Mhamdi Zeineb, Fausther-Bovendo Hugues, Uyar Olus, Carbonneau Julie, Venable Marie-Christine, Abed Yacine, Kobinger Gary, Boivin Guy, Baz Mariana
Research Center in Infectious Diseases of the CHU of Québec, Laval University, Québec City, QC G1V 4G2, Canada.
Microorganisms. 2020 Dec 11;8(12):1968. doi: 10.3390/microorganisms8121968.
The prolonged treatment of immunosuppressed (IS) individuals with anti-influenza monotherapies may lead to the emergence of drug-resistant variants. Herein, we evaluated oseltamivir and polymerase inhibitors combinations against influenza A/H3N2 infections in an IS mouse model. Mice were IS with cyclophosphamide and infected with 3 × 10 PFU of a mouse-adapted A/Switzerland/9715293/2013 (H3N2) virus. Forty-eight hours post-infection, the animals started oseltamivir, favipiravir or baloxavir marboxil (BXM) as single or combined therapies for 10 days. Weight losses, survival rates and lung viral titers (LVTs) were determined. The neuraminidase (NA) and polymerase genes from lung viral samples were sequenced. All untreated animals died. Oseltamivir and favipiravir monotherapies only delayed mortality (the mean day to death (MDD) of 21.4 and 24 compared to 11.4 days for those untreated) while a synergistic improvement in survival (80%) and LVT reduction was observed in the oseltamivir/favipiravir group compared to the oseltamivir group. BXM alone or in double/triple combination provided a complete protection and significantly reduced LVTs. Oseltamivir and BXM monotherapies induced the E119V (NA) and I38T (PA) substitutions, respectively, while no resistance mutation was detected with combinations. We found that the multiple dose regimen of BXM alone provided superior benefits compared to oseltamivir and favipiravir monotherapies. Moreover, we suggest the potential for drug combinations to reduce the incidence of resistance.
用抗流感单药疗法对免疫抑制（IS）个体进行长期治疗可能会导致耐药变异株的出现。在此，我们在一个IS小鼠模型中评估了奥司他韦与聚合酶抑制剂联合用药对甲型H3N2流感感染的效果。小鼠通过环磷酰胺实现免疫抑制，并感染3×10 PFU的鼠适应株A/瑞士/9715293/2013（H3N2）病毒。感染后48小时，动物开始接受奥司他韦、法匹拉韦或巴洛沙韦酯（BXM）单药或联合治疗，持续10天。测定体重减轻情况、存活率和肺病毒滴度（LVT）。对肺病毒样本的神经氨酸酶（NA）和聚合酶基因进行测序。所有未治疗的动物均死亡。奥司他韦和法匹拉韦单药治疗仅延迟了死亡时间（平均死亡天数（MDD）分别为21.4天和24天，而未治疗的动物为11.4天），而与奥司他韦组相比，奥司他韦/法匹拉韦组在存活率（80%）和LVT降低方面观察到协同改善。单独使用BXM或双药/三药联合使用可提供完全保护并显著降低LVT。奥司他韦和BXM单药治疗分别诱导了E119V（NA）和I38T（PA）替代，而联合用药未检测到耐药突变。我们发现，与奥司他韦和法匹拉韦单药治疗相比，单独使用BXM的多剂量方案具有更大的益处。此外，我们认为药物联合使用有可能降低耐药发生率。
