Covid-19 and hydroxychloroquine

We hope our comments can encourage further discussion and debate on how to further optimize the management of Covid-19 continuum. Research is under way to identify vaccines and therapeutics for Covid-19, including repurposing of medications. Based on evidence from in vitro studies on the suppression of activity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronavirus strains, interest increased in the use of hydroxychloroquine and chloroquine with the possible addition of azithromycin for the treatment of Covid-19. However, research has been limited by outcomes assessed, short follow-up, exclusion of patients still admitted, small sample size, and types of patients studied. Few studies have evaluated adverse events potentially linked to the use of hydroxychloroquine or chloroquine in patients with Covid-19, including electrophysiological cardiac conditions of prolonged QT and arrhythmia. Hydroxychloroquine is widely used in the treatment of rheumatic diseases, and it has been suggested as effective treatments for Covid-19 on the grounds of both antiinflammatory and antiviral effects. In the United States, the Food and Drug Administration issued an Emergency Use Authorization on March 30, 2020, that allowed the use of these drugs in patients with Covid-19 who were not enrolled in clinical trials. Guidelines suggested that these drugs should be administered to patients who have evidence of pneumonia, and to date, they have been used in many thousands of patients with acute Covid-19 around the world, being, at the right dosages and for the right patients, an important therapeutic resource for the management of patients in and out the hospitals. The World Health Organization (WHO) announced on May 25 that due to safety concerns, it is temporarily halting a clinical trial hydroxychloroquine for treating coronavirus patients. The announcement follows the publication on May 22 by The Lancet medical journal of an observational study on hydroxychloroquine and chloroquine and its effects on hospitalized COVID-19 patients. In The Lancet, Mandeep Mehra and colleagues report a large observational study published to date on the effects of chloroquine or hydroxychloroquine, with or without a macrolide, in 96032 hospitalised patients who tested positive for Covid-19.  The same Authors specified that their study has several limitations. “The association of decreased survival with hydroxychloroquine or chloroquine treatment regimens should be interpreted cautiously. Due to the observational study design, we cannot exclude the possibility of unmeasured confounding factors, although we have reassuringly noted consistency between the primary analysis and the propensity score matched analyses. Nevertheless, a cause-and-effect relationship between drug therapy and survival should not be inferred. These data do not apply to the use of any treatment regimen used in the ambulatory, out-of-hospital setting. Randomised clinical trials will be required before any conclusion can be reached regarding benefit or harm of these agents in Covid-19 patients. We also note that although we evaluated the relationship of the drug treatment regimens with the occurrence of ventricular arrhythmias, we did not measure QT intervals, nor did we stratify the arrhythmia pattern (such as torsade de pointes). We also did not establish if the association of increased risk of in-hospital death with use of the drug regimens is linked directly to their cardiovascular risk, nor did we conduct a drug dose-response analysis of the observed risks”. On May 26 AIFA (Italian Medicines Agency) suspended the authorization to use hydroxychloroquine for the treatment of Covid-19 outside clinical trials, since – motivates AIFA in a note – “new clinical evidence” “indicates an increase in risk for adverse reactions with little or no benefit. “On May 27 The French government revoked a decree authorising hospitals to prescribe the controversial drug for Covid-19 patients.

Global Alliance for Infections in Surgery respects the decision of WHO that we have always considered a cornerstone of global heath and accepts the decision of the National Agencies. However we are convinced that this decision is NOT evidence-based (it is based on the results of an observational study) and deprives doctors of an important tool, when prescribed at the right dosage and for the right patient, already used in many patients around the world by doctors on front line, with the potential (yet to be demonstrated) to mitigate the inflammatory response of Covid-19, avoiding the terrible consequences of the cytokine storm.