Nirmatrelvir is a protease inhibitor with in-vitro activity against SARS-CoV-2, and ritonavir-boosted nirmatrelvir can reduce the risk of progression to severe COVID-19 among individuals at high risk infected with delta and early omicron variants. However, less is known about the effectiveness of nirmatrelvir–ritonavir during more recent BA.2, BA2.12.1, BA.4, and BA.5 omicron variant surges. We used our real-world data platform to evaluate the effect of nirmatrelvir–ritonavir treatment on 28-day hospitalisation, mortality, and emergency department visits among outpatients with early symptomatic COVID-19 during a SARS-CoV-2 omicron (BA.2, BA2.12.1, BA.4, and BA.5) predominant period in Colorado, USA.
We did a propensity-matched, retrospective, observational cohort study of non-hospitalised adult patients infected with SARS-CoV-2 between March 26 and Aug 25, 2022, using records from a statewide health system in Colorado. We obtained data from the electronic health records of University of Colorado Health, the largest health system in Colorado, with 13 hospitals and 141 000 annual hospital admissions, and with numerous ambulatory sites and affiliated pharmacies around the state. Included patients had a positive SARS-CoV-2 test or nirmatrelvir–ritonavir medication order. Exclusion criteria were an order for or administration of other SARS-CoV-2 treatments within 10 days of a positive SARS-CoV-2 test, hospitalisation at the time of positive SARS-CoV-2 test, and positive SARS-CoV-2 test more than 10 days before a nirmatrelvir–ritonavir order. We propensity score matched patients treated with nirmatrelvir–ritonavir with untreated patients. The primary outcome was 28-day all-cause hospitalisation.
Among 28 167 patients infected with SARS-CoV-2 between March 26 and Aug 25, 2022, 21 493 met the study inclusion criteria. 9881 patients received treatment with nirmatrelvir–ritonavir and 11 612 were untreated. Nirmatrelvir–ritonavir treatment was associated with reduced 28-day all-cause hospitalisation compared with no antiviral treatment (61 [0·9%] of 7168 patients vs 135 [1·4%] of 9361 patients, adjusted odds ratio (OR) 0·45 [95% CI 0·33–0·62]; p<0·0001). Nirmatrelvir–ritonavir treatment was also associated with reduced 28-day all-cause mortality (two [<0·1%] of 7168 patients vs 15 [0·2%] of 9361 patients; adjusted OR 0·15 [95% CI 0·03–0·50]; p=0·0010). Using subsequent emergency department visits as a surrogate for clinically significant relapse, we observed a decrease after nirmatrelvir–ritonavir treatment (283 [3·9%] of 7168 patients vs 437 [4·7%] of 9361 patients; adjusted OR 0·74 [95% CI 0·63–0·87]; p=0·0002).
Real-world evidence reported during a BA.2, BA2.12.1, BA.4, and BA.5 omicron surge showed an association between nirmatrelvir–ritonavir treatment and reduced 28-day all-cause hospitalisation, all-cause mortality, and visits to the emergency department. With results that are among the first to suggest effectiveness of nirmatrelvir–ritonavir for non-hospitalised patients during an omicron period inclusive of BA.4 and BA.5 subvariants, these data support nirmatrelvir–ritonavir as an ongoing first-line treatment for adults acutely infected with SARS-CoV-2.
US National Institutes of Health.
In the EPIC-HR trial, treatment with ritonavir-boosted nirmatrelvir (Paxlovid; Pfizer Labs; NY, USA) resulted in a risk of progression to severe disease that was 89% lower than placebo among unvaccinated adults during the pre-delta and delta (B.1.617.2) pandemic phases.
On the basis of these results, in December, 2021, nirmatrelvir–ritonavir was granted US Food and Drug Administration (FDA) emergency use authorisation for the treatment of mild-to-moderate COVID-19 in adult and paediatric patients who were at high risk for progression to severe COVID-19, including hospitalisation or death.
