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.

Novel activities of safe-in-human broad-spectrum antiviral agents

“…Ritonavir is an antiretroviral medication. It has also antiviral activity against MERS-CoV (Chan et al, 2015). We showed that azacitidine, cyclosporine, minocycline, oritavancin and ritonavir are active against RVFV.…”

Focus on Middle East respiratory syndrome coronavirus (MERS-CoV)

“…In vitro, anti-MERS-CoV activity has been demonstrated for doses of MMF that are acceptable for use in humans. MMF seems to show a synergistic effect with IFN-␤1b in vitro [70]. But in a non human primate common marmosets model, animals treated with MMF developed more severe lesions and showed a higher case fatality rate compared with untreated animals [70].…”

“…MMF seems to show a synergistic effect with IFN-␤1b in vitro [70]. But in a non human primate common marmosets model, animals treated with MMF developed more severe lesions and showed a higher case fatality rate compared with untreated animals [70]. In contrast with animal model, the combination IFN-␤1b/MMF was administered to 8 patients in Saudi Arabia.…”

An opportunistic Pathogen Afforded Ample Opportunities: Middle East Respiratory Syndrome Coronavirus

“…Their practical use in humans is challenging because, if not infected while in a healthcare setting, humans usually present for care with well advanced disease. [107,108] Combined treatments which reduce viral replication and the host immune response to it are likely to be valuable developments. [15] A wide range of repurposed or novel potential antivirals including polymerase, nucleotide synthesis and protease inhibitors and fusion-inhibiting peptides [64,87,[109][110][111][112][113] have been investigated.…”