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By Christian Hoffmann

25 May

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A brief (and probably the last) review on hydroxychloroquine and chloroquine

A few months ago, lab experiments suggested that hydroxychloroquine (HCQ) and chloroquine (CQ) might have some antiviral effects against SARS-CoV-2 due to an increase in the endosomal pH value which disrupts the virus-cell fusion and some post-entry steps (Wang 2020, Yao 2020). An early enthusiastic mini-review stated “results from more than 100 patients” showed that chloroquine phosphate would be able to alleviate the course of the disease (Gao 2020). Other experts, however, dampened the enthusiasm, pointing out that a benefit of chloroquine would be the first positive signal, after decades of unsuccessful studies conducted in a huge number of acute viral diseases (Touret 2020). On March 17, a preliminary report from Marseille/France appeared to show some benefit in a small non-randomized study on 36 patients (Gautret 2020). Although this work lacked essential standards of data generation and interpretation (Kim 2020), someone’s swanky tweet claiming on March 21 that the combination of HCQ and azithromycin has “a real chance to be one of the biggest game changers in the history of medicine”, attracted world-wide attention and led to tens of thousands of uncontrolled treatments. Moreover, many patients decided against clinical trials of other therapies that would require them to give up chloroquine treatments. This has already prompted serious delays in trial enrolment, muddled efforts to interpret data and endangered clinical research (Ledford 2020). Some countries have stockpiled CQ and HCQ, resulting in a shortage of these medications for those that need them for approved clinical indications.

Only a few weeks later, we are now facing an overwhelming amount of data strongly arguing against any use of both HCQ and CQ.

  • The by-far most convincing data were published last Friday, May 22 (Mehra 2020). In this extraordinary multinational registry analysis from 671 hospitals on six continents, 14,888 patients (1,868 received CQ; 3,783 received CQ with azithromycin or clarithromycin; 3,016 received HCQ; and 6,221 received HCQ with a macrolide) were compared to 81,144 control patients who did not receive these drugs. Mortality was higher in all treatment groups than in the controls (18.0-23.8% versus 9.3%) and each treatment regimen was independently associated with an increased risk of in-hospital mortality and with de novo ventricular arrhythmia, especially in the combination groups (4.3-8.1 versus 0.3%). Adjustment for multiple confounding factors, a propensity score matching analysis and a tipping-point analysis (an analysis that shows the effect size and prevalence of an unmeasured confounder that could shift the upper boundary of the CI towards null) did not affect the results. Although the authors concluded that a cause-and-effect relationship between drug therapy and survival should not be inferred and that their data do not apply to the use of any treatment regimen used in the ambulatory, out-of-hospital setting, it is hard to find any argument for any of these strategies. Data do not support the use of these regimens outside randomized clinical trials (RCTs). Researchers who conduct and supervise RCTs should consider whether ongoing recruitment is necessary.

Other key studies arguing against HCQ in recent weeks

Update 3 June 2020: The previous study by Mehra et al. is like to be retracted soon.

  1. In an observational study from New York City of 1,376 consecutive hospitalized patients, 811 received HCQ (60% received also azithromycin) (Geleris 2020). After adjusting for several confounders (HCQ patients were more severely ill at baseline), hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death.
  2. Another retrospective cohort of 1,438 patients from 25 hospitals in the New York metropolitan region looked at 1,438 patients (Rosenberg 2020). In adjusted Cox models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving HCQ + azithromycin, HCQ alone, or azithromycin alone. Cardiac arrest was significantly more likely with HCQ + azithromycin (adjusted OR 2.13).
  3. A randomized, Phase IIb clinical trial in Brazil allocated severe COVID-19 patients to receive high-dose CQ (600 mg BID for 10 days) or low-dose CQ (450 mg BID on day 1, QD for 4 days). The DSMB terminated the trial after 81/440 individuals were enrolled (Borba 2020). By day 13 of enrolment, 6/40 patients (15%) in the low-dose group had died, compared with 16/41 (39%) in the high-dose group. Viral RNA was detected in 78% and 76%, respectively.
  4. In a retrospective study of 251 patients receiving HCQ plus azithromycin, extreme new QTc prolongation to >500 ms, a known marker of high risk for torsade de pointes, had developed in 23% (Chorin 2020).
  5. HCQ does not work as prophylaxis. A case series described 17 lupus patients with COVID-19, among them several severe cases (Mathian 2020).
  6. Free plasma HCQ concentration achieved with HCQ doses tolerable for humans are probably too low to have any antiviral effects (Fan 2020).

References

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 Netw Open. 2020 Apr 24;3(4.23):e208857. PubMed: https://pubmed.gov/32330277 . Full-text: https://doi.org/10.1001/jamanetworkopen.2020.8857

Chorin E, Wadhwani L, Magnani S, et al. QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin. Heart Rhythm. 2020 May 11:S1547-5271(20)30435-5. PubMed: https://pubmed.gov/32407884 . Full-text: https://doi.org/10.1016/j.hrthm.2020.05.014

Fan J, Zhang X, Liu 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 May 21:ciaa623. PubMed: https://pubmed.gov/32435791 . Full-text: https://doi.org/10.1093/cid/ciaa623

Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Mar 16;14(1):72-73. PubMed: https://pubmed.gov/32074550 . Full-text: https://doi.org/10.5582/bst.2020.01047

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. PubMed: https://pubmed.gov/32205204 . Full-text: https://doi.org/10.1016/j.ijantimicag.2020.105949

Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020 May 7. PubMed: https://pubmed.gov/32379955 . Full-text: https://doi.org/10.1056/NEJMoa2012410

Kim AH, Sparks JA, Liew JW. A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID-19. Ann Intern Med 2020. Full-text: https://doi.org/10.7326/M20-1223

Ledford H. Chloroquine hype is derailing the search for coronavirus treatments. Nature Medicine, 24 April 2020. Full-text: https://www.nature.com/articles/d41586-020-01165-3

Mathian A, Mahevas M, Rohmer J, et al. Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine. Ann Rheum Dis. 2020 Apr 24. PubMed: https://pubmed.gov/32332072 . Full-text: https://doi.org/10.1136/annrheumdis-2020-217566

Mehra MR, Desai SS, Ruschitzka F, Patel AM. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet May 22, 2020 Full-text: https://doi.org/10.1016/S0140-6736(20)31180-6

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 May 11. https://pubmed.gov/32392282 . Full-text: https://doi.org/10.1001/jama.2020.8630

Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res. 2020 Mar 5;177:104762. PubMed: https://pubmed.gov/32147496 . Full-text: https://doi.org/10.1016/j.antiviral.2020.104762

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 Mar;30(3):269-271. PubMed: https://pubmed.gov/32020029 . Full-text: https://doi.org/10.1038/s41422-020-0282-0

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. PubMed: https://pubmed.gov/32150618 . Full-text: https://doi.org/10.1093/cid/ciaa237