Combined Protection of Vaccination and Nirmatrelvir-Ritonavir Against Hospitalization in Adults With COVID-19

Abstract

Among adults at risk for severe coronavirus disease 2019 (COVID-19), the lowest hospitalization rate was among those who received nirmatrelvir-ritonavir after 3 or more messenger RNA vaccine doses (adjusted hazard ratio, 0.22; 95% confidence interval, .19–.24). Eligible adults, including those previously vaccinated, should be considered for COVID-19 antiviral treatment.

Graphical abstract

This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/combined-protection-of-vaccination-and-nirmatrelvir-ritonavir-against-hospitalization-in-adults-with-covid-19

SARS-CoV-2, nirmatrelvir-ritonavir, vaccination, COVID-19

(See the Editorial Commentary by Faust and Meyerowitz-Katz on pages 111–4.)

Nirmatrelvir-ritonavir (Paxlovid) is an antiviral medication that is indicated for individuals with mild to moderate coronavirus disease 2019 (COVID-19) who are at risk of progression to severe COVID-19 [1]. Although the initial clinical trial of nirmatrelvir-ritonavir enrolled unvaccinated adults [2], observational studies have provided evidence of substantial protection by nirmatrelvir-ritonavir against hospitalization among vaccinated individuals at elevated risk for severe COVID-19 [3–6]. However, few data are available to assess the risk reduction from antivirals together with vaccination. We aimed to estimate the stepwise benefit of monovalent vaccination and nirmatrelvir-ritonavir against COVID-19 hospitalization in the United States.

METHODS

We conducted a retrospective analysis of patient records in Cosmos, a dataset that, at the time of this study, included electronic health record information for more than 160 million individual users of US health systems that use Epic electronic health record software (https://cosmos.epic.com). Inclusion criteria and definitions were described in a prior study of real-world effectiveness of nirmatrelvir-ritonavir in this population [4]. Nonpregnant adults were eligible for inclusion if aged ≥50 years or if aged ≥18 years with an underlying health condition associated with progression to severe COVID-19 disease that was documented in their medical record [4]. All included patients had a COVID-19 diagnosis (defined as a diagnostic code or positive severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] test result) associated with an outpatient encounter during 1 April 2022–31 August 2022, indicating mild to moderate COVID-19.

We considered patients to have received nirmatrelvir-ritonavir if it was prescribed during the 5 days after their COVID-19 diagnosis. Vaccination status was categorized on the date of COVID-19 diagnosis using data available in Cosmos. Vaccination categories included unvaccinated if no COVID-19 vaccine had been received; 2 messenger RNA (mRNA) vaccine-dose recipients if ≥14 days had elapsed since receipt of the second dose and no subsequent doses had been received or <7 days since receipt of the third dose; ≥3 mRNA vaccine-dose recipients if ≥7 days had elapsed since receipt of the third dose; and other vaccine recipients if any Janssen (Johnson & Johnson) vaccine, other vaccine, or only 1 mRNA vaccine dose had been received any time before COVID-19 diagnosis. The primary outcome, COVID-19 hospitalization, was defined as having a COVID-19–specific diagnosis code (ICD-10 U07.1 or SNOMED-CT 840539006) associated with the admission during the 30 days after the index diagnosis.

We estimated protection against hospitalization by nirmatrelvir-ritonavir combined with COVID-19 mRNA vaccination using Cox regression. We present adjusted hazard ratios (aHRs) for hospitalization adjusting for age group, sex, race and ethnicity, social vulnerability index of the address of residence, number of underlying health conditions, region of residence, and previous infection defined as having a COVID-19 diagnosis code or positive SARS-CoV-2 test result (nucleic acid amplification or antigen) >90 days prior to the included COVID-19 diagnosis. The referent group comprised unvaccinated individuals who had not received nirmatrelvir-ritonavir.

RESULTS

Among 731 349 patients with a COVID-19 diagnosis in an outpatient setting eligible for nirmatrelvir-ritonavir, 177 757 (24.3%) were unvaccinated, 157 011 (21.5%) received 2 mRNA vaccines, 330 448 (45.2%) received 3 or more mRNA vaccines, and 66 133 (9.0%) were categorized in the other vaccination category. Among those who were unvaccinated, 35 826 of 141 931 (20.2%) received nirmatrelvir-ritonavir compared with 42 355 of 157 011 (27.0%) who received 2 mRNA doses and 130 778 of 330 448 (33.0%) who received 3 or more mRNA vaccine doses.

During April 2022–September 2022, 5296 of 731 349 patients (0.72%) with COVID-19 were hospitalized within 30 days after their initial diagnosis. The rate of hospitalization without treatment or vaccination was 31.1 per 100 000 person-days, 27.0 per 100 000 person-days for those untreated with 2 mRNA vaccine doses, and 28.1 per 100 000 person-days for those untreated with 3 or more mRNA vaccine doses. The rate of hospitalization after receipt of nirmatrelvir-ritonavir was 19.7 per 100 000 person-days for those unvaccinated, 16.4 per 100 000 person-days for those with 2 mRNA vaccine doses, and 14.2 per 100 000 person-days for those with 3 or more mRNA vaccine doses. After receipt of nirmatrelvir-ritonavir and 3 or more mRNA vaccine doses, there were an estimated 16.9 fewer hospitalizations per 100 000 person-days compared with those who were unvaccinated and untreated (Figure 1).

