Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial.
Ivan Hung1, Kwok Cheung Lung2, Eugene Yuk Keung Tso3, Raymond W. Liu4, Tom Wai-Hin Chung1, Man Yee Chu, Yuk Yung Ng5, Jenny Lo4, Jacky Chan, Anthony Raymond Tam1, Hoi-Ping Shum2, Veronica L. Chan3, Alan Ka Lun Wu2, Kit Man Sin5, Wai Shing Leung, Wai Lam Law, David Christopher Lung, Simon Yung Wa Sin1, Pauline Yeung1, Cyril C. Y. Yip1, Ricky Ruiqi Zhang1, Agnes Yim Fong Fung1, Erica Yuen Wing Yan1, Kit-Hang Leung1, Jonathan Daniel Ip1, Allen Wing-Ho Chu1, Wan Mui Chan1, Anthony Chin-Ki Ng1, Rodney A. Lee2, Kitty S. C. Fung3, Alwin Wt Yeung4, Tak Chiu Wu, Johnny W.M. Chan, Wing Wah Yan2, Wai-Ming Chan1, Jasper Fuk-Woo Chan1, Albert K. W. Lie1, Owen Tak Yin Tsang, Vincent C.C. Cheng1, Tak-Lun Que5, Chak Sing Lau1, Kwok-Hung Chan1, Kelvin K. W. To1, Kwok-Yung Yuen1 •
TL;DR: Yu et al. as mentioned in this paper assessed the efficacy and safety of combined interferon beta-1b, lopinavir-ritonavir, and ribavirin for treating patients with COVID-19.
About: This article is published in The Lancet.The article was published on 2020-05-30 and is currently open access. It has received 1209 citations till now. The article focuses on the topics: Lopinavir/ritonavir & Lopinavir.
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TL;DR: The basic virology of SARS-CoV-2 is described, including genomic characteristics and receptor use, highlighting its key difference from previously known coronaviruses.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory disease, named ‘coronavirus disease 2019’ (COVID-19), which threatens human health and public safety. In this Review, we describe the basic virology of SARS-CoV-2, including genomic characteristics and receptor use, highlighting its key difference from previously known coronaviruses. We summarize current knowledge of clinical, epidemiological and pathological features of COVID-19, as well as recent progress in animal models and antiviral treatment approaches for SARS-CoV-2 infection. We also discuss the potential wildlife hosts and zoonotic origin of this emerging virus in detail. In this Review, Shi and colleagues summarize the exceptional amount of research that has characterized acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) since this virus has swept around the globe. They discuss what we know so far about the emergence and virology of SARS-CoV-2 and the pathogenesis and treatment of COVID-19.
2,904 citations
01 Jan 2021
TL;DR: Although SARS-CoV-2 RNA shedding in respiratory and stool samples can be prolonged, duration of viable virus is relatively short-lived.
