Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.
Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN, USA.
J Antimicrob Chemother. 2019 May 1;74(5):1333-1341. doi: 10.1093/jac/dky560.
Influenza B virus infections remain insufficiently studied and antiviral management in immunocompromised patients is not well defined. The treatment regimens for these high-risk patients, which have elevated risk of severe disease-associated complications, require optimization and can be partly addressed via animal models.
We examined the efficacy of monotherapy with the RNA-dependent RNA polymerase inhibitor T-705 (favipiravir) in protecting genetically modified, permanently immunocompromised BALB scid mice against lethal infection with B/Brisbane/60/2008 (BR/08) virus. Beginning at 24 h post-infection, BALB scid mice received oral T-705 twice daily (10, 50 or 250 mg/kg/day) for 5 or 10 days.
T-705 had a dose-dependent effect on survival after BR/08 challenge, resulting in 100% protection at the highest dosages. With the 5 day regimens, dosages of 50 or 250 mg/kg/day reduced the peak lung viral titres within the treatment window, but could not efficiently clear the virus after completion of treatment. With the 10 day regimens, dosages of 50 or 250 mg/kg/day significantly suppressed virus replication in the lungs, particularly at 45 days post-infection, limiting viral spread and pulmonary pathology. No T-705 regimen decreased virus growth in the nasal turbinates of mice, which potentially contributed to the viral dynamics in the lungs. The susceptibility of influenza B viruses isolated from T-705-treated mice remained comparable to that of viruses from untreated control animals.
T-705 treatment is efficacious against lethal challenge with BR/08 virus in immunocompromised mice. The antiviral benefit was greatest when longer T-705 treatment was combined with higher dosages.
乙型流感病毒感染的研究仍不充分，免疫功能低下患者的抗病毒治疗也尚未明确。这些高危患者的治疗方案需要优化，部分可以通过动物模型来解决。
我们研究了 RNA 依赖性 RNA 聚合酶抑制剂 T-705（法匹拉韦）单药治疗对携带遗传修饰的永久性免疫功能低下 BALB scid 小鼠预防致死性 B/Brisbane/60/2008（BR/08）病毒感染的疗效。从感染后 24 小时开始，BALB scid 小鼠每天口服 T-705 两次（10、50 或 250mg/kg/天），连续 5 或 10 天。
T-705 对 BR/08 攻击后的生存有剂量依赖性影响，最高剂量可达到 100%的保护率。在 5 天的治疗方案中，50 或 250mg/kg/天的剂量可降低治疗窗内肺部病毒滴度峰值，但在治疗结束后无法有效清除病毒。在 10 天的治疗方案中，50 或 250mg/kg/天的剂量可显著抑制肺部病毒复制，特别是在感染后 45 天，从而限制病毒传播和肺部病理学改变。没有一种 T-705 方案能降低小鼠鼻甲骨中的病毒生长，这可能是导致肺部病毒动力学变化的原因。从 T-705 治疗小鼠中分离出的乙型流感病毒的敏感性仍与未经治疗的对照动物中的病毒相似。
T-705 治疗对免疫功能低下小鼠的致死性 BR/08 病毒攻击有效。当更长时间的 T-705 治疗与更高剂量联合使用时，抗病毒效果最佳。
