Evolutionary dynamics of hepatitis C virus NS3 protease domain during and following treatment with narlaprevir, a potent NS3 protease inhibitor.

Autor: Bruijne, J., Thomas, X. V., Rebers, S. P., Weegink, C. J., Treitel, M. A., Hughes, E., Bergmann, J. F., Knegt, R. J., Janssen, H. L. A., Reesink, H. W., Molenkamp, R., Schinkel, J.
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Zdroj: Journal of Viral Hepatitis; Nov2013, Vol. 20 Issue 11, p779-789, 11p
Abstrakt: Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo-controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty-two HCV genotype 1-infected patients following treatment with narlaprevir. Narlaprevir monotherapy was administered for one week (period 1) followed by narlaprevir/pegylated interferon-alpha-2b combination therapy with or without ritonavir (period 2) during two weeks, interrupted by a washout period of one month. Thereafter, all patients initiated pegylated interferon-alpha-2b/ribavirin combination therapy. Longitudinal clonal analysis was performed in those patients with NS3 mutations. After narlaprevir re-exposure, resistance-associated mutations at position V36, T54, R155 and A156 were detected in five patients in >95% of the clones. Narlaprevir retreatment resulted in a 2.58 and 5.06 log10 IU/mL viral load decline in patients with and without mutations, respectively ( P = <0.01). After treatment, resistant variants were replaced with wild-type virus within 2-24 weeks in three patients. However, the R155K mutation was still observed 3.1 years after narlaprevir dosing in two patients in 5% and 45% of the viral population. Resistant variants could be detected early during treatment with narlaprevir. A slower viral load decline was observed in those patients with resistance-associated mutations detectable by direct population sequencing. These mutations disappeared within six months following treatment with the exception of R155K mutation, which persisted in two patients. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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