Is early combination therapy associated with lower risk of respiratory failure in severely immunocompromised hosts with COVID-19? a target trial emulation study from the omicron-dominant era.

INTRODUCTION

COVID-19 is still a potentially serious infection in immunocompromised individuals, with a significant risk of respiratory failure; nevertheless, the optimal treatment strategy is uncertain. Herein, the impact of combination therapy versus monotherapy on risk of respiratory failure was evaluated.

METHODS

This study is a pragmatic target trial emulation performed on observational data collected between 01/01/2022 and 31/03/2024 in 4 tertiary-care hospitals.

PATIENTS: immunocompromised patients with mild/moderate COVID-19.

INTERVENTION: (arm A) monotherapy with antivirals (DAAs) or monoclonal antibodies (MoAbs) versus (arm B) combination therapy of MoAbs plus DAAs.

PRIMARY ENDPOINT: COVID-19-related acute respiratory failure on day 28 post-randomization. Secondary aims: adverse events to therapy, 90-day mortality, 90-day COVID-19 recurrence/complications, and duration of viral shedding.

RESULTS

Overall, 1,035 subjects were screened, and 303 immunocompromised patients were included; main immunodeficiencies were hematologic cancer (71%), exposure to anti-CD20 (36%), solid organ transplantation (15%) and solid cancer (13%). After enrollment, 189 and 114 received mono- or combination therapy, respectively. Of them, 99 patients (33%) met the primary outcome, with a lower incidence in combination therapy group (17% vs. 42%, p < 0.001). In the IPCW-adjusted population, use of combination therapy was associated with a 23.7% (95%CI = 12.4% - 35.1%) reduced risk of developing acute respiratory failure if compared with monotherapy. Results were confirmed at IPCW-adjusted Cox multivariable model: combination therapy was independently associated with a protective effect (aHR = 0.40, 95%CI = 0.22-0.70).

CONCLUSIONS

In immunocompromised patients with COVID-19, combination therapy appears associated with a lower risk of respiratory failure and may be preferred, when possible, over monotherapy.