Chloroquine as a prophylactic agent against COVID-19?

Highlights

• •Efficacy of chloroquine and hydroxychloroquine in COVID-19 treatment is discussed.
• •Prophylactic use of chloroquine or hydroxychloroquine in COVID-19 is considered.

The opinions expressed in this article are those of the authors and not those of the Ministry of Armies.

The antimalarial drug chloroquine has been shown to be effective in vitro against the novel coronavirus SARS-CoV-2 (formerly 2019-nCoV), which causes coronavirus disease 2019 (COVID-19), in Vero E6 cells with an effective concentration 50% (EC₅₀) of 1.1 µM and an EC₉₀ of 6.9 µM [1]. Hydroxychloroquine, which is used in autoimmune diseases such as rheumatoid arthritis and lupus, has also demonstrated in vitro antiviral activity against SARS-CoV-2 with an EC₅₀ of 0.72 µM [2]. Hydroxychloroquine was found to be more potent than chloroquine phosphate (EC₅₀ 5.47 µM) [2]. Chloroquine and hydroxychloroquine appear to inhibit fusion of the virus to the cell membrane by modulating endosomal pH [3]. These drugs 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 shown marked efficacy in the treatment of COVID-19 in more than 100 patients in terms of shortening hospital stay and improving clinical evolution, with few severe adverse reactions reported [5]. These findings led Chinese experts to recommend that patients with mild, moderate and severe COVID-19 who had no 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 patients (n=20) at day 6 after the first drug intake [8]. The efficacy of hydroxychloroquine was improved by combining this drug with azithromycin, an antibiotic with antiviral properties against other RNA-viruses such as Zika virus [9,10]. The 6 patients treated with hydroxychloroquine combined with azithromycin (500 mg at day 1 followed by 250 mg per day for the next 4 days) were virologically cured at day 6 (100%) compared with patients treated with only hydroxychloroquine (57.1%) or without treatment (12.5%) [8]. These results are promising and should be supplemented by larger studies. Importantly, therapeutic interventions using chloroquine at high dose and/or in combination with macrolides may have severe side-effects, including cardiac toxicity. A prophylactic approach using a lower dose could be considered on a global scale and administrated to vulnerable individuals with comorbidities who are at risk of severe COVID-19.

Chloroquine at 100 mg daily was used for many years up until 1990 for antimalarial chemoprophylaxis of the 25 000 to 40 000 French soldiers deployed in malaria transmission areas. After 1990, chloroquine in combination with 200 mg of proguanil chlorhydrate was recommended, and this was replaced by doxycycline in 2006. Chloroquine is usually well tolerated. The more frequently reported side effects with chloroquine-proguanil were epigastralgia, diarrhoea and nausea in long-term chemoprophylaxis (duration >5 months) in non-immune soldiers [11]. Combining chloroquine with an 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 the long-term but the prevalence was lower than that observed with chloroquine-proguanil daily [13]. The World Health Organization has recommended a maximum duration of 5.5 years for continuous use of 300 mg chloroquine base weekly or 3 years of 100 mg daily [14]. If the dose of 100 g chloroquine base is exceeded, annual ophthalmological examinations are recommended. In addition, chloroquine is rapidly dealkylated into antiplasmodial active desethylchloroquine via cytochrome P450 enzymes. Chloroquine and desethylchloroquine concentrations decline slowly, with elimination half-lives 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 indicate a possible use of chloroquine at 100 mg daily or hydroxychloroquine at 300 mg weekly in mass prophylaxis in individuals exposed to COVID-19, and could be part of urgent interventions currently required to help protect frontline healthcare workers combating COVID-19 [16]. Chemoprophylaxis with chloroquine or hydroxychloroquine could prevent COVID-19-associated pneumonia and block 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 breastfeeding women [17]. Chloroquine as prophylaxis is contraindicated in patients with severe renal or hepatic diseases. The prophylactic dose should be reduced in patients with mild or moderate renal or hepatic failure to avoid drug accumulation. A double-blind, randomized, placebo-controlled clinical 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, severity of symptoms, duration of illness, number of symptomatic respiratory infections and number of asymptomatic infections with SARS-CoV-2 will be recorded and compared in the subjects randomised to chloroquine or placebo during 5 months of follow-up.

Declarations

Funding: No funding.

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

Ethical Approval: Not required.