What Pharmacists Need to Know About Treating COVID-19 - Monograph

Maggie Zhao, PharmD, BCCCP

Medication Knowledge Management

Department of Pharmacy Mayo Clinic

Rochester, Minnesota

Release Date: March 31, 2023

Expiration Date: March 31, 2024

HOW TO OBTAIN CREDIT

PROGRAM DESCRIPTION

Pharmacists play many roles in the management of COVID-19, thus it is essential they remain up to date with the COVID-19 pandemic’s many changes, including evolving variants and subvariants, changes to Emergency Use Authorizations and therapeutic regimens, and the expanding role of pharmacists in combating the pandemic. This activity discusses the need for timely testing; the National Institutes of Health guidelines on patient identification and risk stratification for treatment; current clinical data on therapeutic regimens; administration guidelines, including Test to Treat approaches; and strategies to reduce health care disparities.

TARGET AUDIENCE

This activity is intended for US-based and ex–US-based hospital and communitybased pharmacists.

Participants must complete the preactivity questionnaire, complete and receive a minimum score of 70% on the posttest, and complete the program evaluation online at www.ExchangeCME.com/COVIDPharmMonograph

Estimated time to complete the activity: 60 minutes

EDUCATIONAL OBJECTIVES

Upon completion of this activity, participants should be able to:

• Incorporate patient education strategies to support timely testing and early diagnosis of COVID-19

• Describe risk factors for progression to severe COVID-19 among nonhospitalized patients with mild to moderate COVID-19

• Utilize currently available treatment options for nonhospitalized patients with COVID-19 based on recommendations from national guidelines and regulatory agencies

FACULTY AND DISCLOSURE OF CONFLICTS OF INTEREST

PACE requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose all financial relationships they may have with ineligible companies. All relevant financial relationships are thoroughly vetted and mitigated according to PACE policy. PACE is committed to providing learners with high-quality accredited CE activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of an ineligible company.

The faculty reported the following relevant financial relationships or relationships to products or devices they have with ineligible companies related to the content of this educational activity:

Maggie Zhao, PharmD, BCCCP Nothing to disclose.

The PACE planners and others have no relevant financial relationship(s) to disclose with ineligible companies. The Integritas Communication planners and others have no relevant financial relationship(s) to disclose with ineligible companies.

JOINT ACCREDITATION STATEMENT

In support of improving patient care, this activity has been planned and implemented by Partners for Advancing Clinical Education (PACE) and Integritas Communications. PACE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Introduction

PHARMACIST ACCREDITATION STATEMENT

PACE is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education with Commendation.

CREDIT DESIGNATION

PACE designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number JA4008073-9999-23-071-H01-P)

This is a knowledge-based activity.

DISCLOSURE OF UNLABELED USE

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMER

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

PACE CONTACT INFORMATION

For additional information about the accreditation of this activity, please visit https://partnersed.com.

F

or the last 3 years, the novel SARS-CoV-2 virus that causes COVID-19 has been taxing the global health care system, with more than 102,200,000 cases reported in the US since its emergence.1-4 Prompt diagnosis of COVID-19 is critical for reducing the spread of COVID-19 and identifying nonhospitalized patients (or hospitalized patients for whom mild to moderate COVID is a secondary diagnosis) who are eligible for treatment. As of February 2023, there were 3 antivirals available for treatment: 2 given orally and 1 given intravenously (IV). There are numerous risk factors that dictate eligibility for existing treatments, based on a patient’s risk of progression to severe COVID-19. Moreover, many patients who seemingly recover from acute SARSCoV-2 infection will experience potentially debilitating persistent clinical manifestations of the disease (known as post-COVID conditions or Long COVID).5 Information about risk factors, preventive strategies, and treatment options for both acute infection and post-infection complications are continually evolving.5,6 It is imperative that pharmacists, who play an important role in combating this pandemic as frontline clinicians and members of interdisciplinary patient management

teams, are aware of the most-current guidelines for diagnosis, treatment, and prioritization of patients when necessary, as well as social, racial, and ethnic disparities in COVID-19 management.

The SARS-CoV-2 Virus

SARS-CoV-2 is a novel coronavirus whose genetic material is single-stranded RNA.7 Like other members of the coronavirus family, it is highly pathogenic and causes respiratory infections that can develop into severe, life-threatening respiratory pathologies and lung injuries.7 The binding of the coronavirus spike protein to cellular entry receptors, especially angiotensinconverting enzyme 2 (ACE2), is a key element in the initiation of infection.7 The ensuing viral replication and increase in viral load results in an immune response that includes cytokine expression and a dysregulated proinflammatory response, which contribute to the severity of the infection.7

Throughout the course of the pandemic, the virus has undergone a series of mutations and genetic recombination, leading to the emergence of different variants and subvariants, with varying levels of

transmissibility, virulence, and resistance to treatments and vaccines.8 As of February 2023, the predominant variant in the US was XBB.1.5, which quickly replaced the previously dominant BQ.1 and BQ.1.1.8 Within the US, XBB.1.5 first spread most rapidly in the Northeast but has since become predominant across the country.9 These variants mutated away from their original ancestral Omicron variant, which has had implications for transmission, as well as treatment and prophylaxis options. For example, XBB.1.5 has an additional mutation vs XBB.1 and a higher binding affinity for ACE2, which could explain its rapid transmissibility.10 XBB.1.5 shows antibody evasion comparable to XBB.1, and these subvariants are more immune-evasive than previous Omicron subvariants.10 The extremely immuneevasive nature of recent subvariants has resulted in their resistance to previously successful anti–SARS-CoV-2 monoclonal antibodies (mAbs) used for treatment and pre-exposure prophylaxis (eg, bebtelovimab, tixagevimab/cilgavimab).11,12 Thus, it is important that pharmacists are aware of the prevalent strains in their region and the treatments these strains respond to.

The Importance of Timely Testing for COVID-19

Currently, people exposed to COVID-19 or with COVID-19 symptoms can be tested for SARS-CoV-2 infection using a polymerase chain reaction (PCR) test or rapid antigen test.13 A PCR test is the gold standard for detecting infection, though the delay in return of results may affect eligibility for treatment, particularly if the individual waited a few days before getting tested.

