July 2020 

Chloroquine, hydroxychloroquine and clinical trial issues in COVID-19

Chloroquine (CQ) and its analogue, hydroxychloroquine (HCQ), have been used for many years to prevent and treat malaria. Both drugs can reduce the production of inflammatory chemical signals produced by the immune system, and thus reduce inflammation. As a result, CQ and HCQ in particular are used to treat rheumatoid arthritis, lupus and other conditions.

Lab experiments with cells have found that both drugs can inhibit the production of a broad range of viruses, including HIV. Note that lab experiments are greatly simplified systems, consisting of cells, culture medium and viruses. This simplicity can never reproduce the complex workings of an organ, a system or an entire person. Still, lab experiments are an important first step on the path to develop a drug for a condition. Subsequent steps include testing the drug in question in an animal model of the relevant disease and then a series of complex experiments in people called clinical trials. At each of these steps, analysis can reveal problems, toxicity or a lack of effectiveness. This is a normal part of the drug development process and estimates are that about nine out of 10 drugs fail to transition from the lab to the pharmacy.

CQ and HCQ – looking great in the test tube

As mentioned earlier, CQ and HCQ can inhibit the activity of many different viruses, including HIV and coronaviruses in lab experiments with cells. However, when CQ and HCQ were tested in people with HIV, their antiviral effects were modest. This underscores a common issue in biomedical research: Results that look great in the test tube are not always reproducible in people. Thus, caution is needed when extrapolating from lab experiments to what might happen in people.

Clinical trials of CQ and HCQ in COVID-19

Earlier in this issue of TreatmentUpdate we mentioned that there were issues with many initial clinical trials of potential medicines for COVID-19. Some were small, not prospective, not randomized, did not have a placebo or other control, or had flaws. As a result, particularly with early clinical trials of CQ and HCQ (whether alone or in combination with azithromycin or other drugs), these issues were overlooked because of the emergency nature of the COVID-19 pandemic. This may have inadvertently caused some scientists to exaggerate the significance of the results of early studies with CQ or HCQ.

However, results from large well-designed clinical trials with CQ and HCQ are being released. These trials suggest that neither CQ nor HCQ are associated with significant clinical benefit. Furthermore, there are reports from some studies that these drugs are associated with serious heart problems.

—Sean R. Hosein


  1. Liu W, Zhou P, Chen K, et al. Efficacy and safety of antiviral treatment for COVID-19 from evidence in studies of SARSCoV-2 and other acute viral infections: a systematic review and meta-analysis. CMAJ. 2020; in press.
  2. Qaseem A, Yost J, Etxeandia-Ikobaltzeta I, et al. Update Alert: Should clinicians use chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of COVID-19? Living practice points from the American College of Physicians. Annals of Internal Medicine. 2020; in press.
  3. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Network Open. 2020;3(4):e208857.
  4. Fihn SD, Perencevich E, Bradley SM. Caution needed on the use of chloroquine and hydroxychloroquine for coronavirus disease 2019. JAMA Network Open. 2020;3(4):e209035.
  5. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA. 2020; in press.
  6. Juurlink DN. Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection. CMAJ. 2020;192(17):E450-E453.
  7. Keyaerts E, Li S, Vijgen L, et al. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrobial Agents and Chemotherapy. 2009;53(8):3416-3421.
  8. Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochemical and Biophysical Research Communications. 2004;323(1):264-268.
  9. Rodrigo C, Fernando SD, Rajapakse S. Clinical evidence for repurposing chloroquine and hydroxychloroquine as antiviral agents: a systematic review. Clinical Microbiology and Infection. 2020; in press.
  10. Savarino A, Lucia MB, Rastrelli E, et al. Anti-HIV effects of chloroquine: inhibition of viral particle glycosylation and synergism with protease inhibitors. Journal of Acquired Immune Deficiency Syndromes. 2004;35(3):223-232.
  11. Savarino A, Di Trani L, Donatelli I, Cauda R, Cassone A. New insights into the antiviral effects of chloroquine. Lancet Infectious Diseases. 2006;6(2):67-69.
  12. Savarino A, Boelaert JR, Cassone A, et al. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infectious Diseases. 2003;3(11):722-727.
  13. Bessière F, Roccia H, Delinière A, et al. Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit. JAMA Cardiology. 2020; in press.
  14. Hraiech S, Bourenne J, Kuteifan K, et al. Lack of viral clearance by the combination of hydroxychloroquine and azithromycin or lopinavir and ritonavir in SARS-CoV-2-related acute respiratory distress syndrome. Annals of Intensive Care. 2020;10(1):63.
  15. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849.
  16. Mahévas M, Tran VT, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data BMJ. 2020;369:m1844.