Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates

Maisonnasse et al., Nature, 2020, doi:10.1038/s41586-020-2558-4 (date from preprint)

May 2020

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HCQ for COVID-19

1st treatment shown to reduce risk in March 2020, now with p < 0.00000000001 from 419 studies, recognized in 46 countries.

Lower risk for mortality, hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 109 treatments. c19hcq.org

Monkey study which reports no effect of HCQ or HCQ+AZ. However, there are several signs of effectiveness despite the very small sample sizes and 100% recovery of all treated and control monkeys.

58% reduction in lung lesions: the final day lung lesion data shows 63% of control monkeys have lesions, while 26% of treated monkeys do, p=0.095 (the final day data is missing for 7 monkeys, these are predicted based on the day 5 results and the trend of comparable monkeys).

97% increase in viral load recovery after one week: 3 of 8 control monkeys (38%) have recovered with <= 4 log10 copies/mL viral load, compared to 17 of 23 treated monkeys (74%), p=0.095. 3 of 8 (38%) control monkeys also have a higher peak viral load than 100% of the 23 treated monkeys post-treatment. The group with the lowest peak viral load is the PrEP group.

All animals were infected with the same initial viral load, whereas real-world infections vary in the initial viral load, and lower initial viral loads allow greater time to mount an immune response.

Severity of disease is not analyzed as compared to humans. The steep viral drops observed could also be related to immune system response.

38 preclinical studies support the efficacy of HCQ for COVID-19:

11 In Silico studies1-11

24 In Vitro studies1,12-34

3 In Vivo animal studies16,26,35

Important missing comments or errors? Let us know.

1. González-Paz et al., Biophysical Analysis of Potential Inhibitors of SARS-CoV-2 Cell Recognition and Their Effect on Viral Dynamics in Different Cell Types: A Computational Prediction from In Vitro Experimental Data, ACS Omega, doi:10.1021/acsomega.3c06968.acs.org, doi.org.

2. Alkafaas et al., A study on the effect of natural products against the transmission of B.1.1.529 Omicron, Virology Journal, doi:10.1186/s12985-023-02160-6.biomedcentral.com, doi.org.

3. Guimarães Silva et al., Are Non-Structural Proteins From SARS-CoV-2 the Target of Hydroxychloroquine? An in Silico Study, ACTA MEDICA IRANICA, doi:10.18502/acta.v61i2.12533.kne-publishing.com, doi.org.

4. Nguyen et al., The Potential of Ameliorating COVID-19 and Sequelae From Andrographis paniculata via Bioinformatics, Bioinformatics and Biology Insights, doi:10.1177/11779322221149622.sagepub.com, doi.org.

5. Navya et al., A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection, Informatics in Medicine Unlocked, doi:10.1016/j.imu.2021.100714.sciencedirect.com, doi.org.

6. Yadav et al., Repurposing the Combination Drug of Favipiravir, Hydroxychloroquine and Oseltamivir as a Potential Inhibitor Against SARS-CoV-2: A Computational Study, Research Square, doi:10.21203/rs.3.rs-628277/v1.researchsquare.com, doi.org.

7. Hussein et al., Molecular Docking Identification for the efficacy of Some Zinc Complexes with Chloroquine and Hydroxychloroquine against Main Protease of COVID-19, Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129979.sciencedirect.com, doi.org.

8. Baildya et al., Inhibitory capacity of Chloroquine against SARS-COV-2 by effective binding with Angiotensin converting enzyme-2 receptor: An insight from molecular docking and MD-simulation studies, Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129891.sciencedirect.com, doi.org.

9. Noureddine et al., Quantum chemical studies on molecular structure, AIM, ELF, RDG and antiviral activities of hybrid hydroxychloroquine in the treatment of COVID-19: molecular docking and DFT calculations, Journal of King Saud University - Science, doi:10.1016/j.jksus.2020.101334.sciencedirect.com, doi.org.

10. Tarek et al., Pharmacokinetic Basis of the Hydroxychloroquine Response in COVID-19: Implications for Therapy and Prevention, European Journal of Drug Metabolism and Pharmacokinetics, doi:10.1007/s13318-020-00640-6.springer.com, doi.org.

