Oral Nirmatrelvir and Severe Covid-19 Outcomes During the Omicron Surge

Oral Nirmatrelvir and Severe Covid-19 Outcomes During the Omicron Surge | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Oral Nirmatrelvir and Severe Covid-19 Outcomes During the Omicron Surge Ronen Arbel, Yael Wolff Sagy, Moshe Hoshen, Erez Battat, Gil Lavie, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1705061/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Nirmatrelvir, an inhibitor of the main protease of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has demonstrated a significant decrease in the risk of progression to severe disease in symptomatic high-risk patients infected with the B.1.617.2 (delta) variant of SARS-CoV-2. The effectiveness of nirmatrelvir against the B.1.1.529 variant (omicron) is unknown. Methods The study included all Clalit Health Services members, 40 years of age and older, with confirmed infection of SARS-CoV-2 during the omicron surge that were defined as high-risk for severe disease. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association between nirmatrelvir treatment and hospitalizations and deaths due to Covid-19, with adjustment for individual sociodemographic factors, coexisting conditions, and prior Covid-19 immunity status. Results 109,213 participants were eligible for nirmatrelvir therapy during the two-month study period. Among the 42,819 eligible patients aged 65 years and above, 2,504 were treated with nirmatrelvir. Hospitalizations due to Covid-19 occurred in 14 out of the treated and 762 of the untreated patients: adjusted HR 0.33 (95% CI, 0.19 to 0.55). Death due to Covid-19 occurred in 2 treated and 151 untreated patients; adjusted HR: 0.19 (95% CI, 0.05 to 0.76). Among the 66,394 eligible patients 40 to 64 years of age, 1,435 were treated with nirmatrelvir. Hospitalizations due to Covid-19 occurred in 9 treated and 334 untreated patients: adjusted HR 0.78 (95% CI, 0.40 to 1.53). Death due to Covid-19 occurred in 1 treated and 13 untreated patients; adjusted HR: 1.64 (95% CI, 0.40 to 12.95). Conclusions Nirmatrelvir therapy was associated with a 67% reduction in Covid-19 hospitalizations and an 81% reduction in Covid-19 mortality in patients 65 years and above. However, no significant benefit in avoidance of severe Covid-19 outcomes was shown in younger adults. Infectious Diseases Figures Figure 1 Figure 2 Background The emergence of the fast-spreading B.1.1.529 (omicron) variant of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in late 2021 led to a global coronavirus disease 2019 (Covid-19) resurgence. By the end of December 2021, omicron was outcompeting the B.1.617.2 (delta) variant, and by early January, omicron spread widely worldwide, even in communities with high levels of preexisting immunity ( 1 ). The Food and Drug Administration (FDA) issued on December 22, 2021, an Emergency Use Authorization (EUA) for the oral antiviral nirmatrelvir for the treatment of mild to moderate Covid-19 in patients at a high risk of progression to severe disease ( 2 ). Nirmatrelvir treatment is provided for five consecutive days as soon as possible after a diagnosis of Covid-19 and within 5 days of symptom onset ( 3 ). The primary data supporting the FDA EUA came from the Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients (EPIC-HR) randomized, double-blind, placebo-controlled trial that studied nirmatrelvir treatment in non-hospitalized, high-risk, symptomatic adults with Covid-19 ( 4 ). This trial was performed in a period when the delta variant was most likely responsible for the majority of infections ( 5 ). All participants in EPIC-HR were unvaccinated for Covid-19 and had not been previously confirmed infected with SARS-CoV-2. EPIC-HR demonstrated a relative risk reduction of 89% for hospitalization or death among those treated with nirmatrelvir. However, the effectiveness of nirmatrelvir against the omicron variant and in patients with prior Covid-19 immunity is unknown. Therefore, our objective was to assess the effectiveness of nirmatrelvir therapy for preventing mortality and hospitalizations due to Covid-19 in high-risk patients during the omicron surge. Methods Study Design This observational, retrospective cohort study was based on data obtained from the electronic medical records of Clalit Health Services (CHS), a large healthcare organization covering approximately 52% of the entire Israeli population and almost two-thirds of the older adults. The study period started on January 9, 2022, the first day the drug was administered to CHS patients, and ended on March 10, 2022. During the study period, the omicron variant was the dominant strain in Israel (Fig. S1 in the Supplementary Appendix). Patients were eligible to be included in the study if they were diagnosed with Covid-19 by February 24, 2022. Patients’ follow-up ended at the earliest of the following: 35 days from diagnosis of Covid-19; the end of the study period; or if censored earlier due to hospitalization or death from any cause. Study Outcomes The primary outcome was hospitalizations due to Covid − 19. The secondary outcome was death due to Covid-19. Study Population The study population included all CHS members 40 years of age and above with confirmed SARS-CoV-2 infection, estimated to be at high risk for progression to severe Covid-19, and determined eligible for nirmatrelvir therapy. High-risk participants were determined according to a score developed in CHS to evaluate the risk for severe Covid-19 in SARS-CoV-2 infected patients (Table S1). Eligibility to the antiviral therapy took into account also drug safety considerations, drug interactions, and contraindications as described in the nirmatrelvir FDA prescribing information ( 3 ). A nurse in each CHS district was responsible for delivering nirmatrelvir therapy to the patients’ homes and verifying adherence to the treatment regimen. CHS policy was to initiate therapy in eligible patients as soon as possible after a positive SARS-CoV-2 test result to minimize the potential for hospitalizations in the high-risk population, as per FDA prescribing information ( 3 ) Patients residing in long-term care facilities, patients hospitalized during the study period before a positive SARS-CoV-2 test result, and patients treated for Covid-19 during the study period with molnupiravir (the second oral antiviral available in Israel) were all excluded from the study. The study population was divided into two groups, those who received nirmatrelvir therapy (treatment group) and those who had not (control group). All eligible participants were included in the study’s control arm at the date of their positive SARS-CoV-2 test. Patients treated with nirmatrelvir were transferred to the treatment group when they received the initial dose. The study was approved by the Community IRB and data utilization committees of Clalit Health Services. Due to the retrospective design, the study was exempt from obtaining informed consent from the patients. No financial or in-kind support was provided for the conduct of the study. Data Sources and organization We evaluated integrated patient-level data maintained by CHS from two primary sources: the primary-care operational and Covid-19 databases. The operational database includes sociodemographic data and comprehensive clinical information, such as coexisting chronic illnesses, history of community care visits, medications, and results of laboratory tests. The Covid-19 database includes PCR and state-regulated rapid antigen test results, vaccinations provided, and Covid-19-related hospitalizations and death. The Covid-19 database is updated daily from the central Covid-19 repository of the Israeli Ministry of Health. These same databases were used in the primary studies that evaluated the effectiveness of the BNT162b2 vaccine in real-world settings in Israel ( 6 , 7 ). A description of the data repositories used in this study is provided in the Supplementary Appendix. For each participant in the study, the following sociodemographic data were extracted: age, sex, demographic group (general Jewish population, ultra-Orthodox Jewish population, or Arab population), and the score for socioeconomic status (ranging from 1 [lowest] to 10 [highest], as described in the Supplement). The following clinical data were extracted: Covid-19 vaccination dates, PCR and state-regulated rapid antigen test dates and results, Covid-19 antiviral therapies, hospitalizations, and mortality. Data regarding the following clinical risk factors for severe Covid-19 were also collected: Immunosuppression, diabetes mellitus, asthma, hypertension, neurologic diseases, current cancer disease, chronic hepatic disease, chronic obstructive pulmonary disease, chronic kidney failure, chronic heart failure, obesity, history of stroke, history of or current smoking and recent hospitalizations (in the last three years) from all causes. The eGFR lab test results were obtained as well. All patients were classified into one of two categories according to their Covid-19 immune status; participants with no prior immunity (unvaccinated or vaccinated with only one mRNA vaccine dose and also with no previous documented SARS-CoV-2 infection) or participants that had already acquired prior immunity (vaccine-induced, infection-induced, or hybrid). Statistical Analysis Descriptive statistics were used to characterize the study participants. Since the independent variable (nirmatrelvir treatment) varied over time, univariate and multivariate survival analyses were performed with