Evidence is accumulating that HBV variants may influence In renal transplant recipients, chronic hepatitis B vithe clinical course of hepatitis B. For instance, HBV with rus (HBV) infection often leads to cirrhosis and liver a point mutation in the preC-region (preC-variant), which failure. In this study, we investigated whether or not prevents the expression of the hepatitis B e antigen (HBeAg), in these patients viral variants would emerge despite can be associated with severe liver disease and, in some geoimmunosuppression, and whether they are associated graphic areas, with acute fulminant hepatitis. Recently, it with a specific course of liver disease. In a population was proposed that preC-variants may also be predisposed to of 552 renal transplant recipients hepatitis B 24 surface early graft loss following liver transplantation. In some, but antigen (HBsAg)-positive patients were available for a not all, studies, variants with clustered point mutations or 2-year follow-up. By polymerase chain reaction (PCR)
variable long overlapping deletions in the middle of the core and DNA sequencing, HBV genomes with deletions in gene (C-gene) were found in patients with chronic active hepthe middle of the core gene (C-gene) were found in 9 out atitis, but not in patients with mild liver lesions. 3-5 of the 24 patients. Seven of the 9 patients (group I) Some of these and other variants are probably selected by showed either persistent or increasing amounts of these immune-mediated mechanisms, because they were shown to variants; all patients had cirrhosis, and 5 died of endemerge spontaneously in chronic carriers during seroconverstage liver disease. The viral variants emerged at least sion from HBeAg to antibody to HBe (anti-HBe) 6 during in-1 year before liver failure. In 2 out of the 9 patients, terferon therapy 7 and after vaccination. 8 However, other varithe core deletion variants disappeared, and no further ants with deletions or insertions in the C-gene promoter deterioration of the liver function was observed thereafregion seem to have a selective disadvantage when the imter. In the remaining 15 patients (group II) without delemune system is activated. 9 Thus, an effective immune retion mutants detected at any time, only 3 had cirrhosis sponse can trigger both the emergence and the disappearance (P õ .001, group I vs. II), and none died (P õ .001). Beof HBV variants. tween both groups, there were no statistically signifi-It is generally believed that the recognition of a wild-type cant differences in the other relevant variables that or variant HBV by the immune system will result in hepatiwere examined. These results indicate that HBV C-gene tis. The recognition of virtually all viral proteins by the hudeletion mutants can accumulate in long-term immunomoral and cellular immune system [11] supports this view, suppressed patients, and that their persistence is associand suggests that an effective immune response is a prerequiated with progressive liver disease. The accumulation site for liver injury. However, severe hepatitis, the developof these variants may be caused by the development of ment of cirrhosis, and liver failure are often observed in imcirrhosis or could be involved in hepatopathogenesis.
munosuppressed HBV-infected renal transplant recipients. 12-16 (HEPATOLOGY 1996;24:751-758.) Under these conditions, immune-mediated mechanisms are unlikely to play a major role. Therefore, we investigated Hepatitis B virus (HBV) infection is associated with a whether viral variants would emerge during long-term imbroad spectrum of clinical manifestations, ranging from an munosuppression therapy, and whether these variants are asymptomatic carrier state to either fulminant acute hepatiassociated with severe liver disease. tis, chronic liver disease, cirrhosis, or hepatocellular carcinoma. Currently, interferon alfa is the only established treat-
PATIENTS AND METHODS
ment but is effective in only a proportion of patients. Patients. We retrospectively investigated markers of HBV infection in 552 renal transplant recipients who were treated between 1980 and 1994 in the Nephrological Department of the Charite ´, Ber-Abbreviations: HBV, hepatitis B virus; C-gene, core gene; HBeAg, hepatitis B e antigen; lin, Germany. In this group, 149 patients (27%) exhibited markers anti-HBe, hepatitis B e antibody; HBsAg, hepatitis B surface antigen; ALT, alanine trans-of past HBV infection and 68 (12%) had chronic hepatitis B with aminase; HCV, hepatitis C virus; PCR, polymerase chain reaction; S-gene, surface gene. viremia (hepatitis B surface antigen [HBsAg]-and HBeAg-, or anti-From the 1 Institut fu ¨r Medizinische Virologie and 2 Klinik fu ¨r Innere Medizin/Nephrolo-HBe-positive). The final study population included all patients who gie der Charite ´, Humboldt-Universita ¨t, Berlin, Federal Republic of Germany; and 3 Heinrichwere diagnosed with chronic hepatitis (n Å 24: 6 women and 18 men; Pette-Institut fu ¨r Experimentelle Virologie und Immunologie, Hamburg, Federal Republic age 48.6 { 10 years, mean { SD) and who underwent the monitoring of Germany.
of clinical and virological parameters between 1990 and 1994 (follow-