Abstract: Summary Background Viral load kinetics and duration of viral shedding are important determinants for disease transmission. We aimed to characterise viral load dynamics, duration of viral RNA shedding, and viable virus shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in various body fluids, and to compare SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) viral dynamics. Methods In this systematic review and meta-analysis, we searched databases, including MEDLINE, Embase, Europe PubMed Central, medRxiv, and bioRxiv, and the grey literature, for research articles published between Jan 1, 2003, and June 6, 2020. We included case series (with five or more participants), cohort studies, and randomised controlled trials that reported SARS-CoV-2, SARS-CoV, or MERS-CoV infection, and reported viral load kinetics, duration of viral shedding, or viable virus. Two authors independently extracted data from published studies, or contacted authors to request data, and assessed study quality and risk of bias using the Joanna Briggs Institute Critical Appraisal Checklist tools. We calculated the mean duration of viral shedding and 95% CIs for every study included and applied the random-effects model to estimate a pooled effect size. We used a weighted meta-regression with an unrestricted maximum likelihood model to assess the effect of potential moderators on the pooled effect size. This study is registered with PROSPERO, CRD42020181914. Findings 79 studies (5340 individuals) on SARS-CoV-2, eight studies (1858 individuals) on SARS-CoV, and 11 studies (799 individuals) on MERS-CoV were included. Mean duration of SARS-CoV-2 RNA shedding was 17·0 days (95% CI 15·5–18·6; 43 studies, 3229 individuals) in upper respiratory tract, 14·6 days (9·3–20·0; seven studies, 260 individuals) in lower respiratory tract, 17·2 days (14·4–20·1; 13 studies, 586 individuals) in stool, and 16·6 days (3·6–29·7; two studies, 108 individuals) in serum samples. Maximum shedding duration was 83 days in the upper respiratory tract, 59 days in the lower respiratory tract, 126 days in stools, and 60 days in serum. Pooled mean SARS-CoV-2 shedding duration was positively associated with age (slope 0·304 [95% CI 0·115–0·493]; p=0·0016). No study detected live virus beyond day 9 of illness, despite persistently high viral loads, which were inferred from cycle threshold values. SARS-CoV-2 viral load in the upper respiratory tract appeared to peak in the first week of illness, whereas that of SARS-CoV peaked at days 10–14 and that of MERS-CoV peaked at days 7–10. Interpretation Although SARS-CoV-2 RNA shedding in respiratory and stool samples can be prolonged, duration of viable virus is relatively short-lived. SARS-CoV-2 titres in the upper respiratory tract peak in the first week of illness. Early case finding and isolation, and public education on the spectrum of illness and period of infectiousness are key to the effective containment of SARS-CoV-2. Funding None.
1,061 citations
Reed A C Siemieniuk1, Jessica J Bartoszko1, Long Ge2, Dena Zeraatkar1, Ariel Izcovich, Elena Kum1, Hector Pardo-Hernandez3, Anila Qasim1, Juan Pablo Diaz Martinez1, Bram Rochwerg1, Francois Lamontagne, Mi Ah Han4, Qin Liu5, Arnav Agarwal6, Arnav Agarwal1, Thomas Agoritsas1, Derek K. Chu1, Rachel Couban1, Ellen Cusano1, Andrea Darzi1, Tahira Devji1, Bo Fang5, Carmen Fang, Signe Flottorp7, Signe Flottorp8, Farid Foroutan1, Farid Foroutan9, Maryam Ghadimi1, Diane Heels-Ansdell1, Kimia Honarmand10, Liangying Hou2, Xiaorong Hou5, Quazi Ibrahim1, Assem M. Khamis11, Bonnie Lam1, Mark Loeb1, Maura Marcucci1, Shelley McLeod6, Sharhzad Motaghi1, Srinivas Murthy12, Reem A. Mustafa13, Reem A. Mustafa1, John Neary1, Gabriel Rada14, Irbaz Bin Riaz15, Behnam Sadeghirad1, Nigar Sekercioglu1, Lulu Sheng5, Ashwini Sreekanta1, Charlotte Switzer1, Britta Tendal16, Lehana Thabane1, George Tomlinson17, Tari Turner16, Per Olav Vandvik, Robin W.M. Vernooij18, Andrés Viteri-García, Ying Wang1, Liang Yao1, Zhikang Ye1, Gordon H Guyatt1, Romina Brignardello-Petersen1 •
McMaster University1, Lanzhou University2, Cochrane Collaboration3, Chosun University4, Chongqing Medical University5, University of Toronto6, University of Oslo7, Norwegian Institute of Public Health8, Toronto General Hospital9, University of Western Ontario10, Hull York Medical School11, University of British Columbia12, University of Kansas13, Pontifical Catholic University of Chile14, Mayo Clinic15, Monash University16, University Health Network17, Utrecht University18
TL;DR: Glucocorticoids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care and the effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.
Abstract: Objective To compare the effects of treatments for coronavirus disease 2019 (covid-19). Design Living systematic review and network meta-analysis. Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis. Study selection Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. Methods After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. Results 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low. Conclusion Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain. Systematic review registration This review was not registered. The protocol is publicly available in the supplementary material. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fourth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.
