Chloroquine and hydroxychloroquine for COVID‐19: A word of caution

The novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), is the causative pathogen of the coronavirus disease 2019 (COVID‐19) pandemic. There is interest in recommending chloroquine (CQ) or hydroxychloroquine (HCQ) for treatment and prophylaxis, as they are readily available and affordable. Shah et al. have recently reviewed the current literature on the use of CQ and HCQ as prophylaxis against COVID‐19. ¹ Prior research including with human immunodeficiency virus (HIV) and SARS‐CoV‐1 has shown that in vitro antiviral activity of CQ and HCQ does not necessarily translate to in vivo clinical efficacy. However, the 79% genomic similarity between SARS‐CoV‐1 and ‐2, along with their similar receptor‐binding domain structures, has stimulated interest in CQ and HCQ. ²

Yao et al., in their antiviral pre‐treatment activity analysis, reported EC₅₀ (50% maximal effective concentration) for CQ and HCQ at 24 h as >100 and 6.25 μM, respectively, much higher compared to values from their treatment analysis arm. ³ It is unclear how the differences in the EC₅₀ values will impact the in vivo prophylactic antiviral efficacy at their recommended doses of HCQ 400 mg twice daily (bd) on day 1 and then 200 mg bd for 5 days. Ongoing prophylaxis clinical trials in the United States are using doses ranging from 200 to 400 mg daily or weekly, with or without a loading dose for a total duration of 5 days to 3 months. The results of these studies will only answer the effectiveness, if any, of these dosing regimens.

Analysis of cytotoxic effects is based on CCK8 assays, an indirect colorimetric assay evaluating the number of viable cells by measuring their metabolic activity. However, some of the side effects of CQ and HCQ are based on their inherent pharmacological properties rather than their direct cytotoxic effect. In a recent unpublished study by Chorin et al. from New York evaluating 80 hospitalized SARS‐CoV‐2‐infected patients receiving HCQ + Azithromycin, QTc (corrected QT interval) prolongation by >40 ms was noted in 30% of subjects and 11% had a prolongation to >500 ms. Baseline QTc did not predict the risk for QTc prolongation. ⁴ Cardiac injury, renal impairment, concomitant use of drugs that prolong QTc and electrolyte imbalance will further increase the risk of fatal ventricular arrhythmias.

Anecdotal reports of death from self‐administered CQ phosphate were reported. Although retinal toxicity is rare at currently recommended doses, risk increases among patients with renal or hepatic impairment with decreased drug elimination. In a recent mice study, using a combination of CQ and HCQ (60 mg/kg daily for 4 weeks) with metformin (250 mg/kg daily for 4 weeks) resulted in 30–40% lethality. ⁵ The safety profile of this combination at the much lesser doses currently being recommended for prophylaxis is yet to be established, and caution should be excised by prescribers until then. Potential overdose can also happen in obese patients if the dose is calculated using total body weight instead of ideal body weight as these drugs are not retained in the fatty tissue. ⁶

Published studies to date have not reported prophylactic efficacy of these compounds. Even though Gautret et al. supported the treatment efficacy, it was extensively criticized for study design limitations. ⁷ Some subjects attained virologic cure as early as Day 1; however, these patients might have attained virologic cure irrespective of treatment and attributing this to the antiviral efficacy of HCQ is not appropriate. Chen et al., in their analysis, did not report virologic cure. ⁸

The Hippocratic oath of ‘first do no harm’ should drive our instincts in these uncertain times. Authorities should make recommendations based on clinical evidence and not speculations. There is no conclusive evidence to support these drugs either for treatment or prophylaxis. Even if the results from ongoing trials are more conclusive, ideal dosing regimens should be evaluated to avoid unwarranted overdosing. Until then, CQ and HCQ should only be used in the setting of clinical trials with a clear understanding among physicians and patients of uncertain efficacy and potentially harmful side effects.

Annangi S. Chloroquine and hydroxychloroquine for COVID‐19: A word of caution. Respirology. 2020;25:683–684. 10.1111/resp.13845