The clinical impact of coadministration of the oral SARS-CoV-2 protease inhibitor nirmatrelvir and the pharmacokinetic booster ritonavir among vaccinated populations is uncertain. This study emulated a clinical trial to assess whether nirmatrelvir plus ritonavir reduces risk for hospitalization or death among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune-evasive SARS-CoV-2 lineages.
Visual Abstract. Nirmatrelvir Plus Ritonavir for Early COVID-19 in a Large U.S. Health System.
The clinical impact of coadministration of the oral SARS-CoV-2 protease inhibitor nirmatrelvir and the pharmacokinetic booster ritonavir among vaccinated populations is uncertain. This study emulated a clinical trial to assess whether nirmatrelvir plus ritonavir reduces risk for hospitalization or death among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune-evasive SARS-CoV-2 lineages.
Abstract
Background:
In the EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) trial, nirmatrelvir plus ritonavir led to an 89% reduction in hospitalization or death among unvaccinated outpatients with early COVID-19. The clinical impact of nirmatrelvir plus ritonavir among vaccinated populations is uncertain.
Objective:
To assess whether nirmatrelvir plus ritonavir reduces risk for hospitalization or death among outpatients with early COVID-19 in the setting of prevalent SARS-CoV-2 immunity and immune-evasive SARS-CoV-2 lineages.
Design:
Population-based cohort study analyzed to emulate a clinical trial using inverse probability–weighted models to account for anticipated bias in treatment.
Setting:
A large health care system providing care for 1.5 million patients in Massachusetts and New Hampshire during the Omicron wave (1 January to 17 July 2022).
Patients:
44 551 nonhospitalized adults (90.3% with ≥3 vaccine doses) aged 50 years or older with COVID-19 and no contraindications for nirmatrelvir plus ritonavir.
Measurements:
The primary outcome was a composite of hospitalization within 14 days or death within 28 days of a COVID-19 diagnosis.
Results:
During the study period, 12 541 (28.1%) patients were prescribed nirmatrelvir plus ritonavir, and 32 010 (71.9%) were not. Patients prescribed nirmatrelvir plus ritonavir were more likely to be older, have more comorbidities, and be vaccinated. The composite outcome of hospitalization or death occurred in 69 (0.55%) patients who were prescribed nirmatrelvir plus ritonavir and 310 (0.97%) who were not (adjusted risk ratio, 0.56 [95% CI, 0.42 to 0.75]). Recipients of nirmatrelvir plus ritonavir had lower risk for hospitalization (adjusted risk ratio, 0.60 [CI, 0.44 to 0.81]) and death (adjusted risk ratio, 0.29 [CI, 0.12 to 0.71]).
Limitation:
Potential residual confounding due to differential access to COVID-19 vaccines, diagnostic tests, and treatment.
Conclusion:
The overall risk for hospitalization or death was already low (1%) after an outpatient diagnosis of COVID-19, but nirmatrelvir plus ritonavir reduced this risk further.
Primary Funding Source:
National Institutes of Health.
The oral SARS-CoV-2 protease inhibitor nirmatrelvir, coadministered with the pharmacokinetic booster ritonavir, was found in a randomized trial to decrease risk for progression to severe COVID-19 by 89% among unvaccinated high-risk patients with mild to moderate disease who enrolled when Delta (B.1.617.2) was the predominant circulating variant (1). Nirmatrelvir plus ritonavir was granted emergency use authorization for treatment of mild to moderate COVID-19 in the United States in December 2021, and the national strategy encouraged broad use in persons with increased risk, regardless of vaccination status, to prevent hospital crowding (2, 3). The World Health Organization recommended nirmatrelvir plus ritonavir in April 2022, but only for the highest-risk persons (>10% probability of hospitalization), and advised against use in most vaccinated and other lower-risk persons (4). Emerging data involving the initial Omicron variants show a potential benefit of nirmatrelvir plus ritonavir regardless of vaccination status, but only a small proportion of the eligible patient populations in these studies were treated (5, 6). A better understanding of the clinical effectiveness of nirmatrelvir plus ritonavir is needed to inform individual and public health decisions, particularly among vaccinated persons infected by Omicron strains (B.1.1.529, BA.2, BA.5, and other immune-evasive sublineages).