time-dependent covariates according to the study design. Participants were censored in cases of hospitalization or death from any cause or at the end of follow-up. Participants who received nirmatrelvir were censored from the control group on the day they received the antiviral therapy. We used a multivariate Cox proportional-hazards regression model to estimate the association of all covariates and uptake of nirmatrelvir therapy. The association of nirmatrelvir and Covid-19 outcomes was estimated using a multivariate Cox proportional-hazards regression model with time-dependent covariates, adjusted for sociodemographic factors and coexisting illnesses. All covariates were tested for interactions with the variable of interest (nirmatrelvir treatment). A Kaplan–Meier analysis with a log-rank test was used for the univariate analysis. Comparison of the survival curves and Schoenfeld’s global test were used to test the proportional hazards assumption for each dependent variable. Variables that met the testing criteria served as inputs for multivariate regression analysis. R statistical software version 3.5.0 (R Foundation) was used for the univariate and multivariate survival analysis with time-dependent covariates. SPSS software, version 26 (IBM), was utilized for all other statistical analyses. A two-sided P value of less than 0.05 was considered to indicate statistical significance in all analyses. Results Patient Population A total of 109,213 participants met the study criteria. The assessment for eligibility is detailed in Figure 1. The mean age of the study participants was 60, with 39% of the participants aged 65 years and older and 60% female. The most common coexisting conditions were obesity, diabetes, and smoking. 78% of participants had previous Covid-19 immunity, either by vaccination, prior SARS-CoV-2 infection, or hybrid immunity (Table 1). Nirmatrelvir Uptake Of the entire population cohort, 3,939 participants (3.6%) received at least one dose of nirmatrelvir therapy during the study period. The association between patient characteristics and the nirmatrelvir uptake rate is described in Table S2. Uptake was notably higher in participants aged 65 years and above and among participants with a current cancer diagnosis. Uptake was significantly lower in participants with no prior Covid-19 immunity and within the Arab minority population. Primary Outcome Testing the interaction of nirmatrelvir status with the other variables revealed a significant interaction with age group (above or below 65). We, therefore, report all results separately for these two age groups. Among the 66,394 patients aged 40 to 64, hospitalizations due to Covid-19 occurred in 343 patients (0.5%): 9 (0.6%) out of 1,435 treated patients and 334 (0.5%) out of 64,959 untreated patients; adjusted hazard ratio (HR) for hospitalization was 0.78 (95% confidence interval (CI), 0.40 to 1.53). Among 42,819 patients 65 years of age and above, hospitalizations due to Covid-19 occurred in 776 patients (1.8%): 14 (0.6%) out of 2,504 treated patients and 762 (1.9%) out of 40,315 untreated patients; adjusted HR 0.33 (95% CI, 0.19 to 0.55) (Table 2). The cumulative hazard-ratio curves are shown in Figures 2a, 2b. Across both age groups, lack of prior Covid-19 immunity and a previous hospitalization were variables most significantly associated with high rates of hospitalizations due to Covid-19. Immunosuppression was significantly associated with hospitalizations in the 40-64 age group. Subgroup Analysis by Immunity Status Among patients the 40-64 years of age, hospitalizations due to Covid-19 occurred in 182 of 20,531 patients (0.9%) without prior immunity and in 161 out of 45,863 (0.4%) with prior immunity. Among participants aged 65 years and above, hospitalizations due to Covid-19 occurred in 273 of 3,306 patients without prior immunity (8.3%) and in 503 of 39,513 patients with prior immunity (1.3%). The adjusted hazard ratios and absolute risk reductions of hospitalizations due to Covid-19 for nirmatrelvir therapy according to prior immunity status and age-group are presented in Table 3. Detailed Cox regression results are presented in tables S3, S4, S5, and S6. Secondary Outcome Among patients, 65 years of age and above, Covid-19 death occurred in 2 treated and 151 untreated patients; adjusted HR: 0.19 (95% CI, 0.05 to 0.76). Among patients 40 to 64 years of age, Covid-19 death occurred in 1 treated and 13 untreated patients; adjusted HR: 1.64 (95% CI), 0.40 to 12.95). Detailed Cox regression results are presented in tables S7 and S8. Discussion At the beginning of the omicron surge in January 2022, the Israeli authorities decided to set two lines of defense to protect the vulnerable and high-risk populations from severe Covid-19. The first line was approving a second-booster vaccine dose (8). The second was suggesting nirmatrelvir to patients at high risk for Covid-19 hospitalizations. Eligibility for nirmatrelvir was much broader than that was defined in the EPIC-HR registration trial (4), as it also included patients with prior immunity, which were the majority of high-risk patients in the Israeli population. Treatment with nirmatrelvir is currently recommended by the United States National Institutes of Health (NIH) Covid-19 treatment guidelines as the first choice for antiviral therapy for non-hospitalized adults at high risk of disease progression (9). However, the NIH stated that there is currently a lack of data on the clinical efficacy of nirmatrelvir against the omicron variant of concern (10). Besides in-vitro studies in experimental models that have demonstrated potent inhibition of the omicron variant by nirmatrelvir (11-14), effectiveness data in real-life patients infected with omicron are still unavailable. Similarly, nirmatrelvir efficacy has only been demonstrated in patients without prior immunity, while in the real world, many of the individuals hospitalized with omicron have prior immunity by vaccinations or prior infections (15). The findings from our current study suggest that during the omicron variant surge, Covid-19 hospitalizations rates were significantly lower in adults aged 65 years and above in nirmatrelvir treated participants, both in patients with and without prior Covid-19 immunity. The absolute benefit of therapy was substantially higher in patients without prior immunity. Covid-19 mortality rates were also 81% lower in nirmatrelvir treated participants of this age group. However, no significant benefit was shown in the younger cohort. An observed difference in nirmatrelvir efficacy between patients older and younger than 65 was also demonstrated in the subgroup analysis of EPIC HR; The benefit from nirmatrelvir in participants younger than 65 was substantially less than in the older age group (a reduction of 13.93 percentage points relative to placebo in the > 65-year group versus 4.35 in participants younger than 65). The observed risk for hospitalizations due to Covid-19 in our study period (dominated by omicron) was significantly lower than what was reported in EPIC-HR during the delta wave, as expected (16). The risk in the 40-64 age group was ten-fold lower than in the comparable age group of EPIC-HR (0.5% vs. 5.1%). The baseline risk was low even in the subgroup without prior Covid-19 immunity (0.9%). The risk in the 65+ group was also significantly lower than the comparable EPIC-HR age group (1.8% vs.14.6%). However, within this higher age group, the subgroup without prior immunity had a much higher event rate in the non-treated patients (8.3%) and had a substantially higher absolute benefit (7.1 percentage points). Our study has several strengths. First, the results are based on the integrated medical records system of CHS, with detailed demographic, clinical, and laboratory testing data, including data on coexisting conditions that could have significantly affected hospitalization rates and were therefore adjusted for in the statistical analysis. The second important strength is the large cohort of participants available for analysis and the relevant large number of events to be analyzed, substantially higher than in the published randomized controlled trials. Limitations As in any retrospective cohort trial, confounding clinical and sociodemographic characteristics may have biased the observed effectiveness. We attempted to overcome these biases by adjusting for the variables known to affect Covid-19 hospitalizations. However, some sources of bias may not have been measured or corrected adequately. Our study observed that only a minority of patients defined as high-risk patients and eligible for nirmatrelvir therapy received antiviral therapy. We do not know why controls did not receive treatment, and therefore, it is our main concern regarding residual bias. We also do not know the actual level of treatment adherence and, therefore, may be underestimating the effectiveness; if participants took less of the treatment, they are still included in the treatment group but did not benefit from the complete treatment course. A major concern of potential unmeasured bias is the lack of data regarding the specific symptoms of the infected patients. Moreover, CHS policy was to administer therapy as soon as possible, even before the onset of symptoms, per FDA prescribing information (3). Patients with worse symptoms are presumably more likely to be offered and agree to receive therapy. This potential bias may underestimate the effectiveness of therapy. However, they may also be at a higher risk of hospitalization, overestimating