title: Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset.
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.
authors.affiliation: 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.
authors.forename: Jasper Fuk-Woo
authors.initials: JF
authors.lastname: Chan
authors.affiliation: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Microbiology.
authors.forename: Man-Lung
authors.initials: ML
authors.lastname: Yeung
authors.affiliation: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.affiliation: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Bao
authors.affiliation: Department of Microbiology.
authors.forename: Lilong
authors.initials: L
authors.lastname: Jia
authors.affiliation: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Fengdi
authors.initials: F
authors.lastname: Li
authors.affiliation: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.affiliation: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Pin
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Microbiology.
authors.forename: Jian-Piao
authors.initials: JP
authors.lastname: Cai
authors.affiliation: Department of Microbiology.
authors.forename: Hin
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Microbiology.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Honglin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Qin
authors.affiliation: 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.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D002144:Callithrix; D018352:Coronavirus Infections / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D058492:Drug Repositioning; D016899:Interferon-beta / Q000008:administration & dosage*; D061466:Lopinavir / Q000008:administration & dosage*; D008297:Male; D065207:Middle East Respiratory Syndrome Coronavirus / Q000302:isolation & purification; D019438:Ritonavir / Q000008:administration & dosage*; D016019:Survival Analysis; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D061466:Lopinavir; D016899:Interferon-beta; D019438:Ritonavir
keywords: Kaletra; MERS; animal; common marmoset; coronavirus; interferon; lopinavir; mycophenolate; primate; treatment