Hydroxychloroquine for COVID-19: Have We Forgotten Something?

COVID-19 remains a public health emergency as the death rate continues to grow.  As we learn more about this deadly virus many new therapies are being researched in an attempt to identify a treatment.  To this end, hydroxychloroquine was synthesized in 1946, was approved by the FDA in April 1955 for uncomplicated malaria due to P. falciparum, P. malariae, P. ovale, and P. vivax, chronic discoid lupus erythematosus and systemic lupus erythematosus in adults and acute and chronic rheumatoid arthritis in adults.¹ The drug has several immumodulatory actions which support its possible use in COVID-19, but at what dose appears to be elusive.²  The adult dosage of hydroxychloroquine for malaria suppressive therapy or treatment of an acute attack is 800mg loading dose followed by 400mg weekly or 400mg in 6-8 hours and then 400mg for two consecutive days.  The dosage for adults can also be given as 25mg/kg administered as 10mg/kg (1^st dose), the 5mg/kg (2^nd dose) 6 hours after 1^st dose, then 5mg/kg 18 hours after the 2^nd dose, and 5mg/kg 24 hours after the 3^rd dose.¹ There is no single way to dose this agent, even in malaria.  So how can we safely and effectively dose hydroxychloroquine in COVID-19?  The answer is we can’t and unfortunately this outcome is being played out in human trials around the world. 

Recent published and anecdotal reports, case reports, and clinical studie3^2-5 have identified that COVID-19 and/or the acute illness setting with high cardiometabolic demands may cause cardiac complications including arrhythmias, acute onset heart failure, myocardial infarction, myocarditis, and cardiac arrest.  Furthermore, the use of azithromycin in combination with hydroxychloroquine may lead to arrhythmias such as polymorphic ventricular tachycardia with an increased risk of sudden death.  A study from a single center in Wuhan, China in data from 416 patients hospitalized for COVID-19 (median age 64 years, 50.7% women) showed the in-hospital mortality rate was 51.2% with cardiac injury versus 4.5% in patients without injury.⁵ A recent trial in Brazil was halted due to patients taking the 600mg for 10 days developing serious heart disorders, resulting in 11 deaths.⁶ Interestingly, there is no package insert warning or guidance for these cardiac complications.¹  The American College of Cardiology has issue a clinical bulletin stating that cardiologists should be prepared to assist with managing cardiac complications in severe cases of COVID-19.⁷ 

Patients and clinicians are currently under tremendous pressure to find a treatment.  Patients who are fearful of dying will try treatments they might not ordinarily try due to desperation.  Clinicians who feel pressure to save a life will try new treatments without first asking the quality assurance questions they normally ask, what are the complications of this disease, the patient, and this drug?  Do they interact in a way that could be harmful or even dangerous to the patient?  There is often not time or in some circumstances (i.e. ventilated patients) and no family available because of visiting restrictions to have a patient-physician discussion of the drug’s profile.  The drug is then administered.  Unfortunately, it appears that hydrochloroquine’s dose and dose schedule is not firmly established for safety.

There are multiple studies underway to evaluate hydroxychloroquine for COVID-19.  Some trials are registered on ClinicalTrials.gov, many are not.  The largest trial is the State of South Dakota study which will test the effectiveness of hydroxychloroquine in treating and potentially preventing COVID-19.⁸ This study will include 2,000 outpatient individuals exposed to COVID-19, including front-line health care workers and other high-risk patients.⁷  Novartis is launching a 450-person randomized, double-blind, placebo-controlled study which will assign patients to hydrocychloroquine, 600mg loading dose, then 200mg three times daily; combination of hydroxychloroquine with azithromycin, or placebo.⁹  The chief medical officer for Novartis stated, that there is a “tight window” to get drug levels high enough for antiviral activity without causing too many side effects.⁹  

History tells us that many drugs with cardiovascular effects have been studied with the resultant outcome being an increase mortality of treated patients.  Many of these agents have been studied at too high doses.  Hydroxychloroquine has dose-dependent adverse event increase on the cardiovascular system.  We would be well suited to slow or stop the use of hydroxychloroquine in COVID-19 clinical trials until we FIRST conduct Phase 2A studies designed to sustain the drugs’ immunomodulating actions while maximizing safety (if this is possible), then proceed to Phase 2B to access efficacy at the safe dose.

Mark A. Munger, PharmD, FCCP, FACC, is a professor of pharmacotherapy and adjunct professor of internal medicine, at the University of Utah, where he also serves as the associate dean of Academic Affairs for the College of Pharmacy.  

References:

1. PLAQUENIL: Hydroxychroquine Sulfate, USP Package Insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf Accessed 04/2020
2. Devaux CA, Rolain J< Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimocro Agents 2020;March 11:105938
3. Coronoavirus COVID-19 Global Cases by Johns Hopkins CSSE (March 3, 2020). https://reliefweb.int/report/world/coronavirus-covid-19-global-cases-johns-hopkins-csse Accessed 04/2020
4. Chen H, Zhou M, Dong X, et al. Epidemiological and Clinical Characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;published online January 29. https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2930211-7 Accessed 04 2020
5. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 Novel Coronavrus-infected Pneumonia in Wuhan, China. JAMA Published online February 7, 2020. doi:10.1001/jama.2020.1585.
6. Chloroquine COVID-19 Trial Stopped After Patient Deaths. https://www.livescience.com/coronavirus-chloroquine-study-stopped-early.html Accessed 04/2020.
7. COVID-19 Clinical Guidance for the Cardiovascular Care Team.  https://www.acc.org/~/media/665AFA1E710B4B3293138D14BE8D1213.pdf Accessed 04/2020