Evidence before this study
Nirmatrelvir–ritonavir, an oral antiviral for the treatment of outpatients with COVID-19 at high risk, has been shown to lower the risk of hospitalisation, thereby decreasing the burden of COVID-19 on the health-care system. We searched PubMed and medRxiv for studies published from database inception to Nov 1, 2022, using the search terms “Nirmatrelvir OR Paxlovid OR PF-07321332” AND “SARS-COV-2 OR COVID-19”, without language restrictions. A major study that examined the safety and effectiveness of nirmatrelvir–ritonavir was the EPIC-HR trial, which showed that treatment initiation within 5 days of symptom onset was associated with an 88% reduced risk of COVID-19-related hospitalisation or death at 28 days. Real-world studies have shown similar benefits, albeit some studies have reported differential effects in selected subgroups, including attenuated effectiveness in those younger than 65 years. Furthermore, these studies were done before the emergence of SARS-CoV-2 omicron variants BA.4 and BA.5.
Added value of this study
To our knowledge, the current study is one of the first to examine the effectiveness of nirmatrelvir–ritonavir in non-hospitalised patients during the omicron period of the COVID-19 pandemic, which includes the BA.4 and BA.5 subvariants. Compared with propensity-matched untreated patients, treatment with nirmatrelvir–ritonavir was associated with a significantly lower risk of all-cause and COVID-19-specific hospitalisation, a finding consistent across most clinically important subgroups. Treatment with nirmatrelvir–ritonavir was also associated with significantly lower all-cause mortality and lower rates of post-treatment emergency department visits, indicating a low likelihood of clinically significant relapse.
Implications of all the available evidence
Current international guidelines recommend nirmatrelvir–ritonavir treatment for patients with non-severe COVID-19 who are at high risk of hospitalisation or death. Our study of real-world use of nirmatrelvir–ritonavir in outpatients at high risk extends previous data by showing strong evidence of nirmatrelvir–ritonavir benefit during the omicron BA.4 and BA.5 SARS-CoV-2 subvariant period and for vaccinated patients and for those younger than 65 years.
Although spike protein mutations present in emergent variants have continuously impacted important COVID-19 therapeutics (eg, monoclonal antibodies), nirmatrelvir–ritonavir, which targets Mpro, has thus far maintained in-vitro activity against emergent variants. Real-world observations have postulated a nirmatrelvir–ritonavir rebound effect, whereby patients might have an increase in viral load or recurrent symptoms after treatment.
However, the incidence of clinically significant relapse in patients treated with nirmatrelvir–ritonavir leading to emergency department visits or hospitalisation is unknown. Vaccination against COVID-19 has become widespread since investigation of the unvaccinated population in the EPIC-HR trial.
Several observational studies have shown the benefits of nirmatrelvir–ritonavir treatment, primarily during the delta-variant and early omicron-variant phases of COVID-19.
However, clinical data regarding the effectiveness of nirmatrelvir–ritonavir against more recent omicron variants, including BA.4 and BA.5, are lacking.
Given the epidemiological shift in circulating variants, a suggestion of a rebound phenomenon, and extensive vaccination of individuals at high risk, real-world data are crucial to evaluate the impact of nirmatrelvir–ritonavir and other therapies targeting COVID-19 to inform ongoing policy and practice decisions. To provide additional data on nirmatrelvir–ritonavir effectiveness against more recent omicron subvariants of SARS-CoV-2, we used our real-world data platform to evaluate the effect of nirmatrelvir–ritonavir treatment on 28-day hospitalisation, mortality, and emergency department visits among outpatients with early symptomatic COVID-19 during a SARS-CoV-2 omicron (BA.2, BA2.12.1, BA.4, and BA.5) predominant period in Colorado, USA.
