Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir

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• 作者：Yoshiyasu Karino¹ ; Joji Toyota¹ ; Kenji Ikeda² ; Fumitaka Suzuki² ; Kazuaki Chayama³ ; Yoshiiku Kawakami³ ; Hiroki Ishikawa⁴ ; Hideaki Watanabe⁴ ; Dennis Hernandez⁵ ; Fei Yu⁵ ; Fiona McPhee⁵ ; ^{fiona.mcphee@bms.com} ; Hiromitsu Kumada²
• 关键词：DAA ; direct-acting antiviral ; HCV ; hepatitis C virus ; SVR ; sustained virologic response ; GT ; genotype ; PegIFN-¦Á/RBV ; peginterferon alfa and ribavirin ; DCV ; daclatasvir ; ASV ; asunaprevir ; LLOQ ; lower limit of quantitation ; PCR ; polymerase chain reaction
• 刊名：Journal of Hepatology
• 出版年：2013
• 出版时间：April, 2013
• 年：2013
• 卷：58
• 期：4
• 页码：646-654
• 全文大小：929 K

文摘

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Background & Aims

Daclatasvir and asunaprevir are NS5A and NS3 protease-targeted antivirals currently under development for treatment of chronic hepatitis C virus infection. Clinical data on baseline and on-treatment correlates of drug resistance and response to these agents are currently limited.

Methods

Hepatitis C virus genotype 1b Japanese patients (prior null responders to PegIFN-¦Á/RBV [n = 21] or PegIFN-¦Á/RBV ineligible or intolerant [n = 22]) were administered daclatasvir/asunaprevir for 24 weeks during a phase 2a open-label study. Genotypic and phenotypic analyses of NS3 and NS5A substitutions were performed at baseline, after virologic failure, and post-treatment through follow-up week 36.

Results

There were three viral breakthroughs and four relapsers. Baseline NS3 polymorphisms (T54S, Q80L, V170M) at amino acid positions previously associated with low-level resistance (<9-fold) to select NS3 protease inhibitors were detected in four null responders and three ineligibles, but were not associated with virologic failure. Baseline NS5A polymorphisms (L28M, L31M, Y93H) associated with daclatasvir resistance (<25-fold) were detected in five null responders and six ineligibles. All three viral breakthroughs and 2/4 relapsers carried a baseline NS5A-Y93H polymorphism. NS3 and NS5A resistance-associated variants were detected together (NS3-D168A/V, NS5A-L31M/V-Y93H) after virologic failure. Generally, daclatasvir-resistant substitutions persisted through 48 weeks post-treatment, whereas asunaprevir-resistant substitutions were no longer detectable. Overall, 5/10 patients with baseline NS5A-Y93H experienced virologic failure, while 5/10 achieved a sustained virologic response.

Conclusions

The potential association of a pre-existing NS5A-Y93H polymorphism with virologic failure on daclatasvir/asunaprevir combination treatment will be examined in larger studies. The persistence of treatment-emergent daclatasvir- and asunaprevir-resistant substitutions will require assessment in longer-term follow-up studies.