Labhardt Niklaus D, Smit Mikaela, Petignat Ianis, Perneger Thomas, Marinosci Annalisa, Ustero Pilar, Diniz Ribeiro Maria Pia, Ragozzino Silvio, Nicoletti Giovanni Jacopo, Faré Pietro Benedetto, Andrey Diego O, Jacquerioz Frederique, Lebowitz Dan, Agoritsas Thomas, Meyer Benjamin, Spechbach Hervé, Salamun Julien, Guessous Idris, Chappuis François, Kaiser Laurent, Decosterd Laurent Arthur, Grinsztejn Beatriz, Bernasconi Enos, Cardoso Sandra Wagner, Calmy Alexandra, Team For The Copep Study
Department of Infectious Diseases and Hospital Epidemiology, University of Basel, Basel, Switzerland.
Department of Medicine, Swiss Tropical and Public Health Institute, Basel, Switzerland.
EClinicalMedicine. 2021 Dec;42:101188. doi: 10.1016/j.eclinm.2021.101188. Epub 2021 Nov 6.
Since the beginning of the COVID-19 pandemic, no direct antiviral treatment is effective as post-exposure prophylaxis (PEP). Lopinavir/ritonavir (LPV/r) was repurposed as a potential PEP agent against COVID-19.
We conducted a pragmatic open-label, parallel, cluster-randomised superiority trial in four sites in Switzerland and Brazil between March 2020 to March 2021. Clusters were randomised to receive LPV/r PEP (400/100 mg) twice daily for 5 days or no PEP (surveillance). Exposure to SARS-CoV-2 was defined as a close contact of >15 minutes in <2 metres distance or having shared a closed space for ≥2 hours with a person with confirmed SARS-CoV-2 infection. The primary outcome is the occurrence of COVID-19 defined by a SARS-CoV-2 infection (positive oropharyngeal SARS-CoV-2 PCR and/or a seroconversion) and ≥1 compatible symptom within 21 days post-enrolment. ClinicalTrials.gov (Identifier: NCT04364022); Swiss National Clinical Trial Portal: SNCTP 000003732.
Of 318 participants, 157 (49.4%) were women; median age was 39 (interquartile range, 28-50) years. A total of 209 (179 clusters) participants were randomised to LPV/r PEP and 109 (95 clusters) to surveillance. Baseline characteristics were similar, with the exception of baseline SARS-CoV-2 PCR positivity, which was 3-fold more frequent in the LPV/r arm (34/209 [16.3%] vs 6/109 [5.5%], respectively). During 21-day follow-up, 48/318 (15.1%) participants developed COVID-19: 35/209 (16.7%) in the LPV/r group and 13/109 (11.9%) in the surveillance group (unadjusted hazard ratio 1.44; 95% CI, 0.76-2.73). In the primary endpoint analysis, which was adjuted for baseline imbalance, the hazard ratio for developing COVID-19 in the LPV/r group vs surveillance was 0.60 (95% CI, 0.29-1.26; p =0.18).
The role of LPV/r as PEP for COVID-19 remains unanswered. Although LPV/r over 5 days did not significantly reduce the incidence of COVID-19 in exposed individuals, we observed a change in the directionality of the effect in favour of LPV/r after adjusting for baseline imbalance. LPV/r for this indication merits further testing against SARS-CoV-2 in clinical trials.
Swiss National Science Foundation (project no.: 33IC30_166819) and the Private Foundation of Geneva University Hospitals (Edmond Rothschild (Suisse) SA, Union Bancaire Privée and the Fondation pour la recherche et le traitement médical).
自新冠疫情开始以来，尚无直接抗病毒治疗可有效用作暴露后预防（PEP）。洛匹那韦/利托那韦（LPV/r）被重新用作针对新冠病毒的潜在PEP药物。
2020年3月至2021年3月期间，我们在瑞士和巴西的四个地点进行了一项实用的开放标签、平行、整群随机优效性试验。将整群随机分组，分别接受LPV/r PEP（400/100毫克），每日两次，共5天，或不进行PEP（监测）。接触严重急性呼吸综合征冠状病毒2（SARS-CoV-2）被定义为与确诊SARS-CoV-2感染患者在距离<2米处密切接触>15分钟，或在封闭空间内共处≥2小时。主要结局是在入组后21天内出现由SARS-CoV-2感染（口咽SARS-CoV-2 PCR阳性和/或血清学转换）定义的新冠病毒病，并伴有≥1种相符症状。美国国立医学图书馆临床试验数据库（标识符：NCT04364022）；瑞士国家临床试验门户网站：SNCTP 000003732。
318名参与者中，157名（49.4%）为女性；中位年龄为39岁（四分位间距，28 - 50岁）。共有209名（179个整群）参与者被随机分配接受LPV/r PEP，109名（95个整群）接受监测。除基线SARS-CoV-2 PCR阳性率外，基线特征相似，LPV/r组的基线SARS-CoV-2 PCR阳性率高3倍（分别为34/209 [16.3%] 对6/109 [5.5%]）。在21天随访期间，318名参与者中有48名（15.1%）发生新冠病毒病：LPV/r组为35/209（16.7%），监测组为13/109（11.9%）（未调整风险比1.44；95%置信区间，0.76 - 2.73）。在针对基线不平衡进行调整的主要终点分析中，LPV/r组与监测组相比，发生新冠病毒病的风险比为0.60（95%置信区间，0.29 - 1.26；p = 0.18）。
LPV/r作为新冠病毒病PEP的作用仍未明确。虽然5天的LPV/r治疗未显著降低暴露个体中新冠病毒病的发病率，但在针对基线不平衡进行调整后，我们观察到效应方向发生了有利于LPV/r的变化。LPV/r用于该适应症值得在临床试验中针对SARS-CoV-2进行进一步测试。
瑞士国家科学基金会（项目编号：3IC30_166819）以及日内瓦大学医院私人基金会（埃德蒙·罗斯柴尔德（瑞士）股份有限公司、瑞士联合银行私人银行和医学研究与治疗基金会）。