Study design and participants
The study was approved by the Colorado Multiple Institutional Review Board with a waiver of informed consent. We obtained data from the electronic health records (Epic; Verona, WI, USA) of University of Colorado Health, the largest health system in Colorado, with 13 hospitals and 141 000 annual hospital admissions, with numerous ambulatory sites and affiliated pharmacies around the state, using Health Data Compass, an enterprise-wide data warehouse. Electronic health record data were merged with statewide data on vaccination status from the Colorado Comprehensive Immunization Information System and mortality from Colorado Vital Records. This analysis conforms to STROBE reporting guidance (appendix 1 pp 3–4).
Participant sex was defined by legal sex in the electronic health record, as reported by the patient. Options provided were male or female.
Briefly, nirmatrelvir–ritonavir was the preferred therapy for non-hospitalised adults with COVID-19 at high risk within 5 days of symptom onset and without contraindications due to drug–drug interactions or comorbidities. Nirmatrelvir–ritonavir treatment comprised 300 mg nirmatrelvir (150 mg with moderate renal impairment) and 100 mg ritonavir orally, twice daily, for 5 days.
Notably, most patients treated with nirmatrelvir–ritonavir did not have a SARS-CoV-2 positive test date in the health system electronic health records. Because a prescription of nirmatrelvir–ritonavir requires a positive SARS-CoV-2 test, we assumed that testing occurred at home or at a location outside the health system for these patients. As many patients received antiviral treatment the same or next day after a positive SARS-CoV-2 test, for analytic purposes we used a SARS-CoV-2 positivity test date (the index date) of one day before the recorded nirmatrelvir–ritonavir order date for the primary analysis.
We attempted to achieve a ratio of up to 2:1; however, given the scarcity of untreated patients (appendix 1 pp 11–13), we achieved a matching ratio of 1·31:1 treated to untreated patients, with a total matched cohort size of 16 529, consistent with the approach recommended by Austin to optimise precision while minimising bias.
The propensity model included binary age (vs ≥65 years), sex, binary race and ethnicity (non-Hispanic White vs other race or ethnicity), insurance status, immunocompromised status, obesity status, number of comorbid conditions other than immunocompromised status and obesity, number of vaccinations at the time of infection, and categorical week of SARS-CoV-2 positive test date. We removed patients treated with nirmatrelvir–ritonavir because of missing covariate data and used the recommended caliper of 0·2, which removed an additional 3043 patients (1892 patients treated with nirmatrelvir–ritonavir; appendix 1 pp 8–9).
Variables with a remaining standardised mean difference above 0·1 were adjusted for in all outcome models to account for residual imbalance.
A comparison of the unmatched sample to the matched sample is provided in appendix 1 (pp 12–13).
In-hospital mortality was the highest level of disease severity.
The number of comorbid conditions was calculated as the sum of these specific conditions, with obesity and immunocompromised status kept as separate comorbid conditions in the analysis. Vaccination status was further categorised by the number of vaccinations (none, one, two, or three or more) administered before the observed or imputed SARS-CoV-2 positive test date. Based on statewide virus strain data, we considered patients with an observed or imputed SARS-CoV-2 positive test on or after June 19, 2022, to be in the omicron BA.4 or BA.5 period, given that the statewide proportion of BA.4 or BA.5 was above 50% by that date, and rose to above 90% by July 10, 2022 (appendix 1 p 6).
The primary outcome was all-cause hospitalisation within 28 days of a positive SARS-CoV-2 test, based on the observed or imputed test date. As a secondary outcome, we defined COVID-19-related 28-day hospitalisation as the presence of any of the following: COVID-19 International Classification of Diseases-10 code (U07·1, J12·82, M35·81, Z20·822, or M35·89), administration of inpatient remdesivir, or use of any supplemental oxygen. Other secondary outcomes included 28-day all-cause mortality, hospital length of stay and odds of intensive care unit admission in the hospitalised subset, and 28-day all-cause emergency department visits. In the hospitalised subset, exploratory outcomes included disease severity based on the maximum level of respiratory support and in-hospital mortality.
