Clinical Characteristics and Treatment Efficacy in Patients With SARS‐CoV‐2 Positivity After Nirmatrelvir‐Ritonavir Therapy

Nirmatrelvir-ritonavir (NMV-r) has been widely used to treat coronavirus disease 2019 (COVID-19) for a standard period of 5-days. However, there are increasing reports of patients with persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity after the standard 5-day course of NMV-r treatment. Moreover, the clinical characteristics of these patients and the efficacy of extending NMV-r treatment duration are not fully understood. We conducted a prospective study involving hospitalized patients with COVID-19. In total, 310 patients were included: 133 with SARS-CoV-2 RNA positivity after completion of the standard course of NMV-r (positive group) and 177 without SARS-CoV-2 positivity (negative group). A subset of patients (n = 37) in the positive group extended the treatment with NMV-r. Patients in the positive group had higher severity scores, neutrophil counts, lactate dehydrogenase levels, and viral loads at admission. Following the standard 5-day NMV-r course, the positive group showed a significantly increased risk of composite disease progression outcomes (hazard ratio [HR] 3.35, 95% confidence interval [CI]: 2.07-5.44; p < 0.0001). This group also demonstrated higher risks of 28-day all-cause mortality, initiation of invasive mechanical ventilation, intensive care unit (ICU) admission and prolonged hospitalization. However, no significant differences in clinical outcomes were observed between the standard and the extended treatment groups in the unadjusted analysis. After adjustment for baseline characteristics, the extended treatment group demonstrated significantly better outcomes compared with the standard treatment group. Specifically, the extended treatment group had lower rates of composite disease progression (HR: 0.39, 95% CI: 0.20-0.79; p = 0.009), invasive mechanical ventilation (HR: 0.24, 95% CI: 0.08-0.73; p = 0.01), and ICU admission (HR: 0.15, 95% CI: 0.02-0.94; p = 0.04), along with a shorter length of hospital stay (HR: -13.54, 95% CI: -26.01 to -1.07; p = 0.033). SARS-CoV-2 positivity after NMV-r treatment is common and associated with worse clinical outcomes. Extending NMV-r therapy may reduce disease progression risk; this finding requires confirmation in future studies.