effectiveness. Specifically, a substantial proportion of the observed effect occurs in the first two days of follow-up. As the hospitalizations in the clinical trial occurred mainly after the second day of follow-up, we cannot estimate whether the observed early effect results from residual bias or true early effectiveness. Another limitation is the heterogeneity of degrees of immunity in the subgroup with prior immunity. This group included patients with infection-induced, vaccine-induced, and hybrid-induced immunity, disregarding any waning of such immunity over time. Nevertheless, our results in the subgroup of patients aged 65 and above without previous immunity are comparable to the results from EPIC-HR. Larger studies will be necessary to evaluate possible differences in nirmatrelvir effectiveness in these different subgroups. A further limitation is the rate of SARS-CoV-2 infections and thus exposure to disease that changed during the study period. However, we assume that after adjustment for all covariates, including socioeconomic ones, these changes affected the treated and untreated populations similarly. It should be noted that the evaluation of adverse events and safety data reports was beyond the scope of this study. Future studies will be needed to assess the short- and long-term safety of nirmatrelvir administration in real-world settings. Conclusions Nirmatrelvir therapy was associated with a significant reduction in Covid-19 hospitalizations and mortality rates in adults aged 65 and higher during the omicron variant surge. Although this study is observational, we believe that its findings and the observed potential for avoiding severe Covid-19 could assist decision-makers in prioritizing the currently constrained supplies to those in whom nirmatrelvir was shown to be substantially effective. References 1. Rubin EJ, Baden LR, Morrissey S. Audio Interview: Understanding the Omicron Variant of SARS-CoV-2. N Engl J Med 2022; 386:e27 DOI: 10.1056/NEJMe2202699 2. FDA News Release, December 22, 2021; Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19. Available online: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19 3. Food and Drug Administration Fact Sheet for Healthcare Providers: Emergency Use Authorization for Paxlovid; 2021. Available online: https://www.fda.gov/media/155050/download. 4. Hammond J, Leister-Tebbe H, Gardner A, et al.; EPIC-HR Investigators. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022 Feb 16. doi: 10.1056/NEJMoa2118542. 5. Rubin EJ, Baden LR. The Potential of Intentional Drug Development. N Engl J Med. 2022 Feb 16:NEJMe2202160. doi: 10.1056/NEJMe2202160. 6. Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med. 2021;384:1412-1423. 7. Arbel R, Hammerman A, Sergienko R, et al. BNT162b2 Vaccine Booster and Mortality Due to Covid-19. N Engl J Med. 2021;385:2413-2420. 8. Arbel R, Sergienko R, Friger M, et al. Effectiveness of a second BNT162b2 booster vaccine against hospitalization and death from COVID-19 in adults aged over 60 years. Nat Med. 2022 Apr 25. doi: 10.1038/s41591-022-01832-0. 9. NIH Covid-19 Treatment Guidelines, Therapeutic Management of Nonhospitalized Adults With COVID-19 (Updated April 1, 2022) Available online: https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management 10. NIH Covid-19 Treatment Guidelines, Ritonavir-Boosted Nirmatrelvir (Paxlovid) (Updated February 24, 2022) Available online: https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir--paxlovid-/?utm_source=site&utm_medium=home&utm_campaign=highlights 11. Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of Antibodies and Antiviral Drugs against Covid-19 Omicron Variant. N Engl J Med. 2022 Mar 10;386(10):995-998. doi: 10.1056/NEJMc2119407. 12. Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2. N Engl J Med. 2022 Mar 9:NEJMc2201933. doi: 10.1056/NEJMc2201933. 13. Li P, Wang Y, Lavrijsen M, et al. SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination. Cell Res. 2022 Mar;32(3):322-324. doi: 10.1038/s41422-022-00618-w. 14. Vangeel L, Chiu W, De Jonghe S, et al. Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022 Feb;198:105252. doi: 10.1016/j.antiviral.2022.105252. 15. Collie S, Champion J, Moultrie H, et al. Effectiveness of BNT162b2 Vaccine against Omicron Variant in South Africa. N Engl J Med. 2022 Feb 3;386(5):494-496. doi: 10.1056/NEJMc2119270. 16. Callaway E, Ledford H. How bad is omicron? What scientists know so far. Nature. 2021;600:197-199. Tables Table 1: Characteristics of the Participants at Baseline Characteristic All Participants (N=109,213) Age Mean + SD - yr Distribution- no. (%) 40-64 yr > 65 yr 59.9 + 12.8 66,394 (61) 42,819 (39) Female sex - no. (%) 65,699 (60) Population sector- no. (%) General Jewish Ultra-Orthodox Jewish Arab 81,865 (75) 6,350 (6) 20,998 (19) Median score for socioeconomic status, Median (IQR) 5 (2) Clinical risk factors - no. (%) Obesity Hypertension Diabetes Current or former smoking Immunosuppression Neurologic disease Current cancer disease Asthma History of stroke Chronic hepatic disease Chronic obstructive pulmonary disease Chronic heart failure Chronic kidney failure Recent hospitalization 37,757 (35) 37,132 (34) 28,656 (26) 26,640 (24) 10,816 (10) 9,254 (9) 7,621 (7) 6,440 (6) 5,687 (5) 4,853 (4) 3,494 (3) 3,176 (3) 1,470 (1) 31,814 (29) Covid-19 immune status - no. (%) No prior immunity With prior immunity 23,837 (22) 85,376 (78) Table 2: Association between Hospitalizations due to Covid-19 and Demographic and Clinical Variables, According to Age Group* Variable Hazard Ratio for Hospitalization Due to Covid-19 (95% CI) 40-64 Yr of Age (N=66,394) > 65 Yr of Age (N=42,819) Nirmatrelvir therapy 0.78 (0.40-1.53) 0.33 (0.19-0.55) Male Sex 1.55 (1.25-1.92) 1.62 (1.40-1.87) Score for socioeconomic status NA 0.89 (0.86-0.93) No prior immunity 6.20 (4.92-7.81) 5.81 (4.98-6.78) Clinical risk factors Recent hospitalization Obesity Diabetes Immunosuppression Chronic hepatic disease Neurologic disease Chronic heart failure Chronic obstructive pulmonary disease History of stroke Chronic kidney failure 3.11 (2.47-3.91) 1.28 (1.02-1.60) 1.34 ( 1.04 - 1.72 ) 2.91 ( 2.24 - 3.79 ) 1.72 ( 1.20 - 2.44 ) 1.73 ( 1.24 - 2.40 ) 2.57 (1.72-3.83) NA 1.86 (1.28-2.72) NA 2.10 (1.80-2.45) NA 1.36 (1.18-1.57) NA NA 1.59 (1.34-1.88) 1.48 (1.20-1.82) 1.75 (1.42-2.17) 1.39 (1.16-1.66) 1.80 (1.35-2.40) *The association between nirmatrelvir therapy and hospitalizations due to Covid-19 was estimated utilizing a multivariate Cox proportional-hazards regression model after adjustment for sociodemographic factors, coexisting illnesses, and Covid-19 immune status. Variables that met the testing criteria and were significantly associated with the outcome served as the inputs for the multivariate regression analysis. Table 3: Rates and Hazard Ratios for Hospitalizations due to Covid-19, Subgroup Analysis According to Immunity Status Variable Hazard Ratio for Hospitalization (95% CI) Absolute Benefit - Percentage Points (95% CI) 40-64 Yr of age > 65 Yr of Age 40-64 Yr of age > 65 Yr of age All patients 0.78 (0.40-1.53) 0.33 (0.19-0.55) 0.11 (-0.27- 0.33) 1.21 (0.82-1.47) No prior immunity 0.21 (0.03-1.53) 0.14 (0.04-0.57) 0.70 (-0.47- 0.86) 7.10 (3.55-7.93) With prior immunity 1.18 (0.57-2.41) 0.40 (0.23-0.71) -0.06 (-0.49-0.15) 0.76 (0.37-0.98) Supplementary Files SupplementaryMaterialPaxlovidHosptanddeathV1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Negev","correspondingAuthor":false,"prefix":"","firstName":"Ruslan","middleName":"","lastName":"Sergienko","suffix":""},{"id":109578515,"identity":"44fcad63-8ad7-4fce-a7a7-5e2dae7976fc","order_by":6,"name":"Michael Friger","email":"","orcid":"","institution":"Ben-Gurion University of the Negev","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Friger","suffix":""},{"id":109578520,"identity":"d8c3d5de-56e1-41e7-9d9d-55b81af6f10e","order_by":7,"name":"Alon Peretz","email":"","orcid":"","institution":"Clalit Health Services","correspondingAuthor":false,"prefix":"","firstName":"Alon","middleName":"","lastName":"Peretz","suffix":""},{"id":109578521,"identity":"28ee4e17-3be6-462c-a371-fd7faee58b8a","order_by":8,"name":"Shlomit Yaron","email":"","orcid":"","institution":"Clalit Health Services","correspondingAuthor":false,"prefix":"","firstName":"Shlomit","middleName":"","lastName":"Yaron","suffix":""},{"id":109578522,"identity":"75d62bd3-01f4-47ad-b8ad-685fa2ea9560","order_by":9,"name":"Danielle Serby","email":"","orcid":"","institution":"Clalit Health Services","correspondingAuthor":false,"prefix":"","firstName":"Danielle","middleName":"","lastName":"Serby","suffix":""},{"id":109578523,"identity":"57849abe-5227-49cc-82d3-9519f421ec79","order_by":10,"name":"Ariel Hammerman","email":"","orcid":"","institution":"Clalit Health Services","correspondingAuthor":false,"prefix":"","firstName":"Ariel","middleName":"","lastName":"Hammerman","suffix":""},{"id":109578524,"identity":"d62ff36e-9cfa-4422-a4cc-40e056bfb09d","order_by":11,"name":"Doron Netzer","email":"","orcid":"","institution":"Clalit Health Services","correspondingAuthor":false,"prefix":"","firstName":"Doron","middleName":"","lastName":"Netzer","suffix":""}],"badges":[],"createdAt":"2022-05-29 14:54:10","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false,"coiExplicitlySet":false},"doi":"10.21203/rs.3.rs-1705061/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1705061/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":22148711,"identity":"598eb5f9-7661-49b7-b0f3-2c5b0cdb1e4f","added_by":"auto","created_at":"2022-06-01 19:00:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":24572,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssessment for Eligibility\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Onlinedrawingimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-1705061/v1/923a20d01978970c9d8e68ee.png"},{"id":22149033,"identity":"bc313482-994f-44fe-844c-c491d3b414a6","added_by":"auto","created_at":"2022-06-01 19:05:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":132350,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCumulative Hazard Ratio for Hospitalizations Due to Covid-19\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-1705061/v1/45454f1c5fae5b2c5286a031.png"},{"id":22149035,"identity":"b44bc238-dc32-499d-b3f5-84a53409517f","added_by":"auto","created_at":"2022-06-01 19:05:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":607922,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1705061/v1/ed7100f4-9dba-4cd5-8581-3548721bfa0d.pdf"},{"id":22149034,"identity":"d61c17e2-2a29-4a45-8747-ca2e43663d78","added_by":"auto","created_at":"2022-06-01 19:05:41","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":195753,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterialPaxlovidHosptanddeathV1.docx","url":"https://assets-eu.researchsquare.com/files/rs-1705061/v1/80a8c91e4200257d251c2cbf.