Chloroquine & Hydroxychloroquine – Is there value in COVID-19?

Authors: Christopher Gardner, MD (Emergency Medicine Resident, Carolinas Medical Center, Charlotte, NC) and Kathryn T Kopec, DO (Emergency Medicine Attending, Medical Toxicologist, Carolinas Medical Center, Charlotte, NC) // Reviewed by: Cynthia Santos, MD (@CynthiaSantosMD); Alex Koyfman, MD (@EMHighAK); Manny Singh, MD (@MPrizzleER); and Brit Long, MD (@long_brit)

Background

Over the past month there has been increasing discussion about the potential use of chloroquine or hydroxychloroquine (HC) in the treatment of SARS-CoV-2 or COVID-19. In past research, chloroquine has shown in vitro activity against many different viruses, such as SARS-CoV-1, Ebola, MERS, HIV, and influenza.^[1] However, this effect has fallen short of demonstrating a significant benefit when translated to animal models.^[1] A likely reason for the poor quality of evidence of these medications in emerging viral outbreaks is the lack of adequately performed clinical trials at the timing of the outbreak. In the wake of the SARS-CoV-2 pandemic, we are seeing a spike in randomized controlled trials around the world, seeking to identify potential treatments.^[2-5]

Chloroquine and hydroxychloroquine are 4-aminoquinolones,^[6] which have been used historically for malaria treatment. Currently, chloroquine is FDA approved for the treatment of certain strains of malaria, secondary to regional areas of resistance. Hydroxychloroquine is used as an immunomodulator and as a disease modifying anti-rheumatic drug (DMARD) and is FDA approved for the treatment of rheumatoid arthritis, lupus, and certain strains of malaria.^[7]

Mechanism of Action

Chloroquine and hydroxychloroquine work by interfering with lysosomes, thereby limiting various cellular signaling mechanisms and causing decreased immune cell functioning. This is the basis for its use in rheumatologic conditions and its anti-inflammatory effects.^[6] The neutralization of the pH in these acidic cellular organelles may also play a role in inhibition of macrophage activation and blunting of the release of tissue necrosis factor alpha (TNF-a), one of the proinflammatory cytokines implicated in increasing endothelial cell permeability and thus infectivity.^[1,6] This neutralization of acidic organelles also is proposed to hamper the acidic-dependent step of viral replication, as many of the proteins and enzymes that several viruses rely on function poorly at a more neutral pH.^[1,6]

Current Research

Historically chloroquine has been demonstrated to show benefit against SARS-CoV-1 in vitro.^[8] The outcomes of recent in vitro trials of chloroquine in China suggest that chloroquine and hydroxychloroquine inhibit SARS-CoV-2 replication. Wang et al. demonstrated that a 50% effective concentration (EC50) of 1.1uM chloroquine prevented replication of SARS-CoV-2.^[3] This was based on the demonstrated decrease in the viral yield of SARS-CoV-2 in animal cells pretreated with chloroquine. ^[1,3]  EC50 is a commonly used benchmark of drug “potency” based on the concentration of a drug required to induce a response halfway between the baseline and maximal response (similar to an 50% lethal dose, or LD50, for a toxin).

Yao et al performed an in vitro study comparing chloroquine to hydroxychloroquine in the same animal cell line. Hydroxychloroquine was found to be more potent at inhibiting viral replication than chloroquine with an EC50 of 0.72 μM vs. 5.47uM, respectively.^[5] Yao et al then used their in vitro data results to create mathematical models of drug pharmacokinetics and recommend a treatment protocol of 400mg HC twice daily on day 1, followed by 200mg twice daily for the next 4 days based on their model.^[5]

