In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

Antimicrobial Agents and Chemotherapy
Guofeng ChengWilliam Delaney

Abstract

Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, including in vitro potency, in vitro resistance profile, and activity in combination with other anti-HCV agents. LDV has picomolar antiviral activity against genotype 1a and genotype 1b replicons with 50% effective concentration (EC50) values of 0.031 nM and 0.004 nM, respectively. LDV is also active against HCV genotypes 4a, 4d, 5a, and 6a with EC50 values of 0.11 to 1.1 nM. LDV has relatively less in vitro antiviral activity against genotypes 2a, 2b, 3a, and 6e, with EC50 values of 16 to 530 nM. In vitro resistance selection with LDV identified the single Y93H and Q30E resistance-associated variants (RAVs) in the NS5A gene; these RAVs were also observed in patients after a 3-day monotherapy treatment. In vitro antiviral combination studies indicate that LDV has additive to moderately synergistic antiviral activity when combined with other classes of HCV direct-acting antiviral (DAA) agents, including NS3/4A protease inhibitors and the nucleotide NS5B polymerase inhibitor SOF. Furthermore, LDV is ac...Continue Reading

References

Mar 1, 1993·Antimicrobial Agents and Chemotherapy·M N PrichardC Shipman
Mar 7, 2009·The Journal of General Virology·Mair HughesMark Harris
Jun 3, 2010·Antimicrobial Agents and Chemotherapy·Margaret RobinsonWilliam E Delaney
Nov 26, 2010·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·D Lavanchy
Apr 29, 2011·Journal of Virology·Seungtaek KimStanley M Lemon
Jun 17, 2011·Liver International : Official Journal of the International Association for the Study of the Liver·Francesco Negro, Alfredo Alberti
Mar 21, 2012·Antimicrobial Agents and Chemotherapy·Angela M LamPhillip A Furman
Sep 25, 2012·Gastroenterology·Betty PengGuofeng Cheng
Aug 14, 2013·Antimicrobial Agents and Chemotherapy·Huiling YangWilliam E Delaney
Jan 15, 2014·Antimicrobial Agents and Chemotherapy·Joy Y FengAdrian S Ray
Feb 20, 2014·Antimicrobial Agents and Chemotherapy·Mei YuGuofeng Cheng
Apr 15, 2014·The New England Journal of Medicine·Nezam AfdhalUNKNOWN ION-2 Investigators
Apr 15, 2014·The New England Journal of Medicine·Nezam AfdhalUNKNOWN ION-1 Investigators
Dec 3, 2014·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·Marc BourlièrePaul Castellani
Jan 30, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Zobair M YounossiSharon L Hunt

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Citations

Dec 9, 2016·Hepatology International·Rebecca LeeEleanor Wilson
Nov 20, 2016·Journal of Computational Chemistry·Ester SesmeroIan F Thorpe
May 24, 2017·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Jordan J FeldMark G Swain
Nov 9, 2017·Current HIV/AIDS Reports·David L Wyles
Feb 15, 2017·Antimicrobial Agents and Chemotherapy·Teresa I NgChristine Collins
Aug 10, 2016·Antimicrobial Agents and Chemotherapy·Christopher M OwensYat Sun Or
Aug 10, 2016·Antimicrobial Agents and Chemotherapy·Christopher M OwensYat Sun Or
Nov 1, 2016·Clinical Microbiology Reviews·Eleanor M WilsonShyam Kottilil
Apr 23, 2019·Journal of Viral Hepatitis·Hadas Dvory-SobolHongmei Mo
Jul 6, 2019·Journal of Viral Hepatitis·Charlotte PronierUNKNOWN AFEF/ANRS Hepather study group
Nov 10, 2017·European Journal of Gastroenterology & Hepatology·Stephan MoserMichael Gschwantler
Feb 7, 2018·Hepatology Communications·Edward J GaneEric Lawitz
Oct 11, 2017·Journal of Medical Virology·Itzíar CarrascoCarmen de Mendoza
May 3, 2020·Chemistry : a European Journal·Haibo MeiVadim A Soloshonok
Jan 29, 2019·Alimentary Pharmacology & Therapeutics·Panita MettikanontK Rajender Reddy
Mar 23, 2021·Journal of Clinical and Experimental Hepatology·Gulzar A DarMushtaq A Laway
Sep 24, 2020·European Journal of Medicinal Chemistry·Jiang LiuVadim A Soloshonok
Nov 19, 2021·ACS Medicinal Chemistry Letters·Wieslaw M KazmierskiSam Baskaran

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