Oral Nirmatrelvir and Ritonavir in Nonhospitalized Vaccinated Patients With Coronavirus Disease 2019

Abstract

Background

Treatment of coronavirus disease 2019 (COVID-19) with nirmatrelvir plus ritonavir (NMV-r) in high-risk nonhospitalized unvaccinated patients reduced the risk of progression to severe disease. However, the potential benefits of NMV-r among vaccinated patients are unclear.

Methods

We conducted a comparative retrospective cohort study using the TriNetX research network. Patients ≥18 years of age who were vaccinated and subsequently developed COVID-19 between 1 December 2021 and 18 April 2022 were included. Cohorts were developed based on the use of NMV-r within 5 days of diagnosis. The primary composite outcome was all-cause emergency room (ER) visit, hospitalization, or death at a 30-day follow-up. Secondary outcomes included individual components of primary outcomes, multisystem symptoms, COVID-19–associated complications, and diagnostic test utilization.

Results

After propensity score matching, 1130 patients remained in each cohort. A primary composite outcome of all-cause ER visits, hospitalization, or death in 30 days occurred in 89 (7.87%) patients in the NMV-r cohort compared with 163 (14.4%) patients in the non–NMV-r cohort (odds ratio: .5; 95% confidence interval: .39–.67; P < .005) consistent with 45% relative risk reduction. A significant reduction in multisystem symptom burden and subsequent complications, such as lower respiratory tract infection, cardiac arrhythmia, and diagnostic radiology testing, were noted in NMV-r–treated patients. There was no apparent increase in serious complications between days 10 and 30.

Conclusions

Treatment with NMV-r in nonhospitalized vaccinated patients with COVID-19 was associated with a reduced likelihood of ER visits, hospitalization, or death. Complications and overall resource utilization were also decreased.

Graphical Abstract

nirmatrelvir plus ritonavir (NMV-r), Paxlovid, COVID-19, vaccination, rebound symptoms

As cases of coronavirus disease 2019 (COVID-19) continue to increase globally, antiviral agents may play an increasingly important role in reducing the severity of illness. Currently approved outpatient management options include the antivirals nirmatelvir plus ritonavir (NMV-r) [1], molnupiravir [2], remdesivir [3], and the monoclonal antibody bebtelovimab [4]. A major advantage of NMV-r and molnupiravir is oral administration. In clinical trials among unvaccinated high-risk people with COVID-19, both agents significantly reduced the risk of hospitalization or death compared with placebo. Because NMV-r was associated with a greater reduction in the primary endpoint (89% vs 30%) [1, 2] than molnupiravir and lacks molunpiravir’s association with teratogenicity and mutagenicity, treatment guidelines list NMV-r as the preferred outpatient therapy for patients at high risk of progressing to severe disease [5].

Importantly, this recommendation to use NMV-r in high-risk people with mild-to-moderate COVID-19 applies to both vaccinated and unvaccinated patients, even though data on the efficacy of the drug in vaccinated patients are incomplete. An interim analysis of a study in standard-risk patients demonstrated a trend toward improved clinical outcomes [6]; however, this study has been subsequently modified to exclude people who are vaccinated, and also was stopped early due to failure to meet its primary endpoint [7, 8].

To close this data gap, we sought real-world experience with NMV-r in vaccinated people with COVID-19. With approximately 75% of the US population 12 years of age and older being vaccinated [9] and close to 1 million courses of NMV-r prescribed to both vaccinated and unvaccinated people [10], this is an important clinical question. In addition, with increased anecdotal reports of rebound of both symptoms and antigen test positivity after treatment [11], we wanted to investigate whether follow-up of treated patients would show evidence of reduced benefits. To address the knowledge gaps about the role of NMV-r in the treatment of vaccinated patients with COVID-19, we took advantage of electronic health record (EHR)–based, curated, real-world data of the TriNetX research network [12].

METHODS

Study Oversight

Data were analyzed and interpreted by the authors. All authors reviewed the manuscript and affirmed the accuracy and completeness of the data. Institutional review board (IRB) approval was exempted by the Lahey Clinic IRB, given aggregate de-identified data were used from a research network database. These study findings are reported per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline for cohort studies.

