Assessing antiviral activity of chloroquine and hydroxychloroquine — 2 studies in Nature

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Chloroquine and hydroxychloroquine show no notable antiviral effect against infections with SARS-CoV-2 in macaques or human lung cells according to two studies. Hydroxychloroquine and chloroquine – drugs that are commonly used for the treatment of malaria – have been investigated for their potential to treat COVID-19 in more than 80 registered clinical trials. They have been shown to inhibit SARS-CoV-2 infection in cell cultures, but their effectiveness for the treatment of patients with COVID-19 has been debated.

Roger Le Grand and colleagues at the Université Paris-Saclay, Inserm, Université de Paris, INSERM, Institut Pasteur, Aix-Marseille University, CIRI, Centre International de Recherche en Infectiologie, (Team VirPath) and University Lyon, investigated the effects of hydroxychloroquine treatment in cynomolgus macaques, a non-human primate model of SARS-CoV-2 infection in humans. Hydroxychloroquine showed no substantial antiviral activity, regardless of the timing of treatment initiation, either before infection, soon after infection or late after infection. In addition, using this antimalarial drug in combination with azithromycin, an antibiotic, had no notable effect on virus levels in the macaques either.

In a separate study, Stefan Pöhlmann and colleagues at the Leibniz Institute for Primate Research-Göttingen, and Georg-August-University Göttingen, found that chloroquine has no antiviral activity against SARS-CoV-2 in human lung cells. They explain that in previous experiments, the cells that were used to demonstrate a positive effect for chloroquine did not have an enzyme, which is normally present in lung cells, that facilitates the entry of SARS-CoV-2 into human lung cells. The authors emphasise the importance of using cell lines that mimic lung tissue in studies that assess the activity of drugs against SARS-CoV-2.

Together, these results do not support the use of hydroxychloroquine and chloroquine for the treatment of patients with COVID-19.

Abstract 1
COVID-19 has rapidly become a pandemic for which no antiviral drug or vaccine is yet available2–4. Several clinical studies are ongoing to evaluate the efficacy of repurposed drugs that have demonstrated antiviral efficacy in vitro. Among these candidates, hydroxychloroquine (HCQ) has been given to thousands of individuals worldwide but definitive evidence for HCQ efficacy in treatment of COVID-19 is still missing6,7,17,18. We evaluated the antiviral activity of HCQ both in vitro and in SARS-CoV-2-infected macaques. HCQ showed antiviral activity in African green monkey kidney cells (VeroE6) but not in a model of reconstituted human airway epithelium. In macaques, we tested different treatment strategies in comparison to placebo, before and after peak viral load, alone or in combination with azithromycin (AZTH). Neither HCQ nor HCQ+AZTH showed a significant effect on the viral load levels in any of the tested compartments. When the drug was used as a pre-exposure prophylaxis (PrEP), HCQ did not confer protection against acquisition of infection. Our findings do not support the use of HCQ, either alone or in combination with AZTH, as an antiviral treatment for COVID-19 in humans.

Authors
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

Abstract 2
The COVID-19 pandemic, which is caused by the novel coronavirus SARS-CoV-2, has been associated with more than 470,000 fatal cases worldwide. In order to develop antiviral interventions quickly, drugs used for treatment of unrelated diseases are currently being repurposed to combat COVID-19. Chloroquine is a anti-malaria drug that is frequently employed for COVID-19 treatment since it inhibits SARS-CoV-2 spread in the kidney-derived cell line Vero1–3. Here, we show that engineered expression of TMPRSS2, a cellular protease that activates SARS-CoV-2 for entry into lung cells4, renders SARS-CoV-2 infection of Vero cells insensitive to chloroquine. Moreover, we report that chloroquine does not block SARS-CoV-2 infection of the TMPRSS2-positive lung cell line Calu-3. These results indicate that chloroquine targets a pathway for viral activation that is not operative in lung cells and is unlikely to protect against SARS-CoV-2 spread in and between patients.

Authors
Markus Hoffmann, Kirstin Mösbauer, Heike Hofmann-Winkler, Artur Kaul, Hannah Kleine-Weber, Nadine Krüger, Nils C Gassen, Marcel A Müller, Christian Drosten, Stefan Pöhlmann

 

Nature abstract 1

 

Nature abstract 2

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