Antiviral Combination Treatment for COVID-19 in Immunocompromised Patients: Towards Defining Its Place in Therapy

Antiviral combinations have been successfully used to treat COVID-19 in immunocompromised patients, especially those with prolonged viral shedding or relapses. This study assessed outcomes of antiviral combination therapy, stratified by clinical indication. In this retrospective single-center study (October 2022-March 2024), patients receiving antiviral combinations were stratified according to treatment indication: prolonged/relapsed infection (group 1), severe COVID-19 (group 2), or early treatment of non-severe COVID-19 (group 3). Outcomes included virological clearance at day 14, and success rate at days 30 and 100. Seventy-one patients were included (group 1: 43; group 2 and 3: 14 each); 52% had non-Hodgkin lymphoma, 39.4% prior anti-CD20 therapy, 32% transplant/CAR-T. Most (92.6%) were vaccinated (median three doses). Treatment consisted of two antivirals in 59 patients (82%), mainly 10 days of both remdesivir and nirmatrelvir/ritonavir (n = 52, 73%), two antivirals plus single-dose tixagevimab/cilgavimab in 11 (15%), and three antivirals in 1. Virological clearance by day 14 was achieved in 79% (52/66 evaluable patients): 85% (34/40) in group 1, 58% (7/12) in group 2, 78.6% (11/14) in group 3. In group 1, predictors of day 14 clearance were prior vaccination and combination treatment with ≥ 10 days of oral antiviral. Success rates at days 30 and 100 were 80% (57/71) and 79% (56/71), respectively, with no significant differences between groups. Five patients required further treatment courses. COVID-19-related mortality was 12.5% (9/71). Three grade 2 adverse events occurred. Antiviral combination therapy was effective in prolonged/relapsed and severe COVID-19 while its role in early mild infections warrants further study. Stratifying patients by treatment indication facilitates outcome interpretation and comparisons.