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eOral Nirmatrelvir and Severe Covid-19 Outcomes During the Omicron Surge\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eThe emergence of the fast-spreading B.1.1.529 (omicron) variant of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in late 2021 led to a global coronavirus disease 2019 (Covid-19) resurgence. By the end of December 2021, omicron was outcompeting the B.1.617.2 (delta) variant, and by early January, omicron spread widely worldwide, even in communities with high levels of preexisting immunity (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe Food and Drug Administration (FDA) issued on December 22, 2021, an Emergency Use Authorization (EUA) for the oral antiviral nirmatrelvir for the treatment of mild to moderate Covid-19 in patients at a high risk of progression to severe disease (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Nirmatrelvir treatment is provided for five consecutive days as soon as possible after a diagnosis of Covid-19 and within 5 days of symptom onset (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The primary data supporting the FDA EUA came from the Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients (EPIC-HR) randomized, double-blind, placebo-controlled trial that studied nirmatrelvir treatment in non-hospitalized, high-risk, symptomatic adults with Covid-19 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). This trial was performed in a period when the delta variant was most likely responsible for the majority of infections (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). All participants in EPIC-HR were unvaccinated for Covid-19 and had not been previously confirmed infected with SARS-CoV-2. EPIC-HR demonstrated a relative risk reduction of 89% for hospitalization or death among those treated with nirmatrelvir. However, the effectiveness of nirmatrelvir against the omicron variant and in patients with prior Covid-19 immunity is unknown.\u003c/p\u003e \u003cp\u003eTherefore, our objective was to assess the effectiveness of nirmatrelvir therapy for preventing mortality and hospitalizations due to Covid-19 in high-risk patients during the omicron surge.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003e This observational, retrospective cohort study was based on data obtained from the electronic medical records of Clalit Health Services (CHS), a large healthcare organization covering approximately 52% of the entire Israeli population and almost two-thirds of the older adults.\u003c/p\u003e \u003cp\u003eThe study period started on January 9, 2022, the first day the drug was administered to CHS patients, and ended on March 10, 2022. During the study period, the omicron variant was the dominant strain in Israel (Fig. S1 in the Supplementary Appendix).\u003c/p\u003e \u003cp\u003ePatients were eligible to be included in the study if they were diagnosed with Covid-19 by February 24, 2022. Patients\u0026rsquo; follow-up ended at the earliest of the following: 35 days from diagnosis of Covid-19; the end of the study period; or if censored earlier due to hospitalization or death from any cause.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy Outcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome was hospitalizations due to Covid \u0026minus;\u0026thinsp;19. The secondary outcome was death due to Covid-19.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population\u003c/h2\u003e \u003cp\u003eThe study population included all CHS members 40 years of age and above with confirmed SARS-CoV-2 infection, estimated to be at high risk for progression to severe Covid-19, and determined eligible for nirmatrelvir therapy. High-risk participants were determined according to a score developed in CHS to evaluate the risk for severe Covid-19 in SARS-CoV-2 infected patients (Table S1). Eligibility to the antiviral therapy took into account also drug safety considerations, drug interactions, and contraindications as described in the nirmatrelvir FDA prescribing information (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). A nurse in each CHS district was responsible for delivering nirmatrelvir therapy to the patients\u0026rsquo; homes and verifying adherence to the treatment regimen. CHS policy was to initiate therapy in eligible patients as soon as possible after a positive SARS-CoV-2 test result to minimize the potential for hospitalizations in the high-risk population, as per FDA prescribing information (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003ePatients residing in long-term care facilities, patients hospitalized during the study period before a positive SARS-CoV-2 test result, and patients treated for Covid-19 during the study period with molnupiravir (the second oral antiviral available in Israel) were all excluded from the study.\u003c/p\u003e \u003cp\u003eThe study population was divided into two groups, those who received nirmatrelvir therapy (treatment group) and those who had not (control group). All eligible participants were included in the study\u0026rsquo;s control arm at the date of their positive SARS-CoV-2 test. Patients treated with nirmatrelvir were transferred to the treatment group when they received the initial dose.\u003c/p\u003e \u003cp\u003eThe study was approved by the Community IRB and data utilization committees of Clalit Health Services. Due to the retrospective design, the study was exempt from obtaining informed consent from the patients. No financial or in-kind support was provided for the conduct of the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData Sources and organization\u003c/h2\u003e \u003cp\u003e We evaluated integrated patient-level data maintained by CHS from two primary sources: the primary-care operational and Covid-19 databases. The operational database includes sociodemographic data and comprehensive clinical information, such as coexisting chronic illnesses, history of community care visits, medications, and results of laboratory tests. The Covid-19 database includes PCR and state-regulated rapid antigen test results, vaccinations provided, and Covid-19-related hospitalizations and death. The Covid-19 database is updated daily from the central Covid-19 repository of the Israeli Ministry of Health. These same databases were used in the primary studies that evaluated the effectiveness of the BNT162b2 vaccine in real-world settings in Israel (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). A description of the data repositories used in this study is provided in the Supplementary Appendix.\u003c/p\u003e \u003cp\u003e For each participant in the study, the following sociodemographic data were extracted: age, sex, demographic group (general Jewish population, ultra-Orthodox Jewish population, or Arab population), and the score for socioeconomic status (ranging from 1 [lowest] to 10 [highest], as described in the Supplement).\u003c/p\u003e \u003cp\u003eThe following clinical data were extracted: Covid-19 vaccination dates, PCR and state-regulated rapid antigen test dates and results, Covid-19 antiviral therapies, hospitalizations, and mortality. Data regarding the following clinical risk factors for severe Covid-19 were also collected: Immunosuppression, diabetes mellitus, asthma, hypertension, neurologic diseases, current cancer disease, chronic hepatic disease, chronic obstructive pulmonary disease, chronic kidney failure, chronic heart failure, obesity, history of stroke, history of or current smoking and recent hospitalizations (in the last three years) from all causes. The eGFR lab test results were obtained as well.\u003c/p\u003e \u003cp\u003eAll patients were classified into one of two categories according to their Covid-19 immune status; participants with no prior immunity (unvaccinated or vaccinated with only one mRNA vaccine dose and also with no previous documented SARS-CoV-2 infection) or participants that had already acquired prior immunity (vaccine-induced, infection-induced, or hybrid).