11. Rowland Yeo et al., Impact of Disease on Plasma and Lung Exposure of Chloroquine, Hydroxychloroquine and Azithromycin: Application of PBPK Modeling, Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.1955.wiley.com, doi.org.

12. Hitti et al., Hydroxychloroquine attenuates double-stranded RNA-stimulated hyper-phosphorylation of tristetraprolin/ZFP36 and AU-rich mRNA stabilization, Immunology, doi:10.1111/imm.13835.wiley.com, doi.org.

13. Yan et al., Super-resolution imaging reveals the mechanism of endosomal acidification inhibitors against SARS-CoV-2 infection, ChemBioChem, doi:10.1002/cbic.202400404.wiley.com, doi.org.

14. Mohd Abd Razak et al., In Vitro Anti-SARS-CoV-2 Activities of Curcumin and Selected Phenolic Compounds, Natural Product Communications, doi:10.1177/1934578X231188861.sagepub.com, doi.org.

15. Alsmadi et al., The In Vitro, In Vivo, and PBPK Evaluation of a Novel Lung-Targeted Cardiac-Safe Hydroxychloroquine Inhalation Aerogel, AAPS PharmSciTech, doi:10.1208/s12249-023-02627-3.springer.com, doi.org.

16. Wen et al., Cholinergic α7 nAChR signaling suppresses SARS-CoV-2 infection and inflammation in lung epithelial cells, Journal of Molecular Cell Biology, doi:10.1093/jmcb/mjad048.oup.com, doi.org.

17. Kamga Kapchoup et al., In vitro effect of hydroxychloroquine on pluripotent stem cells and their cardiomyocytes derivatives, Frontiers in Pharmacology, doi:10.3389/fphar.2023.1128382.frontiersin.org, doi.org.

18. Milan Bonotto et al., Cathepsin inhibitors nitroxoline and its derivatives inhibit SARS-CoV-2 infection, Antiviral Research, doi:10.1016/j.antiviral.2023.105655.sciencedirect.com, doi.org.

19. Miao et al., SIM imaging resolves endocytosis of SARS-CoV-2 spike RBD in living cells, Cell Chemical Biology, doi:10.1016/j.chembiol.2023.02.001.sciencedirect.com, doi.org.

20. Yuan et al., Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture, Communications Biology, doi:10.1038/s42003-022-03841-8.nature.com, doi.org.

21. Faísca et al., Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2, Pharmaceutics, doi:10.3390/pharmaceutics14040877.mdpi.com, doi.org.

22. Delandre et al., Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants, Pharmaceuticals, doi:10.3390/ph15040445.mdpi.com, doi.org.

23. Purwati et al., An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia, PLOS One, doi:10.1371/journal.pone.0252302.plos.org, doi.org.

24. Zhang et al., SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination, Cell Death & Differentiation, doi:10.1038/s41418-021-00782-3.nature.com, doi.org.

25. Dang et al., Structural basis of anti-SARS-CoV-2 activity of hydroxychloroquine: specific binding to NTD/CTD and disruption of LLPS of N protein, bioRxiv, doi:10.1101/2021.03.16.435741.biorxiv.org, doi.org.

26. Shang et al., Inhibitors of endosomal acidification suppress SARS-CoV-2 replication and relieve viral pneumonia in hACE2 transgenic mice, Virology Journal, doi:10.1186/s12985-021-01515-1.biomedcentral.com, doi.org.

27. Wang et al., Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus, Phytomedicine, doi:10.1016/j.phymed.2020.153333.nih.gov, doi.org.

28. Sheaff, R., A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity, bioRxiv, doi:10.1101/2020.08.02.232892.biorxiv.org, doi.org.

29. Ou et al., Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2, PLOS Pathogens, doi:10.1371/journal.ppat.1009212.plos.org, doi.org.

30. Andreani et al., In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect, Microbial Pathogenesis, doi:10.1016/j.micpath.2020.104228.sciencedirect.com, doi.org.

31. Clementi et al., Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro, Front. Microbiol., 10 July 2020, doi:10.3389/fmicb.2020.01704.frontiersin.org, doi.org.

32. Liu et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discovery 6, 16 (2020), doi:10.1038/s41421-020-0156-0.nature.com, doi.org.

