title: In vitro combinations containing Tegobuvir are highly efficient in curing cells from HCV replicon and in delaying/preventing the development of drug resistance.
abstract: Tegobuvir (GS-9190) is a non-nucleoside inhibitor of HCV RNA replication with proven antiviral activity in HCV-infected patients. The in vitro antiviral activity of Tegobuvir, when combined with one or two other direct acting antivirals (DAA) was assessed. When Tegobuvir was combined with either interferon α-2b, ribavirin, the protease inhibitor (PI) VX-950, the nucleoside polymerase inhibitor (NI) 2'-C-methylcytidine or various non-nucleoside polymerase inhibitors, an overall additive antiviral activity was observed. Adding Tegobuvir (at concentrations of 6, 30 or 150nM) to replicon-containing cells in the presence of suboptimal concentrations of the PI or of the various polymerase inhibitors either markedly delayed or completely prevented resistance development against these latter compounds. Tegobuvir (15nM), when combined with the PI, was able to cure replicon-containing cells from their replicon after a single passage, whereas either compound alone (at 2-fold higher concentration) was not. The triple combination of Tegobuvir (10nM), the PI and the NI resulted in clearance of replicon RNA after only two passages. In contrast, the inhibitors when used alone at 3-fold higher concentrations were not able to cure the cells from the replicon, after as long as 6 passages. Combinations containing low concentrations of Tegobuvir are thus highly effective in curing cells from HCV replicon and in delaying or preventing the development of resistance against other DAA.
authors.affiliation: Rega Institute, Leuven, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Vliegen
authors.affiliation: Rega Institute, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Paeshuyse
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Rega Institute, Leuven, Belgium. Electronic address: johan.neyts@rega.kuleuven.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D016174:Hepacivirus / Q000187:drug effects*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D012254:Ribavirin / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011687:Purines; D011724:Pyridazines; D012367:RNA, Viral; D012254:Ribavirin; C571890:tegobuvir; C486464:telaprevir
keywords: Cell curing; Combination therapy; DAA; HCV; Resistance development; Tegobuvir