Figure 1.

The aHRs for protection against progression to coronavirus disease 2019 (COVID-19) hospitalization among adults with mild to moderate COVID-19 by nirmatrelvir-ritonavir treatment status and number of monovalent mRNA vaccine doses—Cosmos, United States, April 2022–September 2022. Note that the other vaccination category is not included in the figure but was included in the model. The other vaccination category included 44 664 untreated participants with 446 hospitalized (33.6 hospitalizations per 100 000 person-days) and 21 469 nirmatrelvir-ritonavir treated participants with 101 hospitalized (18.1 hospitalizations per 100 000 person-days). Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; mRNA, messenger RNA.

Compared with patients who were unvaccinated and had not received a COVID-19 treatment, the rate of COVID-19 hospitalization was lower among both those who were vaccinated but did not receive nirmatrelvir-ritonavir (2 mRNA doses: aHR, 0.74; 95% confidence interval [CI]: .67–.80 and 3 or more mRNA doses: aHR, 0.51; 95% CI: .47–.55) and those who were unvaccinated but received nirmatrelvir-ritonavir (aHR, 0.47; 95% CI: .40–.55). The hospitalization rate was lower after receipt of both treatment and vaccination (2 mRNA doses and nirmatrelvir-ritonavir: aHR, 0.33; 95% CI: .29–.39) with the lowest rate of COVID-19 hospitalization among those after receipt of 3 or more mRNA vaccine doses and nirmatrelvir-ritonavir (aHR, 0.22; 95% CI: .19–.24; Figure 1).

DISCUSSION

Among adults aged ≥50 years or aged ≥18 years with an underlying health condition associated with progression to severe COVID-19 disease, we found that receipt of nirmatrelvir-ritonavir within 5 days of diagnosis of mild to moderate COVID-19 among unvaccinated adults confers similar levels of protection against progression from infection to COVID-19 hospitalization compared with receipt of 3 or more monovalent mRNA vaccine doses alone. However, the greatest benefit was conferred by a combination of 3 or more vaccine doses and treatment with nirmatrelvir-ritonavir. In this study, we estimated 78% protection against progression to hospitalization because of this combined benefit compared with receiving neither vaccination nor nirmatrelvir-ritonavir.

Although we found evidence of substantial protection against hospitalization by nirmatrelvir-ritonavir, the absolute reduction in hospitalizations was modest. As an increasing proportion of the population has a degree of immunity from infection or vaccination and as pathogenicity has changed, overall hospitalization rates are lower than earlier in the pandemic. Nevertheless, COVID-19 was the fourth leading cause of death in the United States in 2022 [7]. The absolute benefit of nirmatrelvir-ritonavir is likely to be substantially greater among individuals at the highest risk of severe COVID-19 outcomes. Other potential benefits of antiviral COVID-19 treatments include reduced risk of post–COVID-19 conditions [8], decreased duration of symptoms [9], and shorter duration of replication-competent viral shedding [10].

This study was limited to adults with a diagnosis of COVID-19 during April 2022–August 2022 and may not be applicable in the current landscape of population hybrid immunity and SARS-CoV-2 strain evolution. Over time, updated estimates will be needed to assess and update the impact of vaccination and antiviral treatment. Although vaccination information was collected at each encounter, the timing of last vaccination was not included in this analysis and could impact risk of hospitalization. Hospitalizations may have been incompletely ascertained, but we only included individuals with previous face-to-face encounters to minimize this limitation.

Overall, our findings complement previous studies [3–6] that indicate protection by nirmatrelvir-ritonavir in high-risk individuals, even if vaccinated. We previously reported COVID-19 treatment effectiveness within this population, but we did not specifically examine the protection of treatment and vaccination combined [4]. Treatment with nirmatrelvir-ritonavir without vaccination does not reduce risk of hospitalization to levels seen in treated individuals with 3 or more vaccinations. While the burden and impact of COVID-19 in future respiratory seasons are to be seen, the combination of vaccination and oral antiviral treatment for eligible patients remains an important tool against COVID-19 hospitalization and death. In September 2023, the Advisory Committee on Immunization Practices recommended the 2023–2024 (monovalent, XBB-containing) COVID-19 vaccines in persons aged ≥6 months [11]. Clinicians should consider treatment with nirmatrelvir-ritonavir among all adults who are at high risk of severe COVID-19 disease, including those who are vaccinated [1].

Notes

Disclaimer. This work was reviewed by the Centers for Disease Control and Prevention (CDC) and was conducted consistent with applicable federal law and CDC policy (45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.). The findings and conclusions presented here are those of the authors and do not necessarily represent the official position of the CDC.

Financial support. This study was funded by the CDC. B. J., E. B., M. P., J. D., D. S., and J. L. G. report support for this work from Epic Systems Corporation.

Author notes

M. B. H. and J. L. G. contributed equally to this work.

Potential conflicts of interest. B. J., S. S., E. B., M. P., J. D., D. S., and J. L. G. report being employed by Epic Systems Corporation. J. D. reports stock or stock options from Epic Systems. D. S. reports stock or stock options, privately held, part of employer compensation, from Epic Systems Corporation. All remaining authors: No reported conflicts of interest.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.