Methods
Setting and Data
We used data from Mass General Brigham, a large, nonprofit, integrated health care system (1.5 million patients annually) that includes 2 large academic hospitals, 7 community hospitals, and a network of ambulatory clinics and community health centers throughout Massachusetts and southern New Hampshire. During the study period, Omicron lineages BA.1.1, BA.2, BA.2.12.1, and BA.5 were predominant in the region (7). Nirmatrelvir plus ritonavir became available for prescription by Mass General Brigham providers for the highest-risk persons on 21 January 2022 and for all patients who were eligible according to the emergency use authorization on 22 February 2022. The study was approved by the Mass General Brigham Human Research Committee institutional review board, and requirement for informed consent was waived.
Mass General Brigham hospitals and clinics use a shared electronic health record (EHR) (Epic Systems). Dates of positive SARS-CoV-2 test results (including both polymerase chain reaction tests and home antigen tests that were documented in the EHR), inpatient admissions at any of the 9 Mass General Brigham hospitals, patient demographic characteristics, comorbidities, concomitant home medications, COVID-19 treatments, COVID-19 vaccination status, and deaths were obtained from an integrated COVID-19 data repository. Data were validated by manual review of medical records by 2 physicians. Similar to all other prescriptions, outpatient orders for nirmatrelvir plus ritonavir were required to be electronically transmitted to pharmacies per regulations in Massachusetts and New Hampshire (verbal and paper prescriptions were permitted only during system failures). Patients who were electronically prescribed courses of nirmatrelvir plus ritonavir were categorized as being in the treatment group.
Patients
Persons aged 50 years or older who resided in Massachusetts or New Hampshire and had a new diagnosis of COVID-19 (no positive molecular test result in the preceding 90 days) between 1 January and 17 July 2022 were included. Patient medical conditions, vaccination history, medications used at the time of diagnosis, height and weight, self-reported race and ethnicity, and home address were obtained from the EHR. Recorded medical conditions and age were used to calculate the Monoclonal Antibody Screening Score, a comorbidity index that predicts risk for COVID-19 hospitalization (8, 9), for each patient. Patients were considered immunocompromised if they were receiving immunosuppressive medications (such as prednisone, tumor necrosis factor inhibitors, calcineurin inhibitors, mechanistic target of rapamycin inhibitors, or anti-CD20 antibodies); had active cancer; had received a stem cell or solid organ transplant; or had HIV infection, regardless of CD4 cell count. Neighborhood disadvantage was used as a marker for socioeconomic status for each patient and was determined via geolocation of the home address to the census block group (2010 U.S. Census definitions) and Area Deprivation Index (2020 version) (10, 11). Patients with an estimated glomerular filtration rate less than 30 mL/min and those taking common medications for which coadministration with nirmatrelvir plus ritonavir is not advised (cyclosporine, tacrolimus, everolimus, sirolimus, clopidogrel, rivaroxaban, amiodarone, carbamazepine, phenytoin, and ranolazine) were excluded. Patients with no weight measurement recorded in the 2 years before their COVID-19 diagnosis were also excluded.
Effectiveness
The primary objective was to assess the effectiveness of nirmatrelvir plus ritonavir, using a composite end point of reduction in risk for hospitalization within 14 days or death within 28 days after an outpatient COVID-19 diagnosis among persons aged 50 years or older. Secondary objectives were to assess effectiveness at preventing hospitalization within 14 days and, separately, death within 28 days. Although nirmatrelvir plus ritonavir became the preferred therapy at Mass General Brigham in January 2022, limitations in supply, pharmacy locations, patient acceptance, provider awareness, and clinical capacity to prescribe resulted in staged patient access. We compared patients who were prescribed nirmatrelvir plus ritonavir versus those who were not to estimate the effectiveness of the treatment. The study included recorded COVID-19 cases occurring between 1 January and 17 July 2022 and any subsequent hospitalizations (through 31 July 2022) or deaths (through 14 August 2022).
