Immunocompromised patients with persistent SARS-CoV-2 viral shedding ≥8 weeks, clinical outcomes, and virological dynamics: a retrospective multicenter cohort study, 2020–2024

Immunocompromised patients (ICPs) infected with SARS-CoV-2 are at higher risk of severe illness. Some experience persistent viral shedding beyond eight weeks, which is associated with increased mortality and invasive fungal infections. However, data on the clinical profile, treatment impact, and standardized management for these patients remain limited. We conducted a retrospective cohort study at Groupe Hospitalier Paris Centre between March 1, 2020, and February 10, 2024. We assessed symptomatic ICPs with persistent SARS-CoV-2 shedding (>8 weeks), analyzing clinical progression, time to viral clearance, and emergence of resistance mutations in relation to treatment regimens. Fifty-three patients were included: 53% were solid organ transplant (SOT) recipients, 42% had hematological malignancies (HMs), and 5% had other immunosuppressive conditions. Severe infections occurred in 32%, 91% required hospitalization, and 17% (<i>n</i> = 9) presented invasive mold infections. SOT recipients achieved clinical cure faster than HM patients (<i>P</i> < 0.01). Patients treated with direct antivirals showed significantly faster viral clearance (<i>P</i> = 0.03) than those treated with monoclonal antibodies (mAbs) or convalescent plasma. No resistance mutations emerged against remdesivir or nirmatrelvir/ritonavir. However, 54% of viral strains showed initial or acquired spike protein resistance to mAbs. Direct antiviral therapies, particularly remdesivir and nirmatrelvir/ritonavir, appear safe and effective in promoting faster viral clearance and clinical recovery in ICPs with persistent symptomatic SARS-CoV-2 infection.