Dual antiviral therapy in haematological patients with protracted SARS‐CoV‐2 infection

Haematological patients with SARSCoV2 infection exhibit higher mortality rate and more severe clinical presentation when compared to other immunocompromised subjects, especially if chemotherapy has been administered in the previous 3 months. Haematological treatment may be delayed until COVID19 resolution. ‘Protracted COVID19/SARSCoV2 infection’, defined as persistent positivity for SARSCoV2 and persistent/relapsing symptoms and radiological signs >21 days, became a relevant issue in the management of haematological patients. Since the prolonged disease in this population reflects the persistence of active SARSCoV2, some cases of protracted COVID19 have been treated with antivirals for an extended period of time, as recrudescence of symptoms has been described after 5 days of nirmatrelvir/ritonavir in the general population and after 10 days of remdesivir in immunocompromised patients. In haematological setting, remdesivir has been used as monotherapy for up to 30 days in subjects with pneumonia; another patient has been successfully treated with remdesivir plus nirmatrelvir/ritonavir, as this combination showed in vitro a synergic activity against SARSCoV2 replication. Due to protracted COVID19 and haematological disease progression for chemotherapy delay, an offlabel combination of remdesivir and nirmatrelvir/ritonavir was proposed to haematological patients with protracted COVID19 or with persistent viral positivity needing chemotherapy. Dual antiviral therapy was chosen to minimize the risk of viral resistance, as greater intrahost viral diversity was observed in patients with impaired CD8+ Tcell immunity, and viral resistance has been previously described in immunocompromised subjects with persistent viral replication. Six patients with protracted SARSCoV2 infection were treated from November 2022 to February 2023. Median age was 73 (IQR 72– 75) years old. Clinical characteristics and infection course are shown in Table 1. All patients received four doses of mRNA SARSCoV2 vaccine, one patient received tixagevimabcilgavimab as prophylaxis. All subjects have been infected by Omicron subvariants (BA.2, BA.5, XBK). Standard daily doses of remdesivir (200 mg on day 1, followed by 100 mg daily) and nirmatrelvir/ritonavir (100 mg ritonavir plus 150 or 300 mg nirmatrelvir BID according to renal function) have been used. SARSCoV2 antigen nasal swab, confirmed with rtPCR test, was used to confirm infection at treatment baseline and to assess viral clearance. Antigen test was preferred to PCR at screening since it has been described to better correlate with viral culture. One patient was asymptomatic for SARSCoV2 infection, with a persistent antigen positivity at nasal swab in the last 9 months, confirmed by both RTPCR and viral culture tests, but with urgent need of immunochemotherapy due to pulmonary involvement of diffuse large Bcell lymphoma. One patient had fever without concomitant pneumonia. Four patients experienced pneumonia at treatment baseline (1/4 requiring noninvasive ventilation) and have been successfully treated achieving both clinical and radiological improvement; all, but one, completed oxygen weaning. The patient who required prolonged oxygen therapy, despite a decay of oxygen supplementation from noninvasive ventilation to lowflux oxygen, eventually died due to septic shock. Dexamethasone was administered in patients with pneumonia as indicated in COVID19 guidelines; no IL1 and IL6 blockades were used to avoid the risk of viral replication and superinfections. Treatment lasted 10 days in five patients, who achieved viral clearance at the first antigenic nasal swab performed on day 5. A patient with pneumonia was treated with antivirals for 20 days with negative antigenic and rtPCR test on day 20. Median followup was 29 days, and no patients experienced viral relapse or recurrence of SARSCoV2related symptoms, even after receiving immunochemotherapy: one patient has been started on RCHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) regimen and the other patient on MATRix (methotrexate, cytarabine, thiotepa, rituximab) regimen; no one experiences any SARSCoV2 reactivation. Antiviral therapy was well tolerated; no adverse events nor liver or renal toxicities have been reported. Notably, five subjects had a positive SARSCoV2 serology (antiSpike1RDB IgG, CMIA) at treatment baseline, but antinucleocapsid IgG and interferongamma release assay, to detect cellmediated immune response to SARSCoV2, were positive just in one subject. This patient received only two doses of rituximab, while the others have been treated with more than two doses. The scarce viral control, despite the high rate of Received: 13 March 2023 | Accepted: 12 April 2023