Review of Current Evidence of Hydroxychloroquine in Pharmacotherapy of COVID-19
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Abstract
Importance
The COVID-19 Pandemic has literally left the world breathless in the chase for pharmacotherapy. With vaccine and novel drug development in early clinical trials, repurposing of existing drugs takes the center stage.
Objective
A potential drug discussed in global scientific community is hydroxychloroquine. We intend to systematically explore, analyze, rate the existing evidence of hydroxychloroquine in the light of published, unpublished and clinical trial data.
Evidence review
PubMed Ovid MEDLINE, EMBASE, Google scholar databases, pre-proof article repositories, clinical trial registries were comprehensively searched with focused question of use of hydroxychloroquine in COVID-19 patients. The literature was systematically explored as per PRISMA guidelines.
Findings
Total 156 articles were available as of 7 th May 2020; of which 11 articles of relevance were analyzed. Three in-vitro studies were reviewed. Two open label non-randomized trials, two open label randomized control trials, one large observational study, one follow-up study and two retrospective cohort studies were systematically analyzed and rated by oxford CEBM and GRADE framework for quality and strength of evidence. Also 27 clinical trials registered in three clinical trial registries were analyzed and summarized. Hydroxychloroquine seems to be efficient in inhibiting SARS-CoV-2 in in-vitro cell lines. However, there is lack of strong evidence from human studies. It was found that overall quality of available evidence ranges from ‘very low’ to ‘low’.
Conclusions and relevance
The in-vitro cell culture based data of viral inhibition does not suffice for the use of hydroxychloroquine in the patients with COVID-19. Current literature shows inadequate, low level evidence in human studies. Scarcity of safety and efficacy data warrants medical communities, health care agencies and governments across the world against the widespread use of hydroxychloroquine in COVID-19 prophylaxis and treatment, until robust evidence becomes available.
KEY POINTS
Question
What is the current evidence for use of Hydroxychloroquine in pharmacotherapy of COVID-19?
Findings
We electronically explored various databases and clinical trial registries and identified 11 publications and 27 clinical trials with active recruitment. The in-vitro study data demonstrates the viral inhibition by hydroxychloroquine. The clinical studies are weakly designed and conducted with insufficient reporting and significant limitations. Well designed robust clinical trials are being conducted all over the world and results of few such robust studies are expected shortly.
Meaning
Current evidence stands inadequate to support the use of hydroxychloroquine in pharmacotherapy of COVID-19.
Article activity feed
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SciScore for 10.1101/2020.04.16.20068205: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization Each database was further scanned and analyzed to remove the non-recruiting, inactive and cancelled trials, finally yielding 27 randomized control trials (RCTs) currently undergoing active recruitment for COVID-19 treatment with HCQ. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources PubMed Ovid MEDLINE, EMBASE, Google scholar databases were searched for existing literature from 2019 to 7th May 2020, 2020. PubMedsuggested: (PubMed, RRID:SCR_004846)EMBASEsuggested: (EMBASE, RRID:SCR_001650)Google scholarsuggested: (Google Scholar, RRID:SCR_008…SciScore for 10.1101/2020.04.16.20068205: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization Each database was further scanned and analyzed to remove the non-recruiting, inactive and cancelled trials, finally yielding 27 randomized control trials (RCTs) currently undergoing active recruitment for COVID-19 treatment with HCQ. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources PubMed Ovid MEDLINE, EMBASE, Google scholar databases were searched for existing literature from 2019 to 7th May 2020, 2020. PubMedsuggested: (PubMed, RRID:SCR_004846)EMBASEsuggested: (EMBASE, RRID:SCR_001650)Google scholarsuggested: (Google Scholar, RRID:SCR_008878)For preprint/pre-proof articles, repositories like BioRxiv, MedRxiv and ChemRxiv were searched. BioRxivsuggested: (bioRxiv, RRID:SCR_003933)Literature search: Search words included MeSH Terms (hydroxychloroquine OR HCQ) AND MeSHsuggested: (MeSH, RRID:SCR_004750)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This study had major limitations in the form of small sample size, absence of randomization and masking, lack of intention to treat analysis and long term follow up, there was no clinical endpoint as outcome measure. A follow up study by Gautret et al in 80 COVID-19 patients reported 97.5% of respiratory samples were negative for virus cultures at Day 5. This study too involved only mild illness patients and did not report adverse effect profile and being an uncontrolled observational study, the strength of evidence tends to be low.26 A latest large American observational study in 1376 patients reported no association between hydroxychloroquine administration and intubation/death in moderate to severe COVID-19 patients. This study had limitations of single center observational design, confounding bias and possibility of missing data events.27 We assessed the methodological quality and certainty of evidence of both published and unpublished clinical studies in existing literature and found that overall quality of available evidence ranges from ‘very low’ to ‘low’; the Oxford CEBM rating used showed the quality of studies to be mostly at 3b level and couple studies at 2b level. (Table 4) We also searched, identified and analyzed clinical trial databases to explore the ongoing active clinical trials (Supplementary Table 1) and found out relevant 27 clinical trials. Few trials among these are in advanced phases. Earlier registered Chinese clinical trials are expected to report th...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04342221 Recruiting Hydroxychloroquine for COVID-19 NCT04333654 Terminated Hydroxychloroquine in Outpatient Adults With COVID-19 NCT04332991 Completed Outcomes Related to COVID-19 Treated With Hydroxychloroquine… NCT04331834 Completed Pre-Exposure Prophylaxis With Hydroxychloroquine for High-Ri… NCT04331834 Completed Pre-Exposure Prophylaxis With Hydroxychloroquine for High-Ri… NCT04341727 Suspended Hydroxychloroquine,Hydroxychloroquine,Azithromycin in the Tr… NCT04341207 Recruiting Epidemiology of SARS-CoV-2 and Mortality to Covid19 Disease … NCT04334382 Recruiting Hydroxychloroquine vs. Azithromycin for Outpatients in Utah … NCT04316377 Active, not recruiting Norwegian Coronavirus Disease 2019 Study NCT04316377 Active, not recruiting Norwegian Coronavirus Disease 2019 Study NCT04341493 Recruiting Hydroxychloroquine vs Nitazoxanide in Patients With COVID-19 NCT04341493 Recruiting Hydroxychloroquine vs Nitazoxanide in Patients With COVID-19 NCT04328012 Recruiting COVID MED Trial - Comparison Of Therapeutics for Hospitalize… NCT04328467 Active, not recruiting Pre-exposure Prophylaxis for SARS-Coronavirus-2 NCT04334928 Recruiting Randomized Clinical Trial for the Prevention of SARS-CoV-2 I… NCT04332094 Recruiting Clinical Trial of Combined Use of Hydroxychloroquine, Azithr… NCT04325893 Terminated Hydroxychloroquine Versus Placebo in COVID-19 Patients at Ri… NCT04307693 Terminated Comparison of Lopinavir/Ritonavir or Hydroxychloroquine in P… NCT04307693 Terminated Comparison of Lopinavir/Ritonavir or Hydroxychloroquine in P… NCT04322396 Completed Proactive Protection With Azithromycin and hydroxyChloroquin… NCT04322123 Active, not recruiting Safety and Efficacy of Hydroxychloroquine Associated With Az… NCT04321278 Completed Safety and Efficacy of Hydroxychloroquine Associated With Az… NCT04315948 Active, not recruiting Trial of Treatments for COVID-19 in Hospitalized Adults NCT04315948 Active, not recruiting Trial of Treatments for COVID-19 in Hospitalized Adults Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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