All models were adjusted for age, sex, race and ethnicity, insurance status, obesity status, immunocompromised status, number of additional comorbid conditions, number of vaccinations, and omicron subvariant. We fit cumulative incidence plots to estimate the time from SARS-CoV-2 positive test to all-cause hospitalisation and all-cause emergency department visits. Care should be used in interpreting these curves because of the frequent use of rapid antigen home testing before a health-care encounter for an electronic health record-tracked SARS-CoV-2 test result or treatment. For the 28-day hospitalisation secondary outcomes, we fit an adjusted logistic regression to assess the association between treatment and the odds of being transferred to the intensive care unit. Additionally, to evaluate the difference in hospital length of stay, we fit an adjusted negative binomial regression and reported adjusted incidence risk ratios (RRs) to account for overdispersion in the outcome. A likelihood ratio test was done to compare the adjusted Poisson model to the adjusted negative binomial model, and a test of overdispersion found estimated dispersion in the Poisson model was 5·6 (p
Because of the small number of hospitalised participants, we present only descriptive statistics for respiratory disease severity and intensive care unit length of stay.
We estimated adjusted treatment effects for eight subgroups of interest by fitting interaction models that were also adjusted for all variables of interest. The subgroups of interest included binary age (<65 years vs ≥65 years), binary obesity status (not obese vs obese), and three-level immunocompromised status (not immunocompromised vs mild immunocompromised vs moderate–severe immunocompromised), binary number of comorbidities (0–1 vs ≥2), binary vaccination status (0–2 vs ≥3), three-level vaccination status (0 vs 1–2 vs ≥3), and omicron subvariant period (before BA.4 and BA.5 and during BA.4 and BA.5).
All statistical analyses were done using R Statistical Software (version 3.6.0).
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Table 1Baseline characteristics
Table 2Primary and secondary outcomes for the primary matched cohort
Data are n (%) or mean (SD).
Table 3Primary and sensitivity analyses for all-cause hospitalisation at 28 days
All sensitivity analyses were fit using Firth’s bias-reducing logistic regression, with 28-day all-cause hospitalisation as the outcome, and were adjusted for all covariates in the primary analysis.
despite these factors, nirmatrelvir–ritonavir remained significantly associated with benefits among patients at high risk and among clinically relevant subgroups infected with SARS-CoV-2. Additionally, we believe our data to be among the first to support the effectiveness of nirmatrelvir–ritonavir treatment among outpatients at high risk during a BA.4 and BA.5 omicron subvariant predominant period.
who found that emergency department visits or hospitalisations occurred with less than 1% frequency in the 5–15 days after nirmatrelvir–ritonavir treatment.
Although our data cannot be used to estimate the overall frequency of rebound episodes among treated and untreated patients, they provide some reassurance that clinically significant relapse requiring emergency department visitation does not occur with increased frequency among patients treated with nirmatrelvir–ritonavir.
In our cohort, we observed that nirmatrelvir–ritonavir might have been beneficial in patients both older and younger than 65 years, as did Zhou and colleagues
and Shah and colleagues,
supporting the generalisability of our results. Notably, a study by Arbel and colleagues found that only COVID-19-positive outpatients at high risk aged 65 years or older had reduced hospitalisation after nirmatrelvir–ritonavir treatment, with an adjusted hazard ratio of 0·21, in contrast to those younger than 65 years, who appeared to derive no benefit.
This discrepancy might be due to differences in setting, including thresholds for hospitalisation in younger patients, population differences, the emergence of BA.4 and BA.5, or other unmeasured factors.
