Conclusion: Research challenges on the use of 4-aminoquinones in SARS-CoV-2
The COVID-19 pandemic continues to pose a serious threat to public health. Hydroxychloroquine’s established safety record and plausible efficacy supported clinical investigation of its use for treatment of COVID-19. Investigation of clinical outcomes of large numbers of patients treated with low-dose hydroxychloroquine, as a result of emergency use authorizations across the world, reached conflicting conclusions. In general, the methodology of these studies were flawed; even when randomized controlled trials have been conducted, selection bias and residual confounding bias have been observed.[51] We believe a high-dose short-term dosing of hydroxychloroquine maximizes the likelihood of efficacy for treatment of COVID-19. Unfortunately, the current climate is unlikely to allow for further rigorous and controlled testing now that the lower doses have demonstrated poor efficacy. As a result, hydroxychloroquine may never be adequately evaluated at doses or in clinical settings where it may provide the most benefit. This outcome underlies the importance of utilizing sound pharmacologic principles in the initial design in clinical trials. The risks of hydroxychloroquine at higher doses, particularly in an acutely ill population, likely contributed to reluctance to utilize high-dose regimens in initial studies. We believe the risks are not prohibitive if appropriate exclusion criteria and monitoring is utilized. In particular, real-time QTc monitoring could be considered in future studies.
Perhaps the most important lesson learnt from our collective experience with hydroxychloroquine and COVID-19 is the danger of allowing public and political pressure to influence trial design and study review processes. When there is enormous pressure to produce results in a timely fashion, any early findings are likely to receive intense interest and scrutiny, thereby impacting the feasibility of future trials. Interest in our trial declined as the media emphasized severe, but rare, side effects and spurious endorsements were made by political figures.[52] Conflicting reports of efficacy supported by results made publicly available before peer-revision heightened confusion about the efficacy and safety of the drug for treatment of COVID-19.[32] This lead to correction of messaging, and in some cases retraction of published studies after receiving further scrutiny.[38] Of particular concern, the rapid ebb and flow of both positive and negative information deepens public mistrust of the scientific community. These forces had a substantial impact on the recruitment of patients to our study and contributed to its early termination.[52] This same scenario has reoccurred in the context of the Emergency Use Authorization for convalescent plasma, despite ongoing NIH-funded phase III trials to ascertain whether convalescent plasma is effective. We hope that the critical COVID-19 vaccine studies do not meet a similar fate. This experience could provide a valuable teaching module in pharmacological and medical training programs in future to highlight the pitfalls in abandoning scientific protocol and procedure, even with the best intentions of ameliorating public health.
BIBLIOGRAPHY
1. Yang, C.W., et al., Repurposing old drugs as antiviral agents for coronaviruses. Biomed J, 2020.
2. Gao, J., Z. Tian, and X. Yang, Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends, 2020.14 (1): p. 72-73.
3. Furst, D.E., Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus, 1996.5 Suppl 1 : p. S11-5.
4. Cutler, D.J., A.C. MacIntyre, and S.E. Tett, Pharmacokinetics and cellular uptake of 4-aminoquinoline antimalarials. Agents Actions Suppl, 1988. 24 : p. 142-57.
5. Daniel, W.A., M.H. Bickel, and U.E. Honegger, The contribution of lysosomal trapping in the uptake of desipramine and chloroquine by different tissues. Pharmacol Toxicol, 1995. 77 (6): p. 402-6.
6. Projean, D., et al., In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation. Drug Metab Dispos, 2003.31 (6): p. 748-54.
7. Schrezenmeier, E. and T. Dorner, Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol, 2020. 16 (3): p. 155-166.
8. Wallace, D.J., et al., The effect of hydroxychloroquine therapy on serum levels of immunoregulatory molecules in patients with systemic lupus erythematosus. J Rheumatol, 1994. 21 (2): p. 375-6.
9. van den Borne, B.E., et al., Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells. J Rheumatol, 1997. 24 (1): p. 55-60.
10. Keyaerts, E., et al., In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun, 2004. 323 (1): p. 264-8.
11. Vincent, M.J., et al., Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J, 2005. 2 : p. 69.
12. Liu, J., et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov, 2020. 6 : p. 16.
13. Yao, X., 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.
14. Furst, D.E., et al., Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: a randomized, double-blind six-week trial with eighteen-week extension.Arthritis Rheum, 1999. 42 (2): p. 357-65.
15. Carmichael, S.J., B. Charles, and S.E. Tett, Population pharmacokinetics of hydroxychloroquine in patients with rheumatoid arthritis. Ther Drug Monit, 2003. 25 (6): p. 671-81.
16. Fan, J., et al., Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: a critical step in treating COVID-19 patients. Clin Infect Dis, 2020.
