Hydroxychloroquine/Chloroquine in COVID-19 With Focus on Hospitalized Patients – A Systematic Review

  1. Daniel Freilich
  2. Jennifer Victory
  3. Anne Gadomski

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Abstract

Background

In the beginning of the COVID-19 pandemic, many hospitalized patients received empiric hydroxychloroquine/chloroquine (HC/CQ). Although some retrospective-observational trials suggested potential benefit, all subsequent randomized clinical trials (RCTs) failed to show benefit and use generally ceased. Herein, we summarize key studies that clinicians advising patients on HC/CQ’s efficacy:safety calculus in hospitalized COVID-19 patients would want to know about in a practical one-stop-shopping source.

Methods

Pubmed and Google were searched on November 4, 2021. Search words included: COVID-19, hydroxychloroquine, chloroquine, in vitro , animal studies, clinical trials, and meta-analyses. Studies were assessed for import and included if considered impactful for benefit:risk assessment.

Results

These searches led to inclusion of 12 in vitro and animal reports; 12 retrospective-observational trials, 19 interventional clinical trials (17 RCTs, 1 single-arm, 1 controlled but unblinded), and 51 meta-analyses in hospitalized patients.

Inconsistent efficacy was seen in vitro and in animal studies for coronaviruses and nil in SARS-CoV-2 animal models specifically. Most retrospective-observational studies in hospitalized COVID-19 patients found no efficacy; QT prolongation and increased adverse events and mortality were reported in some. All RCTs and almost all meta-analyses provided robust data showing no benefit in overall populations and subgroups, yet concerning safety issues in many.

Conclusions

HC/CQ have inconsistent anti-coronavirus efficacy in vitro and in animal models, and no convincing efficacy yet substantial safety issues in the overwhelming majority of retrospective-observational trials, RCTs, and meta-analyses in hospitalized COVID-19 patients. HC/CQ should not be prescribed for hospitalized COVID-19 patients outside of clinical trials.

Key Summary Points

Preclinical hydroxychloroquine/chloroquine in vitro studies found inconsistent activity against coronaviruses including SARS-CoV-2.

Preclinical hydroxychloroquine/chloroquine animals studies found inconsistent efficacy for coronaviruses in general and none for SARS-CoV-2.

The overhwelming majority of RCTs and retrospective-observational trials found no benefit for hydroxychloroquine/chloroquine in hospitalized COVID-19 patients, and many found concerning safety signals.

The majority of RCTs and retrospective-observational trials found no benefit for hydroxychloroquine/chloroquine in COVID-19 outpatients or for pre- or post-exposure prophylaxis, and some found concerning safety signals.

The overwhelming majority of meta-analyses found no benefit for hydroxychloroquine/chloroquine in COVID-19 inpatients, outpatients, or for prophylaxis, and many found concerning safety signals.

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  1. ScreenIT

    SciScore for 10.1101/2022.01.11.22269069: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Pubmed and Google searches were conducted, with the latest repeated November 4, 2021.
    Pubmed
    suggested: (PubMed, RRID:SCR_004846)
    Adding key words, “animal studies”, resulted in 89 publications of which only 4 were in fact animal studies and thus included in our preclinical summary; no additional studies were found with the Google or other Pubmed searches.
    Google
    suggested: (Google, RRID:SCR_017097)

    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:
    Limitations included absence of placebo control and published mitigation strategies to reduce QTc prolongation (e.g., excluding baseline QTc prolongation and co-administration of additional QTc prolonging medications [100% received azithromycin]), single-center design, small sample size, and baseline imbalance. Prolonged QTc was also reported in two additional retrospective case series of hospitalized COVID-19 patients treated with HC with or without azithromycin. In the small French series of 40 patients, baseline QTc>460 msec was an exclusion. 93% developed some QTc prolongation; 36% developed more severe QTc prolongation (more commonly with concomitant azithromycin [33% vs. 5%, p=0.03]). No ventricular arrhythmias including torsades de pointes occurred. Seven patients (17.5%) stopped medication due to adverse events, ECG changes, or acute renal failure [15]. In the Boston series in 90 patients, combined therapy was associated with a larger median increase in the QT interval than HC monotherapy (23 vs. 5.5 msec, p=0.03), resulting in 13% vs. 3% of patients, respectively, having QTc change >/= 60 msec. The risk of QTc prolongation to >/=500 msec was similar (21% vs. 19%). The authors implied a baseline QTc prolongation exclusion. Ten patients (11%) discontinued medication because of adverse events (nausea, hypoglycemia, and one case of delayed torsades de pointes) [16]. None of these series had control arms, so the relative risk of QTc prolongation remained elusive. Yet, it ...

    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.

    Results from scite Reference Check: We found no unreliable references.

    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.

  2. Version published to 10.1101/2022.01.11.22269069v1 on medRxiv