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Am Fam Physician. 2022;105(5):online

Clinical Question

Does nirmatrelvir/ritonavir (Paxlovid) safely reduce the risk of hospitalization or death in unvaccinated at-risk out-patients with COVID-19?

Bottom Line

Nirmatrelvir/ritonavir significantly reduces the likelihood of hospitalization or death in unvaccinated adults with confirmed COVID-19 who are at risk of a more severe course of disease (number needed to treat [NNT] = 18). (Level of Evidence = 1b)


Nirmatrelvir is a protease inhibitor; its potency is increased by combining it with ritonavir. The researchers identified adults with confirmed COVID-19 and symptom onset within the past five days who were 60 years and older or had a comorbidity that increases the risk of hospitalization and death. Patients with a history of COVID-19 or who were vaccinated were excluded. A total of 2,246 participants were randomized to nirmatrelvir/ritonavir, 300 mg/100 mg, or matching placebo every 12 hours for five days. The mean age of patients was 46 years, two-thirds had symptoms for three days or less, and the primary outcome was the likelihood of hospitalization or death caused by COVID-19 within 28 days. The outcome was calculated for several modified intention-to-treat populations. In patients with five or fewer days of symptoms who were not expected to get a COVID-19–specific monoclonal antibody (n = 2,085), the primary outcome occurred significantly less often in the treatment group (0.8% vs. 6.3%; P < .001; NNT = 18). The secondary outcome of all-cause mortality was less likely in the treatment group (0.0% vs. 1.1%; P = .001; NNT = 91). When analysis was limited to those with symptom onset in the past three days (n = 1,379), results were similar (0.72% vs. 6.45%; P < .001; NNT = 17). Most patients were infected with the Delta variant, so the drug's efficacy in vaccinated people and those with the Omicron variant is not known. Dosage adjustment is needed for patients with moderate or worse renal impairment. Because nirmatrelvir/ritonavir is a cytochrome P450 3A inhibitor, a number of other drugs should be withheld or their dose adjusted during administration, most notably other protease inhibitors and HIV drugs, macrolides, calcium channel blockers, and statins. Nirmatrelvir/ritonavir was well tolerated with few adverse events.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry

Allocation: Uncertain

Setting: Outpatient (any)

Reference: Hammond J, Leister-Tebbe H, Gardner A, et al.; EPIC-HR Investigators. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med. Published online February 16, 2022.

Editor's Note: Dr. Ebell is deputy editor for evidence-based medicine for AFP and cofounder and editor-in-chief of Essential Evidence Plus, published by Wiley-Blackwell.

POEMs (patient-oriented evidence that matters) are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, see Copyright Wiley-Blackwell. Used with permission.

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