Three cases of severe subfulminant hepatitis in heart-transplanted patients after nosocomial transmission of a mutant hepatitis B virus

Abstract

Fulminant and severe viral hepatitis are frequently associated with mutant hepatitis B virus (HBV) strains. In this study, the genetic background of a viral strain causing severe subfulminant outcome in heart-transplanted patients was studied and compared with viral hepatitis B strains that were not linked to severe liver disease in the same setting. A total of 46 patients infected nosocomially with HBV genotype A were studied. Five different viral strains were detected, infecting 3, 9, 5, 24, and 5 patients, respectively. Only one viral strain was found to be associated with the subfulminant outcome and 3 patient deaths as a consequence of severe liver disease. The remaining 43 patients with posttransplantation HBV infection did not show this fatal outcome. Instead, symptoms of hepatitis were generally mild or clinically undiagnosed. Comparison of this virus genome with the four other strains showed an accumulation of mutations in the basic core promoter, a region that influences viral replication, but also in hepatitis B X protein (HBX) (7 mutant motifs), core (10 mutant motifs), the preS1 region (5 mutant motifs), and the HBpolymerase open reading frame (17 motifs). Some of these variations, such as those in the core region, were located on the tip of the protruding spike of the viral capsid (codons 60 to 90), also known in part as an important HLA class II-restricted epitope region. These mutations might therefore influence the immune-mediated response. The viral strain causing subfulminant hepatitis was, in addition, the only strain with a preCore stop codon mutation and, thus, hepatitis B e antigen (HBeAg) expression was never observed. The combination of these specific viral factors is thought to be responsible for the fatal outcome in these immune-suppressed heart-transplant recipients. (HEPATOL-OGY 1999;29:1876-1883.)The clinical consequences of a hepatitis B virus (HBV) infection include a wide spectrum of different forms of liver injury, ranging from acute, self-limiting infection or chronic hepatitis with progression to cirrhosis and liver failure, to an asymptomatic chronic carrier state. The most severe outcome is described as fulminant hepatitis (FH), in which hepatocyte death is so extensive that less than 30% of the patients survive. 1 There is ample evidence that HBV variants with preCore stop codon mutations, unable to express the hepatitis B e antigen (HBeAg), as well as variants with several mutations in the regulatory region enhancer II/Core promoter, may be associated with severe and fulminant outcome, 2-8 and that these mutants might have an enhanced replication rate. 9 There are several other reports describing variants in other HBV genes (preS, Core, hepatitis B X protein [HBX]) that have been associated with a FH outcome. [10][11][12][13][14][15] But other data indicate that a specific genomic mutational pattern has not yet been defined, 7 and that the preCore mutations by themselves were not sufficient to explain the FH outcome. 16,17 Because HBV is not directly cytopathic, or at leas...

Molecular, immunological and clinical properties of mutated hepatitis B viruses

“…Point mutations within the CD 4 + T-cell epitope aa 48-69 [117] were described in severe liver diseases from patients from South-East-Asia [126,127], from immunocompromized patients [132] and from hepatoma tissues [16] [133]. These mutations were found after antiHBe seroconversion in chronic active hepatitis and in immunocompromized patients.…”

“…Point mutations within the highly conserved domain E of the X-gene (Ile-127 to Thr, Lys-130 to Met, Val-131 to Ile) recently were described in Japanese patients with fulminant and chronic hepatitis [176] and in immunocompromized patients with fulminant hepatitis [132]. It was shown that these mutations affecting the crucial domain for transactivation suppress the transcription of both precore and core mRNA [177].…”

Early Detection of Viral Resistance by Determination of Hepatitis B Virus Polymerase Mutations in Patients Treated by Lamivudine for Chronic Hepatitis B

“…26 To detect the variability of the viral genome at codon 28 and 29 of the precore region and at nucleotides 1,762 and 1,764 of the core promoter, a research LiPA was used with specific probes as described in detail previously. [27][28][29] To determine genotypic resistance and detect polymerase gene variability at codon 528 in the B domain of the reverse transcriptase, and at codons 552 and 555 of the C domain, a research LiPA was used as described previously in detail. 21 As the HBV polymerase gene has a different nucleotide length depending on genotypes, genotype A corresponding to the longest polymerase gene sequence was used as a reference for amino acid numbering.…”

Strong Association between Genotype F and Hepatitis B Virus (HBV) e Antigen-Negative Variants among HBV-Infected Argentinean Blood Donors

“…A common phenotype for these variants is decreased synthesis of precore mRNA resulting in decreased production of HBeAg and enhanced virus replication (24,56). These mutations are almost always found together and have been identified in HBV variants derived from patients with fulminant progression, chronic active infection, and primary liver cancer (23,32,58). At present, despite some reported evidence, there is no final consensus as to whether these core promoter variants are indeed more virulent.…”