Hepatitis C virus diversity in sub-Saharan Africa and implications for treatment with Direct Acting Antivirals

Shah, Rajiv Nagin (2024) Hepatitis C virus diversity in sub-Saharan Africa and implications for treatment with Direct Acting Antivirals. PhD thesis, University of Glasgow.

Abstract

Hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide with an estimated 58 million suffering with chronic HCV infection and approximately 1.5 million new infections occurring each year. The World Health Organization (WHO) has set ambitious goals to eliminate viral hepatitis by 2030. A key strategy behind these goals is the discovery of Direct Acting Antivirals (DAAs), which have revolutionised the treatment of HCV infection. However most clinical trials and real world DAA treatment programs have been conducted in high income countries where the predominant circulating -genotypes are epidemic lineages. However, in Sub-Saharan Africa endemic lineages are more common and less well characterised. There is also growing evidence that certain subgenotypes are more challenging to treat, for example sub-genotypes 1l and 4r. The aims of this thesis were to explore the diversity of HCV using datasets from Uganda and Benin. Furthermore, the prevalence of HCV and associated liver disease from people who inject drugs (PWID) in Coastal Kenya was assessed and HCV genetic data was used to explore PWID networks and estimate the origin of HCV in this community. We found highly divergent HCV genomes in Uganda and Benin including the discovery of multiple new subtypes (1q, 1r, 1s and 2xa in Benin and 4xa in Uganda) as well as numerous subtypes that have previously been uncharacterised. Interestingly, we found only epidemic lineages 1a and 4a in Kenyan PWID. Molecular clock analysis suggests the introduction of HCV 1a from Europe into Kenyan PWID, as recently as 2001, whereas HCV 4a is likely to have been introduced around 1980, from Egypt. Network analysis using HCV genetic data suggests that Kenyan PWID networks are very closely linked, with repeated transmissions between individuals likely. The prevalence of chronic HCV infection in Kenyan PWID is high at 36%, of which 62% were viraemic. Among the 34% of PWID that had HCV-HIV coinfection, 76% were HCV viraemic. The prevalence of baseline NS5A RASs in diverse HCV sub-genotypes from Uganda and Benin is high compared to HCV 1a and 4a seen in Kenyan PWID. However, in vitro experiments using a sub-genomic replicon system suggest that genotype 2 from Benin is largely susceptible to DAAs. Data from this thesis supports the WHO’s ambitious goals to achieve an 80% reduction in incident HCV infections worldwide by 2030 using appropriate DAA regimens.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology > QR355 Virology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Funder's Name: Medical Research Council (MRC)
• Supervisor's Name: Thomson, Professor Emma, Vattipally, Dr. Sreenu and Songok, Professor Elijah
• Date of Award: 2024
• Depositing User: Theses Team
• Unique ID: glathesis:2024-84468
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 17 Jul 2024 13:17
• Last Modified: 17 Jul 2024 13:42
• Thesis DOI: 10.5525/gla.thesis.84468
• URI: https://theses.gla.ac.uk/id/eprint/84468

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