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics were used to characterize the study participants. Since the independent variable (nirmatrelvir treatment) varied over time, univariate and multivariate survival analyses were performed with time-dependent covariates according to the study design. Participants were censored in cases of hospitalization or death from any cause or at the end of follow-up. Participants who received nirmatrelvir were censored from the control group on the day they received the antiviral therapy.\u003c/p\u003e \u003cp\u003eWe used a multivariate Cox proportional-hazards regression model to estimate the association of all covariates and uptake of nirmatrelvir therapy. The association of nirmatrelvir and Covid-19 outcomes was estimated using a multivariate Cox proportional-hazards regression model with time-dependent covariates, adjusted for sociodemographic factors and coexisting illnesses. All covariates were tested for interactions with the variable of interest (nirmatrelvir treatment). A Kaplan\u0026ndash;Meier analysis with a log-rank test was used for the univariate analysis. Comparison of the survival curves and Schoenfeld\u0026rsquo;s global test were used to test the proportional hazards assumption for each dependent variable. Variables that met the testing criteria served as inputs for multivariate regression analysis.\u003c/p\u003e \u003cp\u003eR statistical software version 3.5.0 (R Foundation) was used for the univariate and multivariate survival analysis with time-dependent covariates. SPSS software, version 26 (IBM), was utilized for all other statistical analyses. A two-sided P value of less than 0.05 was considered to indicate statistical significance in all analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient Population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of\u0026nbsp;109,213 participants\u0026nbsp;met the study criteria.\u0026nbsp;The assessment for eligibility is detailed in Figure 1.\u0026nbsp;The mean age of the study participants was 60, with 39% of the\u0026nbsp;participants\u0026nbsp;aged 65 years and older and 60% female. The most common coexisting conditions were obesity, diabetes, and smoking. 78% of participants had previous Covid-19 immunity, either by vaccination, prior SARS-CoV-2 infection, or hybrid immunity (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNirmatrelvir Uptake\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the entire population cohort, 3,939 participants (3.6%) received at least one dose\u0026nbsp;of nirmatrelvir therapy during the study period.\u0026nbsp;The association between patient characteristics and the\u0026nbsp;nirmatrelvir\u0026nbsp;uptake rate is described in Table S2. Uptake was notably higher in participants aged 65 years and above and among participants with a current cancer diagnosis. Uptake was significantly lower in participants with no prior Covid-19 immunity and within the Arab minority population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTesting the interaction of nirmatrelvir status with the other variables revealed a significant interaction with age group (above or below 65). We, therefore, report all results separately for these two age groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong the 66,394 patients\u0026nbsp;aged\u0026nbsp;40 to 64, hospitalizations due to Covid-19 occurred in 343 patients (0.5%): 9 (0.6%) out of 1,435 treated patients and 334 (0.5%) out of 64,959 untreated patients; adjusted hazard ratio (HR) for hospitalization was 0.78 (95% confidence interval (CI), 0.40 to 1.53).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong 42,819 patients 65 years of age and above, hospitalizations due to Covid-19 occurred in 776 patients (1.8%): 14 (0.6%) out of 2,504 treated patients and 762 (1.9%) out of 40,315 untreated patients; adjusted HR\u003cem\u003e\u0026nbsp;\u003c/em\u003e0.33 (95% CI, 0.19 to 0.55) (Table 2).\u0026nbsp;The cumulative hazard-ratio curves are shown in Figures 2a, 2b.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcross both age groups, lack of prior Covid-19 immunity and a previous hospitalization were variables most significantly associated with high rates of hospitalizations due to Covid-19. Immunosuppression was significantly associated with hospitalizations in the 40-64 age group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup Analysis by Immunity Status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong patients the 40-64 years of age, hospitalizations due to Covid-19 occurred in 182 of 20,531 patients (0.9%) without prior immunity and in 161 out of 45,863 (0.4%) with prior immunity. Among participants aged 65 years and above, hospitalizations due to Covid-19 occurred in 273 of 3,306 patients without prior immunity (8.3%) and in 503 of 39,513 patients with prior immunity (1.3%). The adjusted hazard ratios and absolute risk reductions of hospitalizations due to Covid-19 for nirmatrelvir therapy according to prior immunity status and age-group are presented in Table 3. Detailed Cox regression results are presented in tables S3, S4, S5, and S6.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary Outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong patients, 65 years of age and above, Covid-19 death occurred in 2 treated and 151 untreated patients; adjusted HR:\u003cem\u003e\u0026nbsp;\u003c/em\u003e0.19 (95% CI, 0.05 to 0.76). Among patients 40 to 64 years of age, Covid-19 death occurred in 1 treated and 13 untreated patients; adjusted HR: 1.64 (95% CI), 0.40 to 12.95). Detailed Cox regression results are presented in tables S7 and S8.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAt the beginning of the omicron surge in January 2022, the Israeli authorities decided to set two lines of defense to protect the vulnerable and high-risk populations from severe Covid-19. The first line was approving a second-booster vaccine dose (8). The second was suggesting nirmatrelvir to patients at high risk for Covid-19 hospitalizations. Eligibility for nirmatrelvir was much broader than that was defined in\u0026nbsp;the EPIC-HR registration trial\u0026nbsp;(4), as it also included\u0026nbsp;patients with prior immunity, which were the majority of high-risk patients in the Israeli population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTreatment with nirmatrelvir is currently recommended by the United States\u0026nbsp;\u003ca href=\"https://www.nih.gov/\" target=\"_blank\"\u003eNational Institutes of Health\u003c/a\u003e (NIH) Covid-19 treatment guidelines as the first choice for antiviral therapy for non-hospitalized adults at high risk of disease progression (9). However, the NIH stated that there is currently a lack of data on the clinical efficacy of nirmatrelvir against the omicron variant of concern (10).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBesides in-vitro studies in experimental models that have demonstrated potent inhibition of the omicron variant by nirmatrelvir (11-14), effectiveness data in real-life patients infected with omicron are still unavailable.\u0026nbsp;Similarly, nirmatrelvir efficacy has only been demonstrated in patients without prior immunity, while in the real world, many of the individuals hospitalized with omicron have prior immunity by vaccinations or prior infections (15).\u003c/p\u003e\n\u003cp\u003eThe findings from our current study suggest that during the omicron variant surge, Covid-19 hospitalizations rates were significantly lower in adults aged 65 years and above in nirmatrelvir treated participants, both in patients with and without prior Covid-19 immunity. The absolute benefit of therapy was substantially higher in patients without prior immunity. Covid-19 mortality rates were also 81% lower in nirmatrelvir treated participants of this age group. However, no significant benefit was shown in the younger cohort.\u003c/p\u003e\n\u003cp\u003eAn observed difference in nirmatrelvir efficacy between patients older and younger than 65 was also demonstrated in\u0026nbsp;the subgroup analysis of EPIC HR; \u0026nbsp;The benefit from nirmatrelvir in participants younger than 65 was substantially less than in the older age group (a reduction of 13.93 percentage points relative to placebo in the \u003cu\u003e\u0026gt;\u003c/u\u003e 65-year group versus 4.35 in participants younger than 65).\u003c/p\u003e\n\u003cp\u003eThe observed risk for hospitalizations due to Covid-19 in our study period (dominated by omicron) was significantly lower than what was reported in EPIC-HR during the delta wave, as expected (16). The risk in the 40-64 age group was ten-fold lower than in the comparable age group of EPIC-HR (0.5% vs. 5.1%). The baseline risk was low even in the subgroup without prior Covid-19 immunity (0.9%). The risk in the 65+ group was also significantly lower than the comparable EPIC-HR age group (1.8% vs.14.6%). However, within this higher age group, the subgroup without prior immunity had a much higher event rate in the non-treated patients (8.3%) and had a substantially higher absolute benefit (7.1 percentage points).\u003c/p\u003e\n\u003cp\u003eOur study has several strengths. First, the results are based on the integrated medical records system of CHS, with detailed demographic, clinical, and laboratory testing data, including data on coexisting conditions that could have significantly affected hospitalization rates and were therefore adjusted for in the statistical analysis. The second important strength is the large cohort of participants available for analysis and the relevant large number of events to be analyzed, substantially higher than in the published randomized controlled trials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs in any retrospective cohort trial, confounding clinical and sociodemographic characteristics may have biased the observed effectiveness. We attempted to overcome these biases by adjusting for the variables known to affect Covid-19 hospitalizations. However, some sources of bias may not have been measured or corrected adequately.