Data Source

We utilized the TriNetX Analytics Network database—Research Network. TriNetX is a multicenter federated health research network aggregating anonymized data from EHRs from participating healthcare organizations, including academic medical centers, specialty physician practices, and community hospitals covering approximately 250+ million patients from more than 120 healthcare organizations (HCOs). The research network contains data on more than 88 million patients from 59 HCOs. While the data are in aggregate de-identified form, the built-in analytics allow for the generation of patient-level data for cohort selection and matching, analyzing incidence and prevalence of events in a cohort, and comparing characteristics and outcomes between matched cohorts. More information on the database can be found online [12].

Study Population and Design

The TriNetX research network was searched, and data curation was performed on 22 May 2022. We conducted a comparative retrospective cohort study, including nonhospitalized patients 18 years of age and older who were vaccinated and subsequently developed COVID-19 at least 1 month after vaccination and between 1 December 2021 and 18 April 2022. Key exclusion criteria were treatment with a monoclonal antibody, convalescent plasma, or molnupiravir for the index case of COVID-19. Patients were further categorized based use of NMV-r within 5 days of diagnosis. Validated diagnostic, procedural, and laboratory codes were utilized to define the vaccination status and COVID-19 diagnosis. Patients with NMV-r were identified using the National Library of Medicine RxNorm terminology. The Supplementary Appendix provides additional inclusion and exclusion criteria and information. Cohorts were matched using propensity score matching (PSM), a technique that attempts to adjust for confounding by selecting a control sample from the untreated population as similar as possible to the treatment group. Primary and secondary outcomes were analyzed 30 days after the index diagnosis of COVID-19 in the control cohort or after initiation of NMV-r in the treatment cohort.

Study Endpoints

Primary Composite Endpoint

The primary composite endpoint of this study was all-cause emergency room (ER) visits, hospitalization, or death at 30-day follow-up.

Secondary Endpoints

Secondary endpoints included individual components of composite primary endpoints: all-cause ER visits, hospitalization, and death. Additionally, prespecified secondary outcomes included the prevalence of various systemic and nonspecific symptoms (constitutional, cardiorespiratory, gastrointestinal, nervous system and musculoskeletal symptoms, smell/taste alteration), systemic complications (cardiovascular, respiratory, gastrointestinal, mood disorders), and diagnostic testing utilization (radiologic diagnostic tests, cardiovascular diagnostic tests [echocardiogram and heart rhythm monitors]) within 30 days of diagnosis of COVID-19. These outcomes were identified based on the International Classification of Diseases, 10th Revision (ICD-10), codes (Supplementary Appendix).

Finally, to explore rebound or prolonged COVID-19 symptoms or complications, we assessed all outcomes between 10 and 30 days following the diagnosis of COVID-19 or initiation of NMV-r.

Statistical Analysis

Nonhospitalized vaccinated patients who subsequently developed COVID-19 were divided into 2 cohorts based on their use of NMV-r within 5 days of diagnosis: NMV-r and non–NMV-r cohorts. We compared the cohorts using independent-samples t tests for continuous variables, which are reported as means (range). Categorical variables are reported as counts (%) and compared using the chi-square (χ²) test. To control for baseline differences in the patient cohorts, 1:1 PSM was performed for characteristics of clinical relevance leveraging a built-in algorithm that uses the greedy nearest-neighbor algorithm with a caliper of 0.1 pooled standard difference (SDs). Any characteristic with a standardized mean difference between cohorts lower than 0.1 was considered well matched. After propensity matching, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for primary and secondary outcomes using the χ² test for the measures of association. Relative risk reduction was calculated as the division of the absolute risk reduction between the treatment (NMV-r) and control (non–NMV-r) cohorts by the absolute risk of the control group. The survival analysis was performed by plotting Kaplan-Meier curves with log-rank tests and calculating hazard ratio (HR) to compare the 2 cohorts. Statistical significance was set at a 2-sided P value less than .05. Statistical analyses were completed using the TriNetX online platform using R for statistical computing (R Foundation for Statistical Computing).

As a sensitivity analysis, we measured the E-value, a measure to check for robustness against bias from unmeasured confounding or omitted covariates in the observational studies, for both primary and secondary outcomes [13]. A higher E-value implies that a stronger unmeasured confounder would be needed to negate the effect estimate for the covariate and increases the likelihood of causality.

RESULTS

Study Population

A total of 111 588 nonhospitalized vaccinated patients with COVID-19 were identified during the study period. Of the total vaccinated patients, 1131 patients received NMV-r within 5 days of the diagnosis and 110 457 did not receive NMV-r. After PSM, 1130 patients remained in each cohort and were included in our study (Figure 1).

