建模表明,尼马瑞韦-利托那韦治疗后,SARS-CoV-2 的反弹是由靶细胞保留和病毒清除不完全引起的

Tin Phan, Ruy Ribeiro, Gregory E Edelstein, Julie Boucau, Rockib Uddin, Caitlin Marino, May Y Liew, Mamadou Barry, Manish C Choudhary, Dessie Tien, Karry Su, Zahra Reynolds, Yijia Li, Shruti Sagar, Tammy D Vyas, Yumeko Kawano, Jeffrey A Sparks, Sarah P Hammond, Zachary Wallace, Jatin M Vyas, Jonathan Z. Li, Mark J Siedner, Amy K. Barczak, Jacob E Lemieux, Alan S. Perelson
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摘要

在接受口服抗病毒药物 nirmatrelvir-ritonavir 治疗的部分 SARS-CoV-2 感染者中,病毒会在治疗后反弹。这种反弹的驱动机制尚不十分清楚。我们使用数学模型描述了 51 名接受尼尔马特韦-利托那韦治疗的患者的纵向病毒载量动态,其中 20 人的病毒载量出现反弹。通过强有力的先天性免疫反应或在接近症状出现时开始使用奈马瑞韦-利托那韦,靶细胞得以保留,再加上病毒清除不彻底,似乎是导致病毒反弹的主要因素。此外,病毒反弹的发生很可能受到相对于感染进展的治疗开始时间的影响,较早的治疗会导致较高的反弹几率。最后,我们的模型表明,延长尼尔马特韦-利托那韦的疗程,尤其是延长至 10 天疗程,可大大降低轻度至中度 COVID-19 感染者以及病情进展至重症的高风险人群的反弹风险。总之,我们的研究结果表明,对于某些人来说,在症状出现前后开始服用尼马瑞韦-利托那韦的 5 天标准疗程可能无法完全清除病毒。因此,在治疗结束后,如果有效的适应性免疫反应尚未完全形成,病毒可能会反弹。这些关于靶细胞保存和病毒未完全清除的研究结果也为 SARS-CoV-2 接受其他抗病毒治疗后病毒反弹提供了可能的解释。
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Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance
In a subset of SARS-CoV-2 infected individuals treated with the oral antiviral nirmatrelvir-ritonavir, the virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used a mathematical model to describe the longitudinal viral load dynamics of 51 individuals treated with nirmatrelvir-ritonavir, 20 of whom rebounded. Target cell preservation, either by a robust innate immune response or initiation of nirmatrelvir-ritonavir near the time of symptom onset, coupled with incomplete viral clearance, appear to be the main factors leading to viral rebound. Moreover, the occurrence of viral rebound is likely influenced by time of treatment initiation relative to the progression of the infection, with earlier treatments leading to a higher chance of rebound. Finally, our model demonstrates that extending the course of nirmatrelvir-ritonavir treatment, in particular to a 10-day regimen, may greatly diminish the risk for rebound in people with mild-to-moderate COVID-19 and who are at high risk of progression to severe disease. Altogether, our results suggest that in some individuals, a standard 5-day course of nirmatrelvir-ritonavir starting around the time of symptom onset may not completely eliminate the virus. Thus, after treatment ends, the virus can rebound if an effective adaptive immune response has not fully developed. These findings on the role of target cell preservation and incomplete viral clearance also offer a possible explanation for viral rebounds following other antiviral treatments for SARS-CoV-2.
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