Status

Infected with COVID-1914

An antigen test can give results in 15 to 30 minutes but is less reliable than the PCR test, particularly in asymptomatic patients.13 In fact, a single negative antigen test does not rule out infection; it should be followed up with a second antigen test at least 48 hours after the first negative result or with a PCR test.13 It is critical that people be tested immediately if they have symptoms, though as of February 2023, the Centers for Disease Control and Prevention (CDC) recommended waiting 5 days to test asymptomatic individuals following a known exposure.13 The CDC’s recommended testing and isolation guidelines are in Table 1

Timely testing for COVID-19 helps to slow its spread in the community and identify people with COVID-19 who are at high risk of progression to severe disease so they may receive prompt treatment. Further, treatment is more effective the earlier it is given, resulting in better outcomes, including potentially reducing transmission by up to 50%.16,17 Available antiviral medications must be administered within 5 to 7 days of symptom onset, depending on the therapy.18 Symptom onset is considered day 0, and day 1 is the first full day after symptom onset.14 If exposed to someone with SARS-CoV-2 infection, day 0 is the last day of exposure and day 1 is the first full day after exposure.15 People with fewer symptoms and those who have symptoms for a shorter time period are less likely to test for SARS-CoV-2 infection. In fact, people may not recognize that their symptoms could be COVID-19.19 Without early testing and treatment, people with initially mild symptoms may later progress to severe COVID-19. It is essential that patients are aware of the importance of timely testing and the accessibility of tests. Tests are freely available from the federal government. Tests can

Isolation Instructions and Precautions

• Isolate for 5 days – If asymptomatic or symptoms resolve after 5 days (including being fever-free for 24 hours without fever-reducing medications), the person may end isolation

– If symptoms have not improved by day 5, continue to isolate until symptoms improve and fever-free for 24 hours without fever-reducing medications

• If the patient is immunocompromised or had moderate or severe illness they should isolate through day 10. If hospitalized, they should follow healthcare setting—specific isolation guidance

• Wear a mask through day 10

• No need to quarantine

• Wear a mask for 10 days after exposure when around others

– If 2 antigen tests taken 48 hours apart (after day 5) are negative, the patient may stop wearing a mask before day 10 Exposed to COVID-1915 (regardless of vaccination status)

• If symptomatic, isolate and test immediately; if asymptomatic, test on day 6

Day 0=first day of symptoms; Day 1=first full day after symptom onset. CDC, Centers for Disease Control and Prevention.

TABLE 1. CDC Testing and Isolation Guidelines for COVID-19

also be purchased at certain stores and pharmacies; in fact, many insurance companies reimburse for purchase of at-home tests, and it is important that patients are cognizant of these opportunities. The federal Test to Treat initiative allows patients to be tested for COVID-19 and, if positive and eligible for COVID-19 outpatient treatment, to access oral antiviral therapy easily and quickly through a “one-stop” pharmacy-based clinic, federally qualified health center, community health center, or long-term care facility.20 This initiative also includes education for the public about early initiation of treatment. Further, regulatory changes expanded the Test to Treat initiative by allowing state-licensed pharmacists to screen patients for eligibility and prescribe ritonavir-boosted nirmatrelvir (nirmatrelvir/r) to patients with a diagnosis of COVID-19 after the pharmacist has reviewed the patient’s potential drugdrug interactions (DDIs).21,22 It is critical that pharmacists are aware of this option so they can help patients who may have COVID-19 find participating locations.

Free Tests and Testing Site Locators (as of March 2023)

• https://www.covid.gov/tests

• https://testinglocator.cdc.gov/

COVID-19 Medication Locator

• https://covid-19-test-to-treat-locatordhhs.hub.arcgis.com/

Race and ethnicity trends in testing vary according to local populations, and there is evidence that although Black patients may have a slightly higher testing rate, they also have a significantly higher positivity rate, suggesting more testing is needed.23 Pharmacists should be aware of current testing recommendations, as well as racial, ethnic, and social disparities in testing and access to testing.

Identifying Eligible Patients for Treatment of Mild to Moderate COVID-19

There is a clinical spectrum of COVID-19 illness that helps guide outpatient therapeutic choices; it is essential that pharmacists are aware of how to stratify patients with COVID-19 by disease severity to determine their eligibility for treatment. The disease is considered mild when patients have any of the various signs and symptoms of COVID-19, including fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, and loss of taste and smell, but do not have shortness of breath, dyspnea, or abnormal chest imaging.24 Patients with moderate illness show evidence of lower respiratory tract disease on clinical assessment or imaging and their oxygen saturation measured by pulse oximetry (SpO2) is ≥94% on room air at sea level.24 Patients with persistent or progressive

dyspnea, especially those who have an SpO2 <94% or have symptoms that suggest high acuity (eg, chest pain or tightness, dizziness, confusion, other mental status changes) should be referred to a physician or advanced practice provider for an in-person evaluation, as this, along with imaging findings indicative of lung infiltrates >50%, may indicate severe COVID-19.25

Clinical trials and real-world studies have demonstrated that treating mild or moderate COVID-19 in eligible patients results in fewer symptoms, fewer systemic complications, faster symptom alleviation, reduction of symptom severity, faster viral load reduction, earlier sustained recovery, and fewer hospitalizations and deaths.26-29

