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 active against known NS3 protease and NS5B polymerase inhibitor RAVs with EC50 values equivalent to those for the wild type.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Cheng G,Tian Y,Doehle B,Peng B,Corsa A,Lee YJ,Gong R,Yu M,Han B,Xu S,Dvory-Sobol H,Perron M,Xu Y,Mo H,Pagratis N,Link JO,Delaney Wdoi
10.1128/AAC.02524-15subject
Has Abstractpub_date
2016-01-11 00:00:00pages
1847-1853issue
3eissn
0066-4804issn
1098-6596pii
AAC.02524-15journal_volume
60pub_type
杂志文章abstract::A double-blind study was performed to compare the clinical response and the incidence of side effects in 2,581 patients administered ampicillin or cyclacillin for infections of the genitourinary or respiratory tract, infections of the skin and soft tissues, or for otitis media. There was no significant difference in c...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/aac.38.9.1930
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pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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