Currently there are multiple emerging clinical trials involving hydroxychloroquine and chloroquine in the treatment of COVID-19 around the world. One of the best-known studies is an open label non-randomized trial by Gautret et al. in southern France.^[4] Preliminary data from this study details 42 COVID-19 positive patients, in which 26 were treated with either hydroxychloroquine alone or hydroxychloroquine plus azithromycin compared to a control group that received standard supportive care. The primary outcome of this study was the number of patients with negative SARS-CoV-2 PCR nasopharyngeal swab at day 6 after hospitalization. Nasopharyngeal swabs were negative at day 6 in 100% of the HC + azithromycin group (N=6) vs. 57.1% of HC only group (N=14) vs. 12.5% in control group (N=16).^[4] The preliminary data from this study is extremely limited due to its small sample size, dropout rate (23% of the treatment group), and multiple confounding variables (no randomization, treatment arm all at one hospital while controls were at outlying hospitals). Of the 6 dropouts in the treatment arm, 3 were moved to ICU and 1 died, thus they were excluded from data analysis.^[4] The outcome of negative nasopharyngeal swab PCR is also suboptimal, as this test does not correlate with the patient’s current clinical status.^[9]

The French group responsible for the above paper has since published more data in a second study on 3/28/2020.^[10] Before we get to the details, understand that this trial is not peer reviewed, did not go through an official editorial process, and was self-published. This observational study contained 80 COVID-19 positive patients in an inpatient unit in Marseille, France, demonstrating 81.3% of patients having a “favorable outcome” described as hospital discharge at the time of publication and negative viral nasopharyngeal cultures in 97.5% of patients at day 5 of treatment. These patients were treated with 200mg of hydroxychloroquine three times a day for 10 days plus azithromycin 500mg on day one followed by 250mg daily for the next 4 days. Patients with low-dose chest CT findings consistent with pneumonia and a “medium” or greater illness severity (NEWS score > 5) were also treated with ceftriaxone.^[10] All patients had a baseline EKG and a repeat EKG 2 days into therapy to assess QTc with plans to hold treatment if QTc >500ms, although the authors do not describe any cases where treatment had to be held due to QTc prolongation.^[10] Obvious limitations of this study are the lack of control group, and that the illness severity of this cohort of patients was generally low (92% of patients with NEWS score < 2). While you may hear about this study, its poor design and lack of peer review make it uninterpretable.

Toxicity

Hydroxychloroquine has a better safety profile compared to chloroquine. Also, physicians are likely more comfortable with HC over chloroquine secondary to its use in various rheumatologic conditions.

However, hydroxychloroquine use is not without concern as it still has a high-risk side effect profile. Both chloroquine and hydroxychloroquine have various adverse drug reaction with therapeutic use including vision changes, hearing loss, cardiomyopathy and hypoglycemia.^[11] They commonly cause hypokalemia, GI upset, dizziness or vertigo.^[6] Most concerning though is that they have potentially severe cardiotoxic effects. They cause blockage of both Na⁺ and K⁺ channels and can lead to prolonged QRS and QTc.^[11,12] This can lead to ventricular dysrhythmias, decreased contractility, and impaired cardiac conduction. ^[11,12] They are also associated with neurotoxicity ranging from somnolence, sedation to seizure activity.^[11]

While the current media attention to chloroquine and HC has sparked new and ongoing research, it has not been without its deleterious effects. To date, we have seen at least one death from toxicity of these medications being used for COVID-19 purposes. A man in Arizona overdosed on fishbowl cleaner containing chloroquine sulfate as an attempt at chemoprophylaxis for SARS-CoV-2.^[13] It is also being reported that patients taking HC as a DMARD are having a difficult time securing their medication as prescriptions have skyrocketed for the off-label treatment or prophylaxis for COVID-19.^[14]

While there may prove to be a benefit in using these medications for the treatment of the novel coronavirus in the near future, currently there is extremely limited evidence of their effectiveness. As physicians, we must be judicious and careful in our recommendations and prescribing strategies. Failure to do so places our patients at risk of toxicity and may indirectly force others maintained on these medications for rheumatic disease to have to ration their treatments.

