於服用口服抗病毒藥的新冠病毒住院患者中，病毒量反彈的風險因素及相關臨床結果: 一項 回顧性隊列研究

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Viral burden rebound in hospitalised patients with COVID-19 receiving oral antivirals in Hong Kong: a population-wide retrospective cohort study

Carlos K H Wong, Kristy T K Lau, Ivan C H Au, et al.

Lancet Infect Dis Published: February 13, 2023

DOI:https://doi.org/10.1016/S1473-3099(22)00873-8

Summary

Background

Viral rebound after nirmatrelvir–ritonavir treatment has implications for the clinical management and isolation of patients with COVID-19. We evaluated an unselected, population-wide cohort to identify the incidence of viral burden rebound and associated risk factors and clinical outcomes.

新冠病毒患者服用口服抗病毒藥奈瑪特韋–利托那韋(以下稱帕克斯洛維德)後出現病毒量反 彈的現象對患者的治療和隔離政策有一定的影響。這回顧性隊列研究旨在了解病毒量反彈的 發生率、風險因素和臨床結果。

Methods

We did a retrospective cohort study of hospitalised patients with a confirmed diagnosis of COVID-19 in Hong Kong, China, for an observation period from Feb 26 to July 3, 2022 (during the omicron BA.2.2 variant wave). Adult patients (age ≥18 years) admitted 3 days before or after a positive COVID-19 test were selected from medical records held by the Hospital Authority of Hong Kong. We included patients with non-oxygen-dependent COVID-19 at baseline receiving either molnupiravir (800 mg twice a day for 5 days), nirmatrelvir–ritonavir (nirmatrelvir 300 mg with ritonavir 100 mg twice a day for 5 days), or no oral antiviral treatment (control group). Viral burden rebound was defined as a reduction in cycle threshold (Ct) value (≥3) on quantitative RT-PCR test between two consecutive measurements, with such decrease sustained in an immediately subsequent Ct measurement (for those patients with ≥3 Ct measurements). Logistic regression models were used to identify prognostic factors for viral burden rebound, and to assess associations between viral burden rebound and a composite clinical outcome of mortality, intensive care unit admission, and invasive mechanical ventilation initiation, stratified by treatment group.

這回顧性隊列研究分析了在香港於 2022 年 2 月 26 日至 7 月 3 日期間(流行的變種病毒為 Omicron BA.2.2)確診新冠病毒感染的住院患者的數據。於確診前後三天內入院並毋需氧氣 治療的十八歲或以上患者會根據藥物的處方紀錄被列入莫納皮拉韋組(800 毫克，一天兩 次，療程共五天)、帕克斯洛維德組(奈瑪特韋 300 毫克和利托那韋 100 毫克，一天兩次， 療程共五天)或沒有服用任何口服抗病毒藥的對照組。病毒量反彈的定義為定量即時聚合酶 鏈式反應分析(RT-qPCR)中兩個連續 Ct 值間的跌幅 ≥ 3，而若病人有三個或以上的 Ct 值， 此跌幅在緊接的 Ct 值亦維持着。邏輯斯迴歸分析研究了病毒量反彈的預後因素，以及病毒量 反彈與死亡、接受深切治療或使用入侵性機械呼吸輔助的綜合臨床結果之間的關係。這些數 據分別於服用帕克斯洛維德、服用莫納皮拉韋及對照組的新冠病毒患者中作分析和比較。

