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Frequently Asked Questions on COVID-19 Epidemiology, Prevention, and Clinical Management

Arthur Kim, MD
Sharon R. Lewin, AO, FRACP, PhD, FAHMS
Renslow Sherer, MD
Released: June 1, 2022

Antiviral Agents: Questions and Answers

What were the comorbidities that qualified nonhospitalized patients for enrollment on the direct-acting antiviral agent clinical trials?

Short Answer: Older age and/or certain chronic comorbidities confer a high risk for development of severe illness from COVID-19, and these were the groups included in studies of direct-acting antiviral agents.

Renslow Sherer, MD (May 23, 2022):
The MOVe-OUT trial of molnupiravir enrolled nonhospitalized adults with mild to moderate COVID-19 who had ≥1 risk factor for developing severe illness, including[Bernal 2022]:

  • Older than 60 years of age
  • Active cancer
  • Chronic kidney disease
  • Chronic obstructive pulmonary disease
  • BMI ≥30 kg/m2
  • Diabetes
  • Heart failure, coronary artery disease, and/or cardiomyopathy

Similarly, the EPIC-HR trial of nirmatrelvir plus ritonavir for nonhospitalized adults with mild to moderate COVID-19 enrolled patients with ≥1 characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19.[Hammond 2022]

The PINETREE study of IV remdesivir use in nonhospitalized patients aged 12 years or older with COVID-19 used similar risk factors for disease progression for inclusion. Risk factors included being 60 years of age or older, hypertension, cardiovascular disease, cerebrovascular disease, diabetes, BMI ≥30 kg/m2, immunocompromise, chronic kidney disease, chronic liver disease, chronic lung disease, active cancer, or sickle cell disease.[Gottlieb 2022]

In addition to the risk factors used in these clinical trials, the CDC considers chronic liver disease, chronic lung diseases (eg, asthma), dementia, Down syndrome, HIV, immunocompromise, mental health conditions (eg, depression), being overweight, pregnancy, sickle cell disease, thalassemia, presence or history of tobacco smoking, organ or stem cell transplant, stroke, substance use disorders, and tuberculosis risk factors that may lead to more severe illness from COVID-19.[CDC Medical Conditions]

What is the role for combining antiviral agents for the treatment of COVID-19?

Short answer: To date, the only approved or authorized antiviral combination studied for the treatment of COVID-19 is nirmatrelvir boosted with ritonavir.

Renslow Sherer, MD (March 25, 2022):
Based on other disease states that have been successfully treated or managed using combination antiviral therapy (eg, HIV), it is reasonable to hypothesize that this strategy may be beneficial in the treatment of COVID-19, as well. However, clinical trial data are needed to investigate combination antiviral treatment for COVID-19 before this practice can be recommended. Nirmatrelvir was studied in combination with ritonavir as a boosting agent to enhance circulating concentrations of nirmatrelvir.[Owen 2021] A preclinical study in a mouse model has found that brequinar—a pyrimidine biosynthesis inhibitor—has synergistic effects against SARS-CoV-2 when combined with nirmatrelvir plus ritonavir.[Schultz 2022] Information from human clinical trials will be necessary to substantiate these findings.

What is the role for combining antiviral agents with monoclonal antibodies for the treatment of COVID-19?

Short answer: To date, there are no studies that have evaluated the combination of an approved or authorized antiviral agent with a monoclonal antibody treatment for COVID-19.

Renslow Sherer, MD (January 10, 2022):
There may be a role for combination therapy with antiviral agents and monoclonal antibodies for the treatment of COVID-19, but this combination has not been studied in a clinical trial and there are no available data for combination treatment with these agents. The current options for the management of nonhospitalized patients with mild to moderate COVID-19 at high risk for disease progression include molnupiravir, monoclonal antibodies, nirmatrelvir plus ritonavir, or 3-day treatment with IV remdesivir.[IDSA]

What is the role for remdesivir in nonhospitalized patients with mild to moderate COVID-19?

