Antiviral interactions of an HCV polymerase inhibitor with an HCV protease inhibitor or interferon in vitro

被引:27
作者
Koev, Gennadiy [1 ]
Dekhtyar, Tatyana [1 ]
Han, Lixin [1 ]
Yan, Ping [1 ]
Ng, Teresa I. [1 ]
Lin, C. Thomas [1 ]
Mo, Hongmei [1 ]
Molla, Akhteruzzaman [1 ]
机构
[1] Abbott Labs, Abbott Pk, IL 60064 USA
关键词
HCV replicon; polymerase inhibitor; protease inhibitor; drug combination; synergy;
D O I
10.1016/j.antiviral.2006.07.009
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 log(10) 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. (c) 2006 Elsevier B.V. All rights reserved.
引用
收藏
页码:78 / 83
页数:6
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