Hydroxychloroquine in the treatment and prophylaxis of SARS-CoV-2 infection in non- human primates
Main result
Hydroxychloroquine exhibited antiviral activity in monkey kidney cells (post-infection therapy of monkey kidney cells with hydroxychloroquine had a dose-dependent antiviral effect) but not in a reconstructed human airway epithelium model.
Neither hydroxychloroquine nor hydroxychloroquine+azithromycin demonstrated any significant effect on the viral charge in any of the compartments tested.
Hydroxychloroquine did not provide protection against infection acquisition when used as pre-exposure prophylaxis.
Takeaways
There was no evidence of antiviral activity or clinical efficacy of hydroxychloroquine therapy in this study, regardless of when treatment was initiated, whether before infection, early post-infection (before peak viral load), or later post-infection (after peak viral load). This is despite high blood drug levels and lung and plasma exposure similar to that seen in COVID patients treated with hydroxychloroquine. Therefore, hydroxychloroquine treatment is unlikely to have antiviral activity in the respiratory compartments in humans.
In conclusion, assessment of the performance of hydroxychloroquine in a model of COVID-19 in a non-human primate does not support its use as an antiviral agent for the treatment of COVID-19 in humans.
Strength of evidence Moderate
- Preprint
- Randomized trial in macaques
- Limited sample size
Objectives
Test different treatment strategies with hydroxychloroquine alone or in combination with azithromycin in macaques infected with SARS-CoV-2 before or after maximal viral replication.
Method
The antiviral activity of hydroxychloroquine was evaluated in vitro and in SARS-CoV-2 infected monkeys.
The in vitro antiviral potency of hydroxychloroquine was first evaluated against SARS-CoV-2 isolated from one of the first COVID-19 patients in France by treating monkey kidney cells post-infection with hydroxychloroquine. Subsequently, the investigation was carried out in a reconstructed human respiratory tract epithelial model.
In monkeys, different treatment strategies with hydroxychloroquine versus placebo were tested before and after peak viral load, alone or in combination with azithromycin. To evaluate the efficacy of hydroxychloroquine and hydroxychloroquine+azithromycin treatments, animals were randomly assigned to gender-balanced experimental groups. The control group (CTRL, n=8) received water as a placebo, which was the vehicle for hydroxychloroquine.
To evaluate the anti-viral efficacy of hydroxychloroquine, monkeys received hydroxychloroquine daily by gavage for 10 or more days. A dosing regimen of 90 mg/kg on the first day after infection (loading dose) followed by a daily maintenance dose of 45 mg/kg was demonstrated, in a group of uninfected animals, to provide exposure to clinically relevant quantity of the drugs. In parallel, a lower dosage schedule was also tested, with a first dose at 30 mg/kg and a maintenance dose of 15 mg/kg. A total of 9 animals were infected on day 0 and treated 1 day after infection using either the high-dose regimen (Hi D1, n=5) or the low-dose regimen (Lo D1, n=4). The effect of delayed treatment starting 5 days post-infection was also examined to assess the benefit of hydroxychloroquine in accelerating virus clearance (Lo D5, n=4).
Combined therapy (hydroxychloroquine + azithromycin) administered from day 1 post-infection was then evaluated (Hi D1 + azithromycin, n=5), with azithromycin administered at a loading dose of 36 mg/kg followed by a daily dose of 18 mg/kg to mimic exposure in humans.
The administration of hydroxychloroquine was also tested as pre-exposure prophylaxis against SARS-CoV-2 infection: animals were treated with a high dose of hydroxychloroquine, starting 7 days before infection as pre-exposure prophylaxis (PrEP, n=5).
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