Early Combination Therapy of COVID-19 in High-Risk Patients

Background: Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended in the international guidelines, does not prevent this with certainty. Dual therapies might therefore act synergistically.Methods: This retrospective, multicentre study compared treatment strategies for corona virus disease-19 (COVID-19) with combinations of nirmatrelvir/ritonavir, remdesivir, molnupiravir, and/ or mABs during the Omicron surge. Co-primary endpoints were prolonged viral shedding (≥106 copies/ml at day 21 after treatment initiation) and days with SARS-CoV-2 viral load ≥106 copies/ml. Therapeutic strategies and risk groups were compared by odds ratios and Fisher’s tests or Kaplan-Meier analysis and long-rank tests. Multivariable regression analysis was performed.Findings: 144 patients were included with a median time of SARS-CoV-2 viral load ≥106 copies/ml of 8·0 days (IQR 6·0-15·3). Underlying haematological malignancies (HM) (p=0·03) and treatment initiations later than five days after diagnosis (p<0·01) were significantly associated with longer viral shedding. Viral shedding was prolonged in 14·6% (n=21/144), especially in patients with underlying HM (OR 3·5; 95% CI 1·2-9·9; p=0·02). Clinical courses of COVID-19 were mild to moderate with only few adverse effects potentially contributed to combination treatment.Interpretation: Early combination treatment of COVID-19 effectively prevented prolonged viral shedding in 85·6% of cases. Considering rapid viral clearance rates and low toxicity, individualized dual therapeutic approaches may thus be advantageous in high-risk patients.Funding: There was no funding.Declaration of Interest: I declare that I have no competing interests regarding this paper.Ethical Approval: The study was performed in accordance with the Declaration of Helsinki. Due to the retrospective study design, ethical approval and/or patient information was not required according to the North Rhine-Westphalian legislation. This was a retrospective, multicentre, observational cohort study conducted during the Omicron surge in four German university hospitals forming the Centre for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD). Clinical data were anonymized and entered in an electronic case report form by the treating physicians.