Nirmatrelvir‐ritonavir treatment of COVID‐19 in a high‐risk patient population: A retrospective observational study

Abstract

Background

Coronavirus disease 2019 (COVID‐19) is a highly contagious, airborne viral infection that can infect anyone. Those with certain underlying conditions may be at higher risk for infection to develop into a severe disease requiring hospitalization. This report summarizes use of nirmatrelvir‐ritonavir for the treatment of COVID‐19 in high‐risk patients at a single academic medical center through a pharmacist delegation protocol and demonstrates real‐world efficacy and safety of treatment.

Methods

This retrospective, single‐center, observational study analyzed all patients who received nirmatrelvir‐ritonavir ordered by a clinical pharmacist for treatment of COVID‐19 infection. The primary outcomes were safety and efficacy of nirmatrelvir‐ritonavir. Safety was evaluated by analyzing drug interaction management and adverse events. Efficacy was evaluated through hospitalization and death within 28 days of nirmatrelvir‐ritonavir use.

Results

Sixty patients were eligible for inclusion. No patients were hospitalized or died within 28 days after initiation of nirmatrelvir‐ritonavir. Pharmacists identified 101 drug interactions with 60% considered clinically significant, requiring modification of home medications. Adverse outcomes associated with the use of nirmatrelvir‐ritonavir were reported in 13 patients (21.7%).

Conclusions

A comprehensive program to mitigate drug interactions and prescribe nirmatrelvir‐ritonavir ensured timely access to COVID‐19 therapy, which may be associated with the prevention of hospitalization and death.

1. BACKGROUND

On 22 December 2021, the US Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for nirmatrelvir‐ritonavir (Paxlovid, Pfizer) to treat mild‐to‐moderate coronavirus disease 2019 (COVID‐19) in adults and pediatric patients who are at a high risk for progression to severe COVID‐19. ¹ Nirmatrelvir prevents viral replication through inhibition of the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) main protease. ² Ritonavir is not active against SARS‐CoV‐2; however, it inhibits the cytochrome P450 3A4 (CYP3A4) enzyme, which is responsible for the metabolism of nirmatrelvir. Ritonavir effectively increases plasma concentrations of nirmatrelvir leading to increased pharmacodynamic activity. ¹ In a randomized, double‐blind, controlled trial comparing nirmatrelvir‐ritonavir to placebo, nirmatrelvir‐ritonavir showed an 89% decrease in composite hospitalizations or deaths (P < .001) if taken within 5 days of symptom onset. ³ Although nirmatrelvir‐ritonavir is a promising treatment option for COVID‐19, the inhibition of the CYP3A4 enzyme by ritonavir poses a risk for significant drug interactions that require close clinical monitoring.

To streamline efficient and safe ordering of oral COVID‐19 antiviral therapies, including nirmatrelvir‐ritonavir and molnupiravir, to patients diagnosed with COVID‐19 who are high risk for progression to severe disease, this institution developed a protocol that delegates clinical assessment and ordering of a 5‐day course of nirmatrelvir‐ritonavir to clinical pharmacists. This study evaluated outcomes associated with nirmatrelvir‐ritonavir and clinical pharmacist management of drug interactions.

2. METHODS

This retrospective, single‐center study analyzed all patients who received nirmatrelvir‐ritonavir ordered by a clinical pharmacist through this institutional delegation protocol (Supplement 1) from January 2022 through February 2022. Patients were eligible for nirmatrelvir‐ritonavir if they were ≥12 years of age and met FDA EUA criteria for COVID‐19 oral antiviral therapy, including weight ≥40 kg and high risk for progression to severe COVID‐19 disease as determined by the Centers for Disease Control and Prevention criteria. ⁴

Symptomatic patients who tested positive either contacted their provider, who gave them a hotline number to call to be entered in a treatment database or entered their own information in the database via the University of Wisconsin Health website. The database prioritized eligible patients by the National Institutes of Health criteria to tier 1 through 4, accounting for age, vaccination status, presence of an immunocompromising state, and other risk factors. ⁵ Pharmacists started with patients most at risk for progression to severe COVID‐19 (tier 1), but as workload and medication supply allowed, they would offer therapy to all appropriate patients at risk. The pharmacist collected and assessed serum creatinine, estimated glomerular filtration rate (eGFR), presence of liver disease, and home medication list to identify clinically significant drug interactions via chart review. Patients were then contacted via telephone to verify home medications, allergies, review EUA information, and offer nirmatrelvir‐ritonavir. Patients could accept or decline therapy. If accepted, an electronic prescription was sent to a pharmacy that stocked nirmatrelvir‐ritonavir.

