June 9, 2020
Why might chloroquine or hydroxychloroquine work against coronavirus?
Chloroquine was first synthesized in 1934 and has been prescribed extensively for the prevention and treatment of malaria as well as the treatment of autoimmune conditions, such as rheumatoid arthritis and systemic lupus erythematosus. Hydroxychloroquine was later introduced in 1955 and quickly became favored due to its better safety profile.
Several in-vitro studies have explored the antiviral effects of chloroquine and hydroxychloroquine with respect to SARS-family coronaviruses. Spurred by the SARS-coronavirus-19 (SARS-CoV-1) outbreak in 2002-2003, researchers demonstrated that, when exposed to increasing concentrations of chloroquine, SARS-CoV-1 replication in infected Vero cells was inhibited. Similar studies were performed in early 2020 using SARS-coronavirus-2 (SARS-CoV-2), demonstrating a similar inhibitory effect on viral replication by both chloroquine and hydroxychloroquine, suggesting these two agents may be useful for this novel coronavirus.
Hydroxychloroquine has several proposed mechanisms of action with regard to SARS-CoV-2 inhibition. In vitro studies have demonstrated this medication’s ability to raise the endosomal pH, disrupting a key step in viral replication. This pH change also interferes with the formation of the surface receptor that SARS-Cov-2 binds to when infecting human cells. Additionally, chloroquine (and by extension, hydroxychloroquine) has been shown to increase cellular intake of zinc, suggesting a potential role as in inhibition of viral reverse transcriptase, though the exact role of zinc in human SARS-CoV-2 infection remains unclear. Given these various pathways through which hydroxychloroquine may inhibit SARS-CoV-2 infection and spread, this medication has been explored as a potential agent for treatment, as well as for pre- and post-exposure prophylaxis.
What did the early studies of hydroxychloroquine demonstrate?
On March 20, 2020, Gautret et al. released a pre-print (non peer-reviewed) manuscript of a non-randomized, open-label study conducted in Marseilles, France, assessing hydroxychloroquine versus standard of care for treatment of SARS-CoV-2 infection. In total, 26 participants were treated with hydroxychloroquine (600mg for ten days), six of whom also received azithromycin (500mg once, followed by 250mg daily for a total of five days). Sixteen patients who did not meet study inclusion criteria served as study controls. At the time of enrollment, nearly 17% of all patients were asymptomatic, 61% had upper respiratory symptoms, and 22% had pneumonia or bronchitis-like symptoms. The authors reported significantly reduced virus shedding present at day 6 in those who received hydroxychloroquine compared to those who did not (70% vs. 12.5%); however, the investigators selectively excluded 6 participants in the hydroxychloroquine treatment arm (23%) as they required intensive care admission, died, withdrew from the study, or were lost. Given the small sample size of the overall study and the exclusion of these six participants in the absence of an intention to treat analysis, the results are significantly biased, and no definitive conclusion should be drawn.
Shortly after the online publication of this study, several other small studies followed, many of them observational. Chen et al. published a small (n = 62) randomized parallel-group trial with hospitalized patients randomized to receive either hydroxychloroquine plus standard of care or standard of care alone, enrolling only those patients with mild pneumonia. While the researchers found a more substantial proportion of those receiving hydroxychloroquine had clinical improvement of pneumonia (80% vs. 55%) as determined by day zero to day six chest imaging, the methodology was not described. Outcomes were likely based on subjective individual clinician opinion, which may not have been blinded to the treatment allocation . Molina et al. reported outcomes of a prospective cohort of 11 hospitalized patients. These patients all received the same dose and duration of hydroxychloroquine and azithromycin as the Gautret study. Eight patients enrolled had significant comorbidities, and at the time of enrollment, 10/11 were receiving supplemental oxygen. They found that 80% of patients alive by days five to six still tested positive for SARS-CoV-2 on nasopharyngeal swab. In this small cohort, two patients were transferred to intensive care, one patient died, and one had the medications stopped due to adverse effects. Unlike the Gautret study, these sicker patients were included in the analysis.
Are there any randomized, controlled trials of hydroxychloroquine used in SARS-CoV-2 infection?
The first publication of a randomized, placebo-controlled, double-blind study of hydroxychloroquine in SARS-CoV-2 infection was a post-exposure prophylaxis trial by Boulware et al. at the University of Minnesota. This study used an innovative design of recruiting participants for a large-scale randomized controlled trial via the internet, maintaining an online database and utilizing a combination of social and traditional media to attract participants. The study enrolled nationwide, focusing on persons who had a high-risk exposure to SARS-CoV-2 (either through a household contact or as a healthcare worker) within the last 4 days. Each enrollee was randomized to receive either placebo or hydroxychloroquine for 5 days. The hydroxychloroquine dosing was 800 mg once followed by 600mg 6 hours later, then 600mg daily for a total of 5 days. In total, 821 participants were randomized (407 to placebo, 414 to hydroxychloroquine). The incidence of new illness compatible with SARS-CoV-2 infection was not significantly different between the two groups (14.3% and 11.8% for placebo and hydroxychloroquine, respectively). A limitation to this study, related to national delays in testing, was that most participants did not have PCR-confirmed SARS-CoV-2 infection, so symptom-based classification of probable cases was performed using the U.S. case definition. This study, however, provides the first strong evidence that hydroxychloroquine likely does not have any beneficial effect in SARS-CoV-2 infection.
