Early combination therapy of COVID-19 in high-risk patients

Abstract

Purpose: 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 by the international guidelines, does not prevent this with certainty. Dual therapies may therefore have a synergistic effect.

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 using odds ratios and Fisher's tests or Kaplan-Meier analysis and long-rank tests. Multivariable regression analysis was performed.

Results: 144 patients were included with a median duration 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 initiation later than five days after diagnosis (p < 0.01) were significantly associated with longer viral shedding. Prolonged viral shedding was observed in 14.6% (n = 21/144), particularly 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 related to combination treatment.

Conclusion: Early combination treatment of COVID-19 effectively prevented prolonged viral shedding in 85.6% of cases. Considering the rapid viral clearance rates and low toxicity, individualized dual therapy approaches may be beneficial in high-risk patients.

Keywords: COVID-19; Dual anti-SARS-CoV-2 therapies; Immunocompromised host; Individualized therapeutic approaches; Prolonged viral shedding.

Fig. 1

Subject disposition. 170 patients received primarily combined dual anti-SARS-CoV-2 therapies. Patients having received ineffective mABs or having highlighted a SARS-CoV-2 viral load < 10^6 RNA copies within the first three days were excluded. Furthermore, patients having received a second round of therapy due to clinical and/ or virological deterioration were excluded from the initial analysis. The latter were examined in a sub-analysis with regard to the effect of this second round of therapy on days with SARS-CoV-2 ≥ 10^6 RNA copies/ml Finally, 144 patients were included in the initial analysis having received 1 × DAA plus 1 × mAB, 2 × DAAs or 2 × DAAs plus 1 × mAB. DAA direct acting antiviral, mAB monoclonal antibody

Fig. 2

Viral Shedding. Kaplan–Meier plots showing the probability of SARS-CoV-2 RNA ≥ 10^6 copies/ml set in relation to time in days. The time of viral shedding was not significantly different between the treatment strategies (a: 1 × DAA + 1 × mAB: 14·0 days vs. 2 × DAA ± 1 × mAB: 11·0 days; p = 0·17). The period was longer in b) patients with a late treatment initiation (> 5 days after diagnosis: 30·7 days vs. ≤ 5 days after diagnosis: 12·3 days; p < 0·01), c) immunocompromised patients (13·9 days vs. 8·0 days in immunocompetent patients; p = 0·04) and/ or d) especially in patients with HM (17·1 days vs. 11·0 days in patients without HM; p < 0·01). In comparison, in patients under immunosuppressive medication following SOT the time was even shorter (11·7 days vs. 14·5 days in patients with no history of solid organ transplantation; p = 0·18). DAA direct acting antiviral, HM haematological malignancies, mAB monoclonal antibody, SOT solid organ transplantation

Fig. 3

Factors influencing viral shedding (multivariable analysis). Forest plot visualizing the results of the multivariable analysis regarding factors being associated with longer viral shedding. Despite dual anti-SARS-CoV-2 therapy, viral shedding was significantly longer when treatment start was > 5 days after diagnosis of COVID-19 and/ or in patients with underlying haematological malignancies. The effects of sex, age, immunodeficiency, and/ or allogenic bone marrow transplantation were minor and insignificant

Fig. 4

Sub-analysis on therapy strategies. Using an effective mAB, there was no difference in time with SARS-CoV-2 viral load ≥ 10^6 RNA copies/ml whether combining it with remdesivir (14.1 days), molnupiravir (9.9 days; p = 0.44) or nirmatrelvir/ritonavir (16.7 days; p = 0.30) (a). In contrast, the combination of remdesivir with molnupiravir appeared to be beneficial compared to the combination of remdesivir and nirmatrelvir/ritonavir (8.9 vs. 21.8 days; p < 0.01; b). Of note, nirmatrelvir/ritonavir could not be used in patients under immunosuppressive medication following organ transplantation due to potential drug-drug-interactions and was therefore rarely administered. The significance is thus weakened. DAA direct acting antiviral, mAB monoclonal antibody, MOL molnupiravir, NIR/r nirmatrelvir/ritonavir, RDV remdesivir