Disulfiram use is associated with lower risk of COVID-19: A retrospective cohort study

  1. Nathanael Fillmore
  2. Steven Bell
  3. Ciyue Shen
  4. Vinh Nguyen
  5. Jennifer La
  6. Maureen Dubreuil
  7. Judith Strymish
  8. Mary Brophy
  9. Gautam Mehta
  10. Hao Wu
  11. Judy Lieberman
  12. Nhan Do
  13. Chris Sander

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Abstract

Effective, low-cost therapeutics are needed to prevent and treat COVID-19. Severe COVID-19 disease is linked to excessive inflammation. Disulfiram is an approved oral drug used to treat alcohol use disorder that is a potent anti-inflammatory agent and an inhibitor of the viral proteases. We investigated the potential effects of disulfiram on SARS-CoV-2 infection and disease severity in an observational study using a large database of clinical records from the national US Veterans Affairs healthcare system. A multivariable Cox regression adjusted for demographic information and diagnosis of alcohol use disorder revealed a reduced risk of SARS-CoV-2 infection with disulfiram use at a hazard ratio of 0.66 (34% lower risk, 95% confidence interval 24–43%). There were no COVID-19 related deaths among the 188 SARS-CoV-2 positive patients treated with disulfiram, in contrast to 5–6 statistically expected deaths based on the untreated population (P = 0.03). Our epidemiological results suggest that disulfiram may contribute to the reduced incidence and severity of COVID-19. These results support carefully planned clinical trials to assess the potential therapeutic effects of disulfiram in COVID-19.

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  1. Version published to 10.1371/journal.pone.0259061
  2. ScreenIT

    SciScore for 10.1101/2021.03.10.21253331: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Institutional Review Board: This study was approved by the institutional review board at VA Boston Healthcare System (IRB3328)
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableWithin this cohort, we identified 2,233 Veterans (median age 51 years [IQR 39, 61], 8.4% female) with at least one pharmacy record for disulfiram between February 20, 2019 and February 1, 2021, and 941,894 Veterans (median age 64 years [IQR 51, 72], 11.6% female) not prescribed disulfiram between those dates.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Analyses were conducted using R v4.0.2 (http://www.r-project.org) and p-values < 0.05 were considered statistically significant.
    http://www.r-project.org
    suggested: (R Project for Statistical Computing, RRID:SCR_001905)

    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 of the study: The principal limitation of our study, as is true even for studies with controlled cohorts, is that association does not prove causation and that even very likely causation does not guarantee the success of the corresponding therapeutic intervention. There are several additional limitations. Since Veterans can receive care outside of the VA, diagnoses and outcomes may be incompletely recorded; and, we do not know if patients actually took the prescribed disulfiram. We also cannot rule out the possibility of confounding by indication: that those prescribed disulfiram had other factors, such as behavioral differences that contributed to the protection against COVID-19 beyond the effect of the medication. The potential of clinical trials of disulfiram in COVID-19: Our results reinforce the results from candidate drug screens and in-depth molecular and physiological evidence in supporting the notion that disulfiram may be efficacious in combating COVID-19. Additional information is expected from two small ongoing Phase II clinical trials of disulfiram involving early mild-to-moderate symptomatic (NCT04485130, 60 participants) or hospitalized (NCT04594343, 200 participants) COVID-19 patients. Reduction in disease progression in the first trial, if observed, might be due to inhibition of viral replication. This hypothesis is based on clear evidence from biochemical experiments that disulfiram inhibits several enzymes involved in viral replication (Mpro, PL...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04485130Not yet recruitingDISulfiram for COvid-19 (DISCO) Trial
    NCT04594343RecruitingClinical Study to Evaluate the Effects of Disulfiram in Pati…

    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 10.1101/2021.03.10.21253331v1 on medRxiv