Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing, China; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.
Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.
Antiviral Res. 2023 Aug;216:105657. doi: 10.1016/j.antiviral.2023.105657. Epub 2023 Jun 25.
Our previous study shows favipiravir and oseltamivir combination therapy may accelerate clinical recovery compared to oseltamivir monotherapy in severe influenza, but its effect on virological evolution and resistance mutation against oseltamivir is still unknown. In this study, we collected longitudinal respiratory samples from influenza patients who underwent combination therapy and applied them to next generation sequencing of the whole genome of the influenza A virus (IAV). We also included a cohort untreated with any antivirals to serve as the control. In total, 62 samples from 19 patients treated with combination therapy and 20 samples from 20 patients untreated were successfully sequenced. The nucleotide diversity in the whole genome of IAV in the combination group showed no difference compared to that in the control group (P > 0.05). Moreover, we observed 174 kinds of nonsynonymous nucleotide substitutions in patients with combination therapy, mostly in NA (n = 44) and HA (n = 43). Of them, the G→A transition was the dominant variant type (27%) and 46/174 (26%) was reported to have biological effects, such as increased pathogenicity and polymerase activity. Among the 29 mutations conferring reduction in oseltamivir sensitivity we investigated, H275Y was the only mutation detected in the 4 samples from 1 of 19 patients and demonstrated increasing frequency during the treatment. Mutations conferring favipiravir resistance were not observed. Our studies showed combination therapy of favipiravir and oseltamivir has little effect on virus nucleotide diversity, nor prevents the increase of oseltamivir-resistant variants.
我们之前的研究表明，与奥司他韦单药治疗相比，法匹拉韦和奥司他韦联合治疗可能会加速重症流感患者的临床康复，但它对病毒学演变和奥司他韦耐药突变的影响仍不清楚。在这项研究中，我们从接受联合治疗的流感患者中收集了纵向呼吸道样本，并将其应用于流感 A 病毒（IAV）全基因组的下一代测序。我们还纳入了一组未接受任何抗病毒药物治疗的患者作为对照。总共对 19 例接受联合治疗的患者的 62 个样本和 20 例未接受治疗的患者的 20 个样本进行了成功测序。与对照组相比，联合治疗组 IAV 全基因组的核苷酸多样性无差异（P>0.05）。此外，我们观察到联合治疗患者的 NA（n=44）和 HA（n=43）中有 174 种非同义核苷酸取代。其中，G→A 转换是主要的变异类型（27%），46/174（26%）具有生物学效应，如增加致病性和聚合酶活性。在我们研究的 29 种降低奥司他韦敏感性的突变中，H275Y 是仅在 19 例患者中的 1 例的 4 个样本中检测到的突变，并在治疗过程中显示出频率增加。未检测到奥司他韦耐药相关的突变。我们的研究表明，法匹拉韦和奥司他韦联合治疗对病毒核苷酸多样性影响较小，也不能阻止奥司他韦耐药变异体的增加。
