Virological pattern of hepatitis B infection in an HIV-positive man with fatal fulminant hepatitis B: a case report

Abstract

Introduction: There seem to be no published data concerning the clinical impact of populations of hepatitis B virus (HBV) in the hepatic and extrahepatic compartments of HIV-infected people with severe acute hepatitis.

Case presentation: A 26-year-old Caucasian man presenting to our hospital with clinical symptoms suggesting acute hepatitis was found to have an acute hepatitis B profile upon admission. He developed fatal fulminant hepatitis and was found to be heavily immunocompromised due to HIV-1 infection. He had a high plasma HBV and HIV load, and analysis of the partial pre-S1/pre-S2 domain showed the presence of mixed infection with D and F genotypes. Analysis of the point mutations within this region revealed the presence of HBV strains with amino acid substitutions at the immunodominant epitopes involved in B or T cell recognition. A homogeneous population of a pre-core mutant strain harbouring the A1896G and A1899G affecting HBeAg expression was invariably found in the liver tissue, plasma and peripheral blood mononuclear cells despite active HBeAg secretion; it was the dominant strain in the liver only, and was characterised by the presence of two point mutations in the direct repeat 1 domain involved in HBV replication activity. Taken together, these mutations are indicative of a highly replicative virus capable of evading immune responses.

Conclusion: This case report provides clinical evidence of a possible association between the rapid spread of highly replicative escape mutants and the development of fulminant hepatitis in a heavily immunocompromised patient. Virological surveillance of severe acute hepatitis B may be important in establishing an early treatment strategy involving antiviral drugs capable of preventing liver failure, especially in individuals for whom liver transplantation is not accepted as a standard indication.

Figure 1

Analysis of the pre-S1 amino acid sequences of 26 clones derived from the plasma sample. A minor population clustering with genotype D showed glutamic acid/aspartic acid (E/D) amino acid substitution within the immunodominant epitope responsible for the hepatocyte binding site, and lysine/asparagine (K/N), valine/leucine (V/L), asparagine/proline (N/P) aa changes in the epitopes recognized by B and T lymphocytes. The alignment of clones 1-24 clustering with type D, and clones 25 and 26 clustering with genotype F, was made on the basis of the sequence of the HBV prototype. The numbers in parentheses refer to the total number of clones with identical amino acid sequences. The empty box indicates identical amino acid; the black box indicates the amino acid substitution (found in at least nine genotype D clones and the two genotype F clones; the grey box indicates a randomly detected amino acid mutation; and the striped box indicates an aa deletion. The pre-S1 epitopes responsible for immune response at T-cell level or thought to contain the hepatocyte binding site are respectively boxed in black and grey; the asterisk indicates the start of the sequence of the pre-S epitope that elicits the B cell immune response.

Figure 2

Alignment of the pre-core clone sequences propagated in different compartments and schematic representation of the secondary structure of the HBV pre-genome encapsidation signal. A) Alignment of the pre-core clone sequences propagated in different compartments. The alignment was made on the basis of the wild-type sequence of the pre-genome encapsidation signal. The dashes (-) represent the nucleotides that are identical to the wild-type sequence. B) Schematic representation of the secondary structure of the HBV pre-genome encapsidation signal: base pairing of the lower stem. The main nucleotide substitutions that better stabilise the epsilon structure detected in the clones derived from liver tissue, peripheral blood mononuclear cells and plasma are shown in parentheses.