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Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset.
J Infect Dis. 2015 Dec 15; 212(12):1904-13.JI

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe disease in human with an overall case-fatality rate of >35%. Effective antivirals are crucial for improving the clinical outcome of MERS. Although a number of repurposed drugs, convalescent-phase plasma, antiviral peptides, and neutralizing antibodies exhibit anti-MERS-CoV activity in vitro, most are not readily available or have not been evaluated in nonhuman primates. We assessed 3 repurposed drugs with potent in vitro anti-MERS-CoV activity (mycophenolate mofetil [MMF], lopinavir/ritonavir, and interferon-β1b) in common marmosets with severe disease resembling MERS in humans. The lopinavir/ritonavir-treated and interferon-β1b-treated animals had better outcome than the untreated animals, with improved clinical (mean clinical scores ↓50.9%-95.0% and ↓weight loss than the untreated animals), radiological (minimal pulmonary infiltrates), and pathological (mild bronchointerstitial pneumonia) findings, and lower mean viral loads in necropsied lung (↓0.59-1.06 log10 copies/glyceraldehyde 3-phosphate dehydrogenase [GAPDH]; P < .050) and extrapulmonary (↓0.11-1.29 log10 copies/GAPDH; P < .050 in kidney) tissues. In contrast, all MMF-treated animals developed severe and/or fatal disease with higher mean viral loads (↑0.15-0.54 log10 copies/GAPDH) than the untreated animals. The mortality rate at 36 hours postinoculation was 67% (untreated and MMF-treated) versus 0-33% (lopinavir/ritonavir-treated and interferon-β1b-treated). Lopinavir/ritonavir and interferon-β1b alone or in combination should be evaluated in clinical trials. MMF alone may worsen MERS and should not be used.

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Authors+Show Affiliations

Chan JF
State Key Laboratory of Emerging Infectious Diseases Department of Microbiology Research Centre of Infection and Immunology Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region.
Yao Y
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
Yeung ML
Department of Microbiology.
Deng W
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
Bao L
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
Jia L
Department of Microbiology.
Li F
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
Xiao C
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
Gao H
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
Yu P
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
Cai JP
Department of Microbiology.
Chu H
Department of Microbiology.
Zhou J
Department of Microbiology.
Chen H
State Key Laboratory of Emerging Infectious Diseases Department of Microbiology Research Centre of Infection and Immunology Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region.
Qin C
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
Yuen KY
State Key Laboratory of Emerging Infectious Diseases Department of Microbiology Research Centre of Infection and Immunology Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region.

MeSH

AnimalsAntiviral AgentsCallithrixCoronavirus InfectionsDisease Models, AnimalDrug RepositioningInterferon-betaLopinavirMaleMiddle East Respiratory Syndrome CoronavirusRitonavirSurvival AnalysisTreatment OutcomeViral Load

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26198719

Clinical Trial Links

Trial of Early Therapies During Non-hospitalized Outpatient Window for COVID-19
Dual Therapy With Interferon Beta-1b and Clofazimine for COVID-19
IFN Beta-1b and Ribavirin for Covid-19
IFN-beta 1b and Remdesivir for COVID19
OUTpatient Treatment of COVID-19 in Patients With Risk Factor for Poor Outcome

Citation

Chan, Jasper Fuk-Woo, et al. "Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset." The Journal of Infectious Diseases, vol. 212, no. 12, 2015, pp. 1904-13.
Chan JF, Yao Y, Yeung ML, et al. Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis. 2015;212(12):1904-13.
Chan, J. F., Yao, Y., Yeung, M. L., Deng, W., Bao, L., Jia, L., Li, F., Xiao, C., Gao, H., Yu, P., Cai, J. P., Chu, H., Zhou, J., Chen, H., Qin, C., & Yuen, K. Y. (2015). Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. The Journal of Infectious Diseases, 212(12), 1904-13. https://doi.org/10.1093/infdis/jiv392
Chan JF, et al. Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis. 2015 Dec 15;212(12):1904-13. PubMed PMID: 26198719.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. AU - Chan,Jasper Fuk-Woo, AU - Yao,Yanfeng, AU - Yeung,Man-Lung, AU - Deng,Wei, AU - Bao,Linlin, AU - Jia,Lilong, AU - Li,Fengdi, AU - Xiao,Chong, AU - Gao,Hong, AU - Yu,Pin, AU - Cai,Jian-Piao, AU - Chu,Hin, AU - Zhou,Jie, AU - Chen,Honglin, AU - Qin,Chuan, AU - Yuen,Kwok-Yung, Y1 - 2015/07/21/ PY - 2015/06/15/received PY - 2015/07/06/accepted PY - 2015/7/23/entrez PY - 2015/7/23/pubmed PY - 2016/3/10/medline KW - Kaletra KW - MERS KW - animal KW - common marmoset KW - coronavirus KW - interferon KW - lopinavir KW - mycophenolate KW - primate KW - treatment SP - 1904 EP - 13 JF - The Journal of infectious diseases JO - J Infect Dis VL - 212 IS - 12 N2 - Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe disease in human with an overall case-fatality rate of >35%. Effective antivirals are crucial for improving the clinical outcome of MERS. Although a number of repurposed drugs, convalescent-phase plasma, antiviral peptides, and neutralizing antibodies exhibit anti-MERS-CoV activity in vitro, most are not readily available or have not been evaluated in nonhuman primates. We assessed 3 repurposed drugs with potent in vitro anti-MERS-CoV activity (mycophenolate mofetil [MMF], lopinavir/ritonavir, and interferon-β1b) in common marmosets with severe disease resembling MERS in humans. The lopinavir/ritonavir-treated and interferon-β1b-treated animals had better outcome than the untreated animals, with improved clinical (mean clinical scores ↓50.9%-95.0% and ↓weight loss than the untreated animals), radiological (minimal pulmonary infiltrates), and pathological (mild bronchointerstitial pneumonia) findings, and lower mean viral loads in necropsied lung (↓0.59-1.06 log10 copies/glyceraldehyde 3-phosphate dehydrogenase [GAPDH]; P < .050) and extrapulmonary (↓0.11-1.29 log10 copies/GAPDH; P < .050 in kidney) tissues. In contrast, all MMF-treated animals developed severe and/or fatal disease with higher mean viral loads (↑0.15-0.54 log10 copies/GAPDH) than the untreated animals. The mortality rate at 36 hours postinoculation was 67% (untreated and MMF-treated) versus 0-33% (lopinavir/ritonavir-treated and interferon-β1b-treated). Lopinavir/ritonavir and interferon-β1b alone or in combination should be evaluated in clinical trials. MMF alone may worsen MERS and should not be used. SN - 1537-6613 UR - https://www.unboundmedicine.com/medline/citation/26198719/Treatment_With_Lopinavir/Ritonavir_or_Interferon_β1b_Improves_Outcome_of_MERS_CoV_Infection_in_a_Nonhuman_Primate_Model_of_Common_Marmoset_ DB - PRIME DP - Unbound Medicine ER -