33. Yao et al., In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clin. Infect. Dis., 2020 Mar 9, doi:10.1093/cid/ciaa237.oup.com, doi.org.

34. Wang (B) et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res. 30, 269–271, doi:10.1038/s41422-020-0282-0.nature.com, doi.org.

35. Shu-Han Lin et al., Inhalable Chitosan-Based Hydrogel as a Mucosal Adjuvant for Hydroxychloroquine in the Treatment for SARS-CoV-2 Infection in a Hamster Model, Journal of Microbiology, Immunology and Infection, doi:10.1016/j.jmii.2023.08.001.sciencedirect.com, doi.org.

Maisonnasse et al., 6 May 2020, peer-reviewed, 24 authors.

This Paper HCQ All

Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates

Pauline Maisonnasse, Jérémie Guedj, Vanessa Contreras, Sylvie Behillil, Caroline Solas, Romain Marlin, Thibaut Naninck, Andres Pizzorno, Julien Lemaitre, Antonio Gonçalves, Nidhal Kahlaoui, Olivier Terrier, Raphael Ho Tsong Fang, Vincent Enouf, Nathalie Dereuddre-Bosquet, Angela Brisebarre, Franck Touret, Catherine Chapon, Bruno Hoen, Bruno Lina, Manuel Rosa Calatrava, Sylvie Van Der Werf, Xavier De Lamballerie, Roger Le Grand

Nature, doi:10.1038/s41586-020-2558-4

This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Reporting summary Further information on research design is available in the Nature Research Reporting Summary linked to this paper. Acknowledgements Delache B, Burban E, Demilly J, Dhooge N, Langlois S, Le Calvez P, Potier M, Relouzat F, Robert JM and Dodan C contributed to animal studies. Fert B and Mayet C contributed to in vivo imaging studies. Pascal Q performed the necropsies. Morin J did the cytokines measurements and reagents preparation. Barthelemy K, Basso M, Doudka N, Giocanti M, contributed to HCQ concentration measurements. Lacarelle B and Guilhaumou R contributed to internal drug concentration data. Bertrand J contributed to pharmacokinetics analysis. Desjardins D contributed to the AZTH pharmacokinetic study. Aubenque C, Barendji M, Bossevot L, Dimant N, Dinh J, Gallouet AS, Leonec M, Mangeot I and Storck K contributed to sample processing. Albert M., Barbet M. and Donati F contributed to the production, titration and sequencing of the virus stocks used in vivo and to processing of samples for RT-PCR. Gallouet AS, Keyser, S, Marcos-Lopez E, Targat B and Vaslin B helped to experimental studies in the context of COVID-19 induced constraints. Ducancel F and Gorin Y contributed to logistics and safety management. We are very grateful for the help of Dr Sultan E from Sanofi for providing guidance in HCQ dose selection and discussion on PK/PD results and the review of the article. We thank Sanofi for providing the hydroxychloroquine batch used in these experiments...