It is generally recommended that every patient who is eligible be treated as soon as possible, especially as treatment is more effective the earlier it is given and can mitigate the spread of COVID-19.16,17,30 Risk factors for clinical progression include older age, various chronic comorbidities, physical inactivity, immunosuppression, obesity, and pregnancy, among other factors.31 Table 2 outlines general risk factors according to the CDC; however, factors are not created equal in terms of predicting disease progression. It is important for clinicians (including pharmacists) to determine clinical priority by identifying subgroups of eligible patients who are most at risk of severe disease. Institutions have developed their own scoring systems to identify the most-at-risk patients based on these factors, such as the monoclonal antibody screening score (MASS) developed at the Mayo Clinic that has been refined to predict the risk of severe disease and hospitalization.32 Given its high prevalence in the US, obesity alone qualifies a large portion of patients with COVID-19 as candidates for treatment, and for good reason. Numerous meta-analyses have demonstrated that obesity is associated not only with higher risk for intensive care unit (ICU) admission, but also poorer long-term COVID-19 outcomes.33-35 With each additional 1 kg/m2 of body mass index (BMI), the risk for severe disease has been reported to increase by 9% and mortality by 6%.36 Obesity also contributes to worse outcomes in younger populations, with patients aged >60 years with a BMI between 30 and 34 being twice as likely to be admitted to the ICU as individuals with a BMI <30.34 Metabolic syndrome and its individual components, hypertension, type 2 diabetes, and obesity, all result in worse outcomes secondary to SARS-CoV-2 infection and are well-recognized comorbidities.37 Individuals with metabolic syndrome have been shown to have a 77%, 56%, and 81% increased risk for COVID-19–related hospitalization, ICU admission, and death, respectively.37 Furthermore, many of these high-risk conditions are interrelated. For example, high BMI is one of the strongest risk factors for chronic kidney disease (CKD)38; CKD, in turn, is an independent risk factor for COVID-19 mortality, and patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 have been shown to have the highest mortality risk from COVID-19.39 Finally, being unvaccinated or incompletely

TABLE 2. Risk Factors for Progression to Severe COVID-1931

Older (Aged ≥65 Years) Mood Disorders or Schizophrenia

Asthma

Cancer

Cerebrovascular disease

Chronic kidney disease

Chronic liver diseases

Chronic lung diseases

Cystic fibrosis

Dementia

Developmental disabilities, including Down syndrome

Diabetes

Heart conditions

HIV

vaccinated or not up to date on COVID-19 boosters also increases the risk of progression to severe COVID-19 if infected.31 The pharmacist can play an important role in educating patients about the importance of vaccination, in addition to monitoring patients’ risk factors.

Educating patients on the factors that place them at risk for progression to severe COVID-19 is essential to efficiently and effectively get treatment to the patients who need it most.

Current Therapies for Mild to Moderate COVID-19

There are currently 3 antiviral agents authorized for treatment of mild to moderate COVID-19 in patients at high risk of progression to severe COVID-19: nirmatrelvir/r, remdesivir, and molnupiravir.18 Table 3 details the current National Institutes of Health (NIH)recommended guidelines for administering these medications. Currently, only nirmatrelvir/r is authorized for prescription by state-licensed pharmacists.

Nirmatrelvir/r

Nirmatrelvir/r is authorized for use in treating COVID-19 under an Emergency Use Authorization (EUA). It inhibits SARS-CoV-2 replication by targeting its main protease and subsequently destroying viral polyproteins needed for its replication; the addition of ritonavir boosts the concentration of nirmatrelvir to inhibit viral replication and prolong the half-life of nirmatrelvir.40 Nirmatrelvir/r is recommended by the NIH over remdesivir due to its ease of use: it is given orally, twice daily for 5 days.41

Obesity/Overweight

Physical inactivity

Primary immunodeficiencies

Pregnancy and recent pregnancy

Sickle cell disease

Smoking (current and former)

Solid organ or hematopoietic cell transplantation

Substance use disorders

Tuberculosis

Unvaccinated/Not current on vaccinations

Use of corticosteroids or other immunosuppressive medications

Currently, the EUA states that nirmatrelvir/r is not recommended in patients aged <12 years or <40 kg.41

The EPIC-HR clinical trial was a phase 2/3 study evaluating nirmatrelvir/r (compared to placebo) in nonhospitalized, unvaccinated, symptomatic (onset ≤5 days) adults (aged ≥18 years) with mild to moderate COVID-19 at increased risk of progression to severe disease (having ≥1 characteristic or coexisting condition associated with high risk of progression).42 This study showed that use of nirmatrelvir/r resulted in an 89% relative risk reduction (RR) in COVID-19–related hospitalization or death, as well as significant reductions in COVID-19–related medical visits and ICU admissions.19 Secondary endpoint analysis from this trial showed that nirmatrelvir/r use also reduced the duration and severity of symptoms.29

One real-world retrospective study of vaccinated patients (aged ≥18 years) showed the efficacy of nirmatrelvir/r in significantly reducing constitutional symptoms (50% RR), lower respiratory tract infections (72% RR), and all-cause hospitalization (60% RR) in addition to a 100% RR in 30-day mortality.27 An Israeli study conducted in vaccinated patients aged ≥40 years and at high risk of progression to severe disease found that the benefit of nirmatrelvir/r in reducing hospitalization as compared to placebo was seen only in patients aged ≥65 years, highlighting differences between real-world data and clinical trial data (Figure 1).43 The most common adverse events (AEs) related to nirmatrelvir/r usage were dysgeusia (6%), diarrhea (3%), hypertension (1%), and myalgia (1%).41

Another real-world retrospective study of nirmatrelvir/r efficacy was in vaccinated patients aged ≥18 years, and

TABLE 3. Current NIH Treatment Guidelines18

Therapy Indication

Nirmatrelvir/r

Treatment for mild to moderate COVID-19 in patients aged ≥12 years weighing ≥40 kg

Dosing Regimen

• Given within 5 days of symptom onset

• eGFR ≥60 mL/min: nirmatrelvir 300 mg + ritonavir 100 mg orally twice daily for 5 days

• eGFR ≥30 and <60 mL/min: nirmatrelvir 150 mg + ritonavir 100 mg orally twice daily for 5 days

• eGFR <30 mL/min: not recommended

• Child-Pugh Class C: not recommended

• Given within 7 days of symptom onset

• Patients ≥40 kg: 200 mg IV on day 1, followed by 100 mg IV once daily on days 2 and 3

Remdesivir

Treatment for mild to moderate COVID-19 in patients aged ≥28 days weighing ≥3 kg

• Patients ≥3 kg to <40 kg: 5 mg/kg IV on day 1 followed by 2.5 mg/kg on days 2 and 3

• Each infusion should be administered over 30-120 minutes

• Patients should be observed for ≥1 hour after infusion, as clinically appropriate

• eGFR <30 mL/min: not recommended

Molnupiravir

Treatment for mild to moderate COVID-19 in nonpregnant adults and only if the above therapies are unavailable or inappropriate

