Does nirmatrelvir and ritonavir reduce the risk of hospitalization or death among outpatients with early COVID-19?

In a recent study published in the Annals of Internal Medicineresearchers investigated the efficacy of ritonavir and nirmarelvir combination treatment in reducing the risk of coronavirus disease 2019 (COVID-19) severity outcomes such as hospital admissions and deaths when administered during the initial period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 2) infections.

Study: Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large US Health System. Image Credit: Cryptographer/Shutterstock


In April 2022, the WHO (World Health Organization) advocated ritonavir plus nirmatrelvir use for high-risk individuals with >10.0% hospitalization probability but not for low-risk and vaccinated individuals. Recent studies conducted during the SARS-CoV-2 Omicron variant of concern (VOC) dominance have reported a probable immune benefit of the combination drug treatment, regardless of the status of vaccination. However, only a few study participants received ritonavir plus nirmatrelvir.

The EPIC-HR (evaluation of protease inhibition for COVID-19 in high-risk patients) clinical trial findings showed an 89% decrease in COVID-19-associated hospital admissions and deaths among non-vaccinated SARS-CoV-2-positive patients after ritonavir plus nirmatrelvir treatment during the initial COVID-19 period.

However, the effects of the drug combination among COVID-19 vaccines have not been well-characterized. Further research on the ritonavir plus nirmarelvir combination’s clinical efficacy could inform health policy-making and decision-making for COVID-19 mitigation.

About the study

In the present population-based study, researchers assessed the efficacy of ritonavir and nirmatrelvir combination in reducing COVID-19-associated hospitalizations and deaths when administered to COVID-19 outpatients during the initial COVID-19 period.

The study was conducted between January 1 and July 17, 2022, during which the Omicron BA.1.1 sub-VOC, BA.2 sub-VOC, BA.2.12.1 sub-VOC, and the BA.5 sub-VOC were dominant . The study comprised 44,551 non-hospitalized adult COVID-19 patients (90% with ≥three-dose vaccinations) aged ≥50.0 years who were not contraindicated for ritonavir or nirmarelvir use and had no SARS-CoV-2-positive molecular testing reports in the preceding 90.0 days of the study.

During the study period, data were obtained from electronic health records (EHRs) of 1.5 million individuals registered with the Mass General Brigham United States (US) healthcare system. Hospitalizations through July 31, 2022, and deaths through August 14, 2022, were documented. The system includes two academic hospitals, seven community-based hospitals, and several community-based healthcare centers and clinics located in New Hampshire and Massachusetts.

Patients with glomerular filtration rates (GFR) <30.0 mL per minute and those on medications such as tacrolimus, cyclosporine, sirolimus, everolimus, rivaroxaban, clopidogrel, amiodarone, carbamazepine, ranolazine, and phenytoin were excluded from the analysis. Additionally, the team excluded individuals with missing weight measurements for two years prior to SARS-CoV-2 infection. The primary study outcomes were hospital admissions within two weeks or deaths within four weeks of SARS-CoV-2 infection diagnosis.

The dates of SARS-CoV-2-positive at-home antigen testing and polymerase chain reaction analysis reports documented in EHRs), inpatient hospital admissions, demographic information, comorbid conditions, concurrent medications, SARS-CoV-2 infection treatments, the status of SARS-CoV-2 vaccinations, and COVID-19-related mortality were retrieved from consolidated SARS-CoV-2 infection data repository.

In addition, a sensitivity analysis was conducted by excluding individuals who had received one or more COVID-19 treatments such as remdesivir, molnupiravir, and monoclonal antibodies (mAbs) such as bebtelovimab, or sotrovimab.

Participant age and comorbidities were used for calculating the mAb screening scores, which are used to estimate COVID-19-associated hospitalization risks. The neighborhood disadvantage socioeconomic status marker was determined based on residential geolocations and the 2010 US Census data, and the area deprivation index values ​​for 2022. The team aimed to emulate the EPIC-HR trial using inverse probability weighting, modified Poisson modeling was performed, and the risk ratios (RR) were calculated.


A total of 12,541 individuals (28.0%) were prescribed ritonavir plus nirmatrelvir, and 32,010 (72%) individuals did not receive the drug combination. Individuals who received ritonavir plus nirmatrelvir showed a greater likelihood of being older, fully vaccinated, and having higher comorbidity scores. The composite COVID-19 severity outcome, including hospitalizations and deaths, was observed in 69 (0.60%) ritonavir plus nirmatrelvir-treated individuals and 310 (1.0%) among untreated individuals, with an adjusted RR value of 0.6.

The treated individuals showed lower risks for hospital admissions and deaths with adjusted RR values ​​of 0.6 and 0.3, respectively. In the sensitivity analysis, similar results were obtained after excluding 1,592 individuals who received ≥1.0 outpatient COVID-19 treatments (1,038, 447, 37, and 77 received ritonavir plus nirmatrelvir monoclonal antibodies, molnupiravir, and remdesivir, respectively).

Outpatients of Latin and Hispanic ethnicities [adjusted odds ratio (OR) 0.8] and Blacks (adjusted OR 0.5) showed a lower likelihood than Whites of being prescribed ritonavir plus nirmatrelvir. The estimated risk reductions were comparable across ages, body mass index (BMI) values, and comorbidity scores.

However, ritonavir plus nirmarelvir was related to enhanced immune protection among partially vaccinated individuals and individuals who had been most recently >20.0 weeks before. In the subgroup analysis, an 81.0% reduction in hospitalization and death risks was observed among unvaccinated individuals.


Overall, the study findings showed that ritonavir plus nirmatrelvir treatment reduced COVID-19 severity outcomes among older COVID-19 outpatients. However, varying access to SARS-CoV-2 vaccines, COVID-19 diagnostics, and treatment could potentially confound the results.


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