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Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1-7

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Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1-7 Gastroenterology 2018;154:1435–1448 Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1–7 and Escape Variants Judith M. Gottwein, Long V. Pham, Lotte S. Mikkelsen, Lubna Ghanem, Santseharay Ramirez, Troels K. H. Scheel, Thomas H. R. Carlsen, and Jens Bukh Copenhagen Hepatitis C Program, Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark Hepatitis C virus NS5A inhibitors pibrentasvir and velpatasvir show pangenotypic efficacy HCV genotype Size~EC50 1 5 2 6 3 7 4 Pibrentasvir showed highest efficacy against hepatitis C virus genotype 1-7 escape variants Daclatasvir Ledipasvir Induction of escape Sequencing of genotype 1-7 Reverse genetics Fold Ombitasvir NS5A domain I Resistance testing Resistance (log10) Elbasvir Ruzasvir 6 Velpatasvir 4 2 Pre-existing Y93H results in escape variants with increased fitness and resistance Pibrentasvir 28 30 31 Δ32 93 Pre-existing Y93H Original .5 .0 .5 .0 .5 0 1 2 3 4 5 6 -1 -1 -0 0 0 Fitness + Fold Resistance (log10) (titer difference, log10) BACKGROUND & AIMS: Inhibitors of the hepatitis C virus For the remaining NS5A inhibitors tested, RAS at amino (HCV) NS5A protein are a key component of effective treatment acids 28 and 93 led to high levels of resistance. Among regimens, but the genetic heterogeneity of HCV has limited the these inhibitors, velpatasvir was more effective against variants efficacy of these agents and mutations lead to resistance. We with RAS at amino acid 30 and some variants with RAS at BASIC AND fi directly compared the ef cacy of all clinically relevant NS5A amino acid 31 than the other agents. Variants with the pre- TRANSLATIONAL LIVER inhibitors against HCV genotype 1–7 prototype isolates and existing RAS T/Y93H acquired additional NS5A changes dur- resistant escape variants, and investigated the effects of pre- ing escape experiments, resulting in HCV variants with specific existing resistance-associated substitutions (RAS) on HCV combinations of RAS, showing high fitness and high resistance. escape from treatment. METHODS: We measured the efficacy CONCLUSIONS: We performed a comprehensive comparison of of different concentrations of daclatasvir, ledipasvir, ombi- the efficacy of the 7 clinically relevant inhibitors of HCV NS5A tasvir, elbasvir, ruzasvir, velpatasvir, and pibrentasvir in and identified variants associated with resistance to each agent. cultured cells infected with HCV recombinants expressing ge- These findings could improve treatment of patients with HCV notype 1–7 NS5A proteins with or without RAS. We engineered infection. HCV variants that included RAS identified in escape experi- ments, using recombinants with or without T/Y93H and daclatasvir, or that contained RAS previously reported from Keywords: Liver Disease; Direct Acting Antiviral; DAA; Drug patients. RESULTS: NS5A inhibitors had varying levels of effi- Resistance. cacy against original and resistant viruses. Only velpatasvir and pibrentasvir had uniform high activity against all HCV geno- types tested. RAS hotspots in NS5A were found at amino acids 28, 30, 31, and 93. Engineered escape variants had high levels Abbreviations used in this paper: aa, amino acid; DAA, direct-acting of fitness. Pibrentasvir had the highest level of efficacy against antiviral; EC50, median effective concentration; FFU, focus forming unit; variants; viruses with RAS at amino acids 28, 30, or 31 HCV, hepatitis C virus; RAS, resistance-associated substitution. had no apparent resistance to pibrentasvir, and HCV with Most current article RAS at amino acid 93 had a low level of resistance to this fi © 2018 by the AGA Institute drug. However, speci c combinations of RAS and deletion of 0016-5085/$36.00 amino acid 32 led to significant resistance to pibrentasvir. https://doi.org/10.1053/j.gastro.2017.12.015 1436 Gottwein et al Gastroenterology Vol. 154, No. 5 Given their frequency and impact on the success of DAA- EDITOR’S NOTES based treatments, it is crucial to identify and characterize BACKGROUND AND CONTEXT NS5A RAS for the 7 major HCV genotypes and important 8,9 fi Hepatitis C virus (HCV) NS5A-inhibitors are critical for subtypes. In addition, it is essential to compare the ef - regimens used to treat patients with chronic hepatitis C. cacy of relevant NS5A inhibitors against isolates of different An independent comparison of the efficacy of the six genotypes and resistant variants. In vitro studies allow licensed compounds is however not available, and systematic head-to-head comparisons of DAA efficacy for a resistance needs to be better defined for the different large number of DAA and HCV variants, and are required to HCV genotypes. determine the