Patients were not eligible for oral COVID‐19 antiviral therapy via this delegation protocol if they had any of the following conditions: renal insufficiency (eGFR <30 ml/min/1.73²), severe hepatic impairment (Child‐Pugh Class C), or pregnancy. Patients were also excluded from this protocol if they were using drugs contraindicated with nirmatrelvir‐ritonavir according to the EUA. Patients who did not pick up their prescription for nirmatrelvir‐ritonavir were excluded from analysis.

Investigators retrospectively reviewed encounters in the electronic medical record to collect information for analysis. Nirmatrelvir‐ritonavir effectiveness was evaluated as the incidence of hospitalization, death, and rebound SARS‐CoV‐2 within 28 days after dispensing of nirmatrelvir‐ritonavir. Patients without records or medical record documentation indicating that the patient was either alive or deceased at 28 days after therapy were classified as unknown. To evaluate nirmatrelvir‐ritonavir safety, the incidence and management of drug interactions and adverse events were reviewed. All clinically significant drug interactions (ie, requiring therapy modification) and management recommendations were discussed with the patient's primary provider. Clinical significance of drug interactions was determined by the pharmacist and primary provider based on individual patient assessment. Patient reported side effects within 28 days of receiving nirmatrelvir‐ritonavir were assessed using subjective information documented in telephone encounters, clinic visits, or patient messaging when available. Methodology for this study follows the EQUATOR STROBE guidelines for observational studies. ⁶

3. RESULTS

During the study period, 773 patients were screened for COVID‐19 antiviral therapy. Nirmatrelvir‐ritonavir was considered first‐line therapy when appropriate and available based on supply. All the available supply of nirmatrelvir‐ritonavir was distributed during the study period. A total of 319 patients did not meet EUA criteria for available COVID‐19 antiviral therapies. Alternative therapy with remdesivir, molnupiravir, or sotrovimab was offered to 196 patients and declined by 43 patients. No COVID‐19 antiviral therapy was available for 138 patients due to limited drug supply. A total of 47 patients had received treatment elsewhere at the time of encounter with the pharmacist. Nirmatrelvir‐ritonavir was offered to 73 patients; however, 12 patients declined treatment. Nirmatrelvir‐ritonavir was ordered for 61 patients, and the prescription was filled by 60 patients. The 60 patients who were known to have filled their prescription of nirmatrelvir‐ritonavir were included for analysis.

Most patients who received nirmatrelvir‐ritonavir had two or more risk factors for progression to severe COVID‐19 (n = 55, 91.7%). The most common qualifying conditions included obesity (n = 42, 70%), cardiovascular disease (n = 26, 43.3%), older age (n = 26, 43.3%), lung disease (n = 15, 25%), and immunosuppression (n = 15, 25%). A comprehensive report of patient characteristics can be found in Table 1.

TABLE 1.

