Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to contr...

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Published in:	Hepatology (Baltimore, Md.) Md.), 2019-09, Vol.70 (3), p.771-787
Main Authors:	Jensen, Sanne Brun, Fahnøe, Ulrik, Pham, Long V., Serre, Stéphanie Brigitte Nelly, Tang, Qi, Ghanem, Lubna, Pedersen, Martin Schou, Ramirez, Santseharay, Humes, Daryl, Pihl, Anne Finne, Filskov, Jonathan, Sølund, Christina Søhoel, Dietz, Julia, Fourati, Slim, Pawlotsky, Jean‐Michel, Sarrazin, Christoph, Weis, Nina, Schønning, Kristian, Krarup, Henrik, Bukh, Jens, Gottwein, Judith Margarete
Format:	Article
Language:	eng
Subjects:	Anilides - therapeutic use Antiviral Agents - therapeutic use Benzimidazoles - therapeutic use Carbamates - therapeutic use Cell culture Chronic infection Denmark Disease hot spots Disease resistance Drug Resistance, Viral - genetics Drug Therapy, Combination Female Genomes Genotype Genotype & phenotype Genotypes Haplotypes Hepacivirus - drug effects Hepacivirus - genetics Hepatitis Hepatitis C Hepatitis C, Chronic - diagnosis Hepatitis C, Chronic - drug therapy Hepatology Humans Interferon Male Original Prognosis Protease Inhibitors - pharmacology Protease Inhibitors - therapeutic use Proteinase inhibitors Quinoxalines - therapeutic use Reproductive fitness Sulfonamides - therapeutic use Uracil - analogs & derivatives Uracil - therapeutic use
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Summary:	Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance–associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1‐4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156‐RASs were not maintained. For genotypes 1 and 2, persistence of 156‐RASs depended on genome‐wide substitution networks, co‐selected under continued PI treatment and identified by next‐generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156‐RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre‐existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156‐RASs, we observed genome‐wide selection of substitutions under treatment. Conclusion: Comprehensive PI resistance profiling for HCV genotypes 1‐6 revealed 156‐RASs as key determinants of high‐level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1‐3 156‐variants, which might pose a threat to clinically relevant combination treatments.
ISSN:	0270-9139 1527-3350