Figure 1.

CONSORT diagram. This figure illustrates the proportion of vaccinated nonhospitalized patients who tested positive for SARS-CoV-2 infection or were diagnosed with COVID-19 stratified by use of NMV-r. Abbreviations: CONSORT, Consolidated Standards of Reporting Trials; COVID-19, coronavirus disease 2019; HCO, healthcare organization; NMV-r, nirmatrelvir plus ritonavir; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Patient Characteristics

Baseline characteristics of patients are shown in Table 1. Patients treated with NMV-r were older (mean age of treated vs nontreated: 57.6 ± 16.3 vs 49.3 ± 17.6 years; SD: 0.485). Females comprised 63% of the study population. Black individuals were 9.7% in the NMV-r cohort versus 17.8% in the non–NMV-r group before propensity matching. Patients receiving NMV-r were predominantly White adults (81.9%). Furthermore, patients receiving NMV-r had a higher prevalence of cardiovascular risk factors, established cardiovascular disease (CVD; and be on medications for CVD), neoplasms, and chronic lower respiratory disease. However, after PSM, baseline characteristics in the 2 groups were similar, and no residual imbalance was found (standard difference <0.1 for included covariates).

Table 1.

Baseline Characteristics

	Before Propensity Matching			After Propensity Matching
Baseline Characteristics	Nirmatrelvir-Ritonavir (n = 1131)	No Nirmatrelvir-Ritonavir (n = 110 457)	SD	Nirmatrelvir-Ritonavir (n = 1130)	No Nirmatrelvir- Ritonavir (n = 1130)	SD
Demographics
ȃMean age, years	57.6 ± 16.3	49.3 ± 17.6	0.485	57.5 ± 16.3	57.7 ± 16.3	0.012
ȃFemale	713 (63.0%)	71 017 (64.3%)	0.026	712 (63.0%)	724 (64.1%)	0.022
ȃWhite	926 (81.9%)	71 081 (64.4%)	0.403	925 (81.9%)	941 (83.3%)	0.037
ȃBlack	110 (9.7%)	19 646 (17.8%)	0.236	110 (9.7%)	103 (9.1%)	0.021
ȃNon-Hispanic/Latino	878 (77.6%)	70 377(63.7%)	0.309	877 (77.6%)	857 (75.8%)	0.042
ȃBMI ≥30 kg/m2	237 (21%)	27 629 (25%)	0.09	237 (21%)	208 (18%)	0.06
Comorbidities
ȃHypertension	591 (52.3%)	45 616 (41.3%)	0.221	590 (52.2%)	578 (51.2%)	0.021
ȃHyperlipidemia	651 (57.6%)	42 811 (38.8%)	0.383	650 (57.5%)	661 (58.5%)	0.020
ȃDiabetes mellitus	250 (22.1%)	21 640 (19.6%)	0.062	250 (22.1%)	249 (22.0%)	0.002
ȃChronic lower respiratory disease	342 (30.2%)	28 159 (25.5%)	0.106	342 (30.3%)	339 (30%)	0.006
ȃChronic kidney disease	91 (8.0%)	10 512 (9.5%)	0.052	91 (8.1%)	80 (7.1%)	0.037
ȃAtrial fibrillation/atrial flutter	59 (5.2%)	7010 (6.3%)	0.048	59 (5.2%)	82 (7.3%)	0.084
ȃIschemic heart disease	172 (15.2%)	14 810 (13.4%)	0.051	172 (15.2%)	155 (13.7%)	0.043
ȃHeart failure	52 (4.6%)	7831 (7.1%)	0.106	52 (4.6%)	54 (4.8%)	0.008