This study has several limitations. Hospitalisation data were collected only within a single health system that has relatively low representation with regard to race and ethnicity but good representation of urban and rural settings at academic and community hospitals, and is the largest health system in the state. Furthermore, symptom duration was not available in our dataset so we are unable to confirm symptom onset within 5 days among patients treated with nirmatrelvir–ritonavir required by the FDA emergency use authorisation. Given the use of single health system electronic health records, it is also possible that treatment, as well as most outcomes, might have occurred elsewhere, leading to misclassification; however, because we have statewide data, the mortality outcome is comprehensive. Although we anticipate similar propensity for hospitalisation within the health system between untreated patients and patients treated with nirmatrelvir–ritonavir, if untreated patients were more likely to be hospitalised outside this health system, or if patients prescribed nirmatrelvir–ritonavir did not fill the prescription or took less than all 5 days of prescribed treatment, our results might be biased towards the null. Although propensity matching was effective across multiple measured variables, residual confounding and unmeasured confounders might remain.
because of changes in testing practices. These approaches might introduce bias in the early days of the time to event analysis and, as such, cumulative incidence curves should be interpreted with caution. However, the post-hoc sensitivity analysis that excluded patients hospitalised the same day as their positive test or nirmatrelvir–ritonavir order had a slightly higher point estimate, but overall revealed statistically similar results to the primary cohort analysis.
In conclusion, this study of real-world data showed that nirmatrelvir–ritonavir treatment was associated with substantially reduced 28-day hospitalisation and all-cause 28-day mortality among outpatients at high risk with COVID-19 during an omicron phase, importantly inclusive of a BA.4 and BA.5 period. Using emergency department visits as a surrogate for clinically significant relapse after initial evaluation and treatment, we observed a lower emergency department visit rate in patients treated with nirmatrelvir–ritonavir compared with untreated patients, and it is reassuring that rebound symptoms after nirmatrelvir–ritonavir treatment appear to be rarely severe. With results that are among the first to suggest effectiveness of nirmatrelvir–ritonavir for non-hospitalised patients during an omicron period inclusive of BA.4 and BA.5 subvariants, these data support nirmatrelvir–ritonavir as an ongoing first-line treatment for adults acutely infected with SARS-CoV-2.
AAG conceived the study and obtained the funding. NRA, KCM, LEB, NEC, and AAG designed the study. LEB and NEC analysed the data. LEB, TDB, NEC, DAM, and SR accessed and verified the data. NRA and KCM drafted the original version of the manuscript. All authors had full access to the data, reviewed the manuscript, contributed to data interpretation, approved the final version, and accept responsibility for the decision to submit for publication.
Declaration of interests
NRA reports grants from the US National Institutes of Health (NIH), during the conduct of the study. KCM reports grants from the National Center for Advancing Translational Sciences (NCATS), during the conduct of the study, and grants from the National Institute of Child Health and Human Development (NICHD) and the National Heart, Lung, and Blood Institute (NHLBI), outside of the submitted work. TDB reports grants from the NCATS, during the conduct of the study, and grants from the NICHD and NHLBI, outside of the submitted work. NEC reports grants from the US NIH, during the conduct of the study. AAG reports grants from the US NIH during the conduct of the study, grants from the US Centers for Disease Control, the US Department of Defense, AbbVie, and Faron Pharmaceuticals, and participation on an NIH data safety monitoring board, outside of the submitted work. All other authors declare no competing interests.
This study was funded by the National Center for Advancing Translational Sciences of the National Institutes of Health, and supported by the Health Data Compass Data Warehouse project.
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Published: February 10, 2023
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- Real-world effectiveness of nirmatrelvir–ritonavir against BA.4 and BA.5 omicron SARS-CoV-2 variants
Over the past year of the COVID-19 pandemic, populations worldwide have been facing the constant threat of the SARS-CoV-2 omicron variant and its sublineages, and the high transmissibility and substantial immune evasion properties of the variants have contributed to considerable numbers of hospitalisations and deaths. Nevertheless, with the increasing availability and access to novel oral antiviral drugs (eg, nirmatrelvir–ritonavir and molnupiravir) and hybrid immunity induced by infection and COVID-19 prime-boost vaccines, the risk of progression to severe disease, hospitalisation, or death has reduced.