Effectiveness of Nirmatrelvir-Ritonavir for COVID-19 in the Postpandemic Era

Kenny Lin, MD, MPH
May 11, 2026

In December 2021, at the height of the pandemic, the US Food and Drug Administration (FDA) granted emergency use authorization for oral nirmatrelvir-ritonavir (Paxlovid) for outpatient treatment of mild to moderate COVID-19 in adults at high risk of progression to severe disease. In February 2022, a randomized trial of 2,246 unvaccinated adults with COVID-19 reported that starting nirmatrelvir-ritonavir within 5 days of symptom onset reduced the relative risk of hospitalization or death by 89%, with 13 deaths occurring in the placebo group and none in the intervention group. These results led to expanded access to the drug via pharmacist prescribing and eventually resulted in full FDA approval in May 2023. An American Family Physician article on outpatient COVID-19 management includes clinical recommendations to consider treating high-risk adults with nirmatrelvir-ritonavir to prevent hospitalization and death.

Does nirmatrelvir-ritonavir still have value in a population with widespread immunity to COVID-19 from vaccination and prior infection? In a subsequent placebo-controlled trial of nirmatrelvir-ritonavir with 1,296 patients (one-half vaccinated and with a risk factor for severe disease and one-half unvaccinated with no risk factors) recruited during the Delta and Omicron waves, no significant differences in symptom duration or likelihood of hospitalization or death were found.

Two open-label trials of nirmatrelvir-ritonavir in the United Kingdom and Canada that collectively enrolled 4,000 participants between April 2022 and September 2024 recently published their findings in a combined paper. Adults older than 50 years and younger adults with high-risk conditions (eg, obesity) were eligible; 98% had received a COVID-19 vaccine. Overall, less than 1% of participants were hospitalized, with no statistical differences between groups, and no one died. Outcomes for immunocompromised patients were similar; in the United Kingdom study, only 3 of 296 were hospitalized, with no benefit of nirmatrelvir-ritonavir. Although participants in the treatment group appeared to recover several days earlier than those in the control group, the study’s lack of blinding indicates that symptom improvement may represent a placebo effect rather than a true benefit.

In a recent related commentary, Dr. Jeremy Faust observed:

The severe event rate (i.e., hospitalizations and deaths) in this paper was so low that it’s difficult to imagine any new antiviral will be able to show such a benefit for the foreseeable future. … So, the next big antiviral against Covid-19 will likely never be shown to prevent deaths or hospitalizations—which … is actually good news.

Dr. Faust noted that determining whether nirmatrelvir-ritonavir or other antivirals can reduce the duration of acute COVID-19 and the risk of developing long COVID are worthwhile goals for future research studies.