Evaluation of the efficiency of combined antiviral therapy in COVID-19 challenging immunocompromised patients

Background: There are limited data on the efficacy of combined antiviral treatment in immunosuppressed COVID-19 patients. We describe the clinical and microbiological outcomes of a cohort of oncohaematological patients with persistent SARS-CoV-2 infection who received different antiviral dual and triple combinations. Methods: We selected the 15 patients (two of them with two episodes) who were prescribed combined anti-SARS-CoV-2 treatment in our institution (October 2021-December 2024). Combined antiviral therapy was administered as a compassionate use in the following indications: i) persistence of SARS-CoV-2 positive RT-PCR for >14 days despite antiviral monotherapy and severe COVID-19 or ii) need to achieve viral clearance before hematopoietic progenitor transplantation or administration of immuno-chemotherapy. Samples corresponding to positive RT-PCR results with a Ct value < 32 were analysed by whole-genome sequencing. Results: In 13 out of a total of 15 episodes, with control RT-PCR after the combination therapy, with positivity periods ranging from 12-235 days, viral clearance was achieved 10-69 days after receiving the combination therapy. Whole genome sequencing revealed the emergence of resistance mutations in three cases prior to combination therapy, which was able to overcome them and lead to clearance. Genomic analysis identified one patient with three consecutive reinfections that had been mismanaged as persistent infection. Conclusions: Combined antiviral treatment leads to satisfactory clinical and microbiological outcomes in a small cohort of immunocompromised patients with persistent SARS-CoV-2 infection. Early treatment with monotherapy in these patients was associated with a high rate of clinical and microbiological failure, with sporadic documentation of resistance mutations that were overcome with combined antiviral therapy.