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Nature 584, 120–124 (2020).', 'journal-title': 'Nature'}, { 'key': '2558_CR21', 'doi-asserted-by': 'publisher', 'first-page': '732', 'DOI': '10.1093/cid/ciaa237', 'volume': '71', 'author': 'X Yao', 'year': '2020', 'unstructured': 'Yao, X. et al. In vitro antiviral activity and projection of optimized ' 'dosing design of hydroxychloroquine for the treatment of severe acute ' 'respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin. Infect. Dis. 71, ' '732–739 (2020).', 'journal-title': 'Clin. Infect. Dis.'}, { 'key': '2558_CR22', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41598-019-48013-7', 'volume': '9', 'author': 'C Nicolas de Lamballerie', 'year': '2019', 'unstructured': 'Nicolas de Lamballerie, C. et al. Characterization of cellular ' 'transcriptomic signatures induced by different respiratory viruses in ' 'human reconstituted airway epithelia. Sci. Rep. 9, 11493 (2019).', 'journal-title': 'Sci. Rep.'}, { 'key': '2558_CR23', 'doi-asserted-by': 'publisher', 'first-page': '100059', 'DOI': '10.1016/j.xcrm.2020.100059', 'volume': '1', 'author': 'A Pizzorno', 'year': '2020', 'unstructured': 'Pizzorno, A. et al. Characterization and treatment of SARS-CoV-2 in ' 'nasal and bronchial human airway epithelia. Cell. Rep. Med 1, 100059 ' '(2020).', 'journal-title': 'Cell. Rep. Med'}, { 'key': '2558_CR24', 'doi-asserted-by': 'publisher', 'first-page': '715', 'DOI': '10.1148/radiol.2020200370', 'volume': '295', 'author': 'F Pan', 'year': '2020', 'unstructured': 'Pan, F. et al. Time course of lung changes at chest CT during recovery ' 'from coronavirus disease 2019 (COVID-19). Radiology 295, 715–721 (2020).', 'journal-title': 'Radiology'}, { 'key': '2558_CR25', 'doi-asserted-by': 'publisher', 'first-page': '425', 'DOI': '10.1016/S1473-3099(20)30086-4', 'volume': '20', 'author': 'H Shi', 'year': '2020', 'unstructured': 'Shi, H. et al. 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Dis.'}, { 'key': '2558_CR28', 'doi-asserted-by': 'publisher', 'first-page': '507', 'DOI': '10.1016/S0140-6736(20)30211-7', 'volume': '395', 'author': 'N Chen', 'year': '2020', 'unstructured': 'Chen, N. et al. Epidemiological and clinical characteristics of 99 cases ' 'of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive ' 'study. Lancet 395, 507–513 (2020).', 'journal-title': 'Lancet'}, { 'key': '2558_CR29', 'doi-asserted-by': 'publisher', 'first-page': '268', 'DOI': '10.3390/v10050268', 'volume': '10', 'author': 'P Roques', 'year': '2018', 'unstructured': 'Roques, P. et al. Paradoxical effect of chloroquine treatment in ' 'enhancing chikungunya virus infection. Viruses 10, 268 (2018).', 'journal-title': 'Viruses'}, { 'key': '2558_CR30', 'doi-asserted-by': 'publisher', 'first-page': '320', 'DOI': '10.1016/j.jchromb.2017.11.026', 'volume': '1072', 'author': 'YS Chhonker', 'year': '2018', 'unstructured': 'Chhonker, Y. S., Sleightholm, R. L., Li, J., Oupický, D. & Murry, D. J. ' 'Simultaneous quantitation of hydroxychloroquine and its metabolites in ' 'mouse blood and tissues using LC-ESI-MS/MS: an application for ' 'pharmacokinetic studies. J. Chromatogr. B Analyt. Technol. Biomed. Life ' 'Sci. 1072, 320–327 (2018).', 'journal-title': 'J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.'}, { 'key': '2558_CR31', 'doi-asserted-by': 'publisher', 'first-page': '697', 'DOI': '10.1016/S1473-3099(20)30200-0', 'volume': '20', 'author': 'FX Lescure', 'year': '2020', 'unstructured': 'Lescure, F. X. et al. Clinical and virological data of the first cases ' 'of COVID-19 in Europe: a case series. Lancet Infect. Dis. 20, 697–706 ' '(2020).', 'journal-title': 'Lancet Infect. Dis.'}], 'container-title': 'Nature', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'http://www.nature.com/articles/s41586-020-2558-4.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'http://www.nature.com/articles/s41586-020-2558-4', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'http://www.nature.com/articles/s41586-020-2558-4.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 5, 20]], 'date-time': '2023-05-20T22:07:11Z', 'timestamp': 1684620431000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.nature.com/articles/s41586-020-2558-4'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2020, 7, 22]]}, 'references-count': 31, 'journal-issue': {'issue': '7826', 'published-print': {'date-parts': [[2020, 9, 24]]}}, 'alternative-id': ['2558'], 'URL': 'http://dx.doi.org/10.1038/s41586-020-2558-4', 'relation': {}, 'ISSN': ['0028-0836', '1476-4687'], 'subject': [], 'container-title-short': 'Nature', 'published': {'date-parts': [[2020, 7, 22]]}, 'assertion': [ { 'value': '30 April 2020', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '10 July 2020', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '22 July 2020', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': 'J.G. has worked as consultant for Roche.', 'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}, { 'value': 'This content has been made available to all.', 'name': 'free', 'label': 'Free to read'}]}

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