title: Combinations of lambda interferon with direct-acting antiviral agents are highly efficient in suppressing hepatitis C virus replication.
abstract: The clinical efficacy of a pegylated form of human lambda 1 interferon (IFN-λ1; also referred to herein as lambda) has been demonstrated in patients chronically infected with hepatitis C virus (HCV) representing genotypes 1 through 4. In these proof-of-concept studies, lambda showed an improved safety profile compared to the pegylated form of alpha interferon (referred to herein as alfa). In the study described in this report, an assessment of the in vitro antiviral activity of type III IFNs toward different HCV replicons revealed that the unpegylated recombinant form of IFN-λ1 (rIFN-λ1) exerted the most robust effect, while rIFN-λ3 exhibited greater activity than rIFN-λ2. More importantly, cross-resistance to rIFN-λ1 was not observed in replicon cell lines known to have reduced susceptibility to investigational direct-acting antiviral (DAA) agents targeting the essential HCV nonstructural protein NS3, NS5A, or NS5B. When combined with either rIFN-α, the NS3 protease inhibitor (NS3 PI) asunaprevir (ASV), the NS5A replication complex inhibitor (NS5A RCI) daclatasvir (DCV), or the NS5B polymerase site I inhibitor (NS5B I) BMS-791325, rIFN-λ1 displayed a mixture of additive and synergistic effects. In three-drug combination studies, inclusion of lambda with ASV and DCV also yielded additive to synergistic effects. In line with these observations, it was demonstrated that a regimen that used a combination of rIFN-λ1 with one or two DAAs was superior to an IFN-free regimen in clearing HCV RNA in genotype 1a cell lines representing wild-type and NS3 protease inhibitor-resistant sequences. Overall, these data support further clinical development of lambda as part of alternative combination treatments with DAAs for patients chronically infected with HCV.
authors.affiliation: Discovery Virology, Bristol-Myers Squibb Research and Development, Wallingford, CT, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Friborg
authors.forename: Steven
authors.initials: S
authors.lastname: Levine
authors.forename: Chaoqun
authors.initials: C
authors.lastname: Chen
authors.forename: Amy K
authors.initials: AK
authors.lastname: Sheaffer
authors.forename: Susan
authors.initials: S
authors.lastname: Chaniewski
authors.forename: Stacey
authors.initials: S
authors.lastname: Voss
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lemm
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002219:Carbamates; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology; D007372:Interferons; D007378:Interleukins / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D020033:Protein Isoforms / Q000494:pharmacology; D011759:Pyrrolidines; D011994:Recombinant Proteins / Q000494:pharmacology; D012093:Replicon / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D000095022:Interferon Lambda; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D007546:Isoquinolines; D011092:Polyethylene Glycols; D011480:Protease Inhibitors; D020033:Protein Isoforms; D011759:Pyrrolidines; D011994:Recombinant Proteins; D013449:Sulfonamides; D014633:Valine; D017361:Viral Nonstructural Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir; C100416:peginterferon alfa-2a; C571889:asunaprevir