Evaluation of the efficacy and safety of nirmatrelvir/ritonavir co-administration inpatients with rheumatic disease infected with SARS-CoV-2: a real-world study
Authors: Zhong Xue , Wang Chao , Huang Lin , Zhao Yue , Li Tianyi , He Jing , Zhang Xiaohong 
Published: December 2023

Background: The breakthrough development of novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines and oral antivirals have played a critical role in curtailing the spread of the pandemic and dramatically reducing the morbidity and mortality rates among those infected. Among these oral antivirals, nirmatrelvir/ritonavir (NR) has been repurposed successfully for use against coronavirus disease-2019 (COVID-19) and is now readily available on the market with promising therapeutic effects. The availability of convenient and effective NR treatments for COVID-19 greatly mitigates the severity of the epidemic and contributes to an early end to the pandemic. Furthermore, certain patient subgroups, specifically those with rheumatic disease (RD) who are currently undergoing intensive immunodeficiency and/or immunosuppressive treatments, continue to be vulnerable and at a higher risk of experiencing severe consequences from COVID-19. Additionally, it has also been observed that NR exhibited prevalent drug-drug interactions of clinical significance, and more instances of COVID-19 rebound were being recognized with increasing frequency.

Methods: A retrospective cohort study was conducted on a real-world RD population who were infected with SARS-CoV-2 and treated with NR. The time of symptom resolution, length of hospitalization, and response rate were assessed. Results were compared among the standard regimen and non-standard regimen groups, early NR regimen and late NR regimen groups, and the NR indication regimen and NR non-indication regimen groups. During the course, all grades of adverse drug reactions (ADRs) directly associated with NR administration and associated with drug-drug interactions (DDIs) were also monitored.

Results: A total of 32 patients with RD, who were infected with SARS-CoV-2 and received NR, were retrospectively identified and divided into different groups. We found that the standard regimen group and the early NR regimen group had a shorter median time of symptom resolution compared to the control group [9.0 (interquartile range [IQR], 8.3-11.3) vs. 21.5 (IQR16.0-24.0) days, p &lt; 0.001 and 9.0 (IQR 8.3-11.3) vs. 23.0 (IQR 18.0-24.0) days, p = 0.0]. We further found that even if the NR administration time exceeds 5 days, patients with RD who receive the NR indication regimen can still derive certain benefits from it. The proportion of patients who showed symptom improvement was higher in the NR indication regimen compared to the NR non-indication regimen group (n = 13/17 vs. 3/6, 76.5% vs. 50.0%) at the end of follow-up, and there was a statistical difference (p = 0.0) in the response rate of patients between the two groups. We also analyzed the effect of comorbidities on patient response rates and found that the percentage of patients who showed symptom improvement was higher in the group with &lt;4 comorbidities compared to the group with ≥ 4 comorbidities (n = 7/7 vs. 16/25, 100.0% vs. 64.0%) at the end of follow-up. During the course, all grades of ADRs and grade ≥3ADRs directly associated with NR administration were not observed in any of the 32 cases. Despite discontinuing warfarin prior to NR application (using NR immediately on the first day of warfarin withdrawal), one patient still experienced an increased international normalized ratio [INR, 5.32(0.90-1.20)] and coagulation disorders (weak positive fecal occult blood test) on the second day after using NR. The INR levels decreased to nearly normal values, and coagulation disorders returned to normal after 2 days of discontinuing NR (the seventh day after the initial administration of NR).

Conclusion: We showed NR therapy to be associated with a favorable outcome and an acceptable safety profile in an immunosuppressed population with RD during the Omicron surge. Early use of NR (within 5 days of symptom onset) could improve the prognosis of patients. NR administration for symptoms and confirmed SARS-CoV-2 infection after &gt;5 days may also mitigate progression to severe disease and is a viable strategy. Our results highlight the importance of early utilization and/or NR indication, which may yield clinical advantages for patients with RD infected with SARS-CoV-2.