How recent Paxlovid studies explode Covid-19 mortality myths

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 Paxlovid 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 Paxlovid to prevent hospitalization and death.

Does Paxlovid still have value in a population with widespread immunity to COVID-19 from vaccination and prior infection? In a subsequent placebo-controlled trial of the drug 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 Paxlovid 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 Paxlovid. Although participants in the treatment group appeared to recover several days earlier than did 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 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."

Why good news? A pernicious myth about the early years of the Covid-19 pandemic is that most people died "with" rather than "from" the infection, even though there were over a million excess deaths in the U.S. and more than 22 million worldwide from 2020-2023 compared to pre-pandemic mortality rates. A related myth is that the older adults who died from Covid-19 would have died from something else soon anyway. A recent analysis of data from the United Kingdom showed that in fact, the "mortality displacement" (death earlier than expected) due to Covid-19 was quite significant: adults over 65 lost a median of 4 to 5 years of life, and two-thirds of women aged 65 to 74 