ȃIschemic stroke	51 (4.5%)	4502 (4.1%)	0.021	51 (4.5%)	53 (4.7%)	0.008
ȃMalignancy	512 (45.3%)	36 169 (32.7%)	0.259	512 (45.3%)	524 (46.4%)	0.021
ȃDemyelinating disease	21 (1.9%)	988 (0.9%)	0.083	21 (1.9%)	21 (1.9%)	<0.001
ȃSystematic connective tissue disorder	90 (8.0%)	4975 (4.5%)	0.143	90 (8.0%)	67 (5.9%)	0.080
Medications
ȃB-Blockers	410 (36.3%)	32 702 (29.6%)	0.142	409 (36.2%)	399 (35.3%)	0.018
ȃDiuretics	346 (30.6%)	29 860 (27.0%)	0.079	346 (30.6%)	334 (29.6%)	0.023
ȃACE inhibitors	208 (18.4%)	19 032 (17.2%)	0.030	208 (18.4%)	208 (18.4%)	<0.001
ȃAngiotensin receptor blocker	230 (20.3%)	15 783 (14.3%)	0.160	229 (20.3%)	228 (20.2%)	0.002
ȃAspirin	308 (27.2%)	25 020 (22.7%)	0.106	308 (27.3%)	318 (28.1%)	0.020
ȃAnticoagulants	305 (27.0%)	29 278 (26.5%)	0.010	305 (27.0%)	272 (24.1%)	0.067
ȃStatins	465 (41.1%)	34 326 (31.1%)	0.210	465 (41.2%)	476 (42.1%)	0.020
ȃImmune suppressants	53 (4.7%)	5650 (5.1%)	0.020	53 (4.7%)	60 (5.3%)	0.028
ȃAntineoplastics	137 (12.1%)	11 796 (10.7%)	0.045	137 (12.1%)	133 (11.8%)	0.011
ȃAntidepressants	458 (40.5%)	42 023 (38.0%)	0.050	458 (40.5%)	515 (45.6%)	0.102
ȃAnticonvulsants	282 (24.9%)	26 693 (24.2%)	0.018	282 (25.0%)	327 (28.9%)	0.090
Laboratory tests
ȃCreatinine, mg/dL	0.88 ± 0.2 (n = 1068)	0.98 ± 1.9 (n = 75 270)	0.071	0.88 ± 0.2 (n = 1068)	0.92 ± 0.5 (n = 1018)	0.093
ȃHemoglobin, g/dL	13.6 ± 1.5 (n = 1023)	13.3 ± 1.8 (n = 85 080)	0.148	13.6 ± 1.5 (n = 1022)	13.6 ± 1.7 (n = 1005)	0.013
ȃLymphocytes, % leukocytes	28.0 ± 10.4 (n = 938)	27.3 ± 10.6 (n = 74 697)	0.068	28.0 ± 10.4 (n = 937)	27.1 ± 10.4 (n = 897)	0.085
ȃPlatelets, per μL blood)	253.8 ± 76.2 (n = 1023)	257.8 ± 77.3 (n = 84 769)	0.053	253.8 ± 76.2 (n = 1022)	250.6 ± 70.7 (n = 1005)	0.043
ȃC-reactive protein >10 mg/L	92 (8.1%)	6324 (5.7%)	0.094	92 (8.1%)	72 (6.3%)	0.068
ȃFerritin, μg/L	181.5 ± 427.8 (n = 283)	218.4 ± 676.6 (n = 21 899)	0.065	181.5 ± 427.8 (n = 283)	172.3 ± 274.9 (n = 273)	0.025
ȃTotal cholesterol, mg/dL	183.4 ± 40.9 (n = 902)	178.9 ± 42.6 (n = 65 344)	0.107	183.4 ± 40.9 (n = 901)	181.3 ± 43.4 (n = 908)	0.050
ȃLDL cholesterol, mg/dL	103.5 ± 34.1 (n = 941)	102.7 ± 35.6 (n = 67 443)	0.023	103.5 ± 34.1 (n = 940)	103.6 ± 36.2 (n = 939)	0.004
ȃHemoglobin A1c, mg/dL	6.1 ± 1.7 (n = 799)	6.1 ± 1.6 (n = 51 351)	0.007	6.1 ± 1.7 (n = 798)	6.0 ± 1.4 (n = 779)	0.080
ȃLVEF, %	61.3 ± 10.7 (n = 167)	58.9 ± 11.9 (n = 7178)	0.212	61.3 ± 10.8 (n = 166)	60.5 ± 9.5 (n = 143)	0.082

Data are presented as n (%) unless otherwise indicated. Abbreviations: ACE, angiotensin-converting enzyme; BMI, body mass index; hemoglobin A1c, glycated hemoglobin; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; SD, standard difference.

