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Remdesivir modifies interferon response in hospitalized COVID-19 patients

  • Sarah L. Murphy
    Affiliations
    Institute of Clinical Medicine, University of Oslo, Oslo 0318, Norway

    Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway
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  • Bente Halvorsen
    Affiliations
    Institute of Clinical Medicine, University of Oslo, Oslo 0318, Norway

    Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway
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  • Andreas Barratt-Due
    Affiliations
    Division of Critical Care and Emergencies, Oslo University Hospital, Oslo, Norway

    Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway
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  • Anne Ma Dyrhol-Riise
    Affiliations
    Institute of Clinical Medicine, University of Oslo, Oslo 0318, Norway

    Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway
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  • Pål Aukrust
    Affiliations
    Institute of Clinical Medicine, University of Oslo, Oslo 0318, Norway

    Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway

    Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
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  • Marius Trøseid
    Affiliations
    Institute of Clinical Medicine, University of Oslo, Oslo 0318, Norway

    Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway

    Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
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  • Author Footnotes
    1 Present address: Research Institute for Internal Medicine, Sognsvanssveien 20, 0037 Oslo, Norway.
    Tuva B. Dahl
    Correspondence
    Corresponding author at: Institute of Clinical Medicine, University of Oslo, Oslo 0318, Norway.
    Footnotes
    1 Present address: Research Institute for Internal Medicine, Sognsvanssveien 20, 0037 Oslo, Norway.
    Affiliations
    Institute of Clinical Medicine, University of Oslo, Oslo 0318, Norway

    Division of Critical Care and Emergencies, Oslo University Hospital, Oslo, Norway
    Search for articles by this author
  • Author Footnotes
    1 Present address: Research Institute for Internal Medicine, Sognsvanssveien 20, 0037 Oslo, Norway.

      Highlights

      • Remdesivir downregulates interferon responses in hospitalized COVID-19 patients.
      • Treatment had a particularly strong effect on interferon γ.
      • This response could be beneficial in mild, but not in severe disease.
      • Treatment options in COVID-19 could differ according to disease severity.
      Dear Editor,
      We have read with great interest the article by Lucijanic et al. that was recently published in Journal of Infection.
      • Lucijanic M.
      • Cikara T.
      • Bistrovic P.
      • et al.
      Remdesivir use in COVID-19 patients might predispose bacteremia, matched case-control analysis.
      In a retrospective matched case-control analysis they showed an increased occurrence of bacteremia in patients treated with remdesivir and, notably, they found no clinical benefit of remdesivir in patients with bacteremia. In fact, whereas the use of certain immunomodulating drugs has been documented to be beneficial in patients with severe COVID-19 disease,
      • van de Veerdonk F.L.
      • Giamarellos-Bourboulis E.
      • Pickkers P.
      • et al.
      A guide to immunotherapy for COVID-19.
      the clinical effect of anti-viral therapy is still debated.
      • Vegivinti C.T.R.
      • Evanson K.W.
      • Lyons H.
      • et al.
      Efficacy of antiviral therapies for COVID-19: a systematic review of randomized controlled trials.
      Thus, in the recently published final report from the WHO Solidarity trial, the meta-analysis of the published literature confirms a modest survival effect of remdesivir in non-ventilated patients, but also a potential harm in ventilated patients.

      Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet 2022 doi:10.1016/s0140-6736(22)00519-0 [published Online First: 2022/05/06].

      Previous published trials that evaluated SARS-CoV-2 virus clearance did not find any effect of remdesivir,
      • Barratt-Due A.
      • Olsen I.C.
      • Nezvalova-Henriksen K.
      • et al.
      Evaluation of the effects of remdesivir and hydroxychloroquine on viral clearance in COVID-19 : a randomized trial.
      • Ader F.
      • Bouscambert-Duchamp M.
      • Hites M.
      • et al.
      Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial.
      • Gottlieb R.L.
      • Vaca C.E.
      • Paredes R.
      • et al.
      Early remdesivir to prevent progression to severe COVID-19 in outpatients.
      despite clinical benefit when given in early disease.
      • Gottlieb R.L.
      • Vaca C.E.
      • Paredes R.
      • et al.
      Early remdesivir to prevent progression to severe COVID-19 in outpatients.
      The background for these seemingly conflicting effects is not clarified, although treatment initiation at the tail of the viral phase in hospitalized patients with critical disease could partly explain the lack of clinical effect in this patient group. An alternative explanation could be disparate interacting effects of remdesivir and host immunity in different stages of the disease, representing off-target effects of remdesivir.
      To elucidate any potential immunomodulating effects of remdesivir, in the present study we performed transcriptome analyses of peripheral blood mononuclear cells (PBMC) in 15 hospitalized COVID-19 patients (mean age±SD: 60,9 ± 13 years, 8 males [53%]) that were included In the NOR Solidarity trial,
      • Barratt-Due A.
      • Olsen I.C.
      • Nezvalova-Henriksen K.
      • et al.
      Evaluation of the effects of remdesivir and hydroxychloroquine on viral clearance in COVID-19 : a randomized trial.
      an independent sub-study of the WHO Solidarity trial.

      Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. Lancet 2022 doi:10.1016/s0140-6736(22)00519-0 [published Online First: 2022/05/06].

      Seven patients received standard of care (SoC) and eight patients received SoC +200 mg of intravenously remdesivir on day 1, then 100 mg daily up to 9 days. Three days after inclusion, peripheral blood was collected in BD CPT™ Cell Preparation Tube containing sodium heparin (BD, Franklin Lakes, New Jersey, USA) and PBMC were isolated according to the manufacturer´s instructions. Total RNA was isolated from PBMC with miRNeasy Kit (Qiagen, Hilden, Germany). Novogene (UK) Company Limited performed the stranded library preparation and sequencing on the Illumina platform. Differentially expressed genes were obtained using the DESeq2 R package. The study was approved by the Committee for Medical Research Ethics Region South East Norway (REK no. 118,684) and registered on ClinicalTrials.gov March 25th 2020 (NCT04321616). All participants gave informed consent prior to inclusion, either directly or through a legally authorized representative.
      Functional enrichment analysis of isolated PBMC transcriptomes revealed alteration of hallmark gene sets related to interferon (INF)γ response in patients randomized to remdesivir compared to SoC (Fig. 1A). To determine the association of genes involved in “Hallmark interferon gamma response” pathway between the two treatment arms we ran a gene set enrichment analysis (GSEA). Of note, this pathway was dampened in immune cells from the remdesivir-treated patients compared to SoC treated patients (Fig. 1B) and differential expression analysis revealed that six of the 13 differentially regulated genes (padj<0.05) were IFN-regulated genes (Fig. 1C).
      Fig 1
      Fig. 1RNA-seq and hallmark gene set enrichment analysis of RNA isolated from peripheral mononuclear cells reveals alterations of “interferon gamma response” in patients randomized to remdesivir (REM, n = 8) compared to standard of care (SOC, n = 7) (A), with dampened enrichment of this pathway in patients receiving remdesivir (B), and differential expression analysis of interferon-stimulated genes between the two treatment arms (C).
      Although it has been speculated that remdesivir metabolites that are adenosine analogues may alter innate and specific immunity in the same fashion as adenosine does,
      • Lucijanic M.
      • Cikara T.
      • Bistrovic P.
      • et al.
      Remdesivir use in COVID-19 patients might predispose bacteremia, matched case-control analysis.
      ,
      • Antonioli L.
      • Pacher P.
      • Vizi E.S.
      • et al.
      CD39 and CD73 in immunity and inflammation.
      the mechanisms for the potential immune modulating effects of remdesivir is at present not clear. Whatever mechanisms, our results suggest an impaired INFγ response by remdesivir treatment that could have different clinical implications depending on the disease stage. In early and moderate disease (i.e., non-hospitalized and moderate disease in hospitalized patients), an impaired INFγ response could prevent an overshooting immune response and potentially explain the clinical benefit by preventing hospitalization and death despite lack of viral clearance in nasopharyngeal samples.
      • Gottlieb R.L.
      • Vaca C.E.
      • Paredes R.
      • et al.
      Early remdesivir to prevent progression to severe COVID-19 in outpatients.
      In more advanced disease, such effects could be potentially harmful, including lack of disease control in patients with prolonged immune exhaustion and reduced capacity for adaptive immune response.
      • Remy K.E.
      • Mazer M.
      • Striker D.A.
      • et al.
      Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections.
      Remdesivir has not yet been recommended in WHO treatment guidelines despite regulatory approval by EMA and FDA. Targeting the right patient population is critical in treatment algorithms, and our results suggest that off-target effects interacting with host immunity could be of relevance for the seemingly disparate clinical effects of remdesivir in different stages of COVID-19.

      Funding

      This work was supported by The National Program of Clinical Therapy Research in the Specialist Health Services, Norway (Grant no. 2020201), Norway; South-Eastern Norway Regional Health Authority (grant number 2021071). The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

      Declaration of Competing Interest

      None to report.

      Acknowledgement

      We would like to thank the Nor Solidarity study group that contributed to patient recruitment.

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