CARACTERIZACIÓN MOLECULAR DEL PERFIL DE RESISTENCIAS DEL VIRUS DE LA HEPATITIS C DESPUÉS DEL FALLO TERAPÉUTICO A ANTIVIRALES DE ACCIÓN DIRECTA MEDIANTE SECUENCIACIÓN MASIVA

Abstract

Chronic hepatitis C infection is considered as a major public health issue worldwide due to its linkage to the development of advanced liver diseases and hepatocellular carcinoma. Currently, the availability of highly efficient and well-tolerated antiviral therapies based on combinations of direct acting antivirals (DAAs) has provided sustained virological response (SVR) in nearly 95% of patients. Despite the excellent efficacy of DAAs, still a non-negligible percentage of patients do not achieve virological cure. At treatment failure, resistance-associated substitutions (RASs) are usually selected at high frequencies in the viral population. While selection of RASs has an important role in treatment failure, the clinical impact of RASs and its relevance in retreatment still remain unknown. Few real-life data on RASs testing are available, mainly performed by Sanger sequencing. In this PhD Thesis, we have performed a RASs analysis in a cohort of 220 patients who experienced treatment failure to several DAA combinations using next generation sequencing. In our analysis, the RASs profile that emerge after each DAA-based treatment was subtype-specific, which strongly suggests the use of subtype-specific primers to avoid amplification bias. Also, several high prevalent RASs combinations were characterized, suggesting the importance of their detection before retreatment due to their high level of resistance. Moreover, attending to the high occurrence of extra-target RASs detected, testing all genomic regions for RASs analysis is strongly recommended for treatment decision making. In summary, the high prevalence of RASs at treatment failure, the high amount of minority RASs and the combination of RASs at the same genome, reinforce the importance of RASs analysis before retreatment using ultra-deep sequencing in order to maximize SVR. The outcome of patients who undergo retreatment should be also analysed in order to characterize clinically meaningful RASs.

Date of Award	19 Nov 2018
Original language	Spanish
Supervisor	Celia Perales Viejo (Director), Josep Quer Sivila (Director) & Josep Gregori i Font (Director)