Study Outcomes

Primary Outcome

A primary composite outcome of all-cause ER visits, hospitalization, or death in 30 days occurred in 89 (7.87%) patients in the NMV-r cohort and 163 (14.4%) patients in the non–NMV-r cohort (OR: .5; 95% CI: .39–.67; P < .005), consistent with a 45% relative risk reduction (Table 2). Furthermore, patients receiving NMV-r had a higher probability of event-free survival at 30 days (88.15% vs 84.16%; HR: .67; 95% CI: .52, .87; P = .002) (Figure 2).

Figure 2.

This figure illustrates the survival analysis with a cumulative percentage comparison of an all-cause ER visit, hospitalization, or death among patients treated with or without NMV-r for COVID-19 within 5 days of diagnosis. The cumulative percentage was estimated for each treatment group using the Kaplan–Meier method. Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; ER, emergency room; NMV-r, nirmatrelvir plus ritonavir.

Table 2.

Outcomes Comparison at 30 Days

Outcomes	Nirmatrelvir-Ritonavir (n = 1130)	No Nirmatrelvir-Ritonavir (n = 1130)	Risk Difference	Relative Risk Reduction	Odds Ratio	E-Value of Odds Ratio	E-Value for Lower Confidence Interval of Odds Ratio	P
Primary composite outcomes
ȃAll-cause ER visit, hospitalization, or death	89 (7.87%)	163 (14.4%)	−0.065 (−.091, −.040)	45%	0.507 (.386, .666)	3.36	2.37	<.001
Secondary outcomes
ȃIndividual components of primary outcomes
ȃȃAll-cause ER visit	83 (7.34%)	142 (12.5%)	−0.052 (−.077, −.028)	41%	0.552 (.415, .733)	3.02	2.07	<.001
ȃȃAll-cause hospitalization	10 (0.8%)	23 (2%)	−0.012 (−.021, −.002)	60%	0.430 (.204, .907)	4.08	1.44	.023
ȃȃ30-Day mortality	0	10 (0.8%)	−0.009 (−.014, −.003)	100%	…	…	…	.002
ȃSymptoms
ȃȃConstitutional symptoms	72 (6.3%)	146 (12.9%)	−0.065 (−.090, −.041)	50%	0.459 (.341, .616)	3.78	2.63	<.001
ȃȃCardiorespiratory symptoms	153 (13.5%)	309 (27.3%)	−0.138 (−.171, −.105)	51%	0.416 (.336, .516)	4.24	3.29	<.001
ȃȃGastrointestinal symptoms	38 (3.3%)	89 (7.87%)	−0.045 (−.064, −.026)	57%	0.407 (.276, .601)	4.35	2.71	<.001
ȃȃNervous system and musculoskeletal symptoms	10 (0.8%)	25 (2.2%)	−0.013 (−.023, −.003)	59%	0.395 (.189, .826)	4.5	1.72	.011
ȃȃSmell/taste alteration	10 (0.8%)	10 (0.8%)	0 (−.008, .008)	0	1 (.415, 2.412)	1	1	1
ȃComplications
ȃȃLower respiratory tract infection	27 (2.38%)	92 (8.14%)	−0.058 (−.076, −.039)	72%	0.276 (.178, .428)	6.71	4.1	.000
ȃȃArrhythmia	22 (1.9%)	43 (3.8%)	−0.019 (−.032, −.005)	50%	0.502 (.298, .845)	3.4	1.65	.008
ȃȃGastroenteritis/colitis/diarrhea	12 (1%)	13 (1.1%)	−0.001 (−.010, .008)	8%	0.922 (.419, 2.030)	1.39	1	.841
ȃȃAnxiety/mood disorder	64 (5.6%)	114 (10%)	−0.044 (−.066, −.022)	44%	0.535 (.389, .735)	3.14	2.06	.000
ȃDiagnostic testing utilization
ȃȃRadiology diagnostic tests	90 (7.9%)	164 (14.5%)	−0.065 (−.091, −.040)	45%	0.510 (.388, .669)	3.33	2.35	<.001
ȃȃCV tests (echocardiogram and heart monitors)	10 (0.88%)	13 (1.1%)	−0.003 (−.011, .006)	25%	0.767 (.335, 1.757)	1.93	1	.530

Data are presented as n (%) unless otherwise indicated. Abbreviations: CV, cardiovascular; ER, emergency room.

The E-value of the OR of the primary outcome was 3.36 and the lower CI was 2.37, both of which supported a stronger association of NMV-r treatment leading to these observed differences in outcomes.

