Division of Infectious Diseases, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.
Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China; Department of Family Medicine and Primary Care, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
Lancet Infect Dis. 2024 Nov;24(11):1213-1224. doi: 10.1016/S1473-3099(24)00353-0. Epub 2024 Jul 15.
Remdesivir (Veklury, Gilead Sciences, Foster City, CA, USA) and nirmatrelvir-ritonavir (Paxlovid, Pfizer, New York, NY, USA) were reported to improve the outcome of patients with mild-to-moderate COVID-19 symptoms. Preclinical data suggest that nirmatrelvir-ritonavir might be more effective than remdesivir alone or in combination with nirmatrelvir-ritonavir for people at high risk of severe COVID-19. We aimed to assess the safety and effectiveness of combining remdesivir and nirmatrelvir-ritonavir compared with using each drug alone for adults hospitalised with COVID-19.
In this target trial emulation study, we used electronic health records of patients aged 18 years or older who received either combination treatment of nirmatrelvir-ritonavir and remdesivir or monotherapy of either drug between March 16 and Dec 31, 2022, within 5 days of hospitalisation for COVID-19 in Hong Kong. Inverse probability of treatment weighting was applied to balance baseline patient characteristics across the treatment groups. The primary outcome was all-cause mortality. Cox proportional hazards regression adjusting weighting was used to compare the risk of all-cause mortality, intensive care unit (ICU) admission, or ventilatory support for 90 days of follow-up between groups.
Between March 16 and Dec 31, 2022, 18 196 participants were identified from electronic health records and assigned to receive remdesivir (n=4232), nirmatrelvir-ritonavir (n=13 656), or nirmatrelvir-ritonavir and remdesivir (n=308). By applying an inverse probability of treatment weighting, a weighted sample composed of 18 410 recipients of nirmatrelvir-ritonavir and remdesivir combination treatment, 18 178 recipients of remdesivir monotherapy, and 18 287 recipients of nirmatrelvir-ritonavir monotherapy was obtained. After a median follow-up of 84 days (IQR 45-90), risk of mortality was lower in patients who received nirmatrelvir-ritonavir monotherapy (hazard ratio [HR] 0·18 [95% CI 0·15 to 0·20]; absolute risk reduction [ARR] -16·33% [95% CI -16·98 to -15·68]) or remdesivir and nirmatrelvir-ritonavir combination therapy (HR 0·66 [95% CI 0·49 to 0·89]; ARR -6·52% [95% CI -7·29 to -5·74]) than in patients who received remdesivir monotherapy. Similar results were observed for ICU admission or ventilatory support (nirmatrelvir-ritonavir monotherapy: HR 0·09 [95% CI 0·07 to 0·11]; ARR -10·04% [95% CI -10·53 to -9·56]; combination therapy: HR 0·68 [95% CI 0·42 to 1·12]; ARR -3·24% [95% CI -3·84 to -2·64]). Compared with combination therapy, nirmatrelvir-ritonavir monotherapy was associated with lower risk of mortality (HR 0·27 [95% CI 0·20 to 0·37]; ARR -9·81% [95% CI -10·39 to -9·24]) and ICU admission or ventilatory support (HR 0·13 [95% CI 0·08 to 0·22]; ARR -6·80% [95% CI -7·22 to -6·39]).
Our study highlighted the potential for reduced risk of mortality, ICU admission, or the need for ventilatory support in patients hospitalised with COVID-19 treated with nirmatrelvir-ritonavir as a monotherapy compared with treatment regimens based on nirmatrelvir-ritonavir and remdesivir combination therapy or remdesivir monotherapy. Further randomised controlled trials are needed to support the validity of the current results.
The Health and Medical Research Fund Commissioned Research on COVID-19.
For the Chinese translation of the abstract see Supplementary Materials section.
瑞德西韦（Veklury，吉利德科学公司，美国福斯特市）和奈玛特韦-利托那韦（Paxlovid，辉瑞公司，美国纽约州）据报道可改善 COVID-19 轻症至中症患者的结局。临床前数据表明，奈玛特韦-利托那韦与瑞德西韦联合应用或单独应用于 COVID-19 高危人群，其效果可能优于瑞德西韦。我们旨在评估与使用每种药物单独治疗相比，联合应用奈玛特韦-利托那韦和瑞德西韦治疗 COVID-19 住院患者的安全性和有效性。
在这项靶向试验模拟研究中，我们使用了 2022 年 3 月 16 日至 12 月 31 日期间香港 COVID-19 住院患者在 5 天内接受奈玛特韦-利托那韦和瑞德西韦联合治疗或其中任何一种药物单药治疗的数据。采用逆概率治疗加权法平衡治疗组之间的基线患者特征。主要结局为全因死亡率。采用 Cox 比例风险回归调整加权法比较两组之间 90 天随访期间的全因死亡率、入住重症监护病房（ICU）或需要通气支持的风险。
2022 年 3 月 16 日至 12 月 31 日期间，从电子病历中确定了 18196 名参与者，将其分为接受瑞德西韦（n=4232）、奈玛特韦-利托那韦（n=13656）或奈玛特韦-利托那韦和瑞德西韦（n=308）治疗。通过应用逆概率治疗加权法，获得了由 18410 名接受奈玛特韦-利托那韦和瑞德西韦联合治疗的、18178 名接受瑞德西韦单药治疗的和 18287 名接受奈玛特韦-利托那韦单药治疗的加权样本。中位随访 84 天（IQR 45-90）后，接受奈玛特韦-利托那韦单药治疗（风险比[HR]0·18[95%CI 0·15 至 0·20]；绝对风险降低[ARR]-16·33%[95%CI 16·98 至 15·68%]）或接受奈玛特韦-利托那韦和瑞德西韦联合治疗（HR 0·66[95%CI 0·49 至 0·89]；ARR-6·52%[95%CI 7·29 至 5·74%]）的患者死亡率低于接受瑞德西韦单药治疗的患者。对于入住 ICU 或需要通气支持的结局（奈玛特韦-利托那韦单药治疗：HR 0·09[95%CI 0·07 至 0·11]；ARR-10·04%[95%CI 10·53 至 9·56%]；联合治疗：HR 0·68[95%CI 0·42 至 1·12]；ARR-3·24%[95%CI 3·84 至 2·64%]）也观察到了类似的结果。与联合治疗相比，奈玛特韦-利托那韦单药治疗的死亡率（HR 0·27[95%CI 0·20 至 0·37]；ARR-9·81%[95%CI 10·39 至 9·24%]）和入住 ICU 或需要通气支持（HR 0·13[95%CI 0·08 至 0·22]；ARR-6·80%[95%CI 7·22 至 6·39%]）的风险较低。
我们的研究强调了与奈玛特韦-利托那韦和瑞德西韦联合治疗方案或瑞德西韦单药治疗方案相比，COVID-19 住院患者接受奈玛特韦-利托那韦单药治疗可能降低死亡率、入住 ICU 或需要通气支持的风险。需要进一步的随机对照试验来支持当前结果的有效性。
卫生和医学研究基金对 COVID-19 的委托研究。