602 citations
Caspar I van der Made, Annet Simons1, Janneke H M Schuurs-Hoeijmakers1, Guus R. M. van den Heuvel1, Tuomo Mantere1, Simone Kersten1, Rosanne C. van Deuren1, Marloes Steehouwer1, Simon V. van Reijmersdal1, Martin Jaeger1, Tom Hofste1, Galuh D.N. Astuti1, Jordi Corominas Galbany1, Vyne van der Schoot2, Hans van der Hoeven1, Eva Klijn3, Catrien van den Meer, Jeroen Fiddelaers, Quirijn de Mast1, Chantal P. Bleeker-Rovers1, Leo A. B. Joosten1, Helger G. Yntema1, Christian Gilissen1, Marcel R. Nelen1, Jos W. M. van der Meer1, Han G. Brunner, Mihai G. Netea, Frank L. van de Veerdonk1, Alexander Hoischen •
TL;DR: In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses and provide insights into the pathogenesis of CO VID-19.
Abstract: Importance Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. Design, Setting, and Participants Case series of pairs of brothers without medical history meeting the selection criteria of young (age Exposure Severe COVID-19. Main Outcome and Measures Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects. Results The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomalTLR7.In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression ofIRF7,IFNB1, andISG15on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. Conclusions and Relevance In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomalTLR7were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.
576 citations
TL;DR: Examining leukocyte and cytokine activity in COVID‐19 focuses on how these levels are altered as the disease progresses and proposed consequences to organ pathology and Viral and host interactions are described to gain further insight into leukocytes biology and how dysregulated cytokine responses lead to disease and/or organ damage.
Abstract: Clinical evidence indicates that the fatal outcome observed with severe acute respiratory syndrome-coronavirus-2 infection often results from alveolar injury that impedes airway capacity and multi-organ failure-both of which are associated with the hyperproduction of cytokines, also known as a cytokine storm or cytokine release syndrome. Clinical reports show that both mild and severe forms of disease result in changes in circulating leukocyte subsets and cytokine secretion, particularly IL-6, IL-1s, IL-10, TNF, GM-CSF, IP-10 (IFN-induced protein 10), IL-17, MCP-3, and IL-1ra. Not surprising, therapies that target the immune response and curtail the cytokine storm in coronavirus 2019 (COVID-19) patients have become a focus of recent clinical trials. Here we review reports on leukocyte and cytokine data associated with COVID-19 disease in 3939 patients in China and describe emerging data on immunopathology. With an emphasis on immune modulation, we also look at ongoing clinical studies aimed at blocking proinflammatory cytokines; transfer of immunosuppressive mesenchymal stem cells; use of convalescent plasma transfusion; as well as immunoregulatory therapy and traditional Chinese medicine regimes. In examining leukocyte and cytokine activity in COVID-19, we focus in particular on how these levels are altered as the disease progresses (neutrophil NETosis, macrophage, T cell response, etc.) and proposed consequences to organ pathology (coagulopathy, etc.). Viral and host interactions are described to gain further insight into leukocyte biology and how dysregulated cytokine responses lead to disease and/or organ damage. By better understanding the mechanisms that drive the intensity of a cytokine storm, we can tailor treatment strategies at specific disease stages and improve our response to this worldwide public health threat.
541 citations
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Jasper Fuk-Woo Chan1, Shuofeng Yuan1, Kin-Hang Kok1, Kelvin K. W. To1, Kelvin K. W. To2, Hin Chu1, Jin Yang2, Fanfan Xing2, Jieling Liu2, Cyril C. Y. Yip1, Rosana W.S. Poon1, Hoi Wah Tsoi1, Simon Kam Fai Lo2, Kwok-Hung Chan1, Vincent Kwok-Man Poon1, Wan Mui Chan1, Jonathan Daniel Ip1, Jian Piao Cai1, Vincent C.C. Cheng1, Honglin Chen1, Honglin Chen2, Christopher K.M. Hui2, Kwok-Yung Yuen2 •
TL;DR: The findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions.