Short answer: A 3-day course of IV remdesivir in unvaccinated, nonhospitalized patients aged 12 years or older with COVID-19 and ≥1 risk factor for disease progression was effective in reducing the risk of hospitalization and death. Remdesivir is now approved for use in high-risk pediatric patients who are ≥28 days of age and weigh ≥3 kg.

Renslow Sherer, MD (May 5, 2022):
The PINETREE study evaluated a 3-day course of IV remdesivir in nonhospitalized, unvaccinated patients aged 12 years or older with COVID-19 and ≥1 risk factor for disease progression.[Gottlieb 2022]

Patients in the remdesivir arm received a loading dose of 200 mg IV on Day 1, followed by 100 mg IV once daily on Days 2 and 3.

The rate of Day 28 hospitalization or death was 0.7% in the remdesivir arm and 5.3% in the placebo arm (P = .008).[Gottlieb 2022] 

The CARAVAN study evaluated 5 cohorts of pediatric patients hospitalized with COVID-19; 85% of patients demonstrated clinical improvement, and 60% were discharged from the hospital by Day 10. These data were used to inform the FDA approval of remdesivir in pediatric patients.[Ahmed 2022; Remdesivir PI]

Will there be an oral remdesivir option available for the treatment of nonhospitalized patients with COVID-19?

Short answer: An oral prodrug of remdesivir is currently being studied in animal models and phase I clinical trials.

Renslow Sherer, MD (January 10, 2022):
Provision of an IV remdesivir infusion each day for 3 days is logistically challenging. To make treatment with remdesivir more accessible, studies of an oral prodrug of remdesivir are underway. The new compound—GS-621763—is an oral agent that is converted to the remdesivir parent compound (GS441524) after intestinal absorption and is converted to the triphosphate compound in the lungs.[Cox 2021]

Efficacy of the prodrug in animal models led to a first-in-human safety, tolerability, and pharmacokinetic study of 1 participant.[Schäfer 2021] Oral remdesivir was provided to a healthy adult in 2 parts: Part 1) oral remdesivir 750 mg once daily for 7 days and Part 2) oral remdesivir 750 mg 3 times daily for 3 days (NCT04859244).

The study has been completed but results are not yet published. Further investigation is needed to determine if oral remdesivir is a safe and effective antiviral treatment option for nonhospitalized patients with COVID-19.

What is the teratogenic risk with molnupiravir?

Short answer: Based on animal model data, molnupiravir may cause fetal harm when administered to a pregnant patient.

Renslow Sherer, MD (January 10, 2022):
The mechanism by which molnupiravir acts is viral lethal mutagenesis. Embryofetal development studies in animals demonstrated fetal harm and death at doses 3 and 8 times the recommended human dose.[FDA Molnupiravir]

Molnupiravir has not been studied in pregnant patients with COVID-19, but based on these animal data, it is not recommended for use in pregnant patients owing to risk of fetal harm. Patients of childbearing potential should use a reliable method of contraception while receiving molnupiravir and for 4 days (females) or 3 months (males) following molnupiravir treatment cessation.[FDA Molnupiravir]

How should drug–drug interactions with nirmatrelvir plus ritonavir be managed?

Short answer: Nirmatrelvir plus ritonavir has the potential to cause clinically significant drug–drug interactions.

Renslow Sherer, MD (January 10, 2022):
Nirmatrelvir and ritonavir are both CYP3A substrates and ritonavir is a potent CYP3A inhibitor.[FDA Nirmatrelvir] Drug information resources should be consulted when prescribing nirmatrelvir plus ritonavir for a patient because numerous drugs are contraindicated for use with ritonavir, and numerous others require dose adjustments and/or additional monitoring when used in combination with ritonavir.[FDA Nirmatrelvir; Ritonavir PI] 

What are the data for the use of oral antivirals in pediatric patients?