\u003c/p\u003e\n\u003cp\u003eOur study observed that only a minority of patients defined as high-risk patients and eligible for nirmatrelvir therapy received antiviral therapy.\u0026nbsp;We do not know why controls did not receive treatment, and therefore, it is our main concern regarding residual bias.\u0026nbsp;We also do not know the actual level of treatment adherence and, therefore, may be underestimating the effectiveness; if participants took less of the treatment, they are still included in the treatment group but did not benefit from the complete treatment course.\u003c/p\u003e\n\u003cp\u003eA major concern of potential unmeasured bias is the lack of data regarding the specific symptoms of the infected patients. Moreover, CHS policy was to administer therapy as soon as possible, even before the onset of symptoms, per FDA prescribing information (3). Patients with worse symptoms are presumably more likely to be offered and agree to receive therapy. This potential bias may underestimate the effectiveness of therapy. However, they may also be at a higher risk of hospitalization, overestimating effectiveness.\u0026nbsp;Specifically, a substantial proportion of the observed effect occurs in the first two days of follow-up. As the hospitalizations in the clinical trial occurred mainly after the second day of follow-up, we cannot estimate whether the observed early effect results from residual bias or true early effectiveness.\u003c/p\u003e\n\u003cp\u003eAnother limitation is the heterogeneity of degrees of immunity in the subgroup with prior immunity. This group included patients with infection-induced, vaccine-induced, and hybrid-induced immunity, disregarding any waning of such immunity over time. Nevertheless, our results in the subgroup of patients aged 65 and above without previous immunity are comparable to the results from EPIC-HR. Larger studies will be necessary to evaluate possible differences in nirmatrelvir effectiveness in these different subgroups.\u003c/p\u003e\n\u003cp\u003eA further limitation is the rate of SARS-CoV-2 infections and thus exposure to disease that changed during the study period. However, we assume that after adjustment for all covariates, including socioeconomic ones, these changes affected the treated and untreated populations similarly.\u003c/p\u003e\n\u003cp\u003eIt should be noted that the evaluation of adverse events and safety data reports was beyond the scope of this study. Future studies will be needed to assess the short- and long-term safety of nirmatrelvir administration in real-world settings.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eNirmatrelvir therapy was associated with a significant reduction in Covid-19 hospitalizations and mortality rates in adults aged 65 and higher during the omicron variant surge. Although this study is observational, we believe that its findings and the observed potential for avoiding severe Covid-19 could assist decision-makers in prioritizing the currently constrained supplies to those in whom nirmatrelvir was shown to be substantially effective.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Rubin EJ, Baden LR, Morrissey S. Audio Interview: Understanding the Omicron Variant of SARS-CoV-2. N Engl J Med 2022; 386:e27\u003c/p\u003e\n\u003cp\u003eDOI: 10.1056/NEJMe2202699\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;FDA News Release, December 22, 2021; Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19. Available online: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Food and Drug Administration Fact Sheet for Healthcare Providers: Emergency Use Authorization for Paxlovid; 2021. Available online: https://www.fda.gov/media/155050/download.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Hammond J, Leister-Tebbe H, Gardner A, et al.; EPIC-HR Investigators. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022 Feb 16. doi: 10.1056/NEJMoa2118542.\u003c/p\u003e\n\u003cp\u003e5.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Rubin EJ, Baden LR. The Potential of Intentional Drug Development. N Engl J Med. 2022 Feb 16:NEJMe2202160. doi: 10.1056/NEJMe2202160.\u003c/p\u003e\n\u003cp\u003e6.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med. 2021;384:1412-1423.\u003c/p\u003e\n\u003cp\u003e7.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Arbel R, Hammerman A, Sergienko R, et al. BNT162b2 Vaccine Booster and Mortality Due to Covid-19. N Engl J Med. 2021;385:2413-2420.\u003c/p\u003e\n\u003cp\u003e8.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Arbel R, Sergienko R, Friger M, et al. Effectiveness of a second BNT162b2 booster vaccine against hospitalization and death from COVID-19 in adults aged over 60\u0026thinsp;years. Nat Med. 2022 Apr 25. doi: 10.1038/s41591-022-01832-0.\u003c/p\u003e\n\u003cp\u003e9.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;NIH Covid-19 Treatment Guidelines, Therapeutic Management of Nonhospitalized Adults With COVID-19 (Updated \u0026nbsp;April 1, 2022) Available online: https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management\u003c/p\u003e\n\u003cp\u003e10.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;NIH Covid-19 Treatment Guidelines, Ritonavir-Boosted Nirmatrelvir (Paxlovid) (Updated February 24, 2022) Available online: https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir--paxlovid-/?utm_source=site\u0026amp;utm_medium=home\u0026amp;utm_campaign=highlights\u003c/p\u003e\n\u003cp\u003e11.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of Antibodies and Antiviral Drugs against Covid-19 Omicron Variant. N Engl J Med. 2022 Mar 10;386(10):995-998. doi: 10.1056/NEJMc2119407.\u003c/p\u003e\n\u003cp\u003e12.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2. N Engl J Med. 2022 Mar 9:NEJMc2201933. doi: 10.1056/NEJMc2201933.\u003c/p\u003e\n\u003cp\u003e13.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Li P, Wang Y, Lavrijsen M, et al. SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination. Cell Res. 2022 Mar;32(3):322-324. doi: 10.1038/s41422-022-00618-w.\u003c/p\u003e\n\u003cp\u003e14.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Vangeel L, Chiu W, De Jonghe S, et al. Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022 Feb;198:105252. doi: 10.1016/j.antiviral.2022.105252.\u003c/p\u003e\n\u003cp\u003e15.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Collie S, Champion J, Moultrie H, et al. Effectiveness of BNT162b2 Vaccine against Omicron Variant in South Africa. N Engl J Med. 2022 Feb 3;386(5):494-496. doi: 10.1056/NEJMc2119270.\u003c/p\u003e\n\u003cp\u003e16. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Callaway E, Ledford H. How bad is omicron? What scientists know so far. Nature. 2021;600:197-199.\u003c/p\u003e"},{"header":"Tables","content":"\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:200%;\"\u003eTable 1: Characteristics of the Participants at Baseline\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width:425.0pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 304.55pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003eCharacteristic\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120.45pt;border-color: windowtext windowtext windowtext currentcolor;border-style: solid solid solid none;border-width: 1pt 1pt 1pt medium;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 15pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003eAll Participants\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e(N=109,213)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 304.55pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 98.8pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003eAge\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Mean \u003cu\u003e+\u003c/u\u003e SD - yr\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Distribution- no. (%)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;40-64 yr\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003cu\u003e\u0026gt;\u003c/u\u003e65 yr\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120.45pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 98.8pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e59.9 \u003cu\u003e+\u003c/u\u003e 12.8\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e66,394 (61)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e42,819 (39)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 304.55pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 14.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003eFemale sex \u0026nbsp; \u0026nbsp;- \u0026nbsp;no. (%) \u0026nbsp;\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120.45pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 14.5pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e65,699 (60)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 304.55pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 63.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003ePopulation sector- no. (%) \u0026nbsp;\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;General Jewish\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp;Ultra-Orthodox Jewish\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp;Arab\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120.45pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 63.