• Given within 5 days of symptom onset

• 800 mg orally twice daily for 5 days

eGFR, estimated glomerular filtration rate; IV, intravenously; NIH, National Institutes of Health; r, ritonavir.

compared patients who received nirmatrelvir/r within 5 days of diagnosis to patients who did not receive nirmatrelvir/r. The primary composite outcome was all-cause emergency room (ER) visit, hospitalization, or death at 30-day follow-up.27 In addition to nirmatrelvir/r use resulting in a 45% RR decrease in all-cause ER visits, hospitalization, or death, the study also found a

significant reduction in multisystem symptom burden and subsequent complications, including lower respiratory tract infection, constitutional symptoms, and cardiac arrhythmia (Figure 2).27

Pharmacists must be aware that there is considerable potential for DDIs with nirmatrelvir/r. This is because ritonavir is a strong inhibitor of both cytochrome P450

N=109,254 patients were either treated with nirmatrelvir/r (n=3902) or remained untreated (n=105,352) from January 9, 2022, to March 31, 2022; approximately 80% to 90% had previous immunity through vaccination, infection, or both. HR, hazard ratio; r, ritonavir.

FIGURE 1. Real-World Efficacy of Nirmatrelvir/r in Preventing COVID-19 Hospitalizations

3A4 (CYP3A4) and P-glycoprotein, thus, potentially increasing its blood concentrations and/or that of certain concomitantly administered medications and the potential for serious drug toxicities.18 In addition, nirmatrelvir and ritonavir are substrates of CYP3A4 and are contraindicated in patients taking CYP3A4 inducers (current or recent use in the last 14 days) because they may significantly decrease concentrations of nirmatrelvir/r and cause potential treatment failure.41,44 Before prescribing nirmatrelvir/r, pharmacists must review concomitant medications (including over-thecounter and herbal supplements) and assess risks, benefits, and significance of potential DDIs. Some of these interactions (eg, with particular statins, calcium channel blockers, direct oral anticoagulants) can be safely managed via collaboration (eg, with subspecialty providers and therapeutic drug monitoring) while others may require alternative COVID-19 therapy.42,45

Currently, the EUA states that nirmatrelvir/r is not recommended in patients with an eGFR ≤30 mL/

min/1.73 m2, based on the lack of adequate data when it was authorized41; however, based on pharmacokinetic/ pharmacodynamic modeling and limited patient data, some have proposed dosing adjustments in patients with eGFR <30 mL/min/1.73 m2 and in patients who are on hemodialysis.46 Many institutions, including the Mayo Clinic, have endorsed this expanded renal dosing strategy when it is deemed that the benefits of treatment with nirmatrelvir/r outweigh the risks in this high-risk patient population. A clinical trial is underway to evaluate the safety of nirmatrelvir/r in adults with severe renal impairment (NCT05487040).

Pharmacists should be aware of these interactions, their management, and alternate treatment regimens for patients for whom they prescribe treatment, as well as patients for whom they are filling prescriptions, and utilize the DDI algorithm in Figure 3. Pharmacists should also collaborate with the multidisciplinary management team (eg, oncologists, transplant physicians) to create appropriate guidelines for managing patients with

Is your patient taking other medications, including over-the-counter?

If

Do these medications have potential interactions with nirmatrelvir/r?

In case of significant interactions

• Can the concomitant medications be temporarily discontinued?

• Can the dose of the concomitant medications be reduced?

• Can an alternative concomitant medication be used?

• Can increased monitoring for AEs or concomitant medication drug levels be done?

aP<0.001; bP<0.05; cP<0.005; dP=0.00.

N=2260 patients were either treated with nirmatrelvir/r (n=1130) within 5 days of diagnosis or remained untreated (n=1130), from December 1, 2021, to April 18, 2022.

ER, emergency room; RR, relative risk; r, ritonavir.

FIGURE 2. Real-World Efficacy of Nirmatrelvir/r in Vaccinated Patients at 30 Days27

none of these is possible, avoid coadministration with the concomitant medications

FIGURE 3. Algorithm for Potential DDIs With Nirmatrelvir/r16

comorbid conditions and a multidrug regimen. Many clinics will have specific guidelines for transplant patients. The chosen DDI management strategies should be applied for the 5-day duration of nirmatrelvir/r treatment and for at least 2 or 3 days after treatment completion.45 CYP3A4 inhibition by ritonavir typically reaches peak effect within 2 days after initiation and resolves 2 to 3 days after discontinuation (with variances possible based on patient-specific factors or drugs with a long half-life).47,48

Under the current nirmatrelvir/r EUA, a state-licensed pharmacist may prescribe it if they are able to establish the patient has sufficient renal and hepatic function through access to health records less than 12 months old.41 The pharmacist should also review a comprehensive list of medications (prescription and nonprescription) the patient is taking to assess for potential DDIs, using health records and patient reporting of medical history.41 Consultation with a physician or advanced practice provider in an established provider-patient relationship with the patient to obtain the health and medication history is also acceptable under the EUA.41 The pharmacist should refer patients for clinical evaluation if sufficient information is not available to assess renal and hepatic function or potential for DDIs, modification of other medications is needed due to potential DDIs, or nirmatrelvir/r is not an appropriate therapeutic option.

