Abigail Zuger, MD
Both agents are clinically effective, but uncertainties still attend their use.
At the end of December 2021, two novel oral antiviral agents received FDA emergency use authorization for outpatient use in mild-to-moderate COVID-19. Although both agents generated substantial premarketing enthusiasm, they come to market with lingering uncertainties.
Nirmatrelvir (Paxlovid, Pfizer) is a viral protease inhibitor with expected in vitro activity against all clinically significant SARS-CoV-2 variants to date. In an unpublished manufacturer-supported study. opens in new tab, nirmatrelvir boosted with the CYP3A inhibitor ritonavir reduced rates of hospitalization or all-cause death by almost 90% among unvaccinated high-risk adult outpatients with confirmed mild-to-moderate COVID-19. A study involving vaccinated standard-risk adults is ongoing. The drug has also been authorized for unvaccinated children and teens 12 and older. The dosing regimen consists of two 150-mg nirmatrelvir tablets and one 100-mg ritonavir tablet taken together twice daily for 5 days. Renal impairment requires dose reduction; patients with severe liver or kidney disease should not receive treatment. Coadministration with drugs metabolized by CYP3A or those inducing the enzyme may be dangerous. No specific adverse effects have been associated with nirmatrelvir plus ritonavir to date.
Molnupiravir (Lagevrio, Merck) is a nucleoside analog that induces fatal mutations in the SARS-CoV-2 genome; it too has demonstrated in vitro activity against all clinically significant viral variants. In a manufacturer-supported study of high-risk unvaccinated adult outpatients with mild-to-moderate COVID-19, the drug reduced rates of hospitalization or all-cause mortality by about 30% (N Engl J Med 2021 Dec 16; [e-pub]). Because of concerns about possible mutagenicity, molnupiravir is not recommended during pregnancy; and because of possible toxicity to bone, cartilage, or both, the drug has not been authorized for children or teens younger than 18. The dose is four 200-mg capsules twice daily for 5 days. Side effects have been limited to mild decreases in hemoglobin. opens in new tab. No renal or hepatic adjustments are necessary, and no drug–drug interactions have been identified. An FDA advisory committee also articulated concerns about the drug’s potential ability to generate viral mutants of concern.
COMMENT
Until these two drugs were approved, authorized treatments for outpatients at high risk for severe COVID-19 were limited to parenteral monoclonal antibody preparations. Some recent monoclonals (NEJM JW Infect Dis Nov 2021 and N Engl J Med 2021 Sep 29; [e-pub]; NEJM JW Infect Dis Jan 2022 and N Engl J Med 2021 Oct 27; [e-pub]) have yielded results similar to nirmatrelvir’s — and considerably more impressive than molnupiravir’s — but the practical difficulties of administering monoclonals are considerable, and not all are active against specific SARS-CoV-2 variants. Good data now support the efficacy of the parenteral antiviral remdesivir in at-risk outpatients with COVID-19 (N Engl J Med 2021 Dec 22; [e-pub]), but the same practical difficulties apply.
Although oral antivirals will be far easier on both patients and providers than any of the parenteral agents, clinicians should remember the unknowns attending their use— namely, a full picture of the drugs’ clinical efficacy against current and future viral variants, as well as their real-world toxicities. Molnupiravir particularly worries the FDA and its advisors enough that the agency has directed clinicians to use it only if alternative agents are contraindicated or unavailable. This advice presumably places molnupiravir as the current last choice among available agents. Still, the hierarchy of outpatient COVID-19 treatments is likely to change substantially as new agents emerge, new variants circulate, and more-complete data on these first two drugs’ clinical performance are released.
CITATION(S):
U.S. Food and Drug Administration. Fact sheet for healthcare providers: Emergency use authorization for Paxlovid™. FDA 2021 Dec 22; [e-pub]. (https://www.fda.gov/media/155050/download. opens in new tab)
U.S. Food and Drug Administration. Fact sheet for healthcare providers: Emergency use authorization for molnupiravir FDA 2021 Dec 23; [e-pub]. (https://www.fda.gov/media/155054/download. opens in new tab)
