Worldwide Prevalence of Baseline Resistance-Associated Polymorphisms and Resistance Mutations in HCV against Current Direct-Acting Antivirals

Antiviral Therapy - Tập 23 Số 6 - Trang 485-493 - 2018
Navaneethan Palanisamy1,2, Prabhav Kalaghatgi3, Dario Akaberi4,5, Åke Lundkvist4,5, Zhiwei Chen6, Peng Hu6, Johan Lennerstrand4
1HBIGS, University of Heidelberg, Heidelberg, Germany
2Molecular and Cellular Engineering Group, BioQuant, University of Heidelberg, Heidelberg, Germany
3Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarbrücken, Germany
4Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
5Department of Medical Biochemistry and Microbiology, Zoonosis Science Center, Uppsala University, Uppsala, Sweden
6Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

10.1111/j.1478-3231.2008.01925.x

10.1016/S2468-1253(16)30181-9

10.1074/jbc.M111392200

10.1128/JVI.77.9.5401-5414.2003

10.1371/journal.ppat.1000032

10.1128/JVI.78.6.2738-2748.2004

10.1111/j.1478-3231.2011.02684.x

10.1002/hep.27259

10.1016/S0140-6736(01)06102-5

10.1093/cid/ciu697

10.1517/13543784.2013.775246

10.1080/14656566.2016.1182156

10.1002/hep.22549

10.1016/j.antiviral.2013.04.018

10.3109/23744235.2015.1028097

10.1111/jvh.12271

10.1371/journal.pone.0165339

10.1016/j.jhep.2014.11.032

10.1128/AAC.02386-13

10.1038/srep20310

10.1371/journal.pone.0155869

10.1093/bioinformatics/bti607

10.1093/nar/gkp455

10.1002/hep.27934

10.1002/hep.28422

10.1128/AAC.01149-07

10.1016/j.jhep.2012.10.028

Wyles D.L., 2017, Top Antivir Med, 25, 103

10.1128/AAC.00556-10

10.1016/j.jcv.2012.12.020

10.1128/AAC.02558-16

10.1128/AAC.02815-14

10.1074/jbc.M506462200

10.1016/S0168-8278(17)30972-8

Reau N., Nguyen M.H., Kowdley K.V. Integrated resistance analyses of HCV-infected patients treated with sofosbuvir, velpatasvir, and voxilaprevir for 8 and 12 weeks from Phase 2 Studies. AASLD The Liver Meeting. 11–15 November 2016, Boston, MA, USA. Abstract 846.

10.3851/IMP3202

10.1128/AAC.00763-16

10.1128/AAC.00581-16

Thông tin
Thông tin xuất bản

Antiviral Therapy

Tập 23 Số 6

485-493

Thông tin tác giả