Qattan, I;
(2013)
Mechanisms involved in resistance to Interferon Alpha Therapy in Chronic Hepatitis C Virus Infection.
Doctoral thesis , UCL (University College London).
Abstract
Chronic hepatitis C virus infection is a massive worldwide healthcare burden, which is estimated to cost in the USA alone over $5 billon per annum. Until recently, the only current effective treatment was combination therapy with peg-interferon alpha and ribavirin (peg-I FNα+RBV), which is expensive and has significant side-effects, and is only effective in up to 50% of those infected with HCV genotype 1. In this thesis, a method was evaluated for detecting genotype 1b infections using a 5’non coding region sequence based approach (TRUEGENE). This allowed the identification of genotype 1b patients who could then be analysed for mutations in key regions of the genome associated with interferon resistance. A total of 14 patients with HCV genotype 1 were prescribed peg-IFNα+RBV and subjected to detailed sequence analysis of their interferon sensitivity determining region (ISDR) Following PCR amplification and sequence analysis there was no evidence for significant mutations occurring in the ISDR in patients who did not respond to therapy either at the start of therapy of during therapy. The recognition that host genetics may play a role in HCV infection and the success of treatment with interferon based therapies is now firmly established through the identification of single nucleotide polymorphisms (SNPs) in the IL28 gene which encodes a lambda interferon. I used an allele specific SNP detection system for two loci in the IL28B gene region (rs12979860C/T and rs8099917G/T) in a large population of Gulf region, and particularly Saudi Arabian, HCV infected patients (n=315) some of whom were co-infected with either HBV (n=1 01) or HIV (n=1 00). The results showed that the genotype distribution at both SNP loci were different to other studies based on North American and European populations. In addition, when the patients were separated into responders, non-responders and transient responders, marked differences in genotype frequencies was observed together with associations between specific alleles and HCV load. The inclusion of co-infected individuals allowed me to show that IL28B polymorphisms at these two loci are not evenly distributed between patients with HCV mono-infection and co-infections. In the final phase of the thesis, I used a proteomic approach to indentify novel proteins that may be useful as biomarkers for treatment response. After optimization of the electrophoretic procedure the patients who had been used for the earlier ISDR studies were analysed. Although preliminary, the data identified haptoglobulin as a protein whose expression pattern inversely correlated with the control of replication after therapy. In conclusion this thesis has attempted to identify viral and host genetic markers that contribute to treatment success and failure in HCV and has shown that differences in the prevalence of IL28B polymorphisms exist between Saudi Arabia and elsewhere and between patients harbouring dual infections compared to single HCV infection.
Type: | Thesis (Doctoral) |
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Title: | Mechanisms involved in resistance to Interferon Alpha Therapy in Chronic Hepatitis C Virus Infection |
Language: | English |
Additional information: | Permissions for digitisation not received. |
UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
URI: | https://discovery.ucl.ac.uk/id/eprint/1415966 |
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