Genotypic and phenotypic characterization of influenza A viral variants in study participants treated with pimodivir in the phase 2b TOPAZ study.

IF 1.3 4区 医学 Q4 INFECTIOUS DISEASES
Johan Vingerhoets, Ilse Van Dromme, Wilbert van Duijnhoven, David Anderson, Sandra De Meyer, Lorant Leopold
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引用次数: 0

Abstract

Background: Pimodivir is a first-in-class polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A polymerase complex. The randomized double-blinded placebo-controlled phase 2b TOPAZ study demonstrated antiviral activity and safety of twice daily pimodivir alone (300 mg, 600 mg) or in combination with oseltamivir (pimodivir 600 mg, oseltamivir 75 mg) in adult study participants with acute uncomplicated influenza A. The detailed genotypic and phenotypic characterization of viral variants observed in this study are reported.

Methods: Population sequencing of PB2 and neuraminidase genes, and phenotypic susceptibility testing, were performed using baseline and last virus-positive post-baseline nasal swab samples.

Results: Sequencing of baseline samples in 206 of 223 (92.4%) randomized study participants with confirmed influenza A infection identified no polymorphisms at any predefined PB2 positions of interest for pimodivir and no phenotypic reduced susceptibility to pimodivir was observed. Post-baseline sequencing data for 105/223 (47.1%) participants identified emergence of PB2 mutations at amino acid positions of interest in 10 (9.5%) participants (pimodivir 300 mg: n = 3; 600 mg: n = 6; combination: n = 1; placebo: n = 0) and included positions S324, F325, S337, K376, T378, and N510. These emerging mutations were typically associated with decreased pimodivir susceptibility, but not viral breakthrough. No reduced phenotypic susceptibility was observed in the one (1.8%) participant with emerging PB2 mutations from the pimodivir plus oseltamivir group.

Conclusions: Participants with acute uncomplicated influenza A treated with pimodivir in the TOPAZ study infrequently developed reduced susceptibility to pimodivir and combining pimodivir with oseltamivir further decreased the risk of reduced susceptibility development.

在2b期TOPAZ研究中,接受pimodivir治疗的研究参与者的甲型流感病毒变异的基因型和表型特征
背景:Pimodivir是一种一流的甲型流感聚合酶复合物聚合酶碱性蛋白2 (PB2)亚基抑制剂。随机双盲安慰剂对照2b期TOPAZ研究表明,每日两次匹莫地韦单独(300 mg, 600 mg)或与奥司他韦联合(匹莫地韦600 mg,奥司他韦75 mg)对急性无并发症甲型流感成年研究参与者的抗病毒活性和安全性。方法:使用基线和基线后最后一次病毒阳性的鼻拭子样本进行PB2和神经氨酸酶基因的群体测序和表型敏感性检测。结果:223名确诊甲型流感感染的随机研究参与者中的206名(92.4%)的基线样本测序发现,在任何预定的PB2感兴趣的位置没有多态性,也没有观察到对匹莫地韦的表型敏感性降低。105/223(47.1%)参与者的基线后测序数据发现,10名参与者(9.5%)在感兴趣的氨基酸位置出现PB2突变(匹莫地韦300 mg: n = 3;600毫克:n = 6;组合:n = 1;安慰剂:n = 0),包括位置S324、F325、S337、K376、T378和N510。这些新出现的突变通常与匹莫地韦易感性降低有关,但与病毒突破无关。在匹莫地韦加奥司他韦组出现PB2突变的1名(1.8%)参与者中,未观察到表型易感性降低。结论:在TOPAZ研究中,接受匹莫地韦治疗的急性无并发症甲型流感患者很少出现对匹莫地韦的敏感性降低,而匹莫地韦与奥司他韦联合治疗进一步降低了敏感性降低的风险。
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来源期刊
Antiviral Therapy
Antiviral Therapy 医学-病毒学
CiteScore
2.60
自引率
8.30%
发文量
35
审稿时长
4-8 weeks
期刊介绍: Antiviral Therapy (an official publication of the International Society of Antiviral Research) is an international, peer-reviewed journal devoted to publishing articles on the clinical development and use of antiviral agents and vaccines, and the treatment of all viral diseases. Antiviral Therapy is one of the leading journals in virology and infectious diseases. The journal is comprehensive, and publishes articles concerning all clinical aspects of antiviral therapy. It features editorials, original research papers, specially commissioned review articles, letters and book reviews. The journal is aimed at physicians and specialists interested in clinical and basic research.
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