Systematic review and meta-analysis of the effectiveness and safety of hydroxychloroquine in treating COVID-19 patients

  1. Tzu-Han Yang
  2. Chian-Ying Chou
  3. Yi-Fan Yang
  4. Chian-Shiu Chien
  5. Aliaksandr A. Yarmishyn
  6. Tzu-Ying Yang
  7. Cheng-Hsuan Liu
  8. Kao-Jung Chang
  9. Yi-Ping Yang
  10. Yuh-Lih Chang

Reviewed by

Read the full article See related articles

Discuss this preprint

Start a discussion What are Sciety discussions?

Listed in

Log in to save this article

Abstract

Since COVID-19 outbreak, hydroxychloroquine (HCQ) has been tested for effective therapies, and the relevant researches have shown controversial results.

Methods:

Systematic review and meta-analysis were conducted after a thorough search of relevant studies from databases. Trials that have evaluated HCQ for COVID-19 treatment were recruited for statistical analysis with fixed- and random-effect models.

Results:

Nine trials involving 4112 patients were included in present meta-analysis. It was seen that HCQ-azithromycin (HCQ-AZI) combination regimen increased the mortality rate in COVID-19 (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.63–3.36) patients; however, it also showed benefits associated with the viral clearance in patients (OR, 27.18; 95% CI, 1.29–574.32). HCQ-alone when used as a therapy in COVID-19 did not reveal significant changes in mortality rate, clinical progression, viral clearance, and cardiac QT prolongation. Subsequent subgroup analysis showed that HCQ treatment could decrease mortality rate and progression to severe illness in severely infected COVID-19 patients (OR, 0.27; 95% CI, 0.13–0.58). A lower risk of mortality rate was also noted in the stratified group of >14 days follow-up period (OR, 0.27; 95% CI, 0.13–0.58) compared to ≤14 days follow-up period group that conversely showed an increased mortality rate (OR, 2.09; 95% CI, 1.41–3.10).

Conclusion:

Our results indicated that HCQ-AZI combination treatment increased mortality rate in patients with COVID-19, but it also showed benefits associated with viral clearance in patients. HCQ-alone used for treatment has revealed benefits in decreasing the mortality rate among severely infected COVID-19 group and showed potential to be used for COVID-19 treatment in long-term follow-up period group. Accordingly, more rigorous, large-scale, and long follow-up period studies in patients with COVID-19 are needed.

Article activity feed

  1. Version published to 10.1097/jcma.0000000000000425
  2. ScreenIT

    SciScore for 10.1101/2020.05.07.20093831: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power AnalysisThis scale consists of 27 items which assesses different study characteristics such as internal validity, statistical power and external validity.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data search: We systematically searched the MEDLINE, medRxiv, PubMed, China Academic Journals Full-text Database, Cochrane database and Web of Science database up till April 27, 2020, with no language restrictions taken into consideration.
    MEDLINE
    suggested: (MEDLINE, RRID:SCR_002185)
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    Cochrane
    suggested: (Cochrane Library, RRID:SCR_013000)
    Meta-analysis was undertaken by using Cochrane Collaboration Review Manager (RevMan) software version 5.3.
    Cochrane Collaboration Review Manager
    suggested: None
    RevMan
    suggested: (RevMan, RRID:SCR_003581)

    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:
    Despite the pertinent information demonstrated above, our systematic review has its own limitations. As far as the lack of compiling sufficient data with regard to virological cure as efficacy outcome is concerned, we tried to solve this problem by conducting a search for unpublished literature and non-English journals to increase the quantity of relevant integrated literature. Most studies which are published are mainly observational studies and case series with substantial methodology concerns such as no framework of exclusion criteria, and therefore susceptible to bias and confounding. Therefore, as there are limited related RCTs in the literature at present, only those were included in our study. In the lack of experimental random allocation to the intervention, the effects of the HCQ might be overestimated. Furthermore, the two single-center RCTs which were conducted in China had some limitations as it included small sample size, did not conduct an international trial, and only limited data was available regarding the viral load. In our present study, bias might be present since little information was provided on demographic data, comorbidity, severity of disease, and the adverse effects of HCQ or AZI such as QT prolongation. In addition, we have not performed a dose–response meta-analysis, due to the lack of original data. Finally, the limited number of available studies which were included, made it unworkable to evaluate the true effect of HCQ. Therefore, the present r...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.05.07.20093831 on medRxiv