Navaneethan Palanisamy1,2, Prabhav Kalaghatgi3, Dario Akaberi4,5, Åke Lundkvist4,5, Zhi-Wei Chen6, Peng Hu6, Johan Lennerstrand4. 1. HBIGS, University of Heidelberg, Heidelberg, Germany. 2. Molecular and Cellular Engineering Group, BioQuant, University of Heidelberg, Heidelberg, Germany. 3. Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarbrücken, Germany. 4. Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 5. Department of Medical Biochemistry and Microbiology, Zoonosis Science Center, Uppsala University, Uppsala, Sweden. 6. Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Abstract
BACKGROUND: HCV infections can now be completely cured, thanks to the currently marketed direct-acting antivirals (DAAs). It is known that HCV patients carry viral populations with baseline polymorphisms and/or mutations that make them resistant against some of these DAAs, which can negatively impact the patient's treatment outcome. Using complete HCV coding sequences isolated from 1,306 treatment-naive patients of genotypes (GTs) 1, 2, 3, 4 and 6 from around the globe, we studied the prevalence of baseline resistance-associated polymorphisms (RAPs) and resistance mutations (RMs) against DAAs that are currently on the market or in clinical trials. METHODS: The HCV genome sequences used in this study were retrieved from the NCBI database. RAPs and RMs, with reference to HCV GT1a, were identified using the HCV Geno2pheno web server. RESULTS: Nearly 50% of the total amino acid positions (including NS3 protease, NS5A and NS5B) studied are baseline polymorphisms that differentiated one GT from the rest. A proportion of these baseline polymorphisms and baseline non-polymorphic RMs could confer a significant increase in resistance against DAAs. CONCLUSIONS: In this study, we show the presence and prevalence of RAPs and RMs in DAA treatment-naive patients against currently used DAAs or DAAs in clinical trials. Our study suggests that RAPs and RMs profiling of HCV patients should be performed before the start of the therapy. Our results should be relevant especially in low- and middle-income countries, where the patients have a large variation of GTs and subtypes, and where the generic HCV treatment is now increasingly available.
BACKGROUND: HCV infections can now be completely cured, thanks to the currently marketed direct-acting antivirals (DAAs). It is known that HCV patients carry viral populations with baseline polymorphisms and/or mutations that make them resistant against some of these DAAs, which can negatively impact the patient's treatment outcome. Using complete HCV coding sequences isolated from 1,306 treatment-naive patients of genotypes (GTs) 1, 2, 3, 4 and 6 from around the globe, we studied the prevalence of baseline resistance-associated polymorphisms (RAPs) and resistance mutations (RMs) against DAAs that are currently on the market or in clinical trials. METHODS: The HCV genome sequences used in this study were retrieved from the NCBI database. RAPs and RMs, with reference to HCV GT1a, were identified using the HCV Geno2pheno web server. RESULTS: Nearly 50% of the total amino acid positions (including NS3 protease, NS5A and NS5B) studied are baseline polymorphisms that differentiated one GT from the rest. A proportion of these baseline polymorphisms and baseline non-polymorphic RMs could confer a significant increase in resistance against DAAs. CONCLUSIONS: In this study, we show the presence and prevalence of RAPs and RMs in DAA treatment-naive patients against currently used DAAs or DAAs in clinical trials. Our study suggests that RAPs and RMs profiling of HCV patients should be performed before the start of the therapy. Our results should be relevant especially in low- and middle-income countries, where the patients have a large variation of GTs and subtypes, and where the generic HCV treatment is now increasingly available.
Authors: Mark W Douglas; Enoch S E Tay; Dao Sen Wang; Adrian T L Ong; Caroline Wilson; Amy Phu; Jen Kok; Dominic E Dwyer; Rowena A Bull; Andrew R Lloyd; Tanya L Applegate; Gregory J Dore; Anita Y Howe; Richard Harrigan; Jacob George Journal: Hepatol Commun Date: 2020-04-06
Authors: Laurent Mailly; Florian Wrensch; Laura Heydmann; Catherine Fauvelle; Nicolas Brignon; Mirjam B Zeisel; Patrick Pessaux; Zhen-Yong Keck; Catherine Schuster; Thomas R Fuerst; Steven K H Foung; Thomas F Baumert Journal: Antiviral Res Date: 2018-12-30 Impact factor: 10.103