High rate of major drug–drug interactions of lopinavir–ritonavir for COVID-19 treatment

  1. Juan Macías
  2. Ana Pinilla
  3. Francisco A. Lao-Dominguez
  4. Anaïs Corma
  5. Enrique Contreras-Macias
  6. Alejandro González-Serna
  7. Antonio Gutierrez-Pizarraya
  8. Marta Fernández-Fuertes
  9. Ramón Morillo-Verdugo
  10. Marta Trigo
  11. Luis M. Real
  12. Juan A. Pineda

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Abstract

The impact of drug–drug interactions (DDI) between ritonavir-boosted lopinavir (LPV-r) to treat patients with coronavirus disease 2019 (COVID-19) and commonly used drugs in clinical practice is not well-known. Thus, we evaluated the rate and severity of DDI between LPV-r for COVID-19 treatment and concomitant medications. This was a cross-sectional study including all individuals diagnosed of SARS-CoV-2 infection treated with LPV-r and attended at a single center in Southern Spain (March 1st to April 30th, 2020). The frequency [95% confidence interval (95% CI)] of potential and major DDI were calculated. Overall, 469 patients were diagnosed of COVID-19, 125 (27%) of them were prescribed LPV-r. LPV-r had potential DDI with concomitant medications in 97 (78%, 95% CI 69–85%) patients, and in 33 (26%, 95% CI 19–35%) individuals showed major DDI. Twelve (36%) patients with major DDI and 14 (15%) individuals without major DDI died (p = 0.010). After adjustment, only the Charlson index was independently associated with death [adjusted OR (95% CI) for Charlson index ≥ 5: 85 (10–731), p < 0.001]. LPV-r was discontinued due to side effects in 31 (25%) patients. Management by the Infectious Diseases Unit was associated with a lower likelihood of major DDI [adjusted odds ratio (95% CI): 0.14 (0.04–0.53), p = 0.003). In conclusion, a high frequency of DDI between LPV-r for treating COVID-19 and concomitant medications was found, including major DDI. Patients with major DDI showed worse outcomes, but this association was explained by the older age and comorbidities. Patients managed by the Infectious Diseases Unit had lower risk of major DDI.

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  1. ScreenIT

    SciScore for 10.1101/2020.07.30.20165027: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Ethics issues: The study was designed and performed according to the Helsinki declaration and approved by the Ethics Committee of the Valme University Hospital (Seville, Spain).
    Consent: Informed consent was waived by the Ethics Committee of the Valme University Hospital due to the observational retrospective design of the study.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The STATA 16.0 and IBM SPSS 25 packages were used for the analysis.
    STATA
    suggested: (Stata, RRID:SCR_012763)
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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:
    The present study may have some limitations. First, due to LPV-r supply shortage, this antiviral drug was restricted mostly to more severe patients, those requiring hospitalization. This population represents an extreme of the pandemic, with more complications needing medical intervention and worse outcomes. LPV-r given to younger and less fragile patients might have been more tolerable, with less DDI and discontinuations. Second, post-discharge deaths at home or nursing facilities were not evaluated, only deaths during admissions or at the emergency room were evaluable for the present study. Death rates could have been even higher than those reported herein with a follow-up after discharge, as suggested by another study 17. Third, the main source of data was the electronic clinical records and the Pharmacy electronic prescriptions. This might have precluded detailed medical record review and it could have led to data loss. However, currently in the Andalusian Health System, health and medical records of every patient are collected in a common electronic database by all caring physicians and nurses. Medications are also prescribed using electronic prescriptions both for outpatients and inpatients. In this regard, individual patient electronic medical records were manually evaluated. These are strengths of the present study. In conclusion, LPV-r for hospitalized patients with COVID-19 frequently interacts with concomitant medications. Major DDI contraindicating the coadministr...

    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

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  2. Version published to 10.1038/s41598-020-78029-3
  3. Version published to 10.1101/2020.07.30.20165027v1 on medRxiv