Secondary Outcomes

All-cause ER visits (82 vs 142; OR: .55; 95% CI: .41–.73; P < .05) and hospitalization (10 vs 23; OR: .43; 95% CI: .2–.9; P = .02) were significantly lower in patients with COVID-19 who received NMV-r. Ten deaths were noted, all in the non–NMV-r cohort, whereas no deaths occurred (P < .05) in the group receiving NMV-r (Table 2). Patients who received NMV-r had fewer constitutional, cardiorespiratory, gastrointestinal, nervous, and musculoskeletal symptoms. No significant difference was noted in reported smell/taste alteration between the 2 cohorts. Overall, systemic complications, such as lower respiratory tract infections, arrhythmias, and anxiety/mood disorders, were seen less frequently in the NMV-r cohort than in the non–NMV-r cohort. No difference was noted in the occurrence of gastroenteritis, colitis, or diarrhea. Further, patients receiving NMV-r had lower utilization of radiologic diagnostic testing than those who did not receive NMV-r. Cardiovascular diagnostic testing was similar in both cohorts (Table 2, Figure 3).

Figure 3.

This forest plot demonstrates the odds ratios with 95% confidence intervals for primary and secondary outcomes in vaccinated patients treated with NMV-r. Abbreviations: CV, cardiovascular; ER, emergency room; GI, gastrointestinal; MSK, musculoskeletal; NMV-r, nirmatrelvir plus ritonavir.

A sensitivity analysis with E-values is reported in Table 2, suggesting a stronger association of NMV-r on observed outcomes and a low likelihood that differences in the outcomes are due to unmeasured confounders.

An exploratory secondary analysis of outcomes between 10 and 30 days following the diagnosis of COVID-19 or NMV-r initiation showed that patients in the NMV-r cohort continued to have overall fewer symptoms and complications (Table 3). Overall symptom burden was reduced in both the cohorts over time and became similar for nervous, musculoskeletal, and constitutional symptoms. However, cardiorespiratory and gastrointestinal symptoms, anxiety/mood disorder, and all-cause ER visits, hospitalization, or death remained lower in the NMV-r cohort at 30 days (Table 3). In addition, the occurrence of smell/taste alteration, which was similar in both cohorts for the entire 30-day follow-up, was significantly less frequent in the NMV-r cohort between 10 and 30 days of follow-up.

Table 3.

Outcomes Comparison Between 10 and 30 Days

Outcomes	Nirmatrelvir-Ritonavir (n = 1130)	No Nirmatrelvir- Ritonavir (n = 1130)	Risk Difference	Relative Risk Reduction	Odds Ratio	P
Primary composite outcome
ȃAll-cause ER visit, hospitalization, or death	23 (2.03%)	56 (4.95%)	−0.029 (−.044, −.014)	58%	0.398 (.243, .652)	<.001
Secondary outcomes
ȃIndividual components of primary outcomes
ȃȃAll-cause ER visit	18 (1.59%)	34 (3.01%)	−0.014 (−.026, −.002)	47%	0.522 (.293, .930)	.025
ȃȃAll-cause hospitalization	10 (0.88%)	24 (2.12%)	−0.012 (−.022, −.002)	57%	0.411 (.196, .864)	.016
ȃȃ30-Day mortality	0	10 (0.88%)	−0.009 (−.014, −.003)	100%	…	.002
ȃSymptoms
ȃȃConstitutional symptoms	23 (2.03%)	35 (3.09%)	−0.011 (−.024, .002)	35%	0.650 (.382, 1.107)	.11
ȃȃCardiorespiratory symptoms	49 (4.33%)	83 (7.34%)	−0.030 (−.049, −.011)	41%	0.572 (.398, .822)	.002
ȃȃGastrointestinal symptoms	23 (2.03%)	43 (3.80%)	−0.018 (−.032, −.004)	47%	0.525 (.314, .877)	.012
ȃȃNervous system and musculoskeletal symptoms	10 (0.88%)	14 (1.24%)	−0.004 (−.012, .005)	33%	0.712 (.315, 1.609)	.412
ȃȃSmell/taste alteration	0	10 (0.88%)	−0.009 (−.014, −.003)	100%	…	.002
ȃComplications
ȃȃLower respiratory tract infection	14 (1.24%)	32 (2.83%)	−0.016 (−.028, −.004)	57%	0.430 (.228, .811)	.007
ȃȃArrhythmia	12 (1.06%)	27 (2.39%)	−0.013 (−.024, −.003)	54%	0.438 (.221, .870)	.015
ȃȃGastroenteritis/colitis/diarrhea	10 (0.88%)	10 (0.88%)	0 (−.008, .008)	0%	1 (.415, 2.412)	1
ȃȃAnxiety/mood disorder	36 (3.18%)	74 (6.54%)	−0.034 (−.051, −.016)	52%	0.470 (.313, .706)	<.001
ȃDiagnostic testing utilization
ȃȃRadiology diagnostic tests	48 (4.24%)	71 (6.23%)	−0.020 (−.039, −.002)	32%	0.662 (.454, .964)	.03
ȃȃCV tests (echocardiogram and heart monitors)	10 (0.88%)	14 (1.24%)	−0.004 (−.012, .005)	33%	0.712 (.315, 1.609)	.412