Where to Check for Nirmatrelvir/r DDIs

• Liverpool COVID-19 drug interactions: https://covid19-druginteractions.org/checker

• NIH guidelines: https://www.covid19treatmentguidelines.nih.gov/ therapies/antivirals-including-antibody-products/ ritonavir-boosted-nirmatrelvir--paxlovid-/paxloviddrug-drug-interactions/

• FDA Paxlovid patient eligibility screening checklist tool for prescribers: https://www.fda.gov/media/158165/download

• Infectious Diseases Society of America

Management of drug interactions with Paxlovid: https://www.idsociety.org/globalassets/idsa/ practice-guidelines/covid-19/treatment/ idsa-paxlovid-drug-interactions-resource-5-6-22v1.1.pdf

• Paxlovid EUA fact sheet: https://www.fda.gov/media/155050/download

Remdesivir

Remdesivir is a nucleoside analog prodrug that acts as a competitive inhibitor of viral RNA–dependent RNA polymerase, preventing viral replication and, therefore, production of viable virus.49 As of February 2023, it was the only antiviral with full US Food and Drug Administration (FDA) approval for the treatment of mild or moderate COVID-19. There are 2 dosing regimens for remdesivir: a 5-day regimen for hospitalized patients with severe COVID-19 not requiring invasive mechanical ventilation

and/or extracorporeal membrane oxygenation and a 3-day regimen for nonhospitalized patients with mild to moderate illness.50 Unlike nirmatrelvir/r, remdesivir has not been associated with significant DDIs and can be a good option for patients unable to take nirmatrelvir/r. There are logistical challenges in delivering remdesivir, including that patients must go to a clinic or infusion center 3 days in a row to receive remdesivir IV.18 A benefit of remdesivir is that it is authorized for use in atrisk patients as young as 28 days (≥3 kg).28 Remdesivir is not recommended in patients with an eGFR ≤30 mL/ min/1.73 m2, and its administration requires renal and hepatic laboratory testing before initiating therapy, in part due to the lack of data in patients with chronic liver and/or kidney disease.28,50,51 Although the remdesivir label does not recommend its use in patients with eGFR ≤30 mL/min/1.73 m2, real-world data showed that remdesivir use was not associated with an increased incidence of AEs, supporting its use in these patients if the potential benefits outweigh the risks.51

In the PINETREE trial, unvaccinated nonhospitalized patients aged ≥12 years who had at least 1 risk factor for disease progression were treated with remdesivir per the recommended dosing guidelines, within 7 days of symptom onset.28 The analysis of this trial revealed that use of remdesivir resulted in an 87% lower risk of hospitalization or death compared with placebo (Figure 4). Further, use of remdesivir resulted in faster time to symptom resolution, with fewer serious AEs than placebo, despite no significant difference in upper airway viral load.28

A prospective cohort comparative study in Mexico of remdesivir was conducted in patients aged ≥18 years with high-risk conditions who had confirmed mild to moderate COVID-19. Nearly all patients were immunosuppressed and 88% had ≥2 high-risk conditions for COVID-19 progression.52 Remdesivir administration (per the dosing guidelines) reduced the rates of hospitalization or death from any cause, demonstrating an 82% RR (Figure 5) compared with patients who did not receive remdesivir.52 An increased risk of hospitalization or death was associated with age ≥60 years, diabetes mellitus, and cirrhosis.52

Hypersensitivity reactions, including infusion-related and anaphylactic reactions, have been observed with remdesivir administration and can often be prevented by slowing the infusion rate; because of this risk, patients receiving remdesivir require monitoring for signs and symptoms of such reactions for at least 1 hour after the infusion is complete.50 Mild to moderate transaminase elevations have also been observed after remdesivir administration, necessitating hepatic laboratory testing in all patients before starting the infusion.50 Nausea is one of the most common AEs (3%-5%) associated with remdesivir use.50

Molnupiravir

Molnupiravir, also authorized for use under an EUA, is a prodrug of β-d-N4-hydroxycytidine, a ribonucleoside

FIGURE 4. Reduction in COVID-19–Related Hospitalization and Death With Remdesivir at Day 28: PINETREE Trial28

Among

analog that, when incorporated into elongating viral RNA during replication, leads to multiple errors and an inability to form viable virus.40 According to its EUA, molnupiravir is reserved for nonhospitalized patients aged ≥18 years who are unable to take nirmatrelvir/r or remdesivir, because it has lower efficacy compared to other treatments, the potential to affect bone and cartilage growth, and contraindications to use during pregnancy (due to embryo-fetal toxicity).18,53

The MOVe-OUT clinical trial analyzed molnupiravir efficacy in unvaccinated adults with mild to moderate COVID-19 and at least 1 risk factor for progression to severe illness, demonstrating a 31% RR of COVID-19–related hospitalization and death.54 A secondary analysis of the trial revealed that, compared to placebo, molnupiravir use resulted in earlier normalizations of C-reactive protein and SpO2 values as early as day 3, less-frequent use of respiratory interventions (34.3% RR), and fewer COVID-19–related acute care visits (33.8% RR).55

The real-world efficacy of molnupiravir was demonstrated in the preliminary analysis of vaccinated patients in the PANORAMIC study. This study of adults aged ≥50 years or aged ≥18 years with comorbidities showed that although molnupiravir administered according to dosing guidelines within 5 days of symptom onset resulted in faster recovery times and reduced viral load (Figure 6), it did not reduce the already-low rate of hospitalizations and deaths among vaccinated adults.56 There are no DDIs to consider with molnupiravir use. It can be used in patients with renal and hepatic impairment; however, it should not be used in pregnant individuals. The most common AEs in molnupiravir clinical trials were diarrhea (2%), nausea (1%), and dizziness (1%), occurring at rates similar to those seen with placebo.53

Comparing the Real-World Data of Antivirals

The PISA Outpatient Clinic study compared all 3 antivirals (administered per their recommended dosing guidelines) for the outpatient management of symptomatic adults

N=562 patients were randomly assigned 1:1 to remdesivir or placebo from September 18, 2020, to April 8, 2021.

N=126 from December 1, 2021, to April 30, 2022; n=54 patients received remdesivir, n=72 patients did not receive remdesivir.