Official Recommendations:

Although there is minimal data to support its use, on 3/28/2020 the FDA issued an Emergency Use Authorization (EUA) for hydroxychloroquine sulfate to be prescribed for adolescent and adult patients “as available, when a clinical trial is not available or feasible” for the treatment of COVID-19.^[15] The Department of Health and Human Services (DHS) has since accepted 30 million doses of HC to the Strategic National Stockpile (SNS) with plans to distribute these immediately to hospitals across the country.^[16]

The CDC currently states “Although optimal dosing and duration of hydroxychloroquine for treatment of COVID-19 are unknown, some U.S. clinicians have reported anecdotally different hydroxychloroquine dosing such as: 400mg BID on day one, then daily for 5 days; 400 mg BID on day one, then 200mg BID for 4 days; 600 mg BID on day one, then 400mg daily on days 2-5.” ^[17]

UPDATE:

Chloroquine and hydroxychloroquine are not recommended for COVID-19 as of 2021.

Key Points:

• Currently there is insufficient data to recommend regular use of chloroquine or hydroxychloroquine in the treatment of SARS-CoV-2 patients.
• However, the FDA has approved the use of hydroxychloroquine under Emergency Use Authorization (EUA) for the treatment of COVID-19.
• There are significant side effects and potential toxicity with hydroxychloroquine use including visual changes, sedation, seizures, prolonged QTc, and cardiac dysrhythmias. These side effects must be considered prior to initiation of therapy.

References/Further Reading:

[1] Al-Bari MAA. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol Res Perspect. 2017 Jan 23;5(1):e00293. doi: 10.1002/prp2.293. eCollection 2017 Feb. Review.

[2] Kalil AC. Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics. JAMA. 2020 Mar 24. doi: 10.1001/jama.2020.4742.

[3] Wang M, Cao R, Zhang L et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res (2020 Feb 4), doi: 10.1038/s41422-020-0282-0

[4] Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20:105949. doi: 10.1016/j.ijantimicag.2020.105949.

[5] Yao X, Ye F, Zhang M et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Mar 9. doi: 10.1093/cid/ciaa237.

[6] Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020 Mar;16(3):155-166. doi: 10.1038/s41584-020-0372-x. Epub 2020 Feb 7. Review.

[7] “Drugs@FDA: FDA-Approved Drugs.” Food and Drug Administration (website). https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed 3/27/2020.

[8] Keyaerts E, Vijgen L, Maes P et al. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun. 2004 Oct 8;323(1):264-8.

[9] Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. 2020 Mar 11. doi:10.1001/jama.2020.3786.

[10] Gautret P, Lagier JC, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study. Ahead of print. Accessed 3/27/2020. IHU Méditerranée Infection. (https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf)

[11] Barry, JD. Antimalarials. Goldfrank’s Toxicologic Emergencies 11^th Ed. Nelson, L, Howland, MA, Lewin, NA, Smith, SW, Goldfrank, LR, Hoffman, LR. McGraw-Hill. 2019:(836-849).

[12] Chatre C, Roubille F, Vernhet H, et al. Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Saf. 2018 Oct;41(10):919-931. doi:10.1007/s40264-018-0689-4.

[13] Waldrop, Theresa. “Fearing coronavirus, Arizona man dies after taking a form of chloroquine used to treat aquariums.” https://edition.cnn.com/2020/03/23/health/arizona-coronavirus-chloroquine-death/index.html. Accessed 3/27/2020.

[14] “Hydroxychloroquine (Plaquenil) Shortage Causing Concern.” Arthritis Foundation. https://www.arthritis.org/drug-guide/medication-topics/plaquenil-shortage. Accessed 3/27/2020.

[15] “Emergency Use Authorization.” US Food and Drug Administration. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization. Accessed 3/30/2020.

[16] “HHS accepts donations of medicine to Strategic National Stockpile as possible treatments for COVID-19 patients.” US Department of Health and Human Services. https://www.hhs.gov/about/news/2020/03/29/hhs-accepts-donations-of-medicine-to-strategic-national-stockpile-as-possible-treatments-for-covid-19-patients.html. Accessed 3/30/2020.

[17] “Information for Clinicians on Therapeutic Options for COVID-19 Patients.” Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html. Accessed 3/30/2020.