Statistical Analysis
We sought to emulate a hypothetical randomized trial similar to EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) (1), using observational data where nirmatrelvir plus ritonavir was randomly assigned among outpatients with early COVID-19 in the context of high prevalence of prior immunity and the currently circulating variants. To mitigate immortal person-time bias and align with the design of EPIC-HR, only patients who were alive, had not received other authorized treatments for early COVID-19 (molnupiravir, remdesivir, or the anti–SARS-CoV-2 monoclonal antibodies sotrovimab and bebtelovimab), and were not hospitalized through 2 calendar days (day of diagnosis and subsequent day) were included. Eligibility was assessed and study group was assigned at the end of the second calendar day, and hospitalizations and deaths after that time were considered end points. Patients prescribed nirmatrelvir plus ritonavir or another authorized treatment after 2 calendar days from diagnosis were retained in their originally assigned study group. The trial emulation is described further in the Supplement Table.
We anticipated bias in the prescription of nirmatrelvir plus ritonavir related to vaccination, medical history, health care access, and other patient factors. To better achieve exchangeability between patients prescribed and not prescribed nirmatrelvir plus ritonavir, we used an inverse probability–weighted design. Treatment weights were generated using a logistic model that included a priori–determined factors of age (50 to 64, 65 to 79, or ≥80 years), comorbidity score (Monoclonal Antibody Screening Score ≤3, 4 or 5, or ≥6), vaccination status (unvaccinated, partially vaccinated, vaccinated, or vaccinated and ≥1 booster dose), recency of last vaccine dose (<20 weeks or >20 weeks, based on observed decreased protection against severe disease [12]), self-reported race and ethnicity (Hispanic or Latinx, White non-Hispanic and non-Latinx, Black non-Hispanic and non-Latinx, Asian non-Hispanic and non-Latinx, or other or unavailable), study period (January to April or May to July), and neighborhood disadvantage (<75th or >75th percentile of Area Deprivation Index [10, 11] of participant cohort census block groups). The treatment weights were used to generate a pseudo-population (13) to estimate the effect of nirmatrelvir plus ritonavir if prescribing was not biased on the basis of the included factors. Modified Poisson models using robust error variance (14) and accounting for the weighted design (15, 16) were used to estimate relative risk reduction with nirmatrelvir plus ritonavir compared with no treatment in the pseudo-population. Adjusted cumulative incidence curves were generated using inverse probability weights (17, 18).
Role of the Funding Source
The funding source had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
Results
Study Population and Prescription of Nirmatrelvir Plus Ritonavir
Between 1 January and 17 July 2022, a total of 117 385 Mass General Brigham patients were diagnosed with COVID-19, of whom 51 842 were aged 50 years or older, resided in the region, and had a weight measurement in the preceding 2 years. Among these patients, 7291 had contraindications for nirmatrelvir plus ritonavir or were first diagnosed or treated with COVID-19 therapy within 1 calendar day of hospitalization or death. The remaining 44 551 patients were diagnosed as outpatients and were eligible for nirmatrelvir plus ritonavir (Figure 1). Cases, prescriptions of nirmatrelvir plus ritonavir, and hospitalizations and deaths throughout the study period are shown in Figure 2.
Figure 1. Study cohort.
eGFR = estimated glomerular filtration rate.
Figure 2. COVID-19 cases, treatment with nirmatrelvir plus ritonavir, and hospitalization or death among study patients.
The figure includes infections and treatment initiation from 1 January to 17 July 2022, hospitalizations through 31 July 2022, and deaths through 14 August 2022.