Data are presented as n (%) unless otherwise indicated. Abbreviations: CV, cardiovascular; ER, emergency room.

DISCUSSION

In vaccinated, nonhospitalized patients with COVID-19, our real-world data demonstrate a strong association between treatment with NMV-r and improved outcomes. The study shows that, when NMV-r was administered within 5 days of COVID-19 diagnosis, there was a 45% relative risk reduction in the occurrence of subsequent ER visits, hospitalizations, or deaths compared with a group receiving no treatment. We also report reduced symptom burden (constitutional, cardiorespiratory, gastrointestinal, nervous system, and musculoskeletal symptoms) and complications such as lower respiratory tract infection or cardiac arrhythmia. While a virologic rebound is known to occur in some treated patients [11], our findings demonstrate that, even if a rebound did occur in some, it did not negate the benefit of NMV-r treatment. Indeed, we found no late increase in complications among those with treatment compared with those with no treatment, although our study likely would have missed cases of transient or mild rebound occurring between 10 and 30 days after diagnosis. As we await further prospective data on NMV-r, our data strongly support the clinical effectiveness of NMV-r in vaccinated patients and the current National Institutes of Health guidelines [5] listing this as the preferred therapy for mild–moderate COVID-19 in those at high risk of severe disease.

EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) compared NMV-r with placebo in unvaccinated, nonhospitalized adults with mild–moderate COVID-19 at high risk of progression to severe disease [1]. This randomized controlled trial also excluded people with a known prior history of COVID-19. The study demonstrated an 89% reduction in the risk of hospitalization or death with NMV-r compared with placebo, with 0 versus 7 deaths, respectively. Given this high efficacy, NMV-r was granted Emergency Use Authorization (EUA) in the United States in December 2021 for treatment of mild–moderate COVID-19 in people at high risk of severe disease [14].

Since the EUA, clinicians have prescribed NMR-r for millions of individuals, many of whom are vaccinated, have a prior history of COVID-19, or both. Since this group with pre-existing immunity to COVID-19 typically experiences milder disease than those who are immunologically naïve [15, 16], whether NMV-r would lead to comparable benefits in this population with other risk factors for severe disease remains unknown and motivated this analysis. An interim evaluation of NMV-r in lower-risk individuals (including some who were vaccinated) failed to demonstrate a benefit in the primary outcome of time to symptom resolution, prompting the cessation of this study [6, 8]. An ongoing randomized study of NMV-r in the United Kingdom is also evaluating efficacy in both vaccinated and unvaccinated people with COVID-19 [17]. These 2 studies will provide more precise estimates of the benefits of this treatment in various patient populations.

Differences between the study population of EPIC-HR and the present analysis include older age (57 vs 46 years) and a higher proportion of females (62–63% vs 48–49%) in this study. Our data captured a higher proportion of White adults, possibly reflecting differences in access to healthcare in the United States. Our study also had a higher burden of comorbid conditions, which is likely due to the specifics of the EUA for NMV-r, which specify inclusion of only people at high risk of progression to severe disease [1].

