key: cord-0880523-03eifdr1
authors: Gendrot, Mathieu; Javelle, Emilie; Dault, Erwan Le; Clerc, Axelle; Savini, Hélène; Pradines, Bruno
title: Chloroquine as prophylactic agent against COVID-19?
date: 2020-04-12
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2020.105980
sha: d4642afe1300503f649dc119486c0a5b620ea36e
doc_id: 880523
cord_uid: 03eifdr1

• Efficacy of hydroxychloroquine and chloroquine in COVID-19 treatment; • Use of hydroxychloroquine or chloroquine in COVID-19 prophylaxis.

Chloroquine as prophylactic agent against COVID-19? Chloroquine, an antimalarial drug, has been shown to be effective in vitro against the novel coronavirus SARS-CoV-2 formerly named 2019-nCoV, in Vero E6 cells with effective concentration 50% (EC 50 ) of 1.1 µM and EC 90 of 6.9 µM [1] . Hydroxychloroquine, used in autoimmune diseases such as rheumatoid arthritis and lupus, has also demonstrated in vitro antiviral activity against SARS-CoV-2 causing coronavirus diseases 2019 (COVID-19) with EC 50 of 0.72 µM [2] . Hydroxychloroquine was found to be more potent than chloroquine phosphate (EC 50 =5.47 µM) [2] . Chloroquine and hydroxychloroquine seem to inhibit the fusion of the virus to the cell membrane by modulation of the endosomal pH [3] . These drugs can also inhibit nucleic acid replication. Twenty three clinical trials have been conducted in China to investigate the efficacy and safety of chloroquine and hydroxychloroquine in the treatment of COVID-19 [4] [5] [6] . Chloroquine phosphate has demonstrated marked efficacy in treatment of COVID-19 with few severe adverse reactions in more than 100 patients by shortening hospital stay and improving the clinical evolution [5] . These findings led to Chinese expert recommendations stating that patients with mild, moderate and severe cases of COVID-19 and without chloroquine contraindications should be treated with chloroquine phosphate at a dose of 500 mg twice per day for 10 days [7] . Preliminary clinical data showed that hydroxychloroquine at 600 mg daily cured 70% of the patients (no=20) at day 6 after the first drug intake [8] . Efficacy of hydroxychloroquine was improved by combination with azithromycin. Azithromycin is an antibiotic with antiviral properties demonstrated against other RNA-viruses such as Zika virus [9, 10] . The 6 patients treated with hydroxychloroquine associated with azithromycin (500 mg at day 1 followed by 250 mg per day the next 4 days)

were virologically cured at day 6 (100%) in comparison with patients treated with only hydroxychloroquine (57.1%) or without treatment (12.5%) [8] . These results are promising and should be supplemented by a larger number of observations. Importantly, therapeutic interventions using high dosage chloroquine and/or in combination with macrolides may have The more frequently reported side effects with chloroquine-proguanil are epigastralgia, diarrhea and nausea in long-term chimioprophylaxis in nonimmune soldiers (duration > 5 months) [11] . Combining chloroquine to antibiotic such as doxycycline in daily prophylaxis did not increase the risk of adverse effects [12] . Some European countries also recommended 300 mg of chloroquine once weekly alone or in combination with proguanil 200 mg daily.

Some gastrointestinal side effects were observed in long-term but their prevalence were lower than that observed with chloroquine-proguanil daily [13] . The World Health Organization has recommended a maximum duration of 5.5 years in continuous use at 300 mg of chloroquine base weekly or 3 year at 100 mg daily [14] . If the dose of 100 g chloroquine base is exceeded, annual ophthalmological examinations are recommended. Additionally, chloroquine is rapidly dealkylated into antiplasmodial active desethychloroquine via cytochrome P450 enzymes.

Chloroquine and desethylchloroquine concentrations decline slowly, with elimination halflives of 20 to 60 days [15] . The promising results of chloroquine in treatment of COVID-19 and the low prevalence of side effects in long-term use suggest a possible use of chloroquine at 100 mg daily or hydroxychloroquine at 300 mg weekly in mass prophylaxis in people exposed to COVID-19, and could be part of urgent interventions currently required to help to protect healthcare workers combating COVID-19 at the very frontline [16] .

Chemoprophylaxis with chloroquine or hydroxychloroquine could prevent the COVID-19 associated pneumonia and block the transmission by reducing the number of asymptomatic carriers. We propose the use of chloroquine with a loading dose of 300 mg followed by 100 mg daily. Chloroquine can be used in pregnant women in all three trimesters of pregnancy and in breast-feeding women [17] . As prophylaxis, chloroquine is contraindicated in patients with severe renal or hepatic diseases. The prophylactic dose should be reduced in patients with mild or moderate failure to avoid drug accumulation. A clinical double-blind, randomized, placebo-controlled trial (NCT04303507) will be initiated in may 2020 to evaluate the potential prevention of COVID-19 by chloroquine at a loading dose of 10 mg base / kg, followed by 150 mg of chloroquine base (250 mg chloroquine phosphate salt) daily for 3 months in 10 000 healthcare workers or other individuals at significant risk. An average of 200 participants per site will be recruited in 50 sites. The number of episodes of symptomatic COVID-19, the severity of the symptoms, the duration of illness, the number of symptomatic respiratory infections and the number of asymptomatic infection with SARS-CoV-2 will be recorded and compared in the subjects randomised to chloroquine or placebo during the 5 months of follow-up.

Competing Interests: The authors have no conflicts of interest to declare.

Ethical Approval: Not required.

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