degree of resistance conferred by putative NEW FINDINGS RAS identified in vitro or in patients. Such studies have Pibrentasvir and velpatasvir showed uniformly high mostly been done for HCV genotype 1, while data for other 12,14,17–28 efficacy against HCV genotype 1-7 isolates. Pibrentasvir genotypes are limited. Even though NS5A in- had the highest efficacy against daclastasvir escape hibitors were shown to act on different steps of the viral life variants. Pre-existing Y/T93H facilitated selection of cycle, the majority of reported in vitro studies used replicon highly fit and resistant escape variants. systems, only mimicking viral replication.17–26,28–30 In LIMITATIONS contrast, infectious culture systems reflect the entire viral life cycle,31 and data on efficacy of and resistance to NS5A Escape variants were selected under daclatasvir treatment; similar studies for newer inhibitors remain to inhibitors obtained in these systems have proven to be in 20,27,32–39 be carried out. agreement with clinical data. However, limited data on NS5A-inhibitor treatment escape have been IMPACT obtained in such systems.27,33,38 The study provides a direct comparison of the efficacy of We aimed at providing an independent head-to-head all licensed HCV NS5A-inhibitors against different HCV comparison of the efficacy of all currently licensed HCV variants and highlights the impact of pre-existing NS5A inhibitors against the major HCV genotypes and resistance mutations on resistance development. important subtypes, as well as resistant escape variants, in infectious culture systems. We first determined the efficacy of daclatasvir, ledipasvir, ombitasvir, elbasvir, ruzasvir, lmost all novel combination treatments against velpatasvir, and pibrentasvir against HCV recombinants A hepatitis C virus (HCV) include direct acting antivi- with genotype 1–7 specific NS5A. To generate a panel of – rals (DAA) targeting domain I of HCV NS5A,1 4 a protein relevant resistant variants, we also used these genotype 1–7 – with an essential role for viral replication and assembly.5 7 recombinants to induce viral escape from treatment with Since 2014, six NS5A inhibitors—daclatasvir, ledipasvir, the first-in-class NS5A inhibitor daclatasvir.20 Engineered — fi TRANSLATIONAL LIVER ombitasvir, elbasvir, velpatasvir, and pibrentasvir were escape variants were characterized regarding tness and approved for clinical use, while ruzasvir has been in resistance to NS5A inhibitors. At last, we aimed at investi- BASIC AND advanced stages of clinical development. While approval gating the influence of pre-existing RAS at NS5A position 93 was initially limited to treatment of HCV genotype 1– on resistance development. infected patients, it was subsequently expanded to treatment of patients infected with other major HCV gen- otypes.1–4,8,9 HCV is classified within the Flaviviridae family Material and Methods and has 7 highly divergent major genotypes, further sub- divided into subtypes.8–10 Up to 200 million individuals are Hepatitis C Virus Recombinant Viruses 40 estimated to be chronically infected with HCV and have an J6/JFH1, in this study designated 2a(JFH1), and J6/ increased risk for liver cirrhosis and liver cancer, resulting JFH1-based recombinants with genotype(isolate) 1a(H77)-, in up to 750,000 deaths per year.11 1a(TN)-, 1a(DH6)-, 1a(HCV1)-, 1a(J1)-, 1b(J4)-, 2a(J6)-, 3a(S52)-, fi Despite high success rates of DAA-based treatment regi- 4a(ED43)-, 5a(SA13)-, 6a(HK6a)-, and 7a(QC69)-speci c NS5A mens, a small percentage of patients experience treatment and derived T/Y93H mutants and their respective GenBank IDs were reported previously.32 3a(S52) was further adapted failure.12,13 HCV resistance is an important cause of treatment by C2419R (amino acid [aa] positions in this paragraph are failure and the majority of these patients harbor HCV- absolute H77 [GenBank ID AF009606] reference numbers, resistant variants with resistance-associated substitutions 12 whereas in the following NS5A substitutions are indicated (RAS) in the drug protein targets. Recent evidence suggests relative to H77 NS5A).41 For 2b(J8) (GenBank ID MG406988), that NS5A RAS persist long term in patients after treatment 34 12,14 the pJ8CF NS5A sequence was cloned into J6/JFH1. For failure, facilitating spread of resistant variants in pop- 1b(DH1) (GenBank ID MG406987),42 the NS5A consensus 15 ulations. In addition, NS5A RAS are found as naturally sequence was determined by analysis of clones of reverse occurring polymorphisms in a relatively high percentage of transcription polymerase chain reaction amplicons and cloned 12,14 treatment-naïve patients. Clinical studies demonstrated into J6/JFH1 with adaptive substitutions R867H/C1185S, that for various DAA-based treatment regimens, pre-existing identified
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