What are the safety issues?
Though a great deal of media attention has been brought to potential safety issues posed by taking hydroxychloroquine, the most commonly reported adverse event of both hydroxychloroquine and chloroquine is gastrointestinal upset, including nausea and diarrhea. Of the severe adverse reactions, one is a slight prolongation of the QT interval of the heart rhythm. The World Health Organization (WHO) in 2017 reported that no sudden cardiac deaths have ever been reported when using malaria-style doses and duration. When using multiple medicines that can affect the heart or excessive doses, heart rhythm problems can occur, which promoted an FDA warning on April 24, 2020. Azithromycin is one such medicine. Some of those promoting the dangers of hydroxychloroquine had financial interests in remote EKG monitoring services.
What is “coming down the research pipeline” in the near future?
Several groups have ongoing randomized controlled trials for treatment of SARS-CoV-2 infection using hydroxychloroquine. At the University of Minnesota, Drs. David Boulware and Radha Rajasingham are spearheading nationwide pre-emptive treatment and pre-exposure prophylaxis randomized controlled trials, respectively, with the former study completed and pending final analysis and publication and the latter study expected to be completed by the end of June 2020. The WHO has an ongoing, multinational clinical trial (the Solidarity trial) exploring several potential treatments for SARS-CoV-2 infection in hospitalized patients, one of which is hydroxychloroquine. After the May 2020 publication of a now-retracted study in The Lancet which raised questions about the safety of hydroxychloroquine therapy, the WHO briefly suspended the hydroxychloroquine arm of their study to reassess participant safety, ultimately restarting this study arm ten days later. A similar safety and efficacy review in the UK’s national RECOVERY trial (a similar study design to the Solidarity trial) prompted an end to recruitment of their hydroxychloroquine arm, with the UK group citing lack of evidence for benefit in their study population.
Based on current data, what are the recommendations for use of hydroxychloroquine in SARS-CoV-2 infection?
- Pre-exposure prophylaxis → No current evidence to support use. Randomized clinical trials are ongoing, with UMN study expected to reach completion by the end of June 2020
- Early outpatient treatment → No current evidence to support use. UMN randomized clinical trial completed, pending publication.
- Post-exposure prophylaxis → UMN randomized clinical trial data does not show benefit, no evidence to support use.
- Hospitalized patients → U.K. RECOVERY randomized clinical trial data showed no benefit; WHO Solidarity randomized clinical trial ongoing after brief suspension of hydroxychloroquine arm.
- Pastick KA, Okafor EC, Wang F, Lofgren SM, Skipper CP, Nicol MR, et al. Review: Hydroxychloroquine and Chloroquine for Treatment of SARS-CoV-2 (COVID-19). Open Forum Infect Dis. 2020;7(4):ofaa130.
- Tönnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy - a review of the literature. Immunopharmacol Immunotoxicol 2013; 35:434–42.
- Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol 2012; 42:145–53.
- Concordia Pharmaceuticals Inc. Plaquenil Hydroxychloroquine Sulfate Tablets, USP; 2017.
- Ducharme J, Farinotti R. Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements. Clin Pharmacokinet 1996; 31:257–74.
- Drent M, Proesmans VLJ, Elfferich MDP, et al. . Ranking self-reported gastrointestinal side effects of pharmacotherapy in sarcoidosis. Lung 2020; 198:395–403.
- Srinivasa A, Tosounidou S, Gordon C. Increased incidence of gastrointestinal side effects in patients taking hydroxychloroquine: a brand-related issue? J Rheumatol 2017; 44:398.
- U.S. Food and Drug Administration. EUA Chloroquine Phosphate Health Care Provider Fact Sheet April 3, 2020.
- U.S. Food and Drug Administration. EUA Hydroxychloroquine sulfate Health Care Provider Fact Sheet March 28, 2020.
- Vincent MJ, Bergeron E, Benjannet S, et al. . Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005; 2:69.
- Keyaerts E, Vijgen L, Maes P, et al. . In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun 2004; 323:264–8.
- 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:ciaa237.
- 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; 30:269–71.
- Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ. Chloroquine is a zinc ionophore. PLoS One 2014;9.
- 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; 105949.
- Chen Z, Hu J, Zhang Z, et al. . Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020
- Molina JM, Delaugerre C, Goff JL, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect 2020; 50(4): 384.
- Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020;
- “‘Solidarity’ Clinical Trial for COVID-19 Treatments.” World Health Organization, World Health Organization, https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-r... .
- “RECOVERY Trial.” RECOVERY Trial, https://www.recoverytrial.net/.