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e81,865 (75)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e6,350 (6)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e20,998 (19)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 304.55pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 0.25in;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003eMedian score for socioeconomic status, Median (IQR)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120.45pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 0.25in;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e5 (2)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 304.55pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 211.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003eClinical risk factors\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"line-height:150%;\"\u003e- \u0026nbsp;no. (%) \u0026nbsp;\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Obesity\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; Hypertension\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; Diabetes\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; Current or former smoking \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; Immunosuppression\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp;\u0026nbsp;Neurologic disease\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp;\u0026nbsp;Current cancer disease\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; Asthma\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; History of stroke\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; Chronic hepatic disease\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; Chronic obstructive pulmonary disease\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; Chronic heart failure \u0026nbsp; \u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Chronic kidney failure\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Recent hospitalization \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120.45pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 211.9pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e37,757 (35)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e37,132 (34)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e28,656 (26)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e26,640 (24)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e10,816 (10)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e9,254 (9)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e7,621 (7)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e6,440 (6)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e5,687 (5)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e4,853 (4)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e3,494 (3)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e3,176 (3)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e1,470 (1)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e31,814 (29)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 304.55pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 62.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003eCovid-19 immune status\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"line-height:150%;\"\u003e- \u0026nbsp;no. (%)\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp;No prior immunity\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp;With prior immunity \u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120.45pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 62.6pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e23,837 (22)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e85,376 (78)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:normal;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003eTable 2: Association between Hospitalizations due to Covid-19 and Demographic and Clinical Variables, According to Age Group*\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width:460.45pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 233.65pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 28.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003eVariable\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 3.15in;border-color: windowtext windowtext windowtext currentcolor;border-style: solid solid solid none;border-width: 1pt 1pt 1pt medium;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 28.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003eHazard Ratio for Hospitalization Due to Covid-19 (95% CI)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 233.65pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 28.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 28.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e40-64 Yr of Age\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e(N=66,394)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 28.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cu\u003e\u003cspan style=\"line-height: 150%;\"\u003e\u0026gt;\u003c/span\u003e\u003c/u\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e65 Yr of Age\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e(N=42,819)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 233.65pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003eNirmatrelvir therapy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e0.78 (0.40-1.53)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e0.33 (0.19-0.55)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 233.65pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003eMale Sex\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;color:#010205;\"\u003e1.55 (1.25-1.92)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e1.62 (1.40-1.87)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 233.65pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003eScore for socioeconomic status\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;color:#010205;\"\u003eNA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e0.89 (0.86-0.93)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 233.65pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003eNo prior immunity\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;color:#010205;\"\u003e6.20 (4.92-7.81)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e5.81 (4.98-6.78)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 233.65pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 68.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003eClinical risk factors\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Recent hospitalization\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Obesity\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Diabetes\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Immunosuppression\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Chronic hepatic disease\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Neurologic disease\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Chronic heart failure\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp;Chronic obstructive pulmonary disease\u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; History of stroke\u0026nbsp;\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Chronic kidney failure\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 68.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height: 150%; color: rgb(1, 2, 5); background-position: 0% 0%; background-repeat: repeat; background-attachment: scroll; background-image: none; background-size: auto; background-origin: padding-box; background-clip: border-box;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e3.11 (2.47-3.91)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e1.28 (1.02-1.60)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan dir=\"RTL\" style=\"line-height:150%;\"\u003e1.34\u003c/span\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;(\u003cspan dir=\"RTL\"\u003e1.04\u003c/span\u003e-\u003cspan dir=\"RTL\"\u003e1.72\u003c/span\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan dir=\"RTL\" style=\"line-height:150%;\"\u003e2.91\u003c/span\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;(\u003cspan dir=\"RTL\"\u003e2.24\u003c/span\u003e-\u003cspan dir=\"RTL\"\u003e3.79\u003c/span\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan dir=\"RTL\" style=\"line-height:150%;\"\u003e1.72\u003c/span\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;(\u003cspan dir=\"RTL\"\u003e1.20\u003c/span\u003e-\u003cspan dir=\"RTL\"\u003e2.44\u003c/span\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan dir=\"RTL\" style=\"line-height:150%;\"\u003e1.73\u003c/span\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;(\u003cspan dir=\"RTL\"\u003e1.24\u003c/span\u003e-\u003cspan dir=\"RTL\"\u003e2.40\u003c/span\u003e)\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan dir=\"RTL\" style=\"line-height:150%;\"\u003e2.57\u003c/span\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;(1.72-3.83)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003eNA\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e1.86 (1.28-2.72)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003eNA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113.4pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 68.