Findings

We included 4592 hospitalised patients with non-oxygen-dependent COVID-19 (1998 [43·5%] women and 2594 [56·5%] men). During the omicron BA.2.2 wave, viral burden rebound occurred in 16 of 242 patients (6·6% [95% CI 4·1–10·5]) receiving nirmatrelvir–ritonavir, 27 of 563 (4·8% [3·3–6·9]) receiving molnupiravir, and 170 of 3787 (4·5% [3·9–5·2]) in the control group. The incidence of viral burden rebound did not differ significantly across the three groups. Immunocompromised status was associated with increased odds of viral burden rebound, regardless of antiviral treatment (nirmatrelvir–ritonavir: odds ratio [OR] 7·37 [95% CI 2·56–21·26], p=0·0002; molnupiravir: 3·05 [1·28–7·25], p=0·012; control: 2·21 [1·50–3·27], p<0·0001). Among patients receiving nirmatrelvir–ritonavir, the odds of viral burden rebound were higher in those aged 18–65 years (vs>65 years; 3·09 [1·00–9·53], p=0·050), those with high comorbidity burden (score >6 on the Charlson Comorbidity Index; 6·02 [2·09–17·38], p=0·0009), and those concomitantly taking corticosteroids (7·51 [1·67–33·82], p=0·0086); whereas the odds were lower in those who were not fully vaccinated (0·16 [0·04–0·67], p=0·012). In patients receiving molnupiravir, those aged 18–65 years (2·68 [1·09–6·58], p=0·032) or on concomitant corticosteroids (3·11 [1·23–7·82], p=0·016) had increased odds of viral burden rebound. We found no association between viral burden rebound and occurrence of the composite clinical outcome from day 5 of follow-up (nirmatrelvir–ritonavir: adjusted OR 1·90 [0·48–7·59], p=0·36; molnupiravir: 1·05 [0·39–2·84], p=0·92; control: 1·27 [0·89–1·80], p=0·18).

於 4,592 名在 Omicron BA.2.2 變種病毒流行期間住院但毋須氧氣治療的新冠病毒患者中(包 括 1,998 名 [43.5%] 女性和 2,594 名 [56.5%] 男性)，病毒量反彈在 242 位服用帕克斯洛維德 的患者中的 16 位(6.6% [95% CI 4.1-10.5])、563 位服用莫納皮拉韋的患者中的 27 位 (4.8% [3.3-6.9])和 3,787 位對照組患者中的 170 位(4.5% [3.9-5.2])中發生。病毒量反彈 的比率於這三個組別間並沒有顯著分別。無論服用口服抗病毒藥與否，免疫功能低下與病毒 量反彈的風險增加相關(帕克斯洛維德:發生比 7.37 [95% CI 2.56-21.26]，p=0.0002;莫納 皮拉韋:3.05 [1.28-7.25]，p=0.012;對照組:2.21 [1.50-3.27]，p<0.0001)。於服用帕克斯 洛維德的患者中，病毒量反彈的風險在 18 至 65 歲(相較 65 歲以上，3.09 [1.00-9.53] ， p=0.050)、有較多共病症(Charlson 共病指標 >6，6.02 [2.09-17.38]，p=0.0009)和同時服 用皮質類固醇的患者(7.51 [1.67-33.82]，p=0.0086)中顯著較高，但在未完成接種新冠疫苗 的患者中風險較低(0.16 [0.04-0.67]，p=0.012)。而在服用莫納皮拉韋的患者中，病毒量反 彈的風險在較年輕(2.68 [1.09-6.58]，p=0.032)或同時服用皮質類固醇的患者(3.11 [1.23- 7.82]，p=0.016)中顯著較高。病毒量反彈的現象與第五日往後(完成口服抗病毒藥療程後) 發生綜合臨床結果的風險並非相關(帕克斯洛維德:校正後發生比 1.90 [0.48-7.59]， p=0.36;莫納皮拉韋:1.05 [0.39-2.84]，p=0.92;對照組:1.27 [0.89-1.80]，p=0.18)。

Interpretation

Viral burden rebound rates are similar between patients with antiviral treatment and those without. Importantly, viral burden rebound was not associated with adverse clinical outcomes.

病毒量反彈的比率於服用口服抗病毒藥的新冠病毒患者和對照組中相約。病毒量反彈尤其與
不良的臨床結果沒有關係