Underutilization of nirmatrelvir/ritonavir in eligible COVID-19 patients

Abstract

Nirmatrelvir/ritonavir (NMV/r) might reduce the risk of hospitalization or death due to SARS-CoV2. Indirect data suggest that antiviral use among non-hospitalized patients is low. The aim of the study is to determine the number of patients admitted for COVID-19 who met the criteria to receive NMV/r prior to admission but did not receive it. We analyzed clinical data from electronic medical records of 132 patients who were hospitalized due to Covid-19 from August to November 2023. Among the 88 patients eligible for NMV/r before hospitalization, only 3.8% received it, even though 24.3% had previous contact with the healthcare system. Among those who were eligible for treatment, a potential drug interaction was identified in 80.6%; NMV/r was contraindicated in only ten cases (11.3%) due to a serious interaction, as it was deemed impossible to stop or alter it. Of the patients who did not receive treatment, three died from Covid-19, while there were no deaths in the treatment group. Our data confirm that many patients who could benefit from early treatment with NMV/r are not receiving it. This limited use may be linked to missed opportunities to prevent hospitalization and mortality from Covid-19.

Introduction

Despite the decreased incidence of SARS-CoV-2 infection and reduced mortality associated with vaccination, COVID-19 remains a public health issue, particularly for immunosuppressed individuals and older adults with comorbidities. Initial clinical trials with Nirmatrelvir/ritonavir (NMV/r) have demonstrated that its use significantly reduces hospitalization and mortality rates [1]_, as confirmed by observational studies involving patients with multiple comorbidities [2]. However, its benefits in relatively low-risk vaccinated populations remain uncertain [3]. Clinical recent data indicate that NMV/r is underutilized [4]. Potential barriers include a lack of medical familiarity with the drug’s interactions, bureaucratic challenges, and the mistaken belief that COVID-19 no longer poses a significant threat. This issue is especially relevant for vulnerable populations, who continue to face substantial risks of hospitalization and mortality, where early use of antivirals may provide clinical benefit. We aimed to assess how many patients hospitalized for COVID-19 met the criteria for NMV/r prior to admission, whether they received medical care just before admission (emergency or primary care), and whether they were ultimately prescribed NMV/r.

Methods

This observational study analyzes adults hospitalized for COVID-19 in a university-affiliated hospital between August and November 2023. It included consecutive patients over 18 years of age with a primary diagnosis of respiratory infection caused by SARS-CoV-2. The hospitalization criteria were: O2 saturation < 94%, respiratory rate > 25 breaths per minute (BPM), confusion, hemodynamic instability, or clinical severity determined by the attending physician. Sociodemographic variables, medical history (age, sex, Charlson index, glomerular filtration rate, and history of chronic kidney disease), and clinical aspects of the current infection were evaluated, such as the onset of symptoms, recent contact (less than seven days) with the healthcare system, vaccination status, and previous hospitalizations due to COVID-19. The primary objective was to identify patients meeting the criteria for initiating NMV/r treatment and assess the feasibility of replacing contraindicated concomitant drugs. The criteria for administering NMV/r on an outpatient basis in patients with mild to moderate COVID-19 are the presence of symptoms within the first five days of onset, at any age in immunocompromised patients and those with other high-risk conditions, or in patients over 80 years of age. NMV/r was administered through a hospital or community pharmacy following a physician’s prescription, whether in primary care, emergency care, or specialized care. The study was approved by the institutional review board’s (CEIC #23/615). The sample size was estimated at 139 individuals to ensure 5% precision, if only 10% would receive NMV/r, based on previous findings [5]. Descriptive statistics and specific tests (Chi-square, Fisher’s exact test, Student’s t-test, Mann-Whitney U test, and Kruskal-Walli’s test) were used depending on the variable type. Statistical analysis was performed using R version 4.3.1 and RStudio.

Results

We analyzed 132 patients admitted with COVID-19; 17 lacked indications for NMV/r. Of the remaining 115 patients, 37 had contraindications for its use, including 10 with irreplaceable concomitant medications, 18 who had late contact with the health system (> 5 days of symptoms), and those presenting an eGFR of less than 30 ml/min. Ultimately, we determined that 78 patients (67.8%) could have benefited from NMV/r, but only 3 (3.8%) received it before admission (Fig. 1). Eligibility for NMV/r was primarily based on age > 80 years (79.1%), followed by unvaccinated or under-vaccinated individuals aged 65–75 years (19.1%) and immunocompromised patients (2.6%). Significant drug interactions were noted in 61 patients (78.2%), most frequently involving atorvastatin (23.9%), tamsulosin (20.5%), and apixaban (12.5%). Among the 23 patients with contraindicated drugs, substitution was considered impossible in 10 cases due to medications such as carbamazepine, clopidogrel, flecainide, and amiodarone. Notably, 12 of the 75 eligible patients who did not receive NMV/r had no drug interactions.

Fig. 1.

