Nirmatrelvir-ritonavir use among adults hospitalized with COVID-19 during the Omicron phase of the COVID-19 pandemic, Canadian Nosocomial Infection Surveillance Program

Background Recent studies have demonstrated the effectiveness of nirmatrelvir-ritonavir in reducing the risk of progression to severe disease among outpatients with mild to moderate coronavirus disease 2019 (COVID-19); however, data are limited regarding the use and role of nirmatrelvir-ritonavir among hospitalized patients. This study describes the use and outcomes of nirmatrelvir-ritonavir among adults hospitalized with COVID-19 in a sentinel network of Canadian acute care hospitals during the Omicron variant phase of the pandemic. Methods The Canadian Nosocomial Infection Surveillance Program conducts surveillance of hospitalized patients with COVID-19 in acute care hospitals across Canada. Demographic, clinical, treatment and 30-day outcome data were collected by chart review by trained infection control professionals using standardized questionnaires. Results From January 1 to December 31, 2022, 13% (n=490/3,731) of adult patients (18 years of age and older) hospitalized with COVID-19 in 40 acute care hospitals received nirmatrelvir-ritonavir either at admission or during hospitalization. Most inpatients who received nirmatrelvir-ritonavir, 79% of whom were fully vaccinated, had at least one pre-existing comorbidity (97%) and were of advanced age (median=79 years). Few were admitted to an intensive care unit (2.3%) and among the 490 nirmatrelvir-ritonavir treated inpatients, there were 13 (2.7%) deaths attributable to COVID-19. Conclusion These findings from a large sentinel network of Canadian acute-care hospitals suggest that nirmatrelvir-ritonavir is being used to treat adult COVID-19 patients at admission who are at risk of progression to severe disease or those who acquired COVID-19 in hospital. Additional research on the efficacy and indications for nirmatrelvir-ritonavir use in hospitalized patients is warranted to inform future policies and guidelines.


Introduction
Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains the most effective intervention to prevent severe coronavirus disease 2019 (COVID-19) related illness and death (1)(2)(3)(4)(5)(6). For those who become infected, antiviral therapies such as nirmatrelvir-ritonavir are valuable tools to improve patient outcomes and reduce the burden on healthcare systems. A recent randomized controlled trial demonstrated that treatment with nirmatrelvir-ritonavir among unvaccinated, non-hospitalized adults during the pre-Delta and Delta pandemic phases resulted in an 89% reduction in hospitalization or death (7). Recent observational studies have shown the benefit of nirmatrelvir-ritonavir in reducing the risk of hospitalization and death among outpatients with mild or moderate COVID-19 who are at risk for progression to severe disease (8)(9)(10)(11).
Nirmatrelvir-ritonavir was approved for use by Health Canada on January 17, 2022, for treating adults with mild to moderate COVID-19 infection who are at high risk for progression to severe disease, including hospitalization and death (12). A recent observational study from Ontario, Canada, found that outpatient use of nirmatrelvir-ritonavir during an Omicron-dominant period between April and August 2022 was associated with a significant reduction in the odds of hospital admission from COVID-19 or all-cause mortality. The largest benefits were observed among those who were under-vaccinated or unvaccinated and those 70 years of age or older (13). Information regarding the use of nirmatrelvir-ritonavir among hospitalized patients with mild to moderate disease during the Omicron phase of the pandemic is limited. To help inform future policies and guidelines, we sought to describe the use and outcomes of nirmatrelvir-ritonavir among adult patients hospitalized with COVID-19 in a sentinel network of Canadian acute care hospitals.

Methods
The Canadian Nosocomial Infection Surveillance Program (CNISP) is a collaboration between the Public Health Agency of Canada, the Association of Medical Microbiology and Infectious Disease Canada and sentinel hospitals across Canada (14). The CNISP conducts surveillance of healthcare-associated (HA) infections among hospitalized adult and paediatric patients, including HA viral respiratory infections. In March 2020, surveillance was expanded to include patients of all ages hospitalized with COVID-19, in addition to patients with HA viral respiratory infection. Beginning on January 1, 2022, eligibility for the inclusion of patients with COVID-19 was restricted to those who were admitted due to COVID-19 or acquired COVID-19 while in hospital.
Demographic, clinical, treatment and 30-day outcome data were collected by trained infection control professionals by chart review and submitted to the Public Health Agency of Canada through a secure online platform, the Canadian Network for Public Health Intelligence, using a standardized protocol and data collection form. Information on initiation of nirmatrelvirritonavir was collected between January 1 and December 31, 2022. Data on initiation of nirmatrelvir-ritonavir prior to admission were not systematically recorded in the patient chart; therefore, patients who started nirmatrelvir-ritonavir prior to admission were excluded from the analysis. Outcomes were identified at 30 days from the date of the first positive reverse transcription-polymerase chain reaction test. Attributable mortality was defined as COVID-19 being the cause of death or contributing to death. A HA case was defined as a patient 1) with symptom onset or positive test seven or more calendar days after admission to hospital, or 2) who was readmitted with a positive test within less than seven days after discharge from hospital, or 3) who was most likely a HA case based on best clinical judgment (e.g. symptom onset prior to the seventh day but known epidemiological link to a positive inpatient or staff case).
The primary analysis describes adult patients, 18 years of age and older, who received nirmatrelvir-ritonavir at admission or during hospitalization. A subgroup analysis was conducted among HA COVID-19 adult patients to compare treated to nontreated patients. Paediatric patients, younger than 18 years, were excluded from the analysis. Chi-squared test or Fisher's exact test were used to compare proportions and the Kruskal-Wallis rank sum test was used to compare medians. Missing and incomplete data for individual variables were excluded from analyses, therefore denominators may vary. Provinces were grouped into three regions: Western (British Columbia, Alberta, Saskatchewan and Manitoba); Central (Ontario and Québec); and Eastern (Nova Scotia, New Brunswick, Prince Edward Island and Newfoundland and Labrador). Analyses were conducted using R version 4.0.5.

