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All Studies   Meta Analysis    Recent:   

Favipiravir at high doses has potent antiviral activity in SARS-CoV-2−infected hamsters, whereas hydroxychloroquine lacks activity

Kaptein et al., bioRxiv, doi:10.1101/2020.06.19.159053
Jun 2020  
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HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
 
*, now with p < 0.00000000001 from 411 studies, recognized in 46 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,300+ studies for 75 treatments. c19hcq.org
Animal study with Syrian hamsters, showing treatment of SARS-CoV-2-infected hamsters with favipiravir or HCQ (with and without AZ). Treatment with HCQ alone resulted in a very modest reduction of 0.3 log10 viral RNA copies/mg lung, and no reduction in viral RNA load in the ileum or stool.
Therapeutic levels of HCQ may not have been reached. Cytosolic concentrations in the lung were far below the EC90 target.
A number of issues have reportedly been raised, including the following, for which the authors did not respond:
- HCQ was administered with DMSO and Cremophor - why were non-neutral carriers chosen? DMSO has anti-inflammatory properties and Cremophor has a range of side effects1: "use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy". Why weren't the same amounts of solvent applied to the non-treated animals? Shouldn't favipiravir have been dissolved in the same way to avoid bias?
- Why is the method of administration different for both products (oral gavage/intraperitoneal injection)?
- One of the HCQ protocols used in France (IHU Marseille) prescribes 600mg of HCQ per day to patients. For a body weight of 60kg, this corresponds to a dose of 10mg/kg. How is a dose of 50 mg/kg in this study justified, i.e. 5 times more, with possible systemic effects on the animals and possible influence on the results?
- Why were the animals killed after 4/5 days and did the treatment not continue? Unfortunately, this does not allow us to know the real course of the disease or the mortality of the animals beyond day 4. Is it because the animals spontaneously improve without treatment as Professor Neyts seems to say in his webinar for the GVN? And if this is indeed the case, isn't the use of these hamsters exactly an objection as a model for COVID-19 research?
33 preclinical studies support the efficacy of HCQ for COVID-19:
Study covers favipiravir and HCQ.
Kaptein et al., 19 Jun 2020, peer-reviewed, 35 authors.
This PaperHCQAll
Abstract: Favipiravir at high doses has potent antiviral activity in SARS-CoV-2−infected hamsters, whereas hydroxychloroquine lacks activity a Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; bBiomedical MRI and Molecular Small Animal Imaging Centre, Department of Imaging and Pathology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; cDrug Delivery & Disposition, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; dUnité des Virus Emergents, Aix Marseille University, Institut de Recherche pour le Développement (IRD) 190, Institut National de la Santé et de la Recherche Médicale (INSERM) 1207, 13005 Marseille, France; eUCL Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, United Kingdom; f Molecular Small Animal Imaging Centre, Department of Imaging and Pathology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; gDepartment of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium; hNuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; iAssistance Publique–Hôpitaux de Marseille, Aix-Marseille University, Unité des Virus Emergents, Institut de Recherche pour le Développement (IRD) 190, Institut National de la Santé et de la Recherche Médicale (INSERM) 1207, Laboratoire de Pharmacocinétique et Toxicologie, 13005 Marseille, France; jTranslational Cell and Tissue Research, Department of Imaging and Pathology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; kPharmacy Department, University Hospitals Leuven, 3000 Leuven, Belgium; lDepartment of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven–University of Leuven, 3000 Leuven, Belgium; and mGlobal Virus Network, Baltimore, MD 21201 Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved September 3, 2020 (received for review July 9, 2020) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2−infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the..