The baseline characteristics of the analysis population are shown in the Table. Nirmatrelvir plus ritonavir was prescribed to 12 541 patients and was more likely to be prescribed to patients with older age, higher comorbidity scores, full vaccination, and recent receipt of a vaccine dose. Findings from the multivariable logistic model used to calculate treatment weights showed that outpatients reporting Hispanic or Latinx ethnicity (adjusted odds ratio, 0.77 [95% CI, 0.68 to 0.86]) or Black race (adjusted odds ratio, 0.53 [CI, 0.46 to 0.62]) were less likely than patients reporting White race to be prescribed nirmatrelvir plus ritonavir. Residents of neighborhoods in the highest quartile of disadvantage were prescribed nirmatrelvir plus ritonavir at rates similar to those for other patients (adjusted odds ratio, 0.99 [CI, 0.95 to 1.04]).
Table.
Baseline Characteristics of Patients With COVID-19 Aged 50 Years or Older (1 January to 17 July 2022) and the Weighted Analytic Cohort
Hospitalizations and Deaths
The primary composite end point of hospitalization within 14 days or death within 28 days of incident SARS-CoV-2 infection occurred in 69 (0.55%) patients who were prescribed nirmatrelvir plus ritonavir and 310 (0.97%) who were not (Figure 3). None of the hospitalizations among recipients of nirmatrelvir plus ritonavir were attributable to the previously described rebound syndrome (19). The adjusted risk ratio for nirmatrelvir plus ritonavir was 0.56 (CI, 0.42 to 0.75). In a sensitivity analysis that excluded 1592 patients who received 1 or more outpatient COVID-19 therapies (1038 received nirmatrelvir plus ritonavir, 447 received monoclonal antibodies, 77 received remdesivir, and 37 received molnupiravir) after study group assignment, the estimated effect of nirmatrelvir plus ritonavir on risk for hospitalization or death was unchanged (adjusted risk ratio, 0.56).
Figure 3. Cumulative primary and secondary end points among outpatients with COVID-19, by study group.
Patients with hospitalization or death on the day of diagnosis or the next calendar day are not considered outpatients and were excluded. The primary end point (hospitalization within 14 days or death within 28 days of diagnosis) is shown in panel A. Hospitalization (B) and death (C) are secondary end points.
The observed reduction in risk was similar across age groups, comorbidity scores, and body mass index groups. However, nirmatrelvir plus ritonavir was associated with increased protective activity among incompletely vaccinated persons and patients who had received their most recent vaccine dose more than 20 weeks prior (Figure 4). An 81% risk reduction was seen in the subgroup analysis of unvaccinated persons.
Figure 4. Subgroup analysis comparing cumulative incidence of hospitalization or death among patients who were prescribed nirmatrelvir plus ritonavir and those who were not.
Estimates, risk differences, and CIs were calculated with an inverse probability–weighted model performed within each stratum. BMI = body mass index.
In secondary analyses assessing effectiveness at preventing hospitalization and, separately, death, prescription of nirmatrelvir plus ritonavir was associated with reduced risk for both end points. Fewer hospitalizations (adjusted risk ratio, 0.60 [CI, 0.44 to 0.81]) and deaths (adjusted risk ratio, 0.29 [CI, 0.12 to 0.71]) occurred among recipients of nirmatrelvir plus ritonavir.
Discussion
We emulated a clinical trial using observational data to evaluate the effectiveness of nirmatrelvir plus ritonavir in preventing hospitalization or death among patients aged 50 years or older in the context of high vaccination prevalence and an intense Omicron epidemic. The observed rate of hospitalization or death was low (1%) among outpatients diagnosed with COVID-19, but we found that nirmatrelvir plus ritonavir was associated with a further 44% reduction in the risk for hospitalization or death.
In both the randomized trial and our analysis of observational data, there was a reduction in the rate of COVID-19–related hospitalization and death in the nirmatrelvir-plus-ritonavir group. However, there are some important differences in study contexts that may account for a smaller magnitude of risk reduction compared with the randomized controlled trial. The EPIC-HR study (1) enrolled only unvaccinated persons (median age, 46 years) and had a 7% hospitalization rate in the placebo group, whereas our study included mainly vaccinated patients (median age, 63 years) and had an overall hospitalization rate of 1%. It is possible that hospitalization risk cannot be reduced much further, particularly among vulnerable patients. However, the 81% risk reduction seen in the subgroup analysis of incompletely vaccinated persons (<3 vaccine doses) in our study was similar to the risk reduction observed among unvaccinated persons in EPIC-HR.
