key: cord-0907311-hqam1kfn authors: Kumar Pathak, Dr Subodh; Ashok Salunke, Dr Abhijeet; Thivari, Dr Praveen; Pandey, Apurva; Nandy, Dr Kunal; Harish V K Ratna, Dr; Pandey, Dr Sanjay; Chawla, Dr Jasneet; Mujawar, Dr Jalil; Dhanwate, Dr Anant; Menon, Dr Vivek title: No benefit of hydroxychloroquine in COVID-19: Results of Systematic Review and Meta-Analysis of Randomized Controlled Trials”() date: 2020-09-01 journal: Diabetes Metab Syndr DOI: 10.1016/j.dsx.2020.08.033 sha: 8419a242f290ee5cee0290078150b3254e4d4887 doc_id: 907311 cord_uid: hqam1kfn BACKGROUND AND AIMS: Coronavirus pandemic is currently a global public health emergency with no definitive treatment guidelines. We conducted a systematic review and meta-analysis of the literature evaluating the efficacy of hydroxychloroquine and its related formulations in COVID-19 patients. METHODS: A systematic search of PubMed, Scopus, MedRxiv data and Cochrane Central Register of Clinical Trials for published articles that reported the outcomes of COVID-19 patients treated with hydroxychloroquine or its compounds was done. We identified 1071 published studies and 7 studies were included in the analysis. RESULTS: The study population consisted of a total of 4984 patients, of which 1721 (34.5%) received hydroxychloroquine or its congeners (HCQ group) while 3091 (62.01%) received standard of care or had included antiviral medication (control group). The pooled estimate of successful treatment in the hydroxychloroquine group and the control group was 77.45% and 77.87% respectively, which indicated similar clinical outcomes in patients treated with hydroxychloroquine compared to the control group. The odds ratio of a favourable outcome with hydroxychloroquine was 1.11 (95 CI 0.72 to 1.69) (p = 0.20). The pooled risk difference of favourable outcome with hydroxychloroquine versus control group was 0.00 (95 CI -0.03 to 0.03) which was statistically not significant (p = 0.10). Conclusions: The present evidence shows no benefit of hydroxychloroquine in patients affected by mild to moderate COVID-19 disease. However, now several trials on HCQ are ongoing and hopefully more data will be available soon. Hence, the management of COVID-19 is set to change for better in the future. The COVID-19 is the worst pandemic with more than 17 million cases and more than 670 As much of the data on COVID-19 is from China and Europe, no language restrictions were 86 imposed. We used the SYSTRAN language translator for the translation of non-English 87 articles. Data analysis 89 The following information was extracted from included studies in the systematic review: The 90 first author, publication date, type of study, total patients, and characteristics of the 91 experimental and control group, outcome measures, complications were extracted from the negative RT-PCR test as successful treatment and need for mechanical ventilation or death as 94 failure. The Cochrane Collaboration and the Quality of Reporting of Meta-analyses 95 guidelines were followed during the meta-analysis. The publication bias of the included 96 studies for meta-analysis was calculated with funnel plot analysis and Egger's regression 97 asymmetry test. A p-value of less than 0.05 level was considered statistically significant. For 98 each study, we calculated the odds ratio (OR), risk difference (RD), and relative risk (RR) 99 with a 95% confidence interval (CI). Heterogeneity between comparable studies was tested 100 with the chi-square and Higgins I 2 test. P-value of less than 0.1 or an I 2 value higher than 101 50% meant significant heterogeneity and a random-effects model should be applied. The There was no funding source for this study. The corresponding author had full access to all 108 the data in the study and had final responsibility for the decision to submit for publication. reviewed on the basis of their full-texts. Of these, 3 were excluded as it lacked a comparison 115 group, one was excluded as it was non randomized and 3 were excluded due to non-116 uniformity in outcome measure. We finally selected 7 articles for the meta-analysis (Fig 1) . (Table 2) . The pooled estimate of successful treatment in the HCQ group was 77.45% and that in the The pooled relative risk for favourable outcome with hydroxychloroquine was 1.00 (95% CI 131 0.96-1.03) which was statistically not significant (p=0.11). The lower limit of confidence 132 interval is less than 1 indicating hydroxychloroquine may not have significant benefit (Fig 2) . The pooled risk difference of favourable outcome with hydroxychloroquine compared to the 134 control group was 0.00 (95 CI -0.03 to 0.03) which was statistically not significant(p=0.10) The odds ratio of favourable outcome with hydroxychloroquine was 1.11 (95 CI 0.72 to 1.69) 137 (p=0.20) (Fig 4) . Six of the seven included studies reported adverse effects in treatment and 138 control group which is summarised in Table 3 . of QT interval prolongation it should also be noted that there is concern for QTc prolongation 249 and torsades de pointes with even short-term use of hydroxychloroquine for COVID- Limitations of this study 269 The limitations of current metaanalysis were that an inherent bias could exist, particularly in 270 terms of patient selection, heterogeneous medical treatment regimens in the selected studies. Secondly the study population and dosage of HCQ drug varies in the included studies. The results need to be concluded with caution since judgment criteria between severe and Favipiravir for COVID-19: An Open-Label Control Study In vitro inhibition of severe 350 acute respiratory syndrome coronavirus by chloroquine Effects of chloroquine on 353 viral infections: An old drug against today's diseases? In Vitro Antiviral Activity and 356 Projection of Optimized Dosing Design of Hydroxychloroquine for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Chloroquine for 360 influenza prevention: a randomised, double-blind, placebo controlled trial Chloroquine interferes with dengue-2 virus replication in U937 cells Screening of an FDA-approved compound library identifies four 367 small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication 368 in cell culture Breakthrough: Chloroquine phosphate has shown apparent 398 efficacy in treatment of COVID-19 associated pneumonia in clinical studies A pilot study of hydroxychloroquine in treatment of 401 patients with common coronavirus disease-19 (COVID-19) Efficacy of hydroxychloroquine 404 in patients with COVID-19: results of a randomized clinical trial Hydroxychloroquine in 409 patients with mainly mild to moderate coronavirus disease 2019: open label, 410 randomised controlled trial Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results 414 from a multi-centre, randomized Early treatment of COVID-19 patients with hydroxychloroquine and 443 azithromycin: A retrospective analysis of 1061 cases in Marseille, France Observational Study 446 of Hydroxychloroquine in Hospitalized Patients with Covid-19 Clinical 449 efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require 450 oxygen: observational comparative study using routine care data Low dose of hydroxychloroquine 453 reduces fatality of critically ill patients with COVID-19 Effect 456 of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients 457 Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) 458 Infection: A Randomized Clinical Trial Improving the Efficacy of Chloroquine and Hydroxychloroquine Against 461 SARS-CoV-2 May Require Zinc Additives -A Better Synergy for Future The QT 464 interval in patients with COVID-19 treated with hydroxychloroquine and Report: Hepatotoxicity Associated with the Use of Hydroxychloroquine in a 468 Patient with Novel Coronavirus Disease (COVID-19) Urgent Guidance for 471 Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of 472 COVID-19) Chloroquine and 475 hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A 476 systematic search and a narrative review with a special reference to India and other 477 developing countries A proposed ABCD scoring system for patient's self assessment and at emergency J o u r n a l P r e -p r o o f *Six patients were excluded as they received Azithromycin in addition to Hydroxychloroquine J o u r n a l P r e -p r o o f We intend to publish an article entitled "No Benefit of Hydroxychloroquine in COVID-19: Results of Systematic Review and Meta-Analysis of Randomized Controlled Trials" in your esteemed journal.On behalf of all the contributors I will act and guarantor and will correspond with the journal from this point onward.