FIGURE 5. Remdesivir Reduced Rates of Hospitalization and Death at Day 28

Immunocompromised Patients52

aged ≥55 years with mild to moderate COVID-19 with at least 1 risk factor for progression to severe disease who did not require supplemental oxygen therapy.57 The average age of participants was 69 years, with a range of ages from 55-78 years.25.57 This study found that the risk of progression (composite primary endpoint of death or hospitalization) was more frequent among patients treated with remdesivir (5.1%) compared with patients treated with molnupiravir (1.8%) and nirmatrelvir/r (0.8%)57; however, rates did not differ significantly (ANOVA among groups, P=0.012; Figure 7).57 On multivariable Cox regression analysis, the presence of ≥3 comorbidities, hematologic disease, gastrointestinal symptoms, and each-day increment from symptom onset were factors associated with death or hospitalization; antiviral treatment was not a predictor.57 Interestingly, the nirmatrelvir/r group had a higher probability of a negative

test within 10 days of the first positive one, and almost half of this cohort developed an AE, mainly dysgeusia.57

Efficacy of Antivirals Against Viral Subvariants

A significant benefit of these 3 antivirals is that they are still effective against current and emerging Omicron subvariants (as shown in Figure 8), while all of the previously authorized anti–SARS-CoV-2 mAbs, including tixagevimab/cilgavimab, have been found to be inactive against the predominant viral strains (≥90% of the strains currently circulating in the US).9,58 Thus, their EUAs have been withdrawn, though they may be reauthorized if new variants or subvariants demonstrate susceptibility to these mAbs. It is imperative that pharmacists be aware that mAbs should not be used for the treatment of

aP=0.012 among-group difference; bP<0.001 among-group difference.

FIGURE 6. Real-World Efficacy of Molnupiravir in Vaccinated Patients: PANORAMIC Trial

patients; n=196 received remdesivir, n=114 received molnupiravir, n=252 received nirmatrelvir/r from January 2022 to July 2022.

FIGURE 7. Real-World Comparison of Antivirals57

FIGURE 8. In Vitro Efficacy of Antiviral Drugs Against Omicron Subvariants58

IC50 (μmol/liter)

Ancestral: 1.8

BA.2: 2.3

BA.5: 2.3

BQ.1.1: 1.0

XBB: 1.4

COVID-19 Convalescent Plasma

IC50 (μmol/liter)

Ancestral: 2.5

BA.2: 3.5

BA.5: 4.6

BQ.1.1: 2.8

XBB: 1.2

IC50 (μmol/liter)

Ancestral: 2.2

BA.2: 3.2

BA.5: 2.9

BQ.1.1: 2.6

XBB: 2.9

COVID-19 convalescent plasma (CCP) currently holds an EUA for treatment of COVID-19 in hospitalized and nonhospitalized patients who have immunosuppressive disease or who are receiving immunosuppressive treatment.59 The plasma, limited to high-titer products, is taken from donors who have recovered from COVID-19, regardless of vaccination status, because it has demonstrated the presence of antibodies that may help suppress viral replication. CCP is administered as a standard plasma transfusion, within 8 days of symptom onset.60 Importantly, NIH guidelines recommend neither for nor against CCP due to insufficient evidence.59,60 It is unclear whether CCP collected from vaccinated individuals who recovered from Omicron infection exhibits neutralizing activity against Omicron subvariants, thus the prescriber, in addition to being cognizant of donor titer levels, may need to consider which subvariant the donor was infected with to determine the benefit of CCP in individual patients.59

Treating Mild to Moderate COVID-19 in Practice

Implementing Guidelines in Practice

Once eligible candidates have been identified, clinicians must select the optimal treatment for each patient according to their characteristics and guideline recommendations (Figure 9).18,61 Pharmacists must also incorporate patient preferences and potential logistical constraints, such as transportation to a clinic for 3 days in a row to receive remdesivir, when identifying the most-appropriate therapy. There are worrisome reports that treatments are underutilized in all populations, partly because public discussion has focused on concerns rather than benefits.62 Because of these hesitations, there are a number of unnecessary

deaths due to COVID-19 every day. In fact, a recent analysis demonstrated that only 25% of eligible patients received nirmatrelvir/r.63 Part of implementing guidelines into practice is providing education on risks and potential DDIs, as well as the numerous benefits of treatment on mild or moderate COVID-19. Studies have shown that physician-delivered education improves patient knowledge regarding COVID-19, across all races and ethnicities.64 It is logical to infer that pharmacist-driven education would be similarly valuable and, therefore, it is imperative that pharmacists educate patients on available treatment options, risks, benefits, and administration instructions. They must also engage patients in shared decision-making regarding which treatment is best for them.

Patient Prioritization

The NIH provides guidance on prioritizing clinical scenarios in the face of logistical constraints or supply shortages, which is important, as the course and intensity of the pandemic waxes and wanes.65 Should stratification of patient access to therapeutics be necessary, NIH guidelines suggest prioritizing individuals based on age, vaccination status (eg, unvaccinated or not up to date on vaccines), immune status, and clinical risk factors (Table 4).65

Viral Rebound and Treatment Hesitancy: Myth vs Reality

There have been reports of COVID-19 rebound in some patients after they have finished a treatment course with an oral antiviral therapy.66,67 Although evidence suggests that 1) rebounds are generally mild, 2) resistance mutations are not widespread, and 3) rebound symptoms typically improve or resolve spontaneously, reports of COVID-19 rebound have raised concerns among clinicians and, at times, introduced some hesitancy in prescribing to “healthier” patients.66-69 Recent updates to the NIH guidelines include the fact

IC50, half-maximal inhibitory concentration; r, ritonavir.

FIGURE 9. Indications for and Selection of COVID-19—Specific Therapy for Adult Outpatients18,30,60

Is patient at high risk for progression to severe disease?

• ≥50 years old

• Immunocompromised or on immunosuppressive therapy

• Underlying medical condition (see Figure 2)

• Prolonged amount of time since most recent vaccine dose (eg, >6 months)

Is either present:

• eGFR <30 mL/min/1.73 m2b

• Severe hepatic impairment (Child-Pugh Class C)

• Use a drug interaction tool to check for potential interactions between the patient’s medications and nirmatrelvir/r

• Does the patient meet the criteria for nirmatrelvir/r?

• Can nirmatrelvir/r be safely used with the patient’s medications?

