Brigham and Women's Hospital, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
JAMA Netw Open. 2024 Sep 3;7(9):e2435431. doi: 10.1001/jamanetworkopen.2024.35431.
Previous studies have identified mutations in SARS-CoV-2 strains that confer resistance to nirmatrelvir, yet how often this resistance arises and its association with posttreatment virologic rebound is not well understood.
To examine the prevalence of emergent antiviral resistance after nirmatrelvir treatment and its association with virologic rebound.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study enrolled outpatient adults with acute COVID-19 infection from May 2021 to October 2023. Participants were divided into those who received antiviral therapy and those who did not. The study was conducted at a multicenter health care system in Boston, Massachusetts.
Treatment regimen, including none, nirmatrelvir, and remdesivir.
The primary outcome was emergent SARS-CoV-2 antiviral resistance, defined as the detection of antiviral resistance mutations, which were not present at baseline, were previously associated with decreased antiviral efficacy, and emerged during or after completion of a participant's treatment. Next-generation sequencing was used to detect low frequency mutations down to 1% of the total viral population.
Overall, 156 participants (114 female [73.1%]; median [IQR] age, 56 [38-69] years) were included. Compared with 63 untreated individuals, the 79 who received nirmatrelvir were older and more commonly immunosuppressed. After sequencing viral RNA from participants' anterior nasal swabs, nirmatrelvir resistance mutations were detected in 9 individuals who received nirmatrelvir (11.4%) compared with 2 of those who did not (3.2%) (P = .09). Among the individuals treated with nirmatrelvir, those who were immunosuppressed had the highest frequency of resistance emergence (5 of 22 [22.7%]), significantly greater than untreated individuals (2 of 63 [3.1%]) (P = .01). Similar rates of nirmatrelvir resistance were found in those who had virologic rebound (3 of 23 [13.0%]) vs those who did not (6 of 56 [10.7%]) (P = .86). Most of these mutations (10 of 11 [90.9%]) were detected at low frequencies (<20% of viral population) and reverted to the wild type at subsequent time points. Emerging remdesivir resistance mutations were only detected in immunosuppressed individuals (2 of 14 [14.3%]) but were similarly low frequency and transient. Global Initiative on Sharing All Influenza Data analysis showed no evidence of increased nirmatrelvir resistance in the United States after the authorization of nirmatrelvir.
In this cohort study of 156 participants, treatment-emergent nirmatrelvir resistance mutations were commonly detected, especially in individuals who were immunosuppressed. However, these mutations were generally present at low frequencies and were transient in nature, suggesting a low risk for the spread of nirmatrelvir resistance in the community with the current variants and drug usage patterns.
先前的研究已经确定了导致奈玛特韦耐药的 SARS-CoV-2 株突变，但这种耐药性的出现频率及其与治疗后病毒学反弹的关系尚不清楚。
检查奈玛特韦治疗后出现的新兴抗病毒耐药情况及其与病毒学反弹的关系。
设计、地点和参与者：这项队列研究纳入了 2021 年 5 月至 2023 年 10 月期间来自马萨诸塞州波士顿一家多中心医疗保健系统的门诊成人急性 COVID-19 感染者。参与者分为接受抗病毒治疗和未接受治疗的两组。
治疗方案，包括无治疗、奈玛特韦和瑞德西韦。
主要结局是出现 SARS-CoV-2 抗病毒耐药性，定义为检测到抗病毒耐药性突变，这些突变在基线时不存在，先前与抗病毒疗效降低相关，并且在参与者治疗期间或之后出现。下一代测序用于检测低频率突变，最低频率可达总病毒群的 1%。
共有 156 名参与者（114 名女性[73.1%]；中位[IQR]年龄，56[38-69]岁）入组。与 63 名未治疗的个体相比，接受奈玛特韦治疗的 79 名个体年龄更大，更常出现免疫抑制。对参与者前鼻拭子的病毒 RNA 进行测序后，在接受奈玛特韦治疗的 9 名个体中检测到奈玛特韦耐药突变（11.4%），而未接受治疗的 2 名个体中检测到 2 名（3.2%）（P = .09）。在接受奈玛特韦治疗的个体中，免疫抑制者出现耐药性的频率最高（22 名中的 5 名[22.7%]），明显高于未接受治疗者（63 名中的 2 名[3.1%]）（P = .01）。在出现病毒学反弹的个体中（23 名中的 3 名[13.0%]）与未出现病毒学反弹的个体（56 名中的 6 名[10.7%]）中，奈玛特韦耐药的发生率相似（P = .86）。这些突变中的大多数（11 个中的 10 个[90.9%]）以低频率（<20%的病毒群体）检测到，随后在时间点恢复为野生型。仅在免疫抑制个体中检测到新兴的瑞德西韦耐药突变（14 名中的 2 名[14.3%]），但同样频率较低且短暂。全球流感共享所有数据倡议的分析显示，在美国批准奈玛特韦后，没有证据表明奈玛特韦的耐药性增加。
在这项针对 156 名参与者的队列研究中，经常检测到治疗后出现的奈玛特韦耐药性突变，尤其是在免疫抑制者中。然而，这些突变通常以低频率存在且具有短暂性，这表明在当前变异和药物使用模式下，社区中奈玛特韦耐药性传播的风险较低。
