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: Jasper Fuk-Woo Chan, Yanfeng Yao, Man-Lung Yeung, Wei Deng, Linlin Bao, Lilong Jia, Fengdi Li, Chong Xiao, Hong Gao, Pin Yu, Jian-Piao Cai, Hin Chu, Jie Zhou, Honglin Chen, Chuan Qin, Kwok-Yung Yuen
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 212 Issue 12 Pg. 1904-13 (Dec 15 2015) ISSN: 1537-6613 [Electronic] United States
• PMID: 26198719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Antiviral Agents
• Lopinavir
• Interferon-beta
• Ritonavir

Topics

• Animals
• Antiviral Agents (administration & dosage)
• Callithrix
• Coronavirus Infections (drug therapy, pathology)
• Disease Models, Animal
• Drug Repositioning
• Interferon-beta (administration & dosage)
• Lopinavir (administration & dosage)
• Male
• Middle East Respiratory Syndrome Coronavirus (isolation & purification)
• Ritonavir (administration & dosage)
• Survival Analysis
• Treatment Outcome
• Viral Load