– Although many medications have expected interactions, some may be mitigated by holding or dose-reducing the co-medication

Treat with molnupiravir unless your clinic protocol dictates that nirmatrelvir/r or remdesivir may be used in these scenarios

Refer

Supportive care only

remdesivir

• Administer nirmatrelvir/r per appropriate dosing instructions

• Molnupiravir may be used if nirmatrelvir/r or remdesivir is not available

• Refer for treatment with remdesivir

• Molnupiravir may be used if remdesivir is not available

aCCP may be considered for certain immunocompromised patients if within 8 days of symptom onset, though NIH guidelines do not recommend for or against its use; bExpanded renal dosing strategies have been proposed for eGFR 30 mL/min/1.73 m2; although it falls outside the NIH guidelines, it may be used in some practices.47,52

eGFR, estimated glomerular filtration rate; r, ritonavir.

that rebound has also occurred in patients not taking oral antivirals, indicating brief rebound symptoms may be part of the natural presentation of COVID-19 and not associated with progression to severe COVID, which may help to decrease provider hesitation in prescribing antivirals or patient hesitation in taking them.18

One recent study of patients aged ≥28 years with COVID-19 who were treated with either nirmatrelvir/r or molnupiravir within 5 days of confirmed diagnosis showed that rebound can occur after administration of either agent. The 30-day rebound rate for COVID-19 for nirmatrelvir/r was 5.4% and for molnupiravir was 8.9%; after propensity-score matching, neither group of patients had a higher risk of rebound.70 Interestingly, the rebound rate for both drugs increased with time after treatment, suggesting that rebound may be associated with persistent viral infection despite treatment with these antiviral agents.70 Furthermore,

patients with COVID-19 rebound had significantly more comorbidities than patients who did not experience rebound.70

An analysis of untreated individuals aged ≥18 years with COVID-19 demonstrated that 12% had viral rebound, which was defined as an increase ≥0.5 log10 viral RNA copies/mL, and those who rebounded were older than nonrebounders.71 Symptom rebound was more common than viral rebound, occurring in 27% of individuals after initial symptom improvement and in 10% after initial symptom resolution.71 Given that COVID-19 rebound is unlikely to be caused by treatment with antivirals, providers and eligible patients should not avoid COVID-19 treatment secondary to concerns about rebound. This is especially true for patients at high risk of progression to severe COVID-19, in whom the benefits of antiviral treatment greatly outweigh the risks.

TABLE 4. Patient Prioritization for Treatment65

Tier Risk Group

1

• Immunocompromised individuals not expected to mount an adequate immune response to COVID-19 vaccination or SARS-CoV-2 infection due to underlying conditions, regardless of vaccine status OR

• Unvaccinated individuals at the highest risk of severe disease (anyone aged ≥75 years or anyone aged ≥65 years with additional risk factors)

2

• Unvaccinated individuals not included in Tier 1 who are at risk of severe disease (anyone aged ≥65 years or anyone aged <65 years with clinical risk factors)

• Vaccinated individuals at risk of severe disease (anyone aged ≥65 years or anyone aged <65 years with clinical risk factors)

Note: Vaccinated individuals who are not up to date with their immunizations are likely at higher risk for severe disease; patients within this tier who are in this situation should be prioritized for treatment.

If patients with COVID-19 have recurrent symptoms after initial resolution, they should restart isolation and take precautions to prevent potential transmission. Consistent with CDC guidance, given the mild nature of most rebound episodes, patients should not routinely be re-treated with antivirals.72

Given that COVID-19 rebound is unlikely to be caused by treatment with antivirals, providers and eligible patients should not avoid COVID-19 treatment secondary to concerns about rebound.

Post-COVID Conditions

Post-COVID conditions (sometimes referred to as Long COVID) are persistent, sometimes debilitating, physical and mental symptoms that persist ≥4 weeks after acute SARS-CoV-2 infection.5 There are more than 200 symptoms attributed to Long COVID, including fatigue, cough, “brain fog,” chest pain, headache, myalgia, and mood changes.73 Prevalence estimates vary widely, in part because there is a lack of consensus on how to define or diagnose Long COVID. The risks of it are much higher for individuals who experienced severe COVID-19 requiring hospitalization, likely because of continuing viral replication.5 Moreover, little is currently known about the best strategies to prevent or treat post-COVID conditions, although many of the conditions can be managed by primary care providers with symptom-specific treatment.74 Multiple studies have found that vaccination also plays a role in reducing the risk of developing Long Covid in people who had mild or moderate COVID-19; differences in the extent of reduction among studies is likely attributable to study population and timing or number of vaccine doses.75 An

Italian study of health care workers required to receive 3 doses of vaccine (first and second doses administered in January-February 2021 and the booster dose in November-December 2021) found that increasing the number of vaccine doses was associated with reduced prevalence of Long COVID (Figure 10).76

Some evidence suggests that mitigating the severity of the initial infection as much as possible may reduce the potential for persistent symptoms.5 In fact, one study of nonhospitalized patients (average age ≥65 years) with at least 1 risk factor for progression to severe disease found that the use of nirmatrelvir/r administered per guidelines reduced the RR of post-acute sequelae at 90 days by 26% (Figure 11).77 This speaks directly to the need for increased use of treatments in eligible patients immediately upon diagnosis to prevent severe COVID-19. For treatment of post-COVID conditions, little evidence from successful randomized controlled trials has been reported to date, leaving clinicians unsure of appropriate therapies. The CDC and other organizations have developed guidelines on postCOVID condition assessment, monitoring, and general management strategies.74

The Importance of Vaccination

Vaccination is key to preventing SARS-COV-2 infection and, should a person contract the virus, reducing hospitalization and mortality risks. For example, a study conducted in November 2021 demonstrated a 66% reduction in hospitalization for patients receiving 3 vaccine doses and a 40% reduction for those receiving 2 doses, as compared to unvaccinated patients.78 As compared to people who have received 2 doses of a monovalent COVID-19 vaccine and 1 dose of bivalent booster, unvaccinated patients were 9.8 times more likely to die from COVID-1979 and

FIGURE 10. Number of Vaccine Doses Was Associated With Prevalence of Long COVID76

16 times 80 more likely to be hospitalized in December 2022. Further, a meta-analysis demonstrated that the risk ratio of developing severe COVID-19 for vaccinated vs unvaccinated people was 0.12 (CI 95%, 0.040-0.363). 81 A recent study assessing the vaccine efficacy of the bivalent booster showed similar rates against BA.5-related infections and XBB-related infections: among patients aged 18 to 49 years, the relative efficacy of a bivalent booster dose given 2 to 3 months earlier compared with no bivalent booster was 52% against symptomatic BA.5-related infection and 48% against symptomatic XBB-related infection. 82 Rates decreased as patient age increased: patients aged ≥65 years had 37% relative efficacy against BA.5-related infection and 43% relative efficacy against XBB-related infection. 82

