence of occult HBV in special patient populations are often incomplete because of the great difference in the sensitivity and specificity of HBV-DNA assays used for detection of circulating viral sequences2 as well as the use of nonvalidated “in-house” assays for detection of intrahepatic HBV-DNA. The clinical significance and associated risks of occult HBV infection may differ in various patient populations. There is today ample proof that immune suppression poses a significant risk for HBV reactivation in HBsAg+ patients receiving chemotherapy who require protection with an antiviral agent.3 In contrast, despite the observation that occult HBV genomes may be infectious, it is not clear whether cryptic infection in the absence of detectable HBsAg is associated with increased morbidity and mortality from chronic liver disease and hepatocellular carcinoma (HCC) in patients with non-HBV cirrhosis or patients after liver transplantation. Furthermore, it is not established whether such patients require long-term protection against HBV reactivation with an anti-HBV agent. In this issue of the journal, Shetty and coworkers4 report their search for occult HBV infection in a group of 44 US patients who underwent liver transplantation for chronic HCV infection. Using a highly sensitive real-time HBV-DNA polymerase chain reaction assay (dynamic range 1.4-10.0 log10 copies/mL, lower limit of detection 25 copies/mL), they found intrahepatic HBV-DNA in 50% of patients tested prospectively after transplantation over a 2-year period. In comparison, only 13/44 patients who underwent orthotopic liver transplantation (OLT; 30%) had circulating HBV-DNA in serum pre-OLT, and all 13 (as expected) had detectable intrahepatic DNA. The remaining 12 candidate patients for OLT with chronic HCV infection did not undergo liver transplantation at the time of analysis and were excluded from evaluation of follow-up. Identification of occult explant HBV correlated with detectable anti-HBc and a history of intravenous drug abuse by univariate and multivariate analysis. A significant number of patients with occult HBV had coexistence of anti-HBc and anti-HBs. HCC was found in 59% of explants with occult HBV and in only 36% of explants without occult infection (the difference was statistically significant), although no significant difference was found in the concentration of intrahepatic HBV-DNA between both groups. Following transplantation, low levels of HBV-DNA in serum were detected in 13/22 patients at 8 weeks and in 7/22 patients at 24 weeks post-OLT. Finally, although HBV-DNA was detected in the serum of 13 patients post-OLT, none of the 22 immune-suppressed patients with pretransplant occult hepatitis B developed HBV reactivation during a post-OLT observation period of 24 weeks. The major finding of this prospective study by Shetty and coworkers4 is the relatively high prevalence of occult HBV infection in US liver transplant candidates with chronic HCV infection. This is of particular interest in a country in which HBV is not endemic, as observed in North American anti-HBc–positive blood donors, of whom <10% were previously reported to have circulating HBV-DNA. The relatively high prevalence of occult HBV infection in this study population, now established with a highly sensitive polymerase chain reaction assay, is most likely related to the high rate of previous intravenous drug abusers, although other factors may also be involved. Less sensitive HBV-DNA assays with a lower dynamic range, previously used for analysis of occult HBV, may also explain, at least in part, the differences in prevalence between the results of the current survey performed in serum and explants of HCV patients and previous analysis performed only in serum. The clinical significance of this high rate of occult HBV infection in liver transplant candidates with chronic HCV infection is still not completely understood. Indeed, HCC was significantly more prevalent in explants of HCV patients with occult HBV compared to those without evidence for persistent infection, a complication that no doubt affects the prognosis of such patients, especially if they are not referred for OLT. Yet, HBV-DNA levels were not significantly different between HCC patients and non-HCC patients with occult HBV infection. Serum HBV-DNA was also detected in a small number of patients after liver transplantation who had no evidence for occult HBV in serum or liver prior to transplantation. Furthermore, none of the patients with pretransplant or posttransplant occult HBV developed HBV reactivation. Thus far, the reported data from this study do not support the introduction of preventive antiviral treatment with a nucleoside analogue or hepatitis B immune globulin for HCV transplant patients with evidence of pretransplant occult HBV infection. However, in view of the short observation period in the posttransplant population with a history of occult HBV infection, it is too early to draw a definite conclusion. The complete absence of clinically relevant posttransplant reactivation may be explained by the relatively low level of pretransplant intrahepatic HBV-DNA, the removal of the major reservoir of HBV at transplantation, and the low concentrations of viral DNA after transplantation in the few patients with detectable viral sequences in serum. In theory, posttransplant immune suppression in general and treatment with corticosteroids in particular are considered risk factors for acceleration of HBV replication. However, in the patient population tested, the viral load remained low even after transplantation. There could be several reasons for the low pretransplant intrahepatic and posttransplant circulating HBV-DNA levels. Suppression of HBV replication by the coinfected HCV as well as continuous pressure from the host immune system, despite drug-induced immune suppression, may affect the balance between suppression and acceleration of HBV replication. In summary, this study provides important information regarding the relatively high prevalence of occult HBV infection in US transplant patients with chronic HCV infection. The investigators should be encouraged to continue the surveillance of this cohort of patients because the short observation period of 24 weeks post-transplantation is a limiting factor in the assessment of the posttransplant clinical significance of their findings, especially with respect to antiviral treatment. Further effort should also be devoted to the analysis of sera of anti-HBc+/HBsAg− liver transplant patients with chronic HCV infection, with an emphasis on searching for HBV envelope mutants not recognized by conventional immunoassays.