Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome.
direct-acting antivirals
genome-wide association studies
hepatitis C virus
next-generation sequencing
resistance-associated substitution
treatment failure
Journal
Journal of viral hepatitis
ISSN: 1365-2893
Titre abrégé: J Viral Hepat
Pays: England
ID NLM: 9435672
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
24
06
2020
revised:
20
09
2020
accepted:
28
09
2020
pubmed:
2
11
2020
medline:
1
9
2021
entrez:
1
11
2020
Statut:
ppublish
Résumé
Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p = .0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.
Substances chimiques
Antiviral Agents
0
Viral Nonstructural Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
302-316Informations de copyright
© 2020 John Wiley & Sons Ltd.
Références
Bukh J. The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control. J Hepatol. 2016;65(1):S2-S21.
Pawlotsky JM, Negro F, Aghemo A, et al. EASL recommendations on treatment of Hepatitis C 2018. J Hepatol. 2018;69(2):461-511.
Childs-Kean LM, Brumwell NA, Lodl EF. Profile of sofosbuvir/velpatasvir/voxilaprevir in the treatment of hepatitis C. Infect Drug Resist. 2019;12:2259-2268.
Pawlotsky JM, Feld JJ, Zeuzem S, Hoofnagle JH. From non-A, non-B hepatitis to hepatitis C virus cure. J Hepatol. 2015;62(S1):S87-S99.
Johnson K, Green PK, Ioannou GN. Implications of HCV RNA level at week 4 of direct antiviral treatments for hepatitis C. J Viral Hepat. 2017;24(11):966-975.
Pawlotsky JM, Hepatitis C. Virus resistance to direct-acting antiviral drugs in interferon-free regimens. Gastroenterology. 2016;151(1):70-86.
Dietz J, Susser S, Vermehren J, et al. Patterns of resistance-associated substitutions in patients with chronic HCV infection following treatment with direct-acting antivirals. Gastroenterology. 2018;154(4):976-988.e4.
Pham LV, Jensen SB, Fahnøe U, et al. HCV genotype 1-6 NS3 residue 80 substitutions impact protease inhibitor activity and promote viral escape. J Hepatol. 2019;70(3):388-397.
Jensen SB, Fahnøe U, Pham LV, et al. Evolutionary pathways to persistence of highly fit and resistant hepatitis C virus protease inhibitor escape variants. Hepatology. 2019;70(3):771-787.
Pham LV, Ramirez S, Gottwein JM, et al. HCV genotype 6a escape from and resistance to velpatasvir, pibrentasvir, and sofosbuvir in robust infectious cell culture models. Gastroenterology. 2018;154(8):2194-2208.e12.
Gottwein JM, Pham LV, Mikkelsen LS, et al. Efficacy of NS5A inhibitors against hepatitis C virus genotypes 1-7 and escape variants. Gastroenterology. 2018;154(5):1435-1448.
Jensen SB, Serre SBN, Humes DG, et al. Substitutions at NS3 residue 155, 156, or 168 of hepatitis C virus genotypes 2 to 6 induce complex patterns of protease inhibitor resistance. Antimicrob Agents Chemother. 2015;59(12):7426-7436.
Sarrazin C. The importance of resistance to direct antiviral drugs in HCV infection in clinical practice. J Hepatol. 2016;64(2):486-504.
Bartlett SR, Grebely J, Eltahla AA, et al. Sequencing of hepatitis C virus for detection of resistance to direct-acting antiviral therapy: a systematic review. Hepatol Commun. 2017;1(5):379-390.
Takeda H, Ueda Y, Inuzuka T, et al. Evolution of multi-drug resistant HCV clones from pre-existing resistant-associated variants during direct-acting antiviral therapy determined by third-generation sequencing. Sci Rep. 2017;7(45605).
Sølund C, Hallager S, Pedersen MS, et al. Direct acting antiviral treatment of chronic hepatitis C in Denmark: factors associated with and barriers to treatment initiation. Scand J Gastroenterol. 2018;53(7):849-856.
Weis N, Thomsen RW,DANHEP-styregruppen. The Danish database for hepatitis B and C. Ugeskr Laeger. 2012;174(42):2521.
Sølund C, Andersen ES, Mössner B, et al. Outcome and adverse events in patients with chronic hepatitis C treated with direct-acting antivirals: A clinical randomized study. Eur J Gastroenterol Hepatol. 2018;30(10):1177-1186.
Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24(2):289-293.
Treatment of chronic hepatitis B and C infection. Danish Soc Infect Dis GaH. 2014.
Treatment of hepatitis B virus and hepatitis C virus infection. Danish Soc Infect Dis GaH. 2015.