The CDC Vaccine Recommendation Guidelines (February 2023) indicate that a 3-dose vaccination series is recommended for everyone aged ≥6 months, with the monovalent messenger RNA (mRNA) vaccine as the first 2 (primary) doses and a bivalent mRNA booster as the third (booster) dose. 83 Though guidelines differ slightly according

to patient age and vaccine manufacturer, people aged ≥6 months should receive 1 bivalent mRNA booster dose ≥2 months after completion of any monovalent primary series (or previous monovalent booster). 83 People aged ≥12 years may also receive the subunit protein-based vaccine rather than an mRNA vaccine as their primary series, though it should still be followed by a bivalent mRNA booster. For immunocompromised patients, an additional monovalent vaccine dose, separate from the bivalent booster, should be administered 4 to 8 weeks after the primary series for patients aged >5 years; for those aged 6 months to 4 years, whether the third dose is a full dose or a booster dose is dependent on the vaccine manufacturer. 83 It is important for pharmacists to note that all primary doses should be from the same manufacturer; a mixed primary series is not authorized unless the same vaccine is unavailable, the previous dose manufacturer is unknown, or the person would otherwise not complete the primary series (eg, contraindications). 83

N=739 patients testing positive for SARS-CoV-2, including 229 with Long COVID, from March 2020 to April 2022. Patients were surveyed for the presence of Long COVID symptoms from February 2022 to April 2022.

n=9217 patients treated with nirmatrelvir/r, n=47,123 untreated patients with COVID-19 from March 1, 2022, to June 30, 2022. RR, relative risk; r, ritonavir.

FIGURE 11. Nirmatrelvir/r Reduced the Occurrence of Post-acute Sequelae at 90 Days77

Understanding and Addressing Disparities in COVID-19 Care

Health equity creates an additional layer of consideration when identifying and treating eligible patients, especially as American Indian or Alaska Native, Asian, Black or African American, and Hispanic or Latino people have higher rates of infection, hospitalization, and death compared with White people.84 Furthermore, the same social determinants that lead to disparities in health care in certain communities also lead to increased incidence of comorbidities—putting people with COVID-19 in these communities at elevated risk of progressing to severe disease.84,85 Several factors contribute to increased risks among certain populations, including increased likelihood of living in areas with high COVID-19 incidence, crowded or unstable housing, employment as an essential worker, relatively low access to health care, and lower education and income levels.86

American Indian or Alaska Native, Asian, Black or African American, and Hispanic or Latino people and those in “socially vulnerable” zip codes have, so far, had reduced uptake of COVID-19 treatments.87,88 Black or African American patients were prescribed nirmatrelvir/r 35.8% less often and Hispanic patients approximately 30% less often than White and non-Hispanic patients, respectively.89 Despite the highest prevalence of provider sites, areas of high social vulnerability see the lowest use of oral antivirals.88 Patients who declined antiSARS-CoV-2 mAb infusions were more likely to belong to populations underrepresented by race, language, and ethnicity, perhaps due to medical mistrust and/or language barriers.90

There are many potential solutions for addressing these health care disparities. For example, clinicians can engage interpreters to reduce language barriers, and clinicians can ask about social determinants of health and partner with community leaders.86 Having an open discussion with patients about any barriers to care can aid in determining the best way to overcome these challenges. Lack of transportation or lack of childcare can be mitigated through telemedicine visits and permitting patients to bring children to clinic visits. Overall, interventions targeting individual-level factors include improving health and lifestyle behaviors and access to basic necessities so that health can be prioritized.91 Health system interventions that address discrimination, access to care, and quality of care are also critical to ensuring eligible individuals receive vaccinations and

treatment with antivirals. These interventions include delivering health programs that are culturally and linguistically tailored to specific individuals or groups.91

The Role of the Pharmacist in Combatting the COVID-19 Pandemic

Pharmacists have continued to provide direct patient care and perform frontline duties during the COVID-19 pandemic. Pharmacists and their teams have administered more than 350 million clinical interventions to more than 150 million people in the form of testing, vaccinations, therapeutic regimens, and inpatient care.92 A recent review found that pharmacists played an important role in addressing the COVID-19 pandemic by providing drug information for health care professionals, participating in clinical decision-making, patient counseling, suggesting therapy changes, and managing the drug supply, including obtaining treatment following regulatory authorization and implementing safety measures for infection control.93-96 The pandemic has accentuated community pharmacists’ contributions to medication therapy, chronic disease management, point-of-care screening/testing, and advocating for vaccinations, by optimizing their broad access to medically and socially vulnerable populations.97 Pharmacists play an important role in developing organization guidelines and protocols, managing drug shortages, participating in COVID-19 clinical trials, and optimizing antimicrobial stewardship.93,98

Pharmacists can be an important source of informed medical information for patients and interdisciplinary colleagues by providing clear and consistent information and education on COVID-19, vaccines, and treatments, which can help combat the spread of misinformation about these topics.94

Concluding Comments

Timely testing and subsequent isolation are integral to slowing the spread of COVID-19. For those who do test positive for SARS-COV-2 infection, there are 3 antivirals authorized for treatment of patients with mild or moderate COVID-19 at risk for progression to severe disease. Prompt treatment helps reduce hospitalization and mortality rates, mitigates the spread of the disease, and potentially prevents some of the longterm consequences of the disease. Pharmacists are an

“Removing barriers to pharmacist prescribing of oral antivirals has the potential to be a game-changer for addressing health equity and providing timely access to these life-saving treatments in pockets of the country where pharmacists may be the only health care provider for miles—just as it has been for the administration of COVID-19 vaccines.”

– Ilisa B.G. Bernstein, PharmD, JD99

integral part of the multidisciplinary care team and need to stay current on evolving SARS-CoV-2 variants and their susceptibility profiles to available therapeutics, the growing evidence for the efficacy of COVID-19

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WHAT PHARMACISTS NEED TO KNOW ABOUT TREATING COVID-19: INCORPORATING NEW DATA AND GUIDELINES INTO PRACTICE

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