Antiviral interactions of an HCV polymerase inhibitor with an HCV protease inhibitor or interferon in vitro.
The combinations of Abbott Hepatitis C virus (HCV) polymerase A-782759 with either Boehringer Ingelheim HCV NS3 protease inhibitor BILN-2061 or interferon (IFN) displayed additive to synergistic relationships over a range of concentrations of two-drug combination. Treatment of HCV replicon with A-782759, IFN or BILN-2061 for about 16 days resulted in dramatic reductions in HCV RNA (5.1, 3.0 and 3.9 log10 RNA copies, respectively). However, none of the compounds tested alone lead to replicon RNA reduction to undetectable levels. Ongoing replication in the presence of A-782759 or BILN-2061 was associated with the appearance of resistant mutations M414T in NS5B and D168V in NS3, respectively. In contrast, a combination of A-782759 with BILN-2061 resulted in greater than 7 logs RNA reduction leading to undetectable replicon RNA after 16 days of treatment. Our findings suggest that a monotherapy with either drug alone is likely to result in development of resistant mutants. However, a combination therapy with polymerase inhibitor has the potential to improve the efficacy of IFN or a protease inhibitor alone in vivo, due to the lower likelihood of resistance development.
Koev
Gennadiy
G
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. gennadiy.koev@abbott.com
Dekhtyar
Tatyana
T
Han
Lixin
L
Yan
Ping
P
Ng
Teresa I
TI
Lin
C Thomas
CT
Mo
Hongmei
H
Molla
Akhteruzzaman
A
D000998:Antiviral Agents / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D002460:Cell Line; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D016898:Interferon-alpha / Q000494:pharmacology*; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008826:Microbial Sensitivity Tests / Q000379:methods; D011804:Quinolines / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology
D000998:Antiviral Agents; C479555:BILN 2061; D002219:Carbamates; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D047028:Macrocyclic Compounds; D011804:Quinolines; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D012324:RNA-Dependent RNA Polymerase