Proportion of patients who were eligible, suitable for, and ultimately received NMV/r treatment. We consider suitable for treatment those patients with a confirmed diagnosis who have an indication for treatment according to current guidelines within the first five days of symptoms and who do not have any contraindications for the use of NMV/r

The 78 eligible patients had a mean age of 85 years, predominantly female (61.5%), and a mean Charlson Index of 6, indicating high comorbidity burden. Most (97.4%) had received at least two SARS-CoV-2 vaccine doses, and symptoms had been present for an average of two days before admission. Patients who received NMV/r shared similar demographics but had lower Charlson Index scores. Mortality was higher among those who did not receive NMV/r (4% vs. 0%), with all deaths attributable to SARS-CoV-2 (Table 1). Respiratory failure was also more common in untreated patients, although the small number of cases prevents obtaining statistically significant conclusions.

Table 1.

Clinical characteristics of the patients; results are expressed by mean and range, or absolute number and percentage. eGFR: estimated glomerular filtration rate (Cockroft-Gault formula); CKD: chronic kidney disease

	All N = 78	Received NMV/r (N = 3)	Missed opportunity (N = 75)	p-value
Mean age (years)	85.0 [80.2;89.0]	83.0 [70.0;84.0]	86.0 [80.5;89.0]	0.180
Sex:				1.000
Female	48 (61.5%)	2 (66.7%)	46 (61.3%)
Male	30 (38.5%)	1 (33.3%)	29 (38.7%)
Charlson Comorbidity Index (points)	6.00 [5.00;7.00]	5.00 [3.00;5.00]	6.00 [5.00;7.00]	0.040
Institutionalized	4 (5.13%)	0 (0.00%)	4 (5.33%)	1.000
Vaccinated for COVID-19	76 (97.4%)	2 (66.7%)	74 (98.7%)	0.076
Number of vaccine doses				1.000
2	5 (6.58%)	0 (0.00%)	5 (6.76%)
3	24 (31.6%)	1 (50.0%)	23 (31.1%)
4	40 (52.6%)	1 (50.0%)	39 (52.7%)
5	7 (9.21%)	0 (0.00%)	7 (9.46%)
Previous admissions due to COVID-19?				0.212
Yes	7 (8.97%)	0 (0.00%)	7 (9.33%)
Unknown	37 (47.4%)	0 (0.00%)	37 (49.3%)
No	34 (43.6%)	3 (100%)	31 (41.3%)
eGFR (mL/min)	66.7 (15.6)	69.7 (18.7)	66.6 (15.6)	0.800
Known CKD	14 (17.9%)	0 (0.00%)	14 (18.7%)	1.000
Symptoms before admission (days)	2.00 [1.00;4.00]	4.00 [3.00;4.50]	2.00 [1.00;4.00]	0.191

Discussion

Our single center study of 132 COVID-19 admissions (Aug–Nov 2023) found that just 3.8% of eligible patients received NMV/r before hospitalization, despite 80.6% having potential drug–drug interactions and only 24.3% engaging early with healthcare. Though local prescribing practices and variant dynamics may differ elsewhere, our realworld data pinpoint clear, modifiable barriers (e.g., faster medication review, better access pathways) and provide a strong foundation for multicenter efforts to boost early NMV/r use and curb COVID-19 hospitalizations and mortality.

Our results highlight the limited utilization of NMV/r in hospitalized COVID-19 patients, with only 3.8% of eligible patients receiving the treatment. This finding has been reported before and may affect all antivirals for SARS-CoV-2 [6]. Despite the discouraging results of the EPIC-SR trial³, early use of NMV/r may still be considered for patients with risk factors for poor prognosis, regardless of their vaccination status. This includes individuals over 65 years of age, immunosuppressed patients, or immunocompetent adults of any age who have multiple risk factors for progressing to severe disease [7]. A significant barrier to NMV/r administration appears to be concerns regarding drug interactions, particularly in elderly patients with complex medical conditions and polypharmacy. Despite these challenges, we found that most drug interactions were manageable, with potential strategies such as replacing or suspending interacting medications like statins or tamsulosin. However, some drugs, such as quetiapine, pose absolute contraindications that are difficult to address. One relevant finding from our study was that 25% of patients had prior healthcare contact before hospitalization, yet few received NMV/r. There are multiple reasons that may explain these missed opportunities, such as lack of experience of primary care or emergency physicians, fear of interactions, bureaucratic obstacles, or the false impression that COVID-19 is a manageable disease.

The study’s strengths include thorough review of patient records to ensure accurate eligibility assessments. However, limitations such as small sample size, observational design, and a focus solely on hospitalized patients reduce generalizability. It did not account for patients who received NMV/r and avoided hospitalization, potentially underestimating its therapeutic success. Though local prescribing practices and variant dynamics may differ elsewhere, our realworld data pinpoint clear, modifiable barriers (e.g., faster medication review, better access pathways) and provide a strong foundation to boost early NMV/r use and curb COVID-19 hospitalizations and mortality in vulnerable populations. The findings reveal suboptimal NMV/r use and emphasize its potential to prevent severe outcomes, including death.

In conclusion, the study draws attention to missed opportunities for NMV/r administration among non-hospitalized COVID-19 patients, where early antivirals may continue to provide clinical benefit. Many drug interactions are easily managed, leaving few absolute contraindications. These results reinforce the need to address barriers to NMV/r use in patients who could benefit, promote physician education, and streamline protocols to optimize its role in mitigating complications from SARS-CoV-2 infection.

Author contributions

Conceptualization: [CFA, RH, AVC and VE]; Methodology: [AVC] Formal analysis and investigation: [CFA, RH]; Writing - original draft preparation: [CFA and VE]; All authors reviewed the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.