Hawkins, Anna Elizabeth; (1996) The detection and analysis of hepatitis B virus genome variation and its use in clinical studies. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The detection and analysis of hepatitis B virus genome variation and its use in clinical studies. This thesis describes the development of molecular techniques for the analysis of the hepatitis B virus (HBV) and their use in clinical studies. The methods for detecting HBV in serum included a DNA dot blot assay; a DNA polymerase assay and a polymerase chain reaction (PCR) assay in a nested and a double nested format. Amplified HBV DNA was also analysed by direct sequencing and by a point mutation assay. In a cohort of homosexual HBV carriers, concomitant HIV infection potentiated HBV replication and delayed HBeAg to anti-HBe seroconversion but did not appear to alter progression to AIDS. Fourteen patients in this cohort who received zidovudine were studied. The drug had no effect on HBV replication. HBV DNA was amplified from the majority of our HBeAg negative carriers, indicating that anti-HBe positive carriers may remain infectious. Hepatitis B virus with precore mutations was identified in two patients in the cohort, both were anti-HBe positive. The mutant strain was not a prerequisite for HBeAg to anti-HBe seroconversion and was not common in asymptomatic male homosexual HBV carriers in London. Reactivation of an HBV infection occurred in one of three HIV positive homosexual patients in whom an HBV infection recurred. Reinfection was implicated in the other two patients. Precore mutant virus was sexually transmissible. Greek patients and their sexual partners had common viral nucleotide sequences which included mutations in the precore region. The mutant virus was detected equally in patients with a chronic, acute uncomplicated or fulminant hepatitis and therefore was not always associated with severe HBV disease. Precore mutant virus was transmitted perinatally. Transmission of both precore mutant and the wild type virus from anti-HBe positive mothers resulted in a fulminant hepatitis. A mutation at codon 145 in the HBsAg A determinant, which has been associated with immune escape, was detected as the major type in one of three liver transplant patients receiving HBIg prophylaxis. Finally we identified a cluster of HBV infections from a group of control patients, illustrating the utility of this methodology in the study of HBV transmission events.

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