Centre Hospitalier Universitaire de Québec-Centre Hospitalier de l'Université Laval (CHUQ-CHUL) and Laval University, Québec City, QC G1V 4G2, Canada.
CIRI-Centre International de Recherche en Infectiologie, (Team VirPath), University Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS-Centre National de la Recherche Scientifique UMR5308, ENS de Lyon, F-69007 Lyon, France.
Viruses. 2020 Oct 8;12(10):1139. doi: 10.3390/v12101139.
Two antiviral classes, the neuraminidase inhibitors (NAIs) and polymerase inhibitors (baloxavir marboxil and favipiravir) can be used to prevent and treat influenza infections during seasonal epidemics and pandemics. However, prolonged treatment may lead to the emergence of drug resistance. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we evaluated in vitro combinations of baloxavir acid (BXA) and other approved drugs against influenza A(H1N1)pdm09 and A(H3N2) subtypes. The determination of an effective concentration inhibiting virus cytopathic effects by 50% (EC50) for each drug and combination indexes (CIs) were based on cell viability. CompuSyn software was used to determine synergism, additivity or antagonism between drugs. Combinations of BXA and NAIs or favipiravir had synergistic effects on cell viability against the two influenza A subtypes. Those effects were confirmed using a physiological and predictive ex vivo reconstructed human airway epithelium model. On the other hand, the combination of BXA and ribavirin showed mixed results. Overall, BXA stands as a good candidate for combination with several existing drugs, notably oseltamivir and favipiravir, to improve in vitro antiviral activity. These results should be considered for further animal and clinical evaluations.
两种抗病毒药物类别，即神经氨酸酶抑制剂（NAIs）和聚合酶抑制剂（巴洛沙韦和法匹拉韦），可用于预防和治疗季节性流行和大流行期间的流感感染。然而，长期治疗可能导致耐药性的出现。治疗组合是预防耐药性和减少抗病毒药物剂量的替代方法。因此，我们评估了巴洛沙韦酸（BXA）与其他已批准的药物对甲型流感 A(H1N1)pdm09 和 A(H3N2)亚型的体外联合用药。根据细胞活力确定了每种药物和联合用药的半数有效浓度（EC50）和联合指数（CI）。使用 CompuSyn 软件确定药物之间的协同作用、相加作用或拮抗作用。BXA 与 NAIs 或法匹拉韦联合使用对两种甲型流感亚型的细胞活力具有协同作用。这些作用通过生理和预测性的重建人类气道上皮体外模型得到了证实。另一方面，BXA 与利巴韦林的联合使用结果喜忧参半。总的来说，BXA 是与几种现有药物（尤其是奥司他韦和法匹拉韦）联合使用的良好候选药物，可提高体外抗病毒活性。这些结果应在进一步的动物和临床评估中考虑。
