Antiviral combination therapies for persistent COVID-19 in immunocompromised patients

After the third year of the COVID-19 pandemic, most of the severe COVID-19 burden falls upon immunocompromised patients who cannot mount endogenous immune response after both vaccination and/or natural infection. They also experience persistent SARS-CoV-2 infection with high viral loads often unsuccessfully managed by the standard antiviral monotherapy regimen initially validated for treatment of COVID-19 immunocompetent patients, only. The off-label prescription of such monotherapy regimens in immunocompromised patients is likely to drive the emergence of treatment-related immune escape, relapses, excess morbidity and mortality from both COVID-19 and delayed treatment of the underlying disorders. A possible treatment approach to mitigate such consequence is based on combined antiviral therapies. In this narrative review, we show that combinations of either small molecule antivirals or small molecule antiviral plus passive immunotherapies are safe and effective in small cohorts reported so far. Considering the progressive loss of efficacy of all authorized anti-Spike monoclonal antibodies, promising regimen options are reserved to combinations of small molecule antivirals and COVID-19 convalescent plasma from vaccinated donors.