新型冠状病毒病 2019 经奈玛特韦/利托那韦治疗后出现症状反弹的临床、病毒学和免疫学评估。

Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment.

机构信息

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

出版信息

Clin Infect Dis. 2023 Feb 18;76(4):573-581. doi: 10.1093/cid/ciac663.

DOI:10.1093/cid/ciac663

PMID:36200701

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9619622/

Abstract

BACKGROUND

Nirmatrelvir/ritonavir, the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, reduces the risk of hospitalization and death by coronavirus disease 2019 (COVID-19) but has been associated with symptomatic rebound after therapy completion.

METHODS

Six individuals with relapse of COVID-19 symptoms after treatment with nirmatrelvir/ritonavir, 2 individuals with rebound symptoms without prior antiviral therapy and 7 patients with acute Omicron infection (controls) were studied. Soluble biomarkers and serum SARS-CoV-2 nucleocapsid protein were measured. Nasal swabs positive for SARS-CoV-2 underwent viral isolation and targeted viral sequencing. SARS-CoV-2 anti-spike, anti-receptor-binding domain, and anti-nucleocapsid antibodies were measured. Surrogate viral neutralization tests against wild-type and Omicron spike protein, as well as T-cell stimulation assays, were performed.

RESULTS

High levels of SARS-CoV-2 anti-spike immunoglobulin G (IgG) antibodies were found in all participants. Anti-nucleocapsid IgG and Omicron-specific neutralizing antibodies increased in patients with rebound. Robust SARS-CoV-2-specific T-cell responses were observed, higher in rebound compared with early acute COVID-19 patients. Inflammatory markers mostly decreased during rebound. Two patients sampled longitudinally demonstrated an increase in activated cytokine-producing CD4+ T cells against viral proteins. No characteristic resistance mutations were identified. SARS-CoV-2 was isolated by culture from 1 of 8 rebound patients; Polybrene addition increased this to 5 of 8.

CONCLUSIONS

Nirmatrelvir/ritonavir treatment does not impede adaptive immune responses to SARS-CoV-2. Clinical rebound corresponds to development of a robust antibody and T-cell immune response, arguing against a high risk of disease progression. The presence of infectious virus supports the need for isolation and assessment of longer treatment courses.

CLINICAL TRIALS REGISTRATION

NCT04401436.

摘要

背景

尼马曲韦/利托那韦，首个严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）蛋白酶抑制剂，可降低 2019 年冠状病毒病（COVID-19）住院和死亡风险，但与治疗完成后出现症状反弹有关。

方法

研究了 6 名接受尼马曲韦/利托那韦治疗后 COVID-19 症状复发的患者、2 名无先前抗病毒治疗但有反弹症状的患者和 7 名急性奥密克戎感染患者（对照组）。测量了可溶性生物标志物和血清 SARS-CoV-2 核衣壳蛋白。对 SARS-CoV-2 阳性的鼻拭子进行病毒分离和靶向病毒测序。测量了 SARS-CoV-2 刺突、受体结合域和核衣壳抗体。对野生型和奥密克戎刺突蛋白进行了替代病毒中和试验以及 T 细胞刺激测定。

结果

所有参与者均发现高水平的 SARS-CoV-2 刺突免疫球蛋白 G（IgG）抗体。反弹患者的抗核衣壳 IgG 和奥密克戎特异性中和抗体增加。观察到强烈的 SARS-CoV-2 特异性 T 细胞反应，反弹患者比早期急性 COVID-19 患者更高。在反弹期间，炎症标志物大多下降。2 名进行纵向采样的患者表现出针对病毒蛋白的激活细胞因子产生 CD4+T 细胞的增加。未鉴定出特征性耐药突变。通过培养从 8 名反弹患者中的 1 名分离出 SARS-CoV-2；添加聚凝胺可将其增加到 8 名中的 5 名。