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

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

Shah, Rajiv Nagin

DOI:

Abstract

Hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide with an estimated 58 million suffering with chronic 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 (DAAs), which have revolutionised the treatment of 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 sub genotypes are more challenging to treat, for example sub-genotypes 1l and 4r.The aims of this thesis were to explore the diversity of using datasets from Uganda and Benin. Furthermore, the prevalence of and associated liver disease from people who inject drugs (PWID) in Coastal Kenya was assessed and genetic data was used to explore PWID networks and estimate the origin of in this community. We found highly divergent 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 1afrom Europe into Kenyan PWID, as recently as 2001, whereas 4a is likely to have been introduced around 1980, from Egypt. Network analysis using genetic data suggests that Kenyan PWID networks are very closely linked, with repeated transmissions between individuals likely. The prevalence of chronic 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 viraemic. The prevalence of baseline NS5A RASs in diverse sub-genotypes from Uganda and Benin is high compared to 1a and 4a seen in Kenyan PWID. However, in vitroexperiments 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% in incident infections worldwide by 2030 using appropriate DAA regimens.

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