Using Antimalarial agents to treat COVID-19?

Antimalarial agents are widely used in the treatment of rheumatoid arthritis, SLE and other systemic autoimmune diseases. Malaria drugs are being tested all over the world in order to examine their positive role in the treatment of the coronavirus infection. Numerous studies are ongoing in order to find out whether everyday drugs can efficiently treat COVID-19, at least up to the time of an effective vaccine being developed (which is at least one more year away).

In China a recent paper reported an inhibitor effect of chloroquine (CQ) on the growth of SARS-CoV-2 in vitro, and an early clinical trial conducted on COVID-19 patients showed that CQ had a significant effect, both in terms of clinical outcome and viral clearance, when compared to the control cases. Chinese experts recommend that patients diagnosed with mild, moderate and severe cases of COVID-19 pneumonia and without contraindications to CQ, be treated with 500mg of CQ twice a day for ten days.

In France, at the University Hospital of Marseille COVID-19 pts have been treated with hydoxychloroquine (HCQ)since the beginning of March. The clinical safety profile of HCQ is better than that of CQ (with long-term use) and thus allows for a higher daily dose.

In an open, non-randomized study led by Dr Didier Raoult, professor of infectology and microbiology, HCQ proved to be effective for the treatment of COVID-19. Viral load reduction/disappearance in CoV-2+ patients was significantly associated with HCQ treatment, and the effect was reinforced by azithromycin. Only 25% of the treated pts (n=20) carried the virus at day 6 post-inclusion compared to 90% of the non-treated (n=16). Despite the small sample size, in the current pandemic context these significant early results have been accepted for publication. (Gautret et al, Int J Antimicrobial Agents, 2020)

Triggered by the promising results of the recent French study, a Europe-wide study on 4 potentially effective agents against SARS-CoV-2 is being carried out, antimalarials (CQ/HCQ) being one of the 4 candidates. 3200 COVID-19 inpatients in Belgium, the Netherlands, Luxembourg, UK, Germany, and Spain, and 800 inpatients in France are included.

HCQ is also being used in the USA for treating COVID-19. 1500 patients (asymptomatic, with lower and upper respiratory symptoms) are enrolled in the study at the University of Minnesota. The main point of the rationale as to why antimalarial drugs are efficiently used in the treatment of COVID-19 is that in addition to their virus killing potential, CQ/HCQ inhibit the production of proteins that contribute to the inflammatory complications of a viral disease.

Antimalarial agents are widely used in rheumatology practice. They are disease modifying anti-rheumatic drugs (DMARD) for chronic polyarthritides (i.e. rheumatoid arthritis) and other systemic autoimmune diseases, i.e. all forms of SLE and Sjögren syndrome. They are given as monotherapy in non-differentiated, early and benign RA or in combination with other DMARDs (methotrexate, leflunomide). Low doses are used in the long term.

A large number of my RA patients take antimalarials, primarily HCQ, under the product names Plaquenil and Quensyl.

Synthetic antimalarials (CQ and HCQ) are derivatives of aminoquinolone, a compound naturally found in the bark of a Peruvian tree. The synthetic drugs are much less toxic, HCQ’s safety profile being better still.  

Although the mechanism of their action is imperfectly known, the antimalarials have immuno-modulatory and anti-inflammatory effects; they concentrate inside cells within acidic cytoplasmic vesicles resulting in changes in acidity and interfere with the processing of auto antigenic peptides. It has been shown that antimalarial agents can also interact with nucleic acids and inhibit the activation of the innate immune system. Furthermore, they inhibit platelet aggregation, improve the lipid profile and reduce the risk of diabetes, which are of the utmost importance in RA patients with cardiovascular risk.

HCQ is absorbed from the gastrointestinal tract and has extended serum half-lives due to tissue depot effects. It takes 2–4 months for antimalarials to become effective. Excretion of HCQ is primarily by renal clearance. Serum levels of HCQ are also controlled in some of the European countries and the USA.

HCQ does not demonstrate significant efficacy in joint damage prevention and is therefore recommended in combination with other DMARDS (MTX).

Monitoring should include appropriate eye management. Recent recommendations of the American College of Ophthalmology propose a baseline assessment within the first year of starting the drug, then at 5 years and annually afterwards to exclude maculopathy. This assessment should include: fundus examination, visual field and optical coherence tomography. At recommended doses the risk of toxicity up to 5 years is under 1%.

Antimalarial drugs are generally well tolerated and serious adverse events are rare. The most feared adverse event is retinopathy, which is less common with HCQ than with CQ, and occurs only infrequently with low doses (HCQ < 5 to 6.5 mg/kg/day or CQ 2.3 to 3 mg/kg/day) generally used in the rheumatology practice. The risk of retinal toxicity increases with long-term use (1% after 5–7 years or 1000 mg of cumulative dose). HCQ/CQ retinopathy is not reversible, and therefore should be recognized as early as possible in order to prevent complete loss of vision. Other non-significant adverse events are headaches, dizziness, rash, pruritus and mild gastrointestinal complaints. Skin pigmentation and alopecia can also occur. Although cardiomyopathy with atrioventricular conduction abnormalities is a very rare complication, it is of great importance due to its fatal outcome.