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The high need for treatment options, ' 'together with the lack of small animal models of infection has led to clinical trials with ' 'repurposed drugs before any preclinical<jats:italic>in vivo</jats:italic>evidence attesting ' 'their efficacy was available. We used Syrian hamsters to establish a model to evaluate ' 'antiviral activity of small molecules in both an infection and a transmission setting. Upon ' 'intranasal infection, the animals developed high titers of SARS-CoV-2 in the lungs and ' 'pathology similar to that observed in mild COVID-19 patients. Treatment of ' 'SARS-CoV-2-infected hamsters with favipiravir or hydroxychloroquine (with and without ' 'azithromycin) resulted in respectively a mild or no reduction in viral RNA and infectious ' 'virus. Micro-CT scan analysis of the lungs showed no improvement compared to non-treated ' 'animals, which was confirmed by histopathology. In addition, both compounds did not prevent ' 'virus transmission through direct contact and thus failed as prophylactic treatments. By ' 'modelling the PK profile of hydroxychloroquine based on the trough plasma concentrations, we ' 'show that the total lung exposure to the drug was not the limiting factor. In conclusion, we ' 'here characterized a hamster infection and transmission model to be a robust model for ' 'studying<jats:italic>in vivo</jats:italic>efficacy of antiviral compounds. The information ' 'acquired using hydroxychloroquine and favipiravir in this model is of critical value to those ' 'designing (current and) future clinical trials. At this point, the data here presented on ' 'hydroxychloroquine either alone or combined with azithromycin (together with previously ' 'reported<jats:italic>in vivo</jats:italic>data in macaques and ferrets) provide no scientific ' 'basis for further use of the drug in humans.</jats:p>', 'DOI': '10.1101/2020.06.19.159053', 'type': 'posted-content', 'created': {'date-parts': [[2020, 6, 20]], 'date-time': '2020-06-20T04:25:12Z', 'timestamp': 1592627112000}, 'source': 'Crossref', 'is-referenced-by-count': 17, 'title': 'Antiviral treatment of SARS-CoV-2-infected hamsters reveals a weak effect of favipiravir and a ' 'complete lack of effect for hydroxychloroquine', 'prefix': '10.1101', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-7935-0219', 'authenticated-orcid': False, 'given': 'Suzanne JF', 'family': 'Kaptein', 'sequence': 'first', 'affiliation': []}, {'given': 'Sofie', 'family': 'Jacobs', 'sequence': 'additional', 'affiliation': []}, {'given': 'Lana', 'family': 'Langendries', 'sequence': 'additional', 'affiliation': []}, {'given': 'Laura', 'family': 'Seldeslachts', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sebastiaan', 'family': 'ter Horst', 'sequence': 'additional', 'affiliation': []}, {'given': 'Laurens', 'family': 'Liesenborghs', 'sequence': 'additional', 'affiliation': []}, {'given': 'Bart', 'family': 'Hens', 'sequence': 'additional', 'affiliation': []}, {'given': 'Valentijn', 'family': 'Vergote', 'sequence': 'additional', 'affiliation': []}, {'given': 'Elisabeth', 'family': 'Heylen', 'sequence': 'additional', 'affiliation': []}, {'given': 'Elke', 'family': 'Maas', 'sequence': 'additional', 'affiliation': []}, {'given': 'Carolien', 'family': 'De Keyzer', 'sequence': 'additional', 'affiliation': []}, {'given': 'Lindsey', 'family': 'Bervoets', 'sequence': 'additional', 'affiliation': []}, {'given': 'Jasper', 'family': 'Rymenants', 'sequence': 'additional', 'affiliation': []}, {'given': 'Tina', 'family': 'Van Buyten', 'sequence': 'additional', 'affiliation': []}, {'given': 'Hendrik Jan', 'family': 'Thibaut', 'sequence': 'additional', 'affiliation': []}, {'given': 'Kai', 'family': 'Dallmeier', 'sequence': 'additional', 'affiliation': []}, {'given': 'Robbert', 'family': 'Boudewijns', 'sequence': 'additional', 'affiliation': []}, {'given': 'Jens', 'family': 'Wouters', 'sequence': 'additional', 'affiliation': []}, {'given': 'Patrick', 'family': 'Augustijns', 'sequence': 'additional', 'affiliation': []}, {'given': 'Nick', 'family': 'Verougstraete', 'sequence': 'additional', 'affiliation': []}, {'given': 'Christopher', 'family': 'Cawthorne', 'sequence': 'additional', 'affiliation': []}, {'given': 'Birgit', 'family': 'Weynand', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0003-3525-7351', 'authenticated-orcid': False, 'given': 'Pieter', 'family': 'Annaert', 'sequence': 'additional', 'affiliation': []}, {'given': 'Isabel', 'family': 'Spriet', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-5633-3993', 'authenticated-orcid': False, 'given': 'Greetje Vande', 'family': 'Velde', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-0033-7514', 'authenticated-orcid': False, 'given': 'Johan', 'family': 'Neyts', 'sequence': 'additional', 'affiliation': []}, {'given': 'Joana', 'family': 'Rocha-Pereira', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-8874-675X', 'authenticated-orcid': False, 'given': 'Leen', 'family': 'Delang', 'sequence': 'additional', 'affiliation': []}], 'member': '246', 'reference': [ { 'key': '2020062211353215000_2020.06.19.159053v1.1', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2001017'}, { 'key': '2020062211353215000_2020.06.19.159053v1.2', 'doi-asserted-by': 'crossref', 'unstructured': 'Tay MZ , Poh CM , Rénia L , MacAry PA , Ng LFP. 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