STRATEGIES TO OPTIMISE TREATMENTS FOR CHRONIC HCV INFECTION IN PATIENTS WITH ADVANCED LIVER DISEASE

Chronic hepatitis C virus (HCV) infection affects 70 million people worldwide. HCV infection leads to chronic liver injury with progression to cirrhosis, hepatocellular carcinoma, end-stage liver disease and death. Since its discovery just under 30 years ago, understanding of the virus and its treatment have revolutionised, and HCV infection is now one of the few curable chronic conditions. The most significant milestone in the treatment of HCV has been the availability of direct-acting antivirals (DAAs) which produce extremely high rates of HCV clearance with minimal side effects, enabling a global strategy to eliminate HCV as a public health threat by 2030. One of the remaining challenges in HCV treatment is to understand and overcome antiviral drug failure. While re-treatment options are available, these are costly and cannot be used in patients with advanced liver disease. On a global scale, the small proportion of treatment failures amount to a substantial and growing number of individuals with persistent HCV and progressive liver disease. It is widely recognised that individuals with genotype 3 (G3) HCV and advanced liver disease have poorer responses to DAAs. Virological response with common drug regimens (available up to 2016) for patients with cirrhosis were well above 90% in G1 (Sulkowski, Gardiner et al. 2014, Curry, O'Leary et al. 2015, Feld, Jacobson et al. 2015) but only 60-90% in G3 infections (Foster, Afdhal et al. 2015, Nelson, Cooper et al. 2015). The mechanisms of treatment failure are incompletely understood. This thesis explores predictors of DAA failure, and strategies to optimise treatment for ‘difficult to treat’ patients. The first part of my research involves studying a unique, large patient cohort which first received DAAs in the United Kingdom (the ‘Expanded Access Programme’). Based on findings from these analyses, I designed and conducted a randomised controlled trial evaluating a ‘response-guided approach’ to selecting optimal duration of DAA treatment (the ‘Extend-3’ trial). Additionally, I describe work looking at viral sequencing and resistance substitutions to explain treatment failure in G3 HCV