Effectiveness of nirmatrelvir-ritonavir against hospital admission or death: a cohort study in a large US healthcare system
Authors: Lewnard Joseph A. , McLaughlin John M. , Malden Debbie , Hong Vennis , Puzniak Laura , Ackerson Bradley K. , Lewin Bruno J. , Kim Jeniffer S. , Shaw Sally F. , Takhar Harpreet , Jodar Luis , Tartof Sara Y. 
Published: October 2022

Background

In the United States, oral nirmatrelvir-ritonavir (Paxlovid™) is authorized for use among patients aged ≥12 years with mild-to-moderate SARS-CoV-2 infection who are at risk for progression to severe COVID-19, including hospitalization. However, effectiveness under current real-world prescribing practices in outpatient settings is unclear.

Methods

We undertook a matched observational cohort study of non-hospitalized cases with SARS-CoV-2 infection to compare outcomes among those who received or did not receive nirmatrelvir-ritonavir within the Kaiser Permanente Southern California healthcare system. Cases were matched on testing date, age, sex, clinical status (including care received, presence or absence of acute COVID-19 symptoms at testing, and time from symptom onset to testing), history of vaccination, Charlson comorbidity index, prior-year healthcare utilization, and body mass index. Primary analyses evaluated effectiveness of nirmatrelvir-ritonavir in preventing hospital admission or death within 30 days after a positive test. Secondary analyses evaluated effectiveness against intensive care unit admission, mechanical ventilation, or death within 60 days after a positive test. We measured treatment effectiveness as (1–adjusted hazards ratio [aHR])×100%, estimating the aHR via Cox proportional hazards models.

Results

Analyses included 7,274 nirmatrelvir-ritonavir recipients and 126,152 non-recipients with positive results from SARS-CoV-2 tests undertaken in outpatient settings between 8 April and 7 October, 2022. Overall, 114,208 (85.6%) and 81,739 (61.3%) of 133,426 participants had received ≥2 and ≥3 COVID-19 vaccine doses, respectively. A total of 111,489 (83.6% of 133,426) cases were symptomatic at the point of testing, with 5,472 (75.2% of 7,274) treatment recipients and 84,657 (67.1% of 126,152) non-recipients testing within 0–5 days after symptom onset. Effectiveness in preventing hospital admission or death within 30 days after a positive test was 79.6% (95% confidence interval: 33.9% to 93.8%) for cases dispensed nirmatrelvir-ritonavir within 0–5 days after symptom onset; within the subgroup of cases tested 0–5 days after symptom onset and dispensed treatment on the day of their test, effectiveness was 89.6% (50.2% to 97.8%).

Effectiveness declined to 43.8% (–33.3% to 81.7%) for treatment course dispensed ≥6 days after symptom onset or to cases who were not experiencing acute clinical symptoms. Overall, for cases dispensed treatment at any time within their clinical course, effectiveness was 53.6% (6.6% to 77.0%). Effectiveness in preventing the secondary endpoint of intensive care unit admission, mechanical ventilation, or death within 60 days after a positive test was 89.2% (–25.0% to 99.3%) for cases dispensed treatment 0–5 days after symptom onset and 84.1% (18.8% to 96.9%) for cases dispensed treatment at any time. Subgroup analyses identified similar effectiveness estimates among cases who had received ≥2 or ≥3 COVID-19 vaccine doses.

Implications

In a setting with high levels of COVID-19 vaccine and booster uptake, receipt of nirmatrelvir-ritonavir 0–5 days after symptom onset was associated with substantial reductions in risk of hospital admission or death within 30 days after a positive outpatient SARS-CoV-2 test.

Funding

US Centers for Disease Control and Prevention, US National Institutes of Health