Paxlovid Associated with Decreased Hospitalization Rate Among Adults with COVID-19 — United States, April–September 2022

Nirmatrelvir-ritonavir (Paxlovid), an oral antiviral treatment, is authorized for adults with mild-to-moderate COVID-19 who are at increased risk for progression to severe illness. However, real-world evidence on the benefit of Paxlovid, according to vaccination status, age group, and underlying health conditions, is limited. To examine the benefit of Paxlovid in adults aged ≥18 years in the United States, a large electronic health record (EHR) data set (Cosmos†) was analyzed to assess the association between receiving a prescription for Paxlovid and hospitalization with a COVID-19 diagnosis in the ensuing 30 days. A Cox proportional hazards model was used to estimate this association, adjusted for demographic characteristics, geographic location, vaccination, previous infection, and number of underlying health conditions. Among 699,848 adults aged ≥18 years eligible for Paxlovid during April-August 2022, 28.4% received a Paxlovid prescription within 5 days of COVID-19 diagnosis. Being prescribed Paxlovid was associated with a lower hospitalization rate among the overall study population (adjusted hazard ratio [aHR] = 0.49), among those who had received ≥3 mRNA COVID-19 vaccines (aHR = 0.50), and across age groups (18-49 years: aHR = 0.59; 50-64 years: aHR = 0.40; and ≥65 years: aHR = 0.53). Paxlovid should be prescribed to eligible adults to reduce the risk of COVID-19-associated hospitalization.

company (https://cosmos.epic.com). Inclusion criteria comprised 1) diagnosis of COVID-19 or a positive SARS-CoV-2 test result during April 1-August 31, 2022; ¶ 2) an outpatient encounter (telemedicine, in-person, urgent care, emergency department, or other)** associated with the COVID-19 diagnosis; 3) at least one previous face-to-face encounter in Cosmos during the 3 years preceding the COVID-19 diagnosis; yy 4) age !50 years, or !18 years with a documented underlying health condition based on International Classification of Diseases, Tenth Revision (ICD-10) codes or medical record fields; xx 5) not known to be pregnant; and 6) not known to have pharmacologic or medical contraindications to Paxlovid use. ¶ ¶ For patients with multiple SARS-CoV-2 infections during the study period, only data from the first infection were used in the analysis; date of diagnosis (earliest COVID-19 diagnosis code or positive SARS-CoV-2 test result) was used as a proxy for symptom onset, and Paxlovid receipt was defined as receiving a prescription for Paxlovid during the 5 days after COVID-19 diagnosis.*** The primary outcome was overnight COVID-19 hospitalization during the 30 days after the date of diagnosis; secondary outcomes were all-cause hospitalization and acute respiratory illness (ARI)-associated hospitalization. yyy Association between Paxlovid receipt and subsequent hospitalization was assessed using a Cox proportional hazards model, including age group, sex, race and ethnicity, social vulnerability index, xxx number of underlying health conditions, U.S. Census Bureau region of residence, previous COVID-19 infection, and COVID-19 vaccination status. ¶ ¶ ¶ In-hospital COVID-19 mortality during an admission commencing during the 30-day follow-up period was described but not used as an analytic outcome because of concern about underascertainment. Persons receiving Paxlovid contributed unexposed time until the prescription date and exposed time after the prescription date; those not receiving Paxlovid contributed unexposed time. Follow-up time ended when a hospitalization occurred or at 30 days after diagnosis, whichever came first. To assess possible bias related to symptom severity at diagnosis, primary analyses were repeated either excluding telemedicine visits, or excluding patients hospitalized during the 2 days after diagnosis. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.**** Among 1,713,120 persons aged !18 years with a COVID-19 diagnosis during April 1-August 31, 2022, 699,848 (40.9%) met the inclusion criteria, including 198,927 who received Paxlovid within 5 days after diagnosis and 500,921 who did not (Fig) Paxlovid receipt was associated with protection against hospitalization overall (aHR ¼ 0.49, 95% CI ¼ 0.46-0.53) ( Table 2), including among persons who had received !3 mRNA vaccine doses (0.50, 95% CI ¼ 0.45-0.55) and 2 previous mRNA vaccine doses (0.50, 95% CI ¼ 0.42-0.58). Paxlovid receipt was associated with lower hospitalization rates among persons aged 18-49 years (aHR ¼ 0.59, 95% CI ¼ 0.48-0.71), 50-64 years (0.40, 95% CI ¼ 0.34-0.48), and !65 years (0.53, 95% CI ¼ 0.48-0.58). Among persons aged 18-49 years, Paxlovid receipt was associated with lower hospitalization rates among persons who had received !3 mRNA vaccine doses (aHR ¼ 0.75, 95% CI ¼ 0.53-1.06) and those with only one underlying health condition (aHR ¼ 0.91, 95% CI ¼ 0.58-1.44), but these estimates did not reach statistical significance. Estimated protection by Paxlovid was similar by month of diagnosis. Findings from sensitivity analyses, excluding telemedicine encounters and patients hospitalized during the first 2 days after diagnosis, also indicated significant reduction in hospitalization among ¶ ICD-10 codes U07.