While the 45% relative risk reduction in an all-cause ER visit, hospitalization, or death in those who received NMV-r is lower than the 89% reported in EPIC-HR, this result still implies substantial clinical benefits over and above those provided by vaccination. These are further reflected in our secondary outcomes, with a 72% relative risk reduction in the subsequent development of pneumonia and 50% reduction in arrhythmia in patients treated with NMV-r. Furthermore, treatment was associated with fewer clinical complaints at 30 days, specifically cardiorespiratory, gastrointestinal, nervous system, and musculoskeletal and constitutional symptoms. With lower rates of these complications, not surprisingly, we also observed additional evidence of reduced resource utilization, with a significant relative reduction in diagnostic radiology testing (45%) in NMV-r–treated patients.

While reports of rebound were unusual in the controlled trial, in real-life use there have been many reports of COVID-19 symptom rebounds several days after completing the 5-day therapy with NMV-r [11]. Our analysis does not have sufficiently detailed patient-level data to describe the frequency of such relapses, especially if mild in clinical severity. However, follow-up between 10 and 30 days in our study continues to show the benefits of treatment, implying that such relapses, when they occur, rarely precipitate ER visits, hospitalization, or death.

Patients with COVID-19 commonly report alterations in smell and taste. A different phenomenon is the taste disturbance associated with NMV-r treatment, reported in 6% of study participants in the EPIC-HR trial (and, anecdotally, more commonly in real-life use). Our study found EHR documentation of smell/taste alteration in less than 1% of patients, with similar fractions in the 2 cohorts. Notably, reports of gastrointestinal symptoms were significantly lower within the NMV-r cohort.

Our study has several limitations. Most important, despite our efforts to carefully control for baseline differences in the treated versus nontreated populations using propensity matching, unmeasured confounding could influence the outcomes. Hence, we performed a sensitivity analysis, the results of which indicate that the findings are highly unlikely to be due to an unmeasured confounder. Retrospective data curated from an EHR are not always accurate, although we did have access to more-objective laboratory testing results. It is possible that clinical data, including receipt of vaccines or clinical outcomes, could have occured in some patients outside of participating HCOs in this research network. If so, such patients may have been misclassified. However, this limitation presumably would apply to both the treated and untreated groups. Unlike the EPIC-HR study, which addressed hospitalizations directly related to COVID-19, here we assessed all-cause hospitalization, ER visits, and mortality rather than a cause-specific outcome. It is possible that these outcomes may have occurred in some patients due to non–COVID-related illnesses, although even in clinical practice it can be difficult to assess whether COVID-19 contributes to hospitalization or is an incidental finding, especially in patients with medical comorbidities in whom viral infections are known to precipitate medical instability. Since ER visits may be influenced by primary care access, and in some cases may have been where patients received prescriptions for NMV-r, our sensitivity analysis looking at only hospitalization or death showed a comparable benefit of NMV-r.

In summary, this evaluation of NMV-r in vaccinated patients at high risk of COVID-19 complications shows a strong association between treatment and a reduced risk of ER visits, hospitalizations, and death. With cases of COVID-19 continuing to occur despite widespread vaccination, these data support administering antiviral therapy to this vulnerable group, vaccination status notwithstanding. Ongoing prospective clinical trials of NMV-r in a variety of patient populations will more precisely define the benefits and risks of treatment.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Author notes

S. G. and S. S. D. contributed equally to this work.

Potential conflicts of interest. G. M. A. reports payment for expert testimony (10 000/year) and is the immediate Past-President of the American College of Physicians. R. M. W. reports that he is a member of the Lucian Leape Institute of the Institute for Healthcare Improvement (no compensation except for travel expenses); receives a yearly stipend for serving on the Board of Directors of The Doctors Company; serves on the Board of Directors of Second Wave Delivery Solution (for which he receives stock options) and the scientific advisory boards for Teladoc, a large telemedicine provider (ended 2021), Amino.com, Curai Health, and EarlySense (stock options); consults with Commure (stipend and stock options), Forward (stock options), and Notable (stock options); received honoraria as a speaker at conferences for many (>150) healthcare organizations, medical societies, hospitals (vast majority are nonprofit; for-profit entities since 2017 include Nuance, GE, Health Catalyst, AvaCare, Siemens, and Voalte); has given more than 200 talks (a few to for-profit entities including Nuance, GE, Health Catalyst, Siemens, AvaCare, and the Governance Institute) for which he has received honoraria; and holds the Benioff Endowed Chair in Hospital Medicine from Marc and Lynne Benioff and the Holly Smith Distinguished Professorship in Science and Medicine at the University of California San Francisco (UCSF). All other authors report no potential conflicts. 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.