17. Garcia-Cremades, M., et al., Optimizing Hydroxychloroquine Dosing for Patients With COVID-19: An Integrative Modeling Approach for Effective Drug Repurposing. Clin Pharmacol Ther, 2020.
18. de Olano, J., et al., Toxicokinetics of hydroxychloroquine following a massive overdose. Am J Emerg Med, 2019. 37 (12): p. 2264 e5-2264 e8.
19. Wolfe, F. and M.F. Marmor, Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken), 2010. 62 (6): p. 775-84.
20. Nord, J.E., et al., Hydroxychloroquine cardiotoxicity in systemic lupus erythematosus: a report of 2 cases and review of the literature. Semin Arthritis Rheum, 2004. 33 (5): p. 336-51.
21. Chatre, C., et al., Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Saf, 2018. 41 (10): p. 919-931.
22. Hooks, M., et al., Effects of hydroxychloroquine treatment on QT interval. Heart Rhythm, 2020.
23. Costedoat-Chalumeau, N., et al., Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology (Oxford), 2007. 46 (5): p. 808-10.
24. McGhie, T.K., et al., Electrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus. Clin Exp Rheumatol, 2018. 36 (4): p. 545-551.
25. Mercuro, N.J., et al., Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA Cardiol, 2020.
26. Bessiere, F., 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 Cardiol, 2020.
27. Cascella, M., et al., Features, Evaluation and Treatment Coronavirus (COVID-19) , in StatPearls . 2020: Treasure Island (FL).
28. Wang, Z., et al., Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China. Clinical Infectious Diseases, 2020.
29. Chen, N., et al., Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet, 2020. 395 (10223): p. 507-513.
30. Gautret, 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: p. 105949.
31. Bright, R., Request for Emergency Use Authorization For Use of Chloroquine Phosphate or Hydroxychloroquine Sulfate Supplied From the Strategic National Stockpile for Treatment of 2019 Coronavirus DiseaseU.S. Department of Health and Human Services (HHS), U.S. Food and Drug Administration, 2020.
32. Magagnoli, J., et al., Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. medRxiv, 2020.
33. Mahevas, 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 : p. m1844.
34. Rosenberg, E.S., et al., Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA, 2020.
35. Geleris, J., et al., Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med, 2020.382 (25): p. 2411-2418.
36. Arshad, S., et al., Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.Int J Infect Dis, 2020. 97 : p. 396-403.
37. Group, R.C., et al., Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med, 2020.
38. Mehra, M.R., F. Ruschitzka, and A.N. Patel,Retraction-Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis.Lancet, 2020. 395 (10240): p. 1820.
39. Yu, B., et al., Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19. Sci China Life Sci, 2020.
40. Peter Horby, M.M., Louise Linsell, Jennifer L Bell, Natalie Staplin, Jonathan R Emberson, Martin Wiselka, Andrew Ustianowski, Einas Elmahi, Benjamin Prudon, Anthony Whitehouse, Timothy Felton, John Williams, Jakki Faccenda, Jonathan Underwood, J Kenneth Baillie, Lucy Chappell, Saul N Faust, Thomas Jaki, Katie Jeffery, Wei Shen Lim, Alan Montgomery, Kathryn Rowan, Joel Tarning, James A Watson, Nicholas J White, Edmund Juszczak, Richard Haynes, Martin J Landray, Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial. medRxiv, 2020.
41. Cavalcanti, A.B., et al., Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med, 2020.
42. Tang, W., et al., Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ, 2020. 369 : p. m1849.
43. Skipper, C.P., et al., Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial. Ann Intern Med, 2020.
44. Million, M., et al., Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Travel Med Infect Dis, 2020. 35 : p. 101738.
45. Zhaowei Chen, J.H., Zongwei Zhang, Shan Jiang, Shoumeng Han, Dandan Yan, Ruhong Zhuang, Ben Hu, Zhan Zhang, Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv, 2020.
46. Chen, J., et al., [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. Zhejiang Da Xue Xue Bao Yi Xue Ban, 2020. 49 (2): p. 215-219.
47. Molina, J.M., 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): p. 384.
48. Gautret, 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: A pilot observational study. Travel Med Infect Dis, 2020. 34 : p. 101663.
49. Lebeaux, D. and M. Revest, No evidence of clinical benefits of early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: Comment on ”Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France”. Travel Med Infect Dis, 2020: p. 101819.
50. Boulware, D.R., et al., A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med, 2020. 383 (6): p. 517-525.
51. Alexander, P.E., et al., COVID-19 coronavirus research has overall low methodological quality thus far: case in point for chloroquine/hydroxychloroquine. J Clin Epidemiol, 2020. 123 : p. 120-126.
52. Stolberg, S.G., Amid Hydroxychloroquine Uproar, Real Studies of Drug Are Suffering , in New York Times . 2020