The results of our study also support the findings of 2 recent observational analyses of nirmatrelvir plus ritonavir (5, 6), although the methods, sample sizes, and periods of study differ. The estimates of protection are similar: a 45% reduction in the composite outcome of emergency department visits, hospitalization, and death among vaccinated U.S. adults receiving care in select participating health care organizations (6), and a 73% reduction in hospitalization among Israeli outpatients aged 65 years or older but no benefit among persons aged 40 to 64 years (5). Both of these studies included periods when only a small proportion of eligible persons (1% and 4%, respectively) accessed treatment, potentially increasing the risk of selection bias. When we restrict our analysis to this period, our data also suggest stronger protection, potentially due to bias caused by greater access among persons at lower risk. In addition, if the observation that the effect of nirmatrelvir plus ritonavir is modified by recency of the last vaccine dose is valid, the earlier distribution of booster vaccination in Israel compared with the United States could account for the observed increased benefit among the Israeli cohort.
One of the strengths of our study is its large sample size, which allowed us to estimate the risk reduction with nirmatrelvir plus ritonavir for specific subpopulations of interest. Overall, we observed a relatively consistent protective effect of nirmatrelvir plus ritonavir despite greatly varying hospitalization rates across groups. Although incompletely vaccinated patients seem to have experienced a greater proportional reduction in risk, fully vaccinated patients also had a reduction in risk. Similarly, there was a trend toward increased protection among those who had received a vaccine dose more than 20 weeks prior. In contrast to a finding in the analysis from Israel (5), a clinical benefit from treatment was observed among patients younger than 65 years. It was not surprising that the risk difference for these younger patients was smaller because they had a lower risk for the primary end point at baseline. Protection among some vulnerable groups could be underestimated due to procedures in place in some skilled nursing facilities or elder home care programs that encourage admission in the context of COVID-19 preemptively or for infection control.
Our findings should be interpreted in the context of several limitations. This was an observational retrospective study with potential residual confounding and selection bias. We attempted to minimize selection bias by excluding patients whose initial diagnosis of COVID-19 was within 2 days of their admission date because they were more likely to have had a delay in diagnosis and therefore more advanced disease at the time of diagnosis. This led to a lower hospitalization rate for the analyzed cohort than what was seen in the overall Mass General Brigham population during this period. Although the majority of hospitalizations in the study population would have been captured in the EHR given Mass General Brigham's large health care system encompassing 9 hospitals, hospitalizations outside our system were not included. Positive results on home antigen tests are incompletely captured in the EHR, and the findings may not extend to persons with less access to testing and reporting. Our analysis used an intention-to-treat approach, but adherence to nirmatrelvir plus ritonavir may have been lower in our real-world study and some patients may not have initiated treatment, potentially resulting in an underestimation of the efficacy of this treatment.
The majority of COVID-19 admissions during the study period occurred among patients diagnosed at the time of admission. In those who were diagnosed as outpatients, Black, Hispanic, or Latinx patients had much lower rates of prescription of nirmatrelvir plus ritonavir. To realize the public health potential of outpatient COVID-19 therapy, we must address this gap and these disparities.
This study confirms the effectiveness of nirmatrelvir plus ritonavir in preventing hospitalization and death among vaccinated and unvaccinated persons aged 50 years or older with COVID-19. Although these data suggest its clinical impact may be reduced in the context of high levels of prior immunity and consequent lower risk, the estimated 40% reduction in hospitalization and 71% reduction in death could have large population benefits if nirmatrelvir plus ritonavir is used widely.
Supplementary Material
Footnotes
This article was published at Annals.org on 13 December 2022.
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