Patient characteristics and outcomes

Characteristic	Value, % n = 60
Age (years)	58.3 ± 17.8
Sex, %
Male	21 (35)
Female	39 (65)
Ethnic group, %
Hispanic	1 (1.7)
Not Hispanic	58 (96.7)
Not available	1 (1.7)
Race, %
American Indian or Alaskan Native	1 (1.7)
Asian	3 (5)
Black or African‐American	3 (5)
Native Hawaiian or Other Pacific Islander	0 (0)
White	52 (86.7)
Not available	1 (1.7)
Other	0 (0)
Vaccination status
Vaccinated (3 or more vaccines)	30 (50)
Partially vaccinated (1–2 vaccines)	13 (21.7)
Unvaccinated	17 (28.3)
NIH risk tier, %
1	9 (15)
2	17 (28.3)
3	20 (33.3)
4	14 (23.3)
Comorbidities, %
Cancer	5 (8.3)
Cardiovascular disease	26 (43.3)
Cerebrovascular disease/neurologic conditions	1 (1.7)
Diabetes	13 (21.7)
Immunosuppression	15 (25)
Kidney disease	3 (5)
Liver disease	3 (5)
Lung disease	15 (25)
Medical‐related technological dependence	0 (0)
Mental health disorder	12 (20)
Neurodevelopmental disorders	0 (0)
Obesity	42 (70)
Older age (>65 years)	26 (43.3)
Sickle cell disease	0 (0)
Smoking	5 (8.3)
Substance use disorder	1 (1.7)
Hospitalization
Confirmed hospitalization	0 (0)
No hospitalization	58 (96.7)
Unknown	2 (3.3)
Death
Confirmed death	0 (0)
Confirmed alive	58 (96.7)
Unknown	2 (3.3)
Adverse outcomes
Reported symptoms	12 (20)
No symptoms	1 (1.7)
No documentation	47 (78.3)
Drug interactions
Total drug interactions identified	101
Total patients with any identified interaction	45
Patients with no clinically significant drug interactions	24
Patients with 1 clinically significant drug interaction	24
Patients with >1 clinically significant drug interactions	12

No patients died within 28 days after initiation of nirmatrelvir‐ritonavir. Hospitalization and death within 28 days after initiation of nirmatrelvir‐ritonavir were unknown in two patients (3.3%). Two patients (3.3%) experienced rebound SARS‐CoV‐2 symptoms with positive tests within 28 days after initiation of nirmatrelvir‐ritonavir. Neither patient required hospitalization. Two patients (3.3%) had no records beyond the initial nirmatrelvir‐ritonavir ordering encounter and were unknown to have been hospitalized, deceased, or re‐infected with SARS‐CoV‐2 within 28 days after initiation of nirmatrelvir‐ritonavir therapy. The remaining 58 patients (95%) completed therapy without issue and remained out of the hospital 28 days after initiation of nirmatrelvir‐ritonavir. Adverse outcomes associated with the use of nirmatrelvir‐ritonavir were reported in 13 patients (21.7%), with the most common symptoms of cough, chest discomfort, migraines, and nausea.

Pharmacists identified 101 drug interactions among all patients who received nirmatrelvir‐ritonavir; however, only 49 drug interactions in 36 patients (60%) were deemed clinically significant, requiring mitigation. Management strategies are displayed in Table 2. Of the interactions requiring intervention, the most common drug interaction identified was between β‐hydroxy β‐methylglutaryl‐CoA reductase inhibitors and ritonavir (n = 21, 42.9%). The second most common actionable drug interaction was between calcium channel blockers and ritonavir (n = 9, 18.4%). For all significant drug interactions, the pharmacist proposed a 7‐day hold or dose adjustment to the interacting drug to the patient's provider. Pharmacist proposed management strategies were accepted by primary care providers at a rate of 100%, and there were no reported problems associated with drug interaction management.

TABLE 2.

Management strategies for clinically significant drug interactions identified by pharmacist

