Protracted SARS-CoV-2 Infection in B-cell Depleted Patients: Immunologic andiral Characteristics and Response to Dual and Extended Antiviral Therapy.

Background: Immunocompromised patients remain at risk for protracted SARS-CoV-2 infections with persistent viral shedding that could pose a wider public health risk. The optimal therapeutic strategy remains unknown.

Methods: We describe a sequential case series of immunocompromised adults with protracted SARS-CoV-2 infection who received dual/extended antiviral therapy (median 23d nirmatrelvir/r; 8d remdesivir). Protracted infection was defined as persistent viral shedding and prolonged symptoms unresponsive to antiviral monotherapy in B-cell-depleted patients. Plasma anti-spike IgG and spike antigen were analyzed using the single molecule array assay (Simoa), viral RNA levels defined by cycle thresholds (Ct) from clinical assays and quantitative RNA polymerase chain reaction (PCR) testing, and whole virus and targeted nsp5/nsp12 sequencing were performed.

Results: Sixteen patients with protracted SARS-CoV-2 infection were treated with dual/extended antivirals. Viral sequencing supported the presence of protracted infections in all tested, but only one participant demonstrated mutations conferring antiviral resistance. Humoral immune responses were blunted both at initiation and completion of therapy. All participants responded to dual/extended antiviral therapy with negative PCR at a median of 13 days post-treatment, no evidence of virologic recurrence, and no clinical relapse at one year. One patient with recurrent positive SARS-CoV-2 testing was demonstrated to have a new infection by sequencing.

Conclusion: Dual/extended antiviral therapy with nirmatrelvir/r and remdesivir can be effective for protracted SARS-CoV-2 infection in B-cell-depleted patients who fail antiviral monotherapy, despite persistently blunted humoral immune responses. Additionally, immunocompromised hosts are at risk of both protracted infection and early re-infection, which can be differentiated by viral sequencing.