Hematologic Parameters Predict Benefit of Baricitinib in COVID-19 Hospitalizations

In a post hoc analysis of the Adaptive COVID-19 Treatment Trial-2 (ACTT-2), a risk profile based on simple hematologic parameters pinpointed the patients hospitalized with COVID-19 who derived the most significant benefits from baricitinib treatment.

Among a high-risk quartile in ACCT-2, characterized by a low absolute lymphocyte count (ALC), high absolute neutrophil count (ANC), and low platelet counts, baricitinib treatment led to significantly reduced mortality and invasive mechanical ventilation (IMV) or death.

“The 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,” wrote the investigative team, led by Rekha R. Rapaka, MD, PhD, a clinical assistant professor at the Center for Vaccine Development and Global Health in the University of Maryland School of Medicine.

Prior results from the ACTT-1 study revealed the antiviral remdesivir reduced the time to recovery compared with placebo for adults hospitalized with COVID-19. In ACCT-2, baricitinib plus remdesivir further reduced the time to recovery compared with remdesivir and placebo. Baricitinib a selective, orally administered Janus kinase (JAK) 1 and 2 inhibitor, inhibited the signaling pathways of inflammatory cytokines associated with severe disease.

The treatment effect of the combination agents was highest in those receiving high-flow oxygen or noninvasive ventilation, leading to government guidelines strongly recommending the regimen for those requiring oxygen support. However, Rapaka and colleagues suggested there may be more patient-specific characteristics, besides oxygen requirement, that may more precisely define the benefit of a particular COVID-19 therapeutic.

The ALC, ANC, and platelet counts at baseline were selected to develop a risk profile (ACTT risk profile) to predict the risk for progression to IMV or death. For this analysis, Rapaka and colleagues applied the ACTT risk profile to the ACTT-2 data set and explored the effect of bacricitinib by risk quartile.

ACTT-2 recruited adults hospitalized with COVID-19 from 67 sites in 8 countries. Ultimately, 999 ACTT-2 participants who received their assigned treatment, with no missing data for the ACTT risk profile, were analyzed. The analysis's primary outcome was the time to recovery, categorized as the time until discharge or the first day of hospitalization without medical care.

The treatment effect of baricitinib and remdesivir versus placebo and remdesivir was evaluated using ACTT-2 data for each quartile of ACTT risk profile. Outcomes consisted of mortality, progression to IMV or death, and recovery within 28 days. Trends in laboratory parameters in the ACTT risk profile, including ALC, ANC, and platelet count trajectories, were compared between treatment groups.

In the study population, the ALC, ANC, and platelet counts were similar between ACTT-1 and ACTT-2 participants overall and within each quartile. However, the higher-risk quartiles exhibited a greater representation of men and older participants.

Upon analysis, in the high-risk quartile, baricitinib and remdesivir were associated with significantly improved clinical outcomes within 28 days compared with placebo and remdesivir treatment. In the assessment, baricitinib and remdesivir treatment showed a reduced mortality risk (hazard ratio [HR], 0.38 [95% CI, 0.16 to 0.86]; P = .020), decreased progression to IMV or dearth (HR, 0.57 [95% CI, 0.35 to 0.93]; P = .024), and improved recovery rates (HR, 1.53 [95% CI, 1.16 to 2.02]; P = .002).

Rapaka and colleagues noted although the treatment effect estimates were not significant for the moderate-, lower-risk, or least-risk categories, the baricitinib treatment effect increased with increasing risk quartiles.

Further exploratory analyses of the change in hematologic parameters revealed those receiving baricitinib and remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC, particularly in the high-risk quartile, after 5 days.

“The data presented here suggest that hematologic parameters related to host immune status may help identify patients at risk for severe disease and also direct therapies to those who are most likely to benefit,” Rapaka and colleagues wrote.

References

1. _{Paules CI, Wang J, Tomashek KM, Bonnett T, Singh K, Marconi VC, Davey RT Jr, Lye DC, Dodd LE, Yang OO, Benson CA, Deye GA, Doernberg SB, Hynes NA, Grossberg R, Wolfe CR, Nayak SU, Short WR, Voell J, Potter GE, Rapaka RR. A Risk Profile Using Simple Hematologic Parameters to Assess Benefits From Baricitinib in Patients Hospitalized With COVID-19: A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-2. Ann Intern Med. 2024 Feb 27. doi: 10.7326/M23-2593. Epub ahead of print. PMID: 38408357.}