Discussion
In a sample of U.S. COVID-19 patients, many of whom had previous SARS-CoV-2 infection or were vaccinated against COVID-19, the overall COVID-19 hospitalization rate was 51% lower among those who had received a prescription for Paxlovid for presumed mild-to-moderate COVID-19, compared with those who did not. Similar benefit was seen among persons who had received !2 COVID-19 mRNA vaccine doses. The initial randomized clinical trial of Paxlovid, which showed an 89% reduction in severe COVID-19 outcomes, was conducted in unvaccinated persons with no previous infection during the period preceding Omicron variant predominance (2). This real-word analysis demonstrated that being prescribed Paxlovid is associated with a substantially reduced hospitalization risk among persons with previous immunity from infection or vaccination in the setting of the current circulating Omicron subvariants. These findings parallel those of other studies indicating added protection from Paxlovid even among persons with previous infection or vaccination (3)(4)(5)(6)(7)(8). Paxlovid conferred stable protection during a period in which multiple Omicron subvariants predominated in the United States. Protection against different predominant SARS-CoV-2 subvariants is consistent with Paxlovid's mechanism of action, which inhibits a highly conserved viral protease (9).
Current guidelines for Paxlovid indicate that persons who are at high risk for progression to severe COVID-19-associated outcomes should be considered for Paxlovid, with older age being a predominant risk factor (10). A study from Israel among persons with mild-to-moderate COVID-19 found comparable benefit from Paxlovid against severe outcomes among persons aged !65 years but did not find statistical evidence of protection among younger age groups (3). The current analysis adds to overall evidence of protection from Paxlovid by finding a statistically significant benefit among adults aged 18-64 years, specifically among adults aged 50-64 years with one or more underlying health condition and those aged 18-49 years with two or more underlying health conditions. Although ascertainment of deaths was limited to those with a documented death during the COVID-19 hospital admission, the proportion of persons with in-hospital death was also lower among persons who received Paxlovid (0.01%) than among those who did not (0.04%).
The findings in this report are subject to at least seven limitations. First, receipt of a Paxlovid prescription is a proxy for use of Paxlovid. Paxlovid course completion could not be confirmed, which might bias the results toward the null. Second, dates of diagnosis or test positivity were used to estimate illness onset but might not reflect date of symptom onset, or the presence of mild-to-moderate COVID-19 symptoms. Third, possible inclusion of asymptomatic COVID-19 infection in the nonrecipient comparison group could bias estimates toward the null. Fourth, participants with mild illness might be overrepresented among Paxlovid prescription recipients compared with nonrecipients, given the higher proportion of telemedicine visits, potentially leading to overestimation of protection from Paxlovid; however, a sensitivity analysis restricted to inperson encounters showed similar overall results. Fifth, underlying health conditions and immunocompromise were approximated using ICD-10 codes or medical record fields and might not capture the exact prevalences of these conditions. Sixth, although available vaccination information is automatically collected at each encounter, incomplete information could have limited differences in estimates by vaccination status. Finally, hospitalizations might be incompletely ascertained in Cosmos; this limitation was mitigated by including only persons with previous face-to-face encounters, indicating higher likelihood of hospitalization within a participating health system.
This study demonstrates that Paxlovid provides protection against severe COVID-19-associated outcomes among persons for whom it is recommended, including those with vaccine-conferred immunity, and that it is underutilized among eligible persons with COVID-19. In this analysis, only 28% of eligible persons were prescribed Paxlovid. The ease of oral administration, short duration of therapy, and lower likelihood for resistance make Paxlovid a useful antiviral. Reduction in nonsevere outcomes, such as duration, number, and intensity of COVID-19 Table 2 Adjusted hazard ratios for COVID-19-associated hospitalization based on Paxlovid prescription receipt (exposure) -Cosmos,* United States, April-September 2022. symptoms, requires further study. Paxlovid should be offered to eligible persons to protect against COVID-19 hospitalizations, irrespective of vaccination status, and especially among groups with the highest risk for severe outcomes, such as older adults and those with multiple underlying health conditions.