Dalgard O, Weiland O, Noraberg G, et al. Sofosbuvir based treatment of chronic hepatitis C genotype 3 infections - A Scandinavian real-life study. PLoS One. 2017;12(7):e0179764.
Fahnøe U, Bukh J. Full-length open reading frame amplification of hepatitis C virus. Methods Mol Biol. 2019;1911:85-91.
Paolucci S, Fiorina L, Piralla A, et al. Naturally occurring mutations to HCV protease inhibitors in treatment-nave patients. Virol J. 2012;9(245).
Andre-Garnier E, Besse B, Rodallec A, et al. An NS5A single optimized method to determine genotype, subtype and resistance profiles of Hepatitis C strains. PLoS One. 2017;12(7):e0179562.
Pedersen MS, Fahnøe U, Hansen TA, et al. A near full-length open reading frame next generation sequencing assay for genotyping and identification of resistance-associated variants in hepatitis C virus. J Clin Virol. 2018;105:49-56.
Guindon S, Dufayard JF, Lefort V, Anisimova M, Hordijk W, Gascuel O. New algorithms and methods to estimate maximum-likelihood phylogenies: Assessing the performance of PhyML 3.0. Syst Biol. 2010;59(3):307-321.
Peltola T, Marttinen P, Jula A, Salomaa V, Perola M, Vehtari A. Bayesian variable selection in searching for additive and dominant effects in genome-wide data. PLoS One. 2012;7(1):e29115.
Bartenschlager R, Baumert TF, Bukh J, et al. Critical challenges and emerging opportunities in hepatitis C virus research in an era of potent antiviral therapy: considerations for scientists and funding agencies. Virus Res. 2018;248:53-62.
Salmon D, Trimoulet P, Gilbert C, et al. Factors associated with DAA virological treatment failure and resistance-associated substitutions description in HIV/ HCV coinfected patients. World J Hepatol. 2018;10(11):856-866.
Perpiñán E, Caro-Pérez N, García-González N, et al. Hepatitis C virus early kinetics and resistance-associated substitution dynamics during antiviral therapy with direct-acting antivirals. J Viral Hepat. 2018;25(12):1515-1525.
Paolucci S, Premoli M, Novati S, et al. Baseline and breakthrough resistance mutations in HCV patients failing DAAs. Sci Rep. 2017;7(1):16017.
Liu D, Ji J, Ndongwe TP, et al. Fast hepatitis C virus RNA elimination and NS5A redistribution by NS5A inhibitors studied by a multiplex assay approach. Antimicrob Agents Chemother. 2015;59(6):3482-3492.
Guedj J, Dahari H, Rong L, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci USA. 2013;110(10):3991-3996.
Kohli A, Osinusi A, Sims Z, et al. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet. 2015;385(9973):1107-1113.
Cento V, Nguyen THT, Di Carlo D, et al. Improvement of ALT decay kinetics by all-oral HCV treatment: role of NS5A inhibitors and differences with IFN-based regimens. PLoS One. 2017;12(5):e0177352.
Zeuzem S, Mizokami M, Pianko S, et al. NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: prevalence and effect on treatment outcome. J Hepatol. 2017;66(5):910-918.
Cento V, Chevaliez S, Perno CF. Resistance to direct-acting antiviral agents: clinical utility and significance. Curr Opin HIV AIDS. 2015;10(5):381-389.
Wing PAC, Jones M, Cheung M, et al. Amino acid substitutions in genotype 3a hepatitis C virus polymerase protein affect responses to sofosbuvir. Gastroenterology. 2019;157(3):692-704.e9.
Wu R, Geng D, Chi X, et al. Computational analysis of naturally occurring resistance-associated substitutions in genes NS3, NS5A, and NS5B among 86 subtypes of hepatitis C virus worldwide. Infect Drug Resist. 2019;12:2987-3015.
Kaul A, Woerz I, Meuleman P, Leroux-Roels G, Bartenschlager R. Cell culture adaptation of hepatitis C virus and in vivo viability of an adapted variant. J Virol. 2007;81(23):13168-13179.
Kaul A, Stauffer S, Berger C, et al. Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics. PLoS Pathog. 2009;5(8):e1000546.
Singer JB, Thomson EC, McLauchlan J, Hughes J, Gifford RJ. GLUE: a flexible software system for virus sequence data. BMC Bioinformatics. 2018;19(1):532.
Kalaghatgi P, Maria Sikorski A, Knops E, et al. Geno2pheno[HCV] - A web-based interpretation system to support hepatitis c treatment decisions in the era of direct-acting antiviral agents. PLoS One. 2016;11(5):e0155869.
Kozbial K, Al-Zoairy R, Gschwantler M, et al. Management of patients with chronic hepatitis C failing repeated courses of interferon-free direct acting antiviral combination therapy. GastroHep. 2019;1(2):76-83.