• Catharine I Paules, Jing Wang, Kay M Tomashek, Tyler Bonnett, Kanal Singh, Vincent C Marconi, Richard T Davey, David C Lye, Lori E Dodd, Otto O Yang, Constance A Benson, Gregory A Deye, Sarah B Doernberg, Noreen A Hynes, Robert Grossberg, Cameron R Wolfe, Seema U Nayak, William R Short, Jocelyn Voell, Gail E Potter, and Rekha R Rapaka.
• Division of Infectious Diseases, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania (C.I.P.).
• Ann. Intern. Med. 2024 Mar 1; 177 (3): 343352343-352.

BackgroundThe ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low absolute lymphocyte count [ALC], high absolute neutrophil count [ANC], and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib.ObjectiveTo apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile.DesignPost hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579).SettingSixty-seven trial sites in 8 countries.ParticipantsAdults hospitalized with COVID-19 (n = 999; 85% U.S. participants).InterventionBaricitinib+remdesivir versus placebo+remdesivir.MeasurementsMortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories.ResultsIn the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio [HR], 0.38 [95% CI, 0.16 to 0.86]; P = 0.020), decreased progression to IMV or death (HR, 0.57 [CI, 0.35 to 0.93]; P = 0.024), and improved recovery rate (HR, 1.53 [CI, 1.16 to 2.02]; P = 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile.LimitationSecondary analysis of data collected before circulation of current SARS-CoV-2 variants.ConclusionThe ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19.Primary Funding SourceNational Institute of Allergy and Infectious Diseases.

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