Discussion
Findings from a sentinel network of Canadian acute care hospitals found that, during the Omicron phase of the pandemic, 13% of adults hospitalized with COVID-19 received nirmatrelvirritonavir either at admission or during hospitalization. Nearly all inpatients, of whom 79% were fully vaccinated, had at least one pre-existing comorbidity and were of advanced age, which put them at increased risk of progression to severe disease or death. The proportion of severe outcomes (e.g. ICU admission and death attributable to COVID-19) at 30 days was low. Significant regional variation was observed in the use of nirmatrelvirritonavir, which is most likely related to differences in provincial policies and/or prescriber patterns, and possibly regional drug availability. However, it is difficult to attribute regional treatment differences to regional differences in patient populations, suggesting the need for more data on treatment indications for inpatients from which national treatment guidelines can be developed. CCDR • July/August 2023 • Vol. 49 No. 7/8 Few studies have evaluated the effectiveness of nirmatrelvirritonavir among hospitalized patients. However, a cohort study in Hong Kong during the Omicron pandemic phase demonstrated that initiation of nirmatrelvir-ritonavir treatment within five days of symptom onset among hospitalized patients 60 years of age and older or younger patients with at least one chronic disease was associated with a lower risk of in-hospital death compared to controls (15). A Chinese study suggested the potential role of early nirmatrelvir-ritonavir treatment for high-risk patients who are immunocompromised, including those who are hospitalized, to facilitate viral eradication (16). A retrospective cohort study of hospitalized patients with COVID-19 who did not initially require supplemental oxygen found that early initiation of nirmatrelvirritonavir was associated with significant reductions in risk of allcause mortality and disease progression (17).
Our subgroup analysis found that HA COVID-19 adult inpatients who received nirmatrelvir-ritonavir were less frequently admitted to an ICU or less frequently died (30-day all-cause mortality) compared to non-treated HA COVID-19 adult inpatients. These results should be interpreted with caution as eligibility to receive nirmatrelvir-ritonavir was not determined (e.g. data on contraindications for nirmatrelvir-ritonavir were not collected) and due to the small sample size, a multivariable analysis was not conducted. Nonetheless, these preliminary results warrant further study. In addition to the treatment benefits among hospitalized patients reported in other recent studies, our findings suggest a role for nirmatrelvir-ritonavir treatment for adult patients with mild to moderate symptoms who are hospitalized for reasons unrelated to COVID-19 or who acquired COVID-19 in-hospital who are at high risk for progression to severe disease.

Limitations
Our study has several limitations. This report describes early findings of the epidemiology of COVID-19 among inpatients who received nirmatrelvir-ritonavir in a subset of Canadian acute care hospitals; these findings may change as additional data become available. These analyses were descriptive in nature, and we cannot draw any causal inferences. Specifically, our findings should be interpreted with caution as there is potential for selection bias, given that our surveillance methodology did not identify eligibility of patients to receive treatment. Due to the regional variation in data submission and of nirmatrelvir-ritonavir use, our results may not be generalizable to all adult patients hospitalized in Canada. In addition, our cohort was limited to those with a positive test result for SARS-CoV-2 by polymerase chain reaction test and did not include inpatients with positive test result by only rapid antigen test, which may also limit the generalizability of our findings. Finally, we did not collect data on indications or drug contraindications to nirmatrelvir-ritonavir.

Conclusion
Among adult patients hospitalized with COVID-19, we found that 13% received nirmatrelvir-ritonavir. Further study to monitor the use and effectiveness of nirmatrelvir-ritonavir among COVID-19 inpatients and other high-risk populations (e.g. long-term care residents) is critical to inform future policies and guidelines.