Short answer: Molnupiravir is authorized for use in patients aged 18 years or older, and nirmatrelvir plus ritonavir is authorized for use in patients who are both aged 12 years or older and weigh ≥40 kg.

Renslow Sherer, MD (January 10, 2022):
There are currently no data to support the use of molnupiravir in patients aged younger than 18 years or the use of nirmatrelvir plus ritonavir in patients who are younger than 12 years of age who weigh <40 kg.[FDA Molnupiravir; FDA Nirmatrelvir]

Nirmatrelvir plus ritonavir has not been studied in the pediatric population but is authorized for use in patients aged 12 years or older who weigh ≥40 kg because the adult dosing regimen is expected to result in comparable serum drug levels in this population,[FDA Nirmatrelvir] as the adolescent population is biologically similar to adults regarding medication pharmacokinetics and pharmacodynamics.

Molnupiravir may cause fetal toxicity and affect bone and cartilage growth, which is why it has only been studied and authorized in adults.[FDA Molnupiravir]

What is the role for favipiravir in hospitalized patients with COVID-19?

Short answer: Early treatment with favipiravir in hospitalized, high-risk patients with COVID-19 did not prevent disease progression or mortality.

Renslow Sherer, MD (January 10, 2022):
Favipiravir, an oral antiviral agent approved for treating influenza in Japan, has demonstrated in vitro efficacy against SARS-CoV-2, but the in vivo data have not demonstrated significant benefit over placebo.[Udwadia 2021; Chuah 2021]

In one study, 150 hospitalized patients were randomized to receive either favipiravir 1800 mg orally twice daily on Day 1 followed by 800 mg orally twice daily on Days 2-5 or placebo. The primary outcome was mean time to cessation of viral shedding, which was not statistically significantly different between the groups (5 vs 7 days; P = .129). However, the time to clinical cure favored favipiravir (3 vs 5 days; P = .030).[Udwadia 2021]

A larger study of 500 hospitalized patients with COVID-19 at risk for disease progression based on age and comorbidities evaluated the effect of favipiravir on progression to hypoxia, rates of mechanical ventilation, intensive care unit admission, and death. Patients were randomized to receive the same dose of favipiravir as in the other study (1800 mg orally twice daily on Day 1 followed by 800 mg orally twice daily on Days 2-5) or placebo. This study demonstrated that use of favipiravir did not prevent any of the outcomes studied.[Chuah 2021]

Are inhaled forms of remdesivir being investigated?

Short Answer: Inhaled remdesivir is being studied in animal models and in phase I and II clinical trials.

Arthur Kim, MD (January 28, 2022):
Alternative routes of administration for remdesivir are being investigated to make administration more convenient for nonhospitalized patients with COVID-19. Pharmacokinetic studies of inhaled remdesivir in animal models have reported promising data, but further studies are needed to confirm efficacy and safety of inhaled remdesivir (NCT04539262).[Vermillion 2022]

How should outpatient treatments for COVID-19 be prioritized?

Short Answer: The National Institutes of Health have a tiered prioritization scheme that outlines which patient populations should be prioritized for anti–SARS-CoV-2 treatments when there are logistical or supply constraints limiting treatment access.

Arthur Kim, MD (January 28, 2022):
The National Institutes of Health have created a tiered patient prioritization scheme for outpatient anti–SARS-CoV-2 treatments when logistical or supply constraints exist:

  • Tier 1: patients with immunocompromise not expected to mount an adequate immune response to COVID-19 vaccination or disease, regardless of vaccine status; unvaccinated patients at highest risk for severe disease from COVID-19 (anyone aged 75 years or older, or aged 65 years or older with additional risk factors)
  • Tier 2: unvaccinated patients at highest risk for severe disease from COVID-19 not included in Tier 1 (anyone aged 65 years or older, or younger than 65 years of age with clinical risk factors)
  • Tier 3: vaccinated patients at high risk of severe disease (anyone aged 75 years or older, or aged 65 years or older with clinical risk factors)
  • Tier 4: vaccinated patients at high risk of severe disease (anyone aged 65 years or older, or younger than 65 years of age with clinical risk factors)

Vaccinated patients in Tiers 3 and 4 who have not received a COVID-19 vaccine booster are likely at higher risk for severe disease and should be prioritized higher than those who have received a vaccine booster.[NIH Prioritization]

What is the time frame for the administration of direct-acting small-molecule antiviral agents and monoclonal antibodies in outpatients with COVID-19?