Interacting medication‐medication class	Patients identified	Management
Statins (atorvastatin, rosuvastatin, simvastatin, and pravastatin*)	21	Hold statin for 7 days
Amlodipine	8	Take 50% of normal amlodipine dose for 7 days
Trazodone	4	Reduce trazodone dose by 50% (or take a maximum dose of 50 mg if taken as needed) for 7 days
Mirtazapine	2	Hold mirtazapine for 7 days
Oral contraceptives	2	Use alternative form of contraception for 7 days
Alprazolam	2	Hold alprazolam during nirmatrelvir‐ritonavir therapy (or take half of normal dose if taken as needed)
Budesonide intranasal	1	Hold intranasal budesonide for 7 days
Nifedipine	1	Hold nifedipine for systolic blood pressure <130 mmHg for 7 days
Fluticasone nasal spray	1	Hold intranasal fluticasone during nirmatrelvir‐ritonavir therapy
Fluticasone inhaler	1	Hold inhaled fluticasone during nirmatrelvir‐ritonavir therapy
Oxycodone	1	Attempt to avoid completely during nirmatrelvir‐ritonavir therapy, but if needed use half of the usual dose
Diazepam	1	Avoid use during nirmatrelvir‐ritonavir therapy
Buspirone	1	Hold buspirone for 7 days
Tadalafil	1	Take half of normal if needed during nirmatrelvir‐ritonavir therapy
Sildenafil	1	Avoid use during nirmatrelvir‐ritonavir therapy
Nintedanib	1	Hold nintedanib for 7 days

^*Drug interaction with pravastatin identified and managed.

4. DISCUSSION

To the knowledge of the investigators, this is the first review of a pharmacist‐driven nirmatrelvir‐ritonavir delegation protocol in the treatment of COVID‐19 infection. Nirmatrelvir‐ritonavir is an important therapeutic tool for health systems to leverage to improve patient outcomes and mitigate the effects of a surge on hospital capacity. Given the requirement for timely initiation of nirmatrelvir‐ritonavir therapy, pharmacists can play a key role in screening patients, assessing appropriateness of therapy, and ensuring efficient access to treatment.

This protocol‐driven assessment and ordering of nirmatrelvir‐ritonavir successfully treated 60 patients while mitigating important drug interactions. Of the 58 patients prescribed nirmatrelvir‐ritonavir with a confirmed prescription fill and follow‐up documentation available, no hospitalizations or deaths occurred. Drug interactions were manageable, and no new adverse events were identified. Notably, two patients experienced rebound symptoms after completing treatment, one of whom was subsequently treated with sotrovimab. These symptoms closely mimicked the presentation of COVID‐19, with one patient describing unresolving COVID‐19 symptoms. Investigators were only able to follow patients who received care within the integrated health system. Patients who presented outside of this health system would not have rebound symptoms documented. However, the rate of rebound symptoms reported in this study is close to those previously reported in the literature. Wang and team report a 5.87% rebound rate for COVID‐19 symptoms in a 30‐day period after treatment with nirmatrelvir‐ritonavir.⁷

Our use of a pharmacist‐led screening process rapidly expanded access to antivirals for a large patient population. An additional benefit of leveraging pharmacists in the ordering of nirmatrelvir‐ritonavir was the careful assessment and management of drug interactions. More than half of the patients required intervention for the management of drug interactions by a pharmacist in collaboration with the patient's provider.

Limitations of this report include the retrospective nature and small population size limited to a single center and a single electronic medical record. Crossover of side effects to common COVID‐19 symptoms made it difficult to decipher between COVID‐19 symptoms and true nirmatrelvir‐ritonavir side effects. In addition, data specific to adverse effects is likely not fully encompassing given the subjective nature of adverse effect reporting and the lack of formal side effect screening or follow‐up. Lastly, the study population was predominantly white. Future studies would ideally include a more diverse population to account for potential differences in response to antivirals and the risk of COVID‐19 progression.

In conclusion, treatment of COVID‐19 with nirmatrelvir‐ritonavir was not associated with hospital admissions or deaths. Drug interactions were common and successfully mitigated through a pharmacist‐led assessment and communication with the physician prescriber. A comprehensive program to identify, assess, mitigate drug interactions, and prescribe nirmatrelvir‐ritonavir ensures timely access to COVID‐19 therapy and prevents untoward patient outcomes.

FUNDING INFORMATION

There was no external funding for this study.

CONFLICT OF INTEREST

All authors declare no conflicts of interest.

Supporting information

Appendix S1: Supporting Information

Kane AM, Keenan EM, Lee K, et al. Nirmatrelvir‐ritonavir treatment of COVID‐19 in a high‐risk patient population: A retrospective observational study. J Am Coll Clin Pharm. 2023;6(1):29‐33. doi: 10.1002/jac5.1729