COVID-19 Management in the Outpatient Setting: Oral Antivirals

Key Takeaways

• Remdesivir is highly efficacious, and its use in the outpatient setting is feasible but may be challenging because of the need for IV administration
• Nirmatrelvir plus ritonavir is also highly efficacious but must be renally dosed and attention must be paid to clinically relevant drug–drug interactions
• Molnupiravir has no renal dosing limitations and no known drug interactions, but it is less efficacious than other antiviral agents

Two months after the discovery of COVID-19 in China, the National Institutes of Health (NIH) announced a clinical trial to test the safety and efficacy of remdesivir, an IV antiviral agent targeting this disease. Today, remdesivir is an efficacious therapeutic option both for hospitalized and ambulatory patients, recommended by numerous COVID-19 therapeutic management guidelines.

Remdesivir is effective at reducing hospitalizations and death in high-risk ambulatory patients with COVID-19 (87% risk reduction compared with placebo), although the logistical barriers of IV administration in the outpatient setting have made oral antivirals highly sought-after alternatives. Two oral antivirals have received FDA Emergency Use Authorization and are available for the treatment of high-risk ambulatory patients with mild to moderate COVID-19. However, there are several factors to consider when determining the best oral antiviral agent for each specific ambulatory patient with COVID-19.

Nirmatrelvir Plus Ritonavir
Nirmatrelvir (SARS-CoV-2 main protease inhibitor) plus ritonavir (HIV-1 protease inhibitor) tablets are the preferred outpatient treatment recommended by the NIH, the Infectious Diseases Society of America, and the World Health Organization. Although data are limited, one clinical trial demonstrated that nirmatrelvir plus ritonavir reduced the risk of hospitalization or death by 88% compared with placebo in unvaccinated, high-risk ambulatory patients with confirmed COVID-19.

Nirmatrelvir must be coadministered with ritonavir to achieve target therapeutic concentration, and thus it requires healthcare professionals to be on high alert for clinically significant drug–drug interactions related to ritonavir, which can lead to serious adverse events. Obtaining a current and comprehensive medication list can be difficult because of challenges like polypharmacy; use of over-the-counter medications, herbals, and supplements; and patients using more than 1 pharmacy. Asking detailed, focused questions of the patient can help avoid preventable medication errors.

Nirmatrelvir plus ritonavir dosing depends on renal function and is determined using the estimated glomerular filtration rate (eGFR). This can be a challenge because, in the outpatient setting, many patients who qualify for nirmatrelvir plus ritonavir are unaware of their eGFR. Fortunately, medical records are often available via online patient portals, and patients with a history of kidney disease usually self-identify, thereby helping to mitigate this dilemma. However, not all patients have access to their medical records via an online portal or have a known history of kidney disease, thereby emphasizing the need to conduct thorough patient interviews to obtain accurate medical histories before prescribing nirmatrelvir plus ritonavir.

Another major factor to consider is the pill burden involved. The dosing regimen for a patient with healthy kidneys is 3 tablets (2 tablets of nirmatrelvir and 1 of ritonavir), twice daily for 5 days. These tablets must be swallowed whole, without breaking, crushing, or chewing, which can be an issue for patients with dysphagia.

Furthermore, the supply of nirmatrelvir plus ritonavir is limited, making it a drug that should be prioritized only for patients who are indicated for treatment and who can complete their treatment course. Therefore, although nirmatrelvir plus ritonavir is efficacious and strongly guideline-recommended, its use should be cautiously evaluated on an individual basis.

Molnupiravir
Molnupiravir works by introducing serial mutations in SARS-CoV-2 replication. It is considered an alternative treatment option for use when nirmatrelvir plus ritonavir or remdesivir is not clinically appropriate or accessible. Molnupiravir has been shown to reduce the risk of hospitalization or death by 30% compared with placebo in unvaccinated, high-risk ambulatory patients with confirmed COVID-19. This is lower than the efficacy seen in separate trials with nirmatrelvir plus ritonavir or remdesivir, although we cannot compare these agents directly because head-to-head trials are lacking.

The mechanism of action of molnupiravir has raised theoretical concerns for causing mutagenesis in human cells. However, available data on the recommended 5-day treatment course show that the risk of genotoxicity is low.

Molnupiravir is not recommended during pregnancy because of observed fetal toxicity in animal studies. Therefore, sexually active patients receiving molnupiravir should be counseled on the use of contraceptives during and after treatment completion.

Unlike nirmatrelvir plus ritonavir, which can be prescribed to patients aged 12 years or older, molnupiravir is only authorized for patients aged 18 years or older because it may affect bone and cartilage growth. In addition, molnupiravir carries its own pill burden, as a typical regimen consists of 4 capsules per day for 5 days, which must be swallowed whole.

However, unlike nirmatrelvir plus ritonavir, molnupiravir does not require renal dose adjustments and exhibits no major drug–drug interactions. Altogether, the efficacy of molnupiravir requires prescribers to extensively evaluate risk–benefit when first-line options are not available.

Considerations for Oral Antiviral Use
The global medical community has produced an array of therapeutics for the treatment of COVID-19, with more on the horizon. Nirmatrelvir plus ritonavir and molnupiravir may have a role in preventing hospitalizations and death in high-risk ambulatory patients with COVID-19. Although these drugs are convenient to access and administer, their efficacy and safety need to be considered carefully. When prescribing either therapy, healthcare professionals should be certain of every drug the patient is taking and knowledgeable about any relevant comorbidities. Conducting thorough interviews with patients or their family members can help avoid detrimental outcomes and ensure clinical success.

Your Thoughts?
What barriers have you encountered when prescribing oral antivirals for ambulatory patients with COVID-19? Join the conversation by posting a comment. To learn more about the treatment of ambulatory patients with COVID-19, register for the upcoming series of Clinical Care Options webinars, Principles of Outpatient COVID-19 Management and Practical Case Studies in Outpatient COVID-19 Management. We hope that you will attend both webinars and put important new COVID-19 treatment data to work in your practice.