Short Answer: All agents should be initiated as soon as possible for maximal effectiveness, within 5-7 days of symptom onset depending on the agent.

Arthur Kim, MD (April 22, 2022):
All antiviral and monoclonal antibody treatments for COVID-19 should be initiated as soon as possible to decrease transmission and enhance the patient’s immunity.[NIH Clinical Management] Based on Emergency Use Authorization (EUA) guidance, nirmatrelvir plus ritonavir and molnupiravir should be initiated within 5 days of symptom onset.[FDA Nirmatrelvir; FDA Molnupiravir] Remdesivir and monoclonal antibodies should be initiated within 7 days of symptom onset.[FDA Remdesivir; FDA Sotrovimab]

How is nirmatrelvir plus ritonavir dosed in a person with HIV who is receiving a ritonavir-boosted drug?

Short answer: No changes are needed.

Arthur Kim, MD (January 28, 2022):
The EUA for nirmatrelvir plus ritonavir states that patients receiving ritonavir-based or cobicistat-based regimens for either HIV or hepatitis C virus should continue their treatment as prescribed while receiving nirmatrelvir plus ritonavir.[FDA Nirmatrelvir]

What are the data to support use of ivermectin as a treatment for COVID-19?

Short Answer: Ivermectin is not recommended for use as a treatment for COVID-19.

Arthur Kim, MD (April 22, 2022):
A study of ivermectin early in the pandemic demonstrated in vitro efficacy against SARS-CoV-2 replication.[Caly 2020] However, ongoing research has not demonstrated in vivo efficacy, and the FDA recommends against its use for treating COVID-19.[FDA Ivermectin]

The TOGETHER study demonstrated that the use of ivermectin provided no benefit in reducing incidence of hospitalization or emergency department visits for COVID-19 in high-risk nonhospitalized patients.[Reis 2022]

The COVID-OUT trial is currently investigating effectiveness of ivermectin, fluvoxamine, and metformin for treating COVID-19 symptoms and long COVID-19.[COVID-OUT] Similarly, the ACTIV-6 trial is investigating repurposed medications (ivermectin, fluvoxamine, and fluticasone) for the treatment of mild to moderate COVID-19 (NCT04885530).

What is COVID-19 rebound after antiviral therapy?

Short Answer: Some patients report development of recurrent COVID-19 symptoms after completing a treatment course with a direct-acting oral antiviral agent.

Sharon R. Lewin, AO, FRACP, PhD, FAHMS (May 23, 2022):
The clinical trials of direct-acting oral antiviral agents were designed to test the hypothesis that these agents reduce the risk of hospitalization and/or death in high-risk patients.[Gottlieb 2022, Hammond 2022] These trials were not designed to test (and these drugs are not authorized for) symptom reduction.

In clinical trials of nirmatrelvir plus ritonavir, 2.0% of patients in the treatment arm and 1.5% of patients in the placebo arm experienced rebound SARS-CoV-2 RNA levels.[Nirmatrelvir Plus Ritonavir PI]

There are several working hypotheses for symptom rebound after a course of antiviral treatment, including 5 days being not a long enough treatment course for some people or a blunting of the immune system response when starting the drug early in the disease process. There are currently no data on the efficacy or safety of administering longer courses or a second course of a direct-acting oral antiviral agent.[NIH Nirmatrelvir]

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