Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Family Medicine and Primary Care, School of Clinical Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong Special Administrative Region, China; Laboratory of Data Discovery for Health, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China.
Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, University of Hong Kong, Hong Kong Special Administrative Region, China.
Lancet Infect Dis. 2022 Dec;22(12):1681-1693. doi: 10.1016/S1473-3099(22)00507-2. Epub 2022 Aug 24.
Data on the effectiveness of oral antivirals in patients with mild-to-moderate COVID-19 are urgently needed. This retrospective cohort study aimed to evaluate the clinical and virological outcomes associated with molnupiravir or nirmatrelvir-ritonavir use in hospitalised patients with mild-to-moderate COVID-19 during a pandemic wave dominated by the omicron BA.2 subvariant.
We analysed data from a territory-wide retrospective cohort of patients in Hong Kong who were hospitalised with a confirmed diagnosis of SARS-CoV-2 infection between Feb 26 and April 26, 2022. Data were extracted from the Hospital Authority, the Department of Health, and the Hong Kong Death Registry. Patients were eligible for inclusion if their admission date was within 3 days before or after confirmation of their COVID-19 diagnosis. Those who were admitted to hospital more than 5 days after symptom onset, were younger than 18 years, had a history of oral antiviral use before admission, required supplemental oxygen on admission, had drug-related contraindications to nirmatrelvir-ritonavir use, or had severe renal or severe liver impairment were excluded. Patients who received the oral antivirals molnupiravir or nirmatrelvir-ritonavir were matched with controls using propensity-score matching in a ratio of 1:1. The primary outcome was all-cause mortality and secondary outcomes included a composite outcome of disease progression (all-cause mortality, initiation of invasive mechanical ventilation [IMV], intensive care unit [ICU] admission, or the need for oxygen therapy) and each of these individual disease progression outcomes, and time to reaching a low viral burden (RT-PCR cycle threshold value ≥30). For each event outcome, crude incidence rates were calculated and hazard ratios (HRs) estimated using Cox regression models.
We identified 40 776 patients hospitalised with SARS-CoV-2 infection during the study period, with a mean follow-up of 41·3 days (total 925 713 person-days). After exclusions and propensity-score matching, we included 1856 molnupiravir recipients and 1856 matched controls, and 890 nirmatrelvir-ritonavir recipients and 890 matched controls. A lower risk of all-cause mortality was observed in molnupiravir recipients (crude incidence rate per 10 000 person-days 19·98 events [95% CI 16·91-23·45]) versus matched controls (38·07 events [33·85-42·67]; HR 0·48 [95% CI 0·40-0·59], p<0·0001) and in nirmatrelvir-ritonavir recipients (10·28 events [7·03-14·51]) versus matched controls (26·47 events [21·34-32·46]; HR 0·34 [0·23-0·50], p<0·0001). Oral antiviral recipients also had lower risks of the composite disease progression outcome (molnupiravir HR 0·60 [95% CI 0·52-0·69], p<0·0001; nirmatrelvir-ritonavir 0·57 [0·45-0·72], p<0·0001) and need for oxygen therapy (molnupiravir 0·69 [0·57-0·83], p=0·0001; nirmatrelvir-ritonavir 0·73 [0·54-0·97], p=0·032) compared with controls. Time to achieving a low viral burden was significantly shorter among oral antiviral recipients than matched controls (molnupiravir HR 1·38 [95% CI 1·15-1·64], p=0·0005; nirmatrelvir-ritonavir 1·38 [1·07-1·79], p=0·013). Significant differences in initiation of IMV and ICU admission were not found.
During a wave of SARS-CoV-2 omicron BA.2, initiation of novel oral antiviral treatments in hospitalised patients not requiring oxygen therapy on admission showed substantial clinical benefit. Our findings support the early use of oral antivirals in this population of patients.
Health and Medical Research Fund (Health Bureau, Government of the Hong Kong Special Administrative Region).
For the Chinese translation of the abstract see Supplementary Materials section.
目前急需有关口服抗病毒药物在轻度至中度 COVID-19 患者中的有效性的数据。本回顾性队列研究旨在评估在以 omicron BA.2 亚变体为主导的大流行浪潮中，住院的轻度至中度 COVID-19 患者使用 molnupiravir 或 nirmatrelvir-ritonavir 的临床和病毒学结局。
我们分析了香港卫生署医院管理局和香港死因登记处的一项全港回顾性队列研究的数据，该研究纳入了 2022 年 2 月 26 日至 4 月 26 日期间确诊为 SARS-CoV-2 感染并住院的患者。如果患者的入院日期在 COVID-19 确诊前 3 天内或后 3 天内，则符合纳入标准。排除那些在症状出现后 5 天以上入院、年龄小于 18 岁、入院前已使用口服抗病毒药物、入院时需要补充氧气、有药物相关的 nirmatrelvir-ritonavir 使用禁忌证、或有严重肾或严重肝功能损害的患者。将接受 molnupiravir 或 nirmatrelvir-ritonavir 的患者与使用倾向评分匹配（1:1）的对照组进行匹配。主要结局是全因死亡率，次要结局包括疾病进展的复合结局（全因死亡率、开始使用有创机械通气 [IMV]、入住 ICU 或需要氧疗）和这些疾病进展结局中的每一个，以及达到低病毒载量的时间（RT-PCR 循环阈值≥30）。对于每个事件结局，计算了粗发病率，并使用 Cox 回归模型估计了风险比（HR）。
我们确定了 40776 名在研究期间因 SARS-CoV-2 感染住院的患者，平均随访 41.3 天（总计 925713 人天）。排除和倾向评分匹配后，我们纳入了 1856 名 molnupiravir 接受者和 1856 名匹配的对照组，以及 890 名 nirmatrelvir-ritonavir 接受者和 890 名匹配的对照组。与匹配的对照组相比，molnupiravir 接受者的全因死亡率风险较低（每 10000 人天 19.98 例[95%CI 16.91-23.45]）（38.07 例[33.85-42.67]；HR 0.48[0.40-0.59]，p<0.0001），nirmatrelvir-ritonavir 接受者的风险也较低（每 10000 人天 10.28 例[7.03-14.51]）（26.47 例[21.34-32.46]；HR 0.34[0.23-0.50]，p<0.0001）。与对照组相比，口服抗病毒药物接受者的复合疾病进展结局（molnupiravir HR 0.60[95%CI 0.52-0.69]，p<0.0001；nirmatrelvir-ritonavir 0.57[0.45-0.72]，p<0.0001）和需要氧疗（molnupiravir HR 0.69[0.57-0.83]，p=0.0001；nirmatrelvir-ritonavir 0.73[0.54-0.97]，p=0.032）的风险也较低。与对照组相比，口服抗病毒药物接受者达到低病毒载量的时间显著缩短（molnupiravir HR 1.38[95%CI 1.15-1.64]，p=0.0005；nirmatrelvir-ritonavir 1.38[1.07-1.79]，p=0.013）。在开始使用有创机械通气和入住 ICU 方面，未发现显著差异。
在 omicron BA.2 引发的 SARS-CoV-2 浪潮中，对入院时无需补充氧气治疗的住院患者开始使用新型口服抗病毒药物，具有显著的临床获益。我们的研究结果支持在这一患者群体中尽早使用口服抗病毒药物。
卫生署（香港特别行政区政府）、卫生和医疗研究基金。
