Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 212, Issue 12, Pages 1904-1913Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiv392
Keywords
animal; common marmoset; coronavirus; interferon; Kaletra; lopinavir; MERS; mycophenolate; primate; treatment
Categories
Funding
- Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Disease of the Department of Health
- Hong Kong Health
- Medical Research Fund [14131392]
- Hong Kong Research Grants Council [N_HKU728/14]
- Research Grants Council, Hong Kong Special Administrative Region [T11/707/15]
- National Science and Technology Major Projects of Infectious Diseases, China [2012ZX10004501-004]
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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-beta 1b) in common marmosets with severe disease resembling MERS in humans. The lopinavir/ritonavir-treated and interferon-beta 1b-treated animals had better outcome than the untreated animals, with improved clinical (mean clinical scores down arrow 50.9%-95.0% and down arrow weight loss than the untreated animals), radiological (minimal pulmonary infiltrates), and pathological (mild bronchointerstitial pneumonia) findings, and lower mean viral loads in necropsied lung (down arrow 0.59-1.06 log(10) copies/glyceraldehyde 3-phosphate dehydrogenase [GAPDH]; P<.050) and extrapulmonary (down arrow 0.11-1.29 log(10) copies/GAPDH; P<.050 in kidney) tissues. In contrast, all MMF-treated animals developed severe and/or fatal disease with higher mean viral loads (up arrow 0.15-0.54 log(10) 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-beta 1b-treated). Lopinavir/ritonavir and interferon-beta 1b alone or in combination should be evaluated in clinical trials. MMF alone may worsen MERS and should not be used.
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