The european prevalence of resistance associated substitutions among direct acting antiviral failures
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Background: Approximately 71 million people are still in need of direct-acting antiviral agents (DAAs). To achieve the World Health Organization Hepatitis C elimination goals, insight into the prevalence and influence of resistance associated substitutions (RAS) is of importance. Collaboration is key since DAA failure is rare and real-life data are scattered. We have established a European collaboration, HepCare, to perform in-depth analysis regarding RAS prevalence, patterns, and multiclass occurrence. Methods: Data were extracted from the HepCare cohort of patients who previously failed DAA therapy. Geno—and subtypes were provided by submitters and mostly based on in-house assays. They were reassessed using the Comet HCV subtyping tool. We considered RAS to be relevant if they were associated with DAA failure in vivo previously reported in literature. Results: We analyzed 938 patients who failed DAA therapy from ten different European countries. There were 239 genotypes (GT) 1a, 380 GT1b, 19 GT2c, 205 GT3a, 14 GT4a, and 68 GT4d infections. Several unusual subtypes (n = 15) (GT1b/g/l, GT3b, GT4k/n/r/t) were present. RAS appeared in over 80% of failures and over a quarter had three or more RAS. Multiclass RAS varied over target region and genotype between 0–48%. RAS patterns such as the Q30R + L31M and Q30R + Y93H in GT1a, the L31V + Y93H and L31V + Y93H for GT1b, and A30K + L31M and A30K/V + Y93H for GT3a all occurred with a prevalence below 5%. Conclusion: RAS occur frequently after DAA failures and follow a specific genotype and drug related pattern. Interpretation of the influence of RAS on retreatment is challenging due to various patterns, patients’ characteristics, and previous treatment history. Moving towards HCV elimination, an ongoing resistance surveillance is essential to track the presence of RAS, RAS patterns and gather data for a re-treatment algorithm.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 16 |
| Tidsskrift | Viruses |
| Vol/bind | 14 |
| Udgave nummer | 1 |
| ISSN | 1999-4915 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
Conflicts of Interest: S.P.: Unrestricted educational grant from Gilead sciences; V.C.: reports personal fees from ViiV Healthcare and Insmed; C.S.-D.: received educational grants from Gilead, Abbvie and Janssen; D.v.d.V.: reports grants from Gilead Sciences, MSD, ViiV Healthcare and Janssen; reports personal fees for advisory boards and/or sponsored lectures from Gilead Sciences, Bristol-Myers Squibb, AbbVie, Janssen-Cilag, ViiV Healthcare; grants and personal fees from Merck Sharp & Dohme; F.G.: reports personal fees for advisory boards and/or sponsored lectures from AbbVie, Gilead, MSD, and Roche Diagnostics; N.W.: reports clinical investigator, lecturer or advisory board for Abbvie, Gilead, GSK and MSD with fees paid to her department; unrestricted research grants from Abbvie, Gilead and Novo Nordisk Foundation; D.S.: personal fees for advisory boards and/or sponsored lectures from AbbVie, Bristol-Myers Squibb, MSD, and Janssen-Cilag; O.S.: reports institutional grants from Abbott and being subinvestigator in HCV clinical trials by Abbvie and Merck Sharp & Dohme, outside the scope of the current article; R.J.d.K.: reports institutional grants from AbbVie and Gilead and being subinvestigator in clinical trials by AbbVie (HCV) and GSK (HBV). C.A.B., A.d.S., E.H., H.K., V.C. and M.S. report no conflict of interest.
Funding Information:
Funding: This study was partially supported by Plan Nacional de I + D+I and Fondo Europeo de Desarrollo Regional-FEDER (www.redes/redes/inicio) (RD16/0025/0040), Fundación Progreso y Salud, Junta de Andalucia (http://www.juntadeandalucia.es/fundacionprogresoysalud/es) (PI-0411-2014), and GEHEP-SEIMC (GEHEP-004) to Federico García. Regarding the Italian data, the work was supported in part by the Italian Ministry of Instruction, University and Research (MIUR) (Bandiera InterOmics Protocollo PB05 1◦), by the Italian Ministry of Health (RF-2016-02362422), and by Aviralia and Vironet C Foundations. Regarding the German data DZIF-TTU-Hepatitis/PEPSI. The Dutch data was partially funded by Gilead Sciences as part of the NoCo grant [IN-NL-987-4558].
Funding Information:
This study was partially supported by Plan Nacional de I + D+I and Fondo Europeo de Desarrollo Regional-FEDER (www.redes/redes/inicio) (RD16/0025/0040), Fundaci?n Progreso y Salud, Junta de Andalucia (http://www.juntadeandalucia.es/fundacionprogresoysalud/es) (PI-04112014), and GEHEP-SEIMC (GEHEP-004) to Federico Garc?a. Regarding the Italian data, the work was supported in part by the Italian Ministry of Instruction, University and Research (MIUR) (Bandiera InterOmics Protocollo PB05 1?), by the Italian Ministry of Health (RF-2016-02362422), and by Aviralia and Vironet C Foundations. Regarding the German data DZIF-TTU-Hepatitis/PEPSI. The Dutch data was partially funded by Gilead Sciences as part of the NoCo grant [IN-NL-987-4558].
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© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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