Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford
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Over twenty in vivo clinical trials have already been registered to test the use of chloroquine and hydroxychloroquine for the treatment of COVID-19. Contraindications for the use of these drugs must be checked for each individual before treatment. Empirical evidence suggests that hydroxychloroquine has a better safety profile, and it might therefore be preferable to focus research efforts on this less toxic metabolite.
BACKGROUND
Chloroquine (CQ) was first used as prophylaxis and treatment for malaria. Hydroxychloroquine (HCQ) is a more soluble and less toxic metabolite of chloroquine, which causes less side effects and is, therefore, safer (1-3). More recently, CQ/HCQ has been used to manage conditions such as systemic lupus erythematosus and rheumatoid arthritis. CQ/HCQ has been used in the treatment of HIV with mixed results (4). The ability of CQ/HCQ to inhibit certain coronaviruses, such as SARS-CoV-1, has been explored with promising results (5, 6). Both drugs are affordable and widely available internationally. With decades of experience administering these drugs, their safety profiles are well-established. It is likely to take many months for novel, specific treatments of COVID-19 to become available. As a result, there has been growing interest in the use of CQ and HCQ as potential treatments in the interim.
Results from In Vivo Clinical Trials
The empirical evidence for the effectiveness of CQ/HCQ in COVID-19 is currently very limited. First clinical results were reported in a news briefing by the Chinese government in February 2020, revealing that the treatment of over 100 patients with chloroquine phosphate in China had resulted in significant improvements of pneumonia and lung imaging, with reductions in the duration of illness (9). No adverse events were reported. It appears that these findings were a result of combining data from several ongoing trials using a variety of study designs. No empirical data supporting these findings have been published so far.
On the 17th of March 2020, the first clinical trial data were published by Gautret and colleagues in France (2). The researchers conducted an open-label non-randomised controlled trial with 36 patients diagnosed with SARS-CoV-2. Six of these patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty patients were assigned to the treatment group, and received HCQ 200mg three times a day for ten days. The control group received usual care. Six of the patients in the treatment group were also prescribed azithromycin to prevent bacterial superinfection.
The main outcome of the trial was SARS-CoV-2 carriage at Day 6, tested using PCR of SARS-CoV-2 RNA from nasopharyngeal swabs. The results showed that patients in the treatment group were significantly more likely to test negative for the virus on Day 6 than patients in the control group (70% vs 12.5% virologically cured, p<0.001). Moreover, all of the six patients who were treated with a combination of HCQ and azithromycin tested negative on Day 6. The authors argue that this finding speaks to the effectiveness of HCQ and a potential synergistic effect of its combined treatment with azithromycin. Following the promising results of these first clinical trials, official guidelines recommending the treatment of COVID-19 using CQ/HCQ were published. The National Health Commission of the People’s Republic of China published their recommendation mid-February, suggesting to treat patients with 500mg chloroquine phosphate (300mg for CQ) twice per day, for a maximum of 10 days (10). In Italy, the L. Spallanzani National Institute for the Infectious Disease published their recommendations for treatment on the 17th of March, which included the provision of 400mg of HCQ per day or 500mg CQ per day, in combination with another antiviral agent (11).
A number of potential mechanisms of action of CQ/HCQ against SARS-CoV-2 have been postulated. The virus is believed to enter cells by binding to a cell surface enzyme called angiotensin-converting enzyme 2 (ACE2) (16). ACE2 expression is also believed to be upregulated by infection with SARS-CoV-2 (17). Chloroquine may reduce glycosylation of ACE2, thereby preventing COVID-19 from effectively binding to host cells (18). Furthermore, Savarino et al (19) hypothesise that CQ might block the production of pro-inflammatory cytokines (such as interleukin-6), thereby blocking the pathway that subsequently leads to acute respiratory distress syndrome (ARDS).(19). Chloroquine has been found to accumulate in lysosomes, interfering with this process (20). Chloroquine is also believed to raise the pH level of the endosome, which may interfere with virus entry and/or exit from host cells (6).
Side Effects of Chloroquine
Both CQ and HCQ have been in clinical use for several years, thus their safety profile is well established (18). Gastrointestinal upset has been reported with HCQ intake (21). Retinal toxicity has been described with long-term use of CQ and HCQ (22, 23), and may also be related to over-dosage of these medications (23, 24). Isolated reports of cardiomyopathy (25) and heart rhythm disturbances (26) caused by treatment with CQ have been reported. Chloroquine should be avoided in patients with porphyria (27). Both CQ and HCQ are metabolised in the liver with renal excretion of some metabolites, hence they should be prescribed with care in people with liver or renal failure (27, 28). In a letter to the editor, Risambaf et al (27) raise concerns about reports of COVID-19 causing liver and renal impairment, which may increase the risk of toxicity of CQ/HCQ when it is used to treat COVID-19.