Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Nov;14(11):2521-2533.
doi: 10.1007/s40121-025-01231-1. Epub 2025 Sep 15.

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

Chiara Sepulcri  1 , Claudia Bartalucci  1 , Elisa Balletto  2 , Chiara Dentone  2 , Federica Magné  2 , Michele Mirabella  2 , Silvia Dettori  2 , Martina Bavastro  1   2 , Carmen Di Grazia  3 , Anna Maria Raiola  3 , Massimiliano Gambella  3 , Valentina Ricucci  4 , Bianca Bruzzone  4 , Sabrina Beltramini  5 , Emanuele Angelucci  3 , Matteo Bassetti  1   2 , Malgorzata Mikulska  6   7
Affiliations

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

Chiara Sepulcri et al. Infect Dis Ther. 2025 Nov.

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Anti-SARS-CoV-2 monoclonal antibodies; Hematologic malignancy; Molnupiravir; Nirmatrelvir; Remdesivir.

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflicts of Interest: Outside of the submitted work, Chiara Dentone received personal fees for advisor/consultant and/or speaker/ chairman from Angelini, Novartis, Gilead, ViiV, MSD, Shinogi, MSD and AstraZeneca. Outside of the submitted work, Matteo Bassetti received funding for scientific advisory boards, travel, and speaker honoraria from Cidara, Gilead, Menarini, MSD, Mundipharma, Pfizer, Shionogi. Outside of the submitted work, Malgorzata Mikulska received grant from Gilead paid to the Institution, and speaker/advisor fees from Allovir, AstraZeneca, BioMérieux, Gilead, Janssen, Moderna, Mundipharma, Pfizer, and Shionogi. Chiara Sepulcri, Claudia Bartalucci, Elisa Balletto, Federica Magné, Michele Mirabella, Silvia Dettori, Martina Bavastro, Carmen Di Grazia, Anna Maria Raiola, Massimiliano Gambella, Valentina Ricucci, Bianca Bruzzone, Sabrina Beltramini, Emanuele Angelucci have no conflicts of interest to disclose. Matteo Bassetti and Malgorzata Mikulska are Editorial Board members of Infectious Diseases and Therapy. Matteo Bassetti and Malgorzata Mikulska were not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethical Approval: The study was conducted in accordance with the current version of the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice (ICH-GCP), and national legislation for data protection. The protocol was approved by the hospital’s Committee for Evaluation of Off-label Treatment Studies. All patients signed a dedicated informed consent form for treatment and for data collection, including specifically for research purposes and publications.

References

    1. Blennow O, Salmanton-García J, Nowak P, Itri F, Van Doesum J, López-García A, et al. Outcome of infection with omicron SARS-CoV-2 variant in patients with hematological malignancies: An EPICOVIDEHA survey report. Am J Hematol. 2022;97(8):E312–7. - PMC - PubMed
    1. Raglow Z, Surie D, Chappell JD, Zhu Y, Martin ET, Kwon JH, et al. SARS-CoV-2 shedding and evolution in patients who were immunocompromised during the omicron period: a multicentre, prospective analysis. Lancet Microbe. 2024;5(3):e235–46. - PMC - PubMed
    1. Sanchez E, Krantz EM, Yoke L, Gallaher M, Bhattacharyya P, So L, et al. Clinical outcomes and frequency of persistent infection among immunosuppressed patients treated with bebtelovimab for COVID-19 infection at an ambulatory cancer center. Transpl Infect Dis. 2024;26(1):e14223. - PMC - PubMed
    1. Belkin A, Leibowitz A, Shargian L, Yahav D. The unique presentation of SARS-CoV-2 infection in patients with B-cell depletion: definition of ‘persistent inflammatory sero-negative COVID.’ Clin Microbiol Infect. 2022;29(1):1–3. - PMC - PubMed
    1. Meijer SE, Paran Y, Belkin A, Ben-Ami R, Maor Y, Nesher L, et al. Persistent COVID-19 in immunocompromised patients—Israeli Society of Infectious Diseases consensus statement on diagnosis and management. Clin Microbiol Infect. 2024;30(8):1012–7. - PubMed

LinkOut - more resources