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e2.10 (1.80-2.45)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003eNA\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e1.36 (1.18-1.57)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003eNA\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003eNA\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e1.59 (1.34-1.88)\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e1.48 (1.20-1.82)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e1.75 (1.42-2.17)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e1.39 (1.16-1.66)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e1.80 (1.35-2.40)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:normal;font-size:16px;font-family:\"Times New Roman\",serif;text-indent:.5in;'\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:normal;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e*The association between nirmatrelvir therapy and hospitalizations due to Covid-19 was estimated utilizing a multivariate Cox proportional-hazards regression model after adjustment for sociodemographic factors, coexisting illnesses, and Covid-19 immune status. Variables that met the testing criteria and were significantly associated with the outcome served as the inputs for the multivariate regression analysis.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:107%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:normal;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003eTable 3: Rates and Hazard Ratios for Hospitalizations due to Covid-19, Subgroup Analysis According to Immunity Status\u003c/strong\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:normal;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 4.6e+2pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 141.5pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 69.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003eVariable\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 155.95pt;border-color: windowtext windowtext windowtext currentcolor;border-style: solid solid solid none;border-width: 1pt 1pt 1pt medium;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 69.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003eHazard Ratio for Hospitalization (95% CI)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 163pt;border-color: windowtext windowtext windowtext currentcolor;border-style: solid solid solid none;border-width: 1pt 1pt 1pt medium;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 69.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003eAbsolute Benefit -\u003cbr\u003e\u0026nbsp;Percentage Points\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;(95% CI)\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 141.5pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 28.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85.05pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 28.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e40-64 Yr \u003cbr\u003e\u0026nbsp;of age\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70.9pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 28.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cu\u003e\u003cspan style=\"line-height: 150%;\"\u003e\u0026gt;\u003c/span\u003e\u003c/u\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e65 Yr \u003cbr\u003e\u0026nbsp;of Age\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.95pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 28.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e40-64 Yr\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003eof age\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85.05pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 28.7pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cstrong\u003e\u003cu\u003e\u003cspan style=\"line-height: 150%;\"\u003e\u0026gt;\u003c/span\u003e\u003c/u\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style=\"line-height:150%;\"\u003e65 Yr \u003cbr\u003e\u0026nbsp;of age\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 141.5pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003eAll patients\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85.05pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e0.78 \u003cbr\u003e\u0026nbsp;(0.40-1.53)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70.9pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e0.33\u003cbr\u003e\u0026nbsp; (0.19-0.55)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.95pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e0.11 \u003cbr\u003e\u0026nbsp;(-0.27- 0.33)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85.05pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e1.21\u003cbr\u003e\u0026nbsp; (0.82-1.47)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 141.5pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; No prior immunity\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85.05pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e0.21\u003cbr\u003e\u0026nbsp; (0.03-1.53)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70.9pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e0.14\u003cbr\u003e\u0026nbsp; (0.04-0.57)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.95pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e0.70\u003cbr\u003e\u0026nbsp; (-0.47- 0.86)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85.05pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e7.10 \u003cbr\u003e\u0026nbsp;(3.55-7.93)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 141.5pt;border-color: currentcolor windowtext windowtext;border-style: none solid solid;border-width: medium 1pt 1pt;border-image: none 100% / 1 / 0 stretch;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"line-height:150%;\"\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; With prior immunity\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85.05pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;color:#010205;\"\u003e1.18\u003cbr\u003e\u0026nbsp; (0.57-2.41)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70.9pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;\"\u003e0.40 \u003cbr\u003e\u0026nbsp;(0.23-0.71)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.95pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;color:#010205;\"\u003e-0.06 \u003cbr\u003e\u0026nbsp;(-0.49-0.15)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85.05pt;border-color: currentcolor windowtext windowtext currentcolor;border-style: none solid solid none;border-width: medium 1pt 1pt medium;padding: 0in 5.4pt;height: 30pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:150%;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"line-height:150%;color:#010205;\"\u003e0.76 \u003cbr\u003e\u0026nbsp;(0.37-0.98)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Clalit Health Services","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-1705061/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1705061/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eNirmatrelvir, an inhibitor of the main protease of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has demonstrated a significant decrease in the risk of progression to severe disease in symptomatic high-risk patients infected with the B.1.617.2 (delta) variant of SARS-CoV-2. The effectiveness of nirmatrelvir against the B.1.1.529 variant (omicron) is unknown.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe study included all Clalit Health Services members, 40 years of age and older, with confirmed infection of SARS-CoV-2 during the omicron surge that were defined as high-risk for severe disease. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association between nirmatrelvir treatment and hospitalizations and deaths due to Covid-19, with adjustment for individual sociodemographic factors, coexisting conditions, and prior Covid-19 immunity status.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e109,213 participants were eligible for nirmatrelvir therapy during the two-month study period. Among the 42,819 eligible patients aged 65 years and above, 2,504 were treated with nirmatrelvir. Hospitalizations due to Covid-19 occurred in 14 out of the treated and 762 of the untreated patients: adjusted HR 0.33 (95% CI, 0.19 to 0.55). Death due to Covid-19 occurred in 2 treated and 151 untreated patients; adjusted HR: 0.19 (95% CI, 0.05 to 0.76). Among the 66,394 eligible patients 40 to 64 years of age, 1,435 were treated with nirmatrelvir. Hospitalizations due to Covid-19 occurred in 9 treated and 334 untreated patients: adjusted HR 0.78 (95% CI, 0.40 to 1.53). Death due to Covid-19 occurred in 1 treated and 13 untreated patients; adjusted HR: 1.64 (95% CI, 0.40 to 12.95).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eNirmatrelvir therapy was associated with a 67% reduction in Covid-19 hospitalizations and an 81% reduction in Covid-19 mortality in patients 65 years and above. However, no significant benefit in avoidance of severe Covid-19 outcomes was shown in younger adults.\u003c/p\u003e","manuscriptTitle":"Oral Nirmatrelvir and Severe Covid-19 Outcomes During the Omicron Surge","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-06-01 19:00:39","doi":"10.21203/rs.3.rs-1705061/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"355093d4-fe3c-4e95-be73-2648be94d3f7","owner":[],"postedDate":"June 1st, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":12981529,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2022-06-01T19:00:39+00:00","versionOfRecord":[],"versionCreatedAt":"2022-06-01 19:00:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1705061","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1705061","identity":"rs-1705061","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}