7,392 citations
Manli Wang1, Ruiyuan Cao, Leike Zhang1, Xing-Lou Yang1, Jia Liu1, Mingyue Xu1, Zhengli Shi1, Zhihong Hu1, Wu Zhong, Gengfu Xiao1 •
TL;DR: This study evaluated the antiviral efficiency of five FAD-approved drugs including ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and two well-known broad-spectrum antiviral drugs remdesivir and favipiravir against a clinical isolate of 2019-nCoV in vitro.
Abstract: Dear Editor, In December 2019, a novel pneumonia caused by a previously unknown pathogen emerged in Wuhan, a city of 11 million people in central China. The initial cases were linked to exposures in a seafood market in Wuhan. As of January 27, 2020, the Chinese authorities reported 2835 confirmed cases in mainland China, including 81 deaths. Additionally, 19 confirmed cases were identified in Hong Kong, Macao and Taiwan, and 39 imported cases were identified in Thailand, Japan, South Korea, United States, Vietnam, Singapore, Nepal, France, Australia and Canada. The pathogen was soon identified as a novel coronavirus (2019-nCoV), which is closely related to sever acute respiratory syndrome CoV (SARS-CoV). Currently, there is no specific treatment against the new virus. Therefore, identifying effective antiviral agents to combat the disease is urgently needed. An efficient approach to drug discovery is to test whether the existing antiviral drugs are effective in treating related viral infections. The 2019-nCoV belongs to Betacoronavirus which also contains SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). Several drugs, such as ribavirin, interferon, lopinavir-ritonavir, corticosteroids, have been used in patients with SARS or MERS, although the efficacy of some drugs remains controversial. In this study, we evaluated the antiviral efficiency of five FAD-approved drugs including ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and two well-known broad-spectrum antiviral drugs remdesivir (GS5734) and favipiravir (T-705) against a clinical isolate of 2019nCoV in vitro. Standard assays were carried out to measure the effects of these compounds on the cytotoxicity, virus yield and infection rates of 2019-nCoVs. Firstly, the cytotoxicity of the candidate compounds in Vero E6 cells (ATCC-1586) was determined by the CCK8 assay. Then, Vero E6 cells were infected with nCoV2019BetaCoV/Wuhan/WIV04/2019 at a multiplicity of infection (MOI) of 0.05 in the presence of varying concentrations of the test drugs. DMSO was used in the controls. Efficacies were evaluated by quantification of viral copy numbers in the cell supernatant via quantitative real-time RT-PCR (qRT-PCR) and confirmed with visualization of virus nucleoprotein (NP) expression through immunofluorescence microscopy at 48 h post infection (p.i.) (cytopathic effect was not obvious at this time point of infection). Among the seven tested drugs, high concentrations of three nucleoside analogs including ribavirin (half-maximal effective concentration (EC50)= 109.50 μM, halfcytotoxic concentration (CC50) > 400 μM, selectivity index (SI) > 3.65), penciclovir (EC50= 95.96 μM, CC50 > 400 μM, SI > 4.17) and favipiravir (EC50= 61.88 μM, CC50 > 400 μM, SI > 6.46) were required to reduce the viral infection (Fig. 1a and Supplementary information, Fig. S1). However, favipiravir has been shown to be 100% effective in protecting mice against Ebola virus challenge, although its EC50 value in Vero E6 cells was as high as 67 μM, suggesting further in vivo studies are recommended to evaluate this antiviral nucleoside. Nafamostat, a potent inhibitor of MERS-CoV, which prevents membrane fusion, was inhibitive against the 2019-nCoV infection (EC50= 22.50 μM, CC50 > 100 μM, SI > 4.44). Nitazoxanide, a commercial antiprotozoal agent with an antiviral potential against a broad range of viruses including human and animal