The COVID-19 Treatment Guidelines:

On December 22 and 23, 2021, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) that allow 2 new oral antiviral agents to be used in this patient population: ritonavir-boosted nirmatrelvir and molnupiravir.

Ritonavir-Boosted Nirmatrelvir

Nirmatrelvir is an orally bioavailable protease inhibitor that is active against M^PRO, a viral protease that plays an essential role in viral replication by cleaving the 2 viral polyproteins. It has demonstrated antiviral activity against all coronaviruses that are known to infect humans. Nirmatrelvir is packaged with ritonavir, a strong cytochrome P450 (CYP) 3A4 inhibitor and pharmacokinetic boosting agent. Ritonavir is required to increase nirmatrelvir concentrations to the target therapeutic ranges.

Molnupiravir

Molnupiravir is the oral prodrug of beta-D-N4-hydroxycytidine (NHC), a ribonucleoside that has broad antiviral activity against RNA viruses. NHC uptake by viral RNA-dependent RNA-polymerases results in viral mutations and lethal mutagenesis.

Treatment Recommendations:

For nonhospitalized patients with mild to moderate COVID-19 who are at high risk of disease progression, the National Institute of Health (NIH) of US Panel recommends using 1 of the following therapeutics (listed in order of preference):

• Nirmatrelvir 300 mg with ritonavir 100 mg orally twice daily for 5 days, initiated as soon as possible and within 5 days of symptom onset in those aged ≥12 years and weighing ≥40 kg.
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• Ritonavir-boosted nirmatrelvir (Paxlovid) has significant and complex drug-drug interactions, primarily due to the ritonavir component of the combination.
• Before prescribing ritonavir-boosted nirmatrelvir, clinicians should carefully review the patient’s concomitant medications and herbal supplements, to evaluate potential drug-drug interactions.
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• Sotrovimab 500 mg as a single IV infusion, administered as soon as possible and within 10 days of symptom onset in those aged ≥12 years and weighing ≥40 kg.
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• Because Omicron has become the dominant variant and real-time testing to identify rare, non-Omicron variants is not routinely available, the Panel recommends against using bamlanivimab plus etesevimab or casirivimab plus imdevimab.
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• Sotrovimab should be administered in a setting where severe hypersensitivity reactions, such as anaphylaxis, can be managed. Patients should be monitored during the infusion and observed for at least 1 hour after infusion.
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• Remdesivir 200 mg IV on Day 1, followed by remdesivir 100 mg IV daily on Days 2 and 3, initiated as soon as possible and within 7 days of symptom onset in those aged ≥12 years and weighing ≥40 kg.
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• Because remdesivir requires IV infusion for 3 consecutive days, there may be logistical constraints to administering remdesivir in many settings.
• Remdesivir is currently approved by the FDA for use in hospitalized individuals; therefore, outpatient treatment would be an off-label indication.
• Remdesivir should be administered in a setting where severe hypersensitivity reactions, such as anaphylaxis, can be managed. Patients should be monitored during the infusion and observed for at least 1 hour after infusion.
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• Molnupiravir 800 mg orally twice daily for 5 days, initiated as soon as possible and within 5 days of symptom onset in those aged ≥18 years ONLY when none of the above options can be used.
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• The FDA EUA states that molnupiravir is not recommended for use in pregnant patients due to concerns about the instances of fetal toxicity observed during animal studies. However, when other therapies are not available, pregnant people with COVID-19 who are at high risk of progressing to severe disease may reasonably choose molnupiravir therapy after being fully informed of the risks, particularly those who are beyond the time of embryogenesis (i.e., >10 weeks’ gestation).
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• There are no data on the use of molnupiravir in patients who have received COVID-19 vaccines, and the risk-to-benefit ratio is likely to be less favorable because of the lower efficacy of this drug.