key: cord-0953769-0qyuyn3z authors: Paul, Mical title: Has the door closed on hydroxychloroquine for SARS-COV-2? date: 2020-10-20 journal: Clin Microbiol Infect DOI: 10.1016/j.cmi.2020.10.011 sha: 2b460130cf7e2ba9a625e1d3b4e89d3f73dcf98b doc_id: 953769 cord_uid: 0qyuyn3z nan Shortly following the onset of the SARS-COV-2 pandemic, Raoult's group from Marseille published a study describing improved virological cure with hydroxychloroquine (HCQ), especially in combination with azithromycin. 1 Beyond being "non-randomized" this was a small, unadjusted comparison including 36 patients in total, reporting only on virological cure and excluding from the analysis the most severely-ill patients. It was probably meant as an alert for a potentially useful treatment and reported as responsible sharing of the local experience given the urgent situation (as the authors noted " we believe that our results should be shared with the scientific community"). Yet this publication launched a heated debate of HCQ believers and non-believers, moving far beyond the realm of science with politicians expressing views, countries stockpiling the drug and people taking it prophylactically. 2, 3 This also led to a flurry of studies, resulting now in more than 25 systematic reviews and/ or meta-analyses summarizing specifically the efficacy of HCQ for COVID-19 from these studies on PubMed and 12 unpublished on medRxiv. A systematic review of observational studies and randomized controlled (RCTs) published recently in CMI concluded no benefit for HCQ and increased mortality with HCQ and azithromycin. 4 Is this the last word on HCQ for corona? Beneficial effects of HCQ are possible given multiple antiviral and anti-inflammatory properties of the drug. It is active in-vitro against SARS-COV-2 and has been identified independently in screening of chemical libraries and through mapping to SARS-COV-2 protein targets. [5] [6] [7] These data are probably sufficient to warrant clinical assessment. Many observational studies were published following the first from Marseille. All suffer from limitations inherent to observations; the stress of the pandemic and possibly the debate arising following the first study from Marseille J o u r n a l P r e -p r o o f resulted in publication of observational studies that would not have been published otherwise. 8 While many sources of bias exist in observational studies, two should be stressed: confounding and deviations from the intended interventions. Whether believing or not in HCQ's efficacy or whether comparing between different centers, the patients treated with HCQ will not be similar to those not given HCQ. Enough data on the patients and a large enough sample size is needed to allow for adjustment. Previously identified risk factors for death in COVID-19 include age, male sex, ethnicity in the UK, deprivation, most comorbidities, disease presentation and hospital-level data. 9-11 All these data must be collected, compared and adjusted for as relevant. Unlike in RCTs, treatment is not standardized in observational studies. As a minimum, observational studies should define the start time, dosing and minimal duration of HCQ that can reasonably affect the course of the disease and collect data on concomitant therapy, especially medications that might affect the outcome (e.g. steroids). None of the studies to date addressed confounding or treatment definitions appropriately. Their risk of bias using the ROBINS-I tool is being summarized in a living systematic review. 12, 13 None of the studies achieved low risk of bias overall and many were classified at critical risk. Three RCTs covering the spectrum of COVID-19 disease severity currently provide high-quality evidence. The RECOVERY trial is a platform trial carried out in many hospitals in the UK including 4716 patients. 14 Although both probable and confirmed COVID-19 patients were included, 90% had virological confirmation of SARS-COV-2. HCQ dosing was high compared to usual dosing. However, considering both beneficial and adverse effects, the rate ratio for all-cause mortality at 28 days was These three trials [14] [15] [16] were well-designed and addressed each a different patient population, the need for virological confirmation as relevant and clinicallymeaningful outcomes. In the presence of such high-level evidence and power to refute an advantage to HCQ with respect to mortality for severely-ill patients, observational studies do not have much contribution to decision making. Other small RCTs recruited mostly patients at low risk of death. 17-23 Some were at risk of bias with unclear randomization and unbalanced treatment groups with respect to baseline characteristics or adherence to assigned treatment. 12, 13 The trials reported primarily on virological or clinical cure finding no advantage to HCQ, but for two small trials of 62 patients that reported on shorter time to clinical cure 21 and 48 patients that reported on faster virological eradication with HCQ. 20 All but one 17 did not address mortality 19, 20 or reported that all patients survived. 18, [21] [22] [23] The significance of virological eradication is unclear. While the initial viral load might be associated mortality, 24 there is no information correlating the virological response with outcomes, unlike the case with HIV. Moreover, information on persistent positive PCR among patients recovering from COVID-19 clinically is accumulating. 25 Recent observational studies and many viewpoints address the cardiotoxicity of HCQ, azithromycin or their combination. Chloroquine has been used for malaria among J o u r n a l P r e -p r o o f many millions of people, and HCQ has long been used in high doses for long durations (years) to treat chronic Q fever, with not much interest in its adverse event profile. While patients with severe COVID-19 are at higher risk for cardiac events, analysis of drug-related cardiovascular mortality typically requires a very large sample size. In a carefully designed, propensity-score-matched analysis using more than 150 covariates, 5 days' azithromycin was associated with 47 additional cardiovascular deaths per 1 million courses. 26 Current studies try to show increased cardiovascular mortality in cohorts of a maximum of few hundred patients analyzing "any" administration of the drugs. 27 confirmation. An RCT in community for the early stage of the disease in hospitalized patients is probably ethical and will provide the definitive answer, although the pretest likelihood of a positive result is low with the existing evidence. J o u r n a l P r e -p r o o f I agree with Prof. Raoult that the world reacted inappropriately to his group's claim on HCQ's efficacy based on clinical impression, which should have been only a call for further well-conducted studies. 30 Investigators and clinicians also took sides and we learned on the importance of academic bias on the studies performed and their results. The current status is an all or none treatment approach, with variability even within countries. I believe that the evidence is sufficient to exclude a benefit for HCQ in all stages of COVID-19 and there is no place for treatment of COVID-19 with HCQ, with or without azithromycin. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Debate over hydroxychloroquine spills over from the White House to congressional campaigns 2020 How the hydroxychloroquine debate proves politics can get in the way of science. The Washington Times Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication A SARS-CoV-2 protein interaction map reveals targets for drug repurposing Natural history and therapeutic options for COVID-19. Expert Rev Medicine Hydroxychloroquine or Chloroquine for the Treatment or Prophylaxis of COVID-19 Hydroxychloroquine or Chloroquine for Treatment or Prophylaxis of COVID-19 Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19 Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 A Multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate Coronavirus disease Zhejiang Da Xue Xue Bao Yi Xue Ban Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial Hydroxychloroquine in patients with mainly