coronaviruses, inhibited the 2019-nCoV at a low-micromolar concentration (EC50= 2.12 μM; CC50 > 35.53 μM; SI > 16.76). Further in vivo evaluation of this drug against 2019-nCoV infection is recommended. Notably, two compounds remdesivir (EC50= 0.77 μM; CC50 > 100 μM; SI > 129.87) and chloroquine (EC50= 1.13 μM; CC50 > 100 μM, SI > 88.50) potently blocked virus infection at low-micromolar concentration and showed high SI (Fig. 1a, b). Remdesivir has been recently recognized as a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV) infection in cultured cells, mice and nonhuman primate (NHP) models. It is currently under clinical development for the treatment of Ebola virus infection. Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination. Our time-ofaddition assay showed remdesivir functioned at a stage post virus entry (Fig. 1c, d), which is in agreement with its putative antiviral mechanism as a nucleotide analogue. Warren et al. showed that in NHP model, intravenous administration of 10mg/kg dose of remdesivir resulted in concomitant persistent levels of its active form in the blood (10 μM) and conferred 100% protection against Ebola virus infection. Our data showed that EC90 value of remdesivir against 2019-nCoV in Vero E6 cells was 1.76 μM, suggesting its working concentration is likely to be achieved in NHP. Our preliminary data (Supplementary information, Fig. S2) showed that remdesivir also inhibited virus infection efficiently in a human cell line (human liver cancer Huh-7 cells), which is sensitive to 2019-nCoV. Chloroquine, a widely-used anti-malarial and autoimmune disease drug, has recently been reported as a potential broadspectrum antiviral drug. Chloroquine is known to block virus infection by increasing endosomal pH required for virus/ cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at postentry stages of the 2019-nCoV infection in Vero E6 cells (Fig. 1c, d). Besides its antiviral activity, chloroquine has an immune-modulating activity, which may synergistically enhance its antiviral effect in vivo. Chloroquine is widely distributed in the whole body, including lung, after oral administration. The EC90 value of chloroquine against the 2019-nCoV in Vero
5,660 citations
Bin Cao1, Yeming Wang1, Danning Wen2, Wen Liu2, Jingli Wang2, Guohui Fan1, Lianguo Ruan2, Bin Song2, Yanping Cai2, Ming Wei2, Xingwang Li3, Jia'an Xia2, Nanshan Chen2, Jie Xiang1, Ting Yu2, Tao Bai2, Xuelei Xie2, Li Zhang1, Caihong Li2, Ye Yuan2, Hua Chen2, Huadong Li2, Hanping Huang2, Shengjing Tu2, Fengyun Gong2, Ying Liu2, Yuan Wei2, Chongya Dong4, Fei Zhou1, Xiaoying Gu1, Jiuyang Xu5, Zhibo Liu1, Yi Zhang1, Li Hui1, Lianhan Shang1, Ke Wang2, Kunxia Li2, Xia Zhou2, Xuan Dong2, Zhaohui Qu1, Sixia Lu2, Xujuan Hu2, Shunan Ruan2, Shanshan Luo, Jing Wu2, Lu Peng2, Fang Cheng2, Lihong Pan2, Jun Zou2, Chunmin Jia2, Juan Wang2, Xia Liu2, Shuzhen Wang2, Xudong Wu2, Qin Ge2, Jing He2, Haiyan Zhan2, Fang Qiu2, Li Guo6, Chaolin Huang1, Thomas Jaki1, Frederick G. Hayden1, Peter Horby7, Dingyu Zhang1, Chen Wang1 •
TL;DR: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care, and future trials in patients withsevere illness may help to confirm or exclude the possibility of a treatment benefit.
Abstract: Background No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods We conducted a randomized, controlled, open-label trial involvin...
4,293 citations
Philippe Gautret1, Jean-Christophe Lagier1, Philippe Parola1, Van Thuan Hoang1, Line Meddeb, M. Mailhe, Barbara Doudier, Johan Courjon2, Valérie Giordanengo, Vera Esteves Vieira, Hervé Tissot Dupont1, Stéphane Honoré1, Philippe Colson1, Eric Chabrière1, Bernard La Scola1, Jean-Marc Rolain1, Philippe Brouqui1, Didier Raoult1 •
TL;DR: Hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin, which was significantly more efficient for virus elimination.
4,213 citations
Kelvin K. W. To1, Owen Tak Yin Tsang2, Wai Shing Leung2, Anthony Raymond Tam3, Tak Chiu Wu4, David Christopher Lung4, Cyril C. Y. Yip1, Jian Piao Cai1, Jacky Man Chun Chan2, Thomas Shiu Hong Chik2, Daphne Pui-Ling Lau2, Chris Yau Chung Choi2, Lin Lei Chen1, Wan Mui Chan1, Kwok-Hung Chan1, Jonathan Daniel Ip1, Anthony Chin-Ki Ng1, Rosana W.S. Poon1, Cui Ting Luo1, Vincent C.C. Cheng1, Jasper Fuk-Woo Chan1, Jasper Fuk-Woo Chan2, Ivan Hung1, Zhiwei Chen1, Honglin Chen1, Kwok-Yung Yuen2 •
TL;DR: The serial respiratory viral load of SARS-CoV-2 in posterior oropharyngeal saliva samples from patients with COVID-19, and serum antibody responses from patients infected with severe acute respiratory syndrome coronavirus 2 are ascertained.
Abstract: Summary Background Coronavirus disease 2019 (COVID-19) causes severe community and nosocomial outbreaks. Comprehensive data for serial respiratory viral load and serum antibody responses from patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not yet available. Nasopharyngeal and throat swabs are usually obtained for serial viral load monitoring of respiratory infections but gathering these specimens can cause discomfort for patients and put health-care workers at risk. We aimed to ascertain the serial respiratory viral load of SARS-CoV-2 in posterior oropharyngeal (deep throat) saliva samples from patients with COVID-19, and serum antibody responses. Methods We did a cohort study at two hospitals in Hong Kong. We included patients with laboratory-confirmed COVID-19. We obtained samples of blood, urine, posterior oropharyngeal saliva, and rectal swabs. Serial viral load was ascertained by reverse transcriptase quantitative PCR (RT-qPCR). Antibody levels against the SARS-CoV-2 internal nucleoprotein (NP) and surface spike protein receptor binding domain (RBD) were measured using EIA. Whole-genome sequencing was done to identify possible mutations arising during infection. Findings Between Jan 22, 2020, and Feb 12, 2020, 30 patients were screened for inclusion, of whom 23 were included (median age 62 years [range 37–75]). The median viral load in posterior oropharyngeal saliva or other respiratory specimens at presentation was 5·2 log10 copies per mL (IQR 4·1–7·0). Salivary viral load was highest during the first week after symptom onset and subsequently declined with time (slope −0·15, 95% CI −0·19 to −0·11; R2=0·71). In one patient, viral RNA was detected 25 days after symptom onset. Older age was correlated with higher viral load (Spearman's ρ=0·48, 95% CI 0·074–0·75; p=0·020). For 16 patients with serum samples available 14 days or longer after symptom onset, rates of seropositivity were 94% for anti-NP IgG (n=15), 88% for anti-NP IgM (n=14), 100% for anti-RBD IgG (n=16), and 94% for anti-RBD IgM (n=15). Anti-SARS-CoV-2-NP or anti-SARS-CoV-2-RBD IgG levels correlated with virus neutralisation titre (R2>0·9). No genome mutations were detected on serial samples. Interpretation Posterior oropharyngeal saliva samples are a non-invasive specimen more acceptable to patients and health-care workers. Unlike severe acute respiratory syndrome, patients with COVID-19 had the highest viral load near presentation, which could account for the fast-spreading nature of this epidemic. This finding emphasises the importance of stringent infection control and early use of potent antiviral agents, alone or in combination, for high-risk individuals. Serological assay can complement RT-qPCR for diagnosis. Funding Richard and Carol Yu, May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Michael Tong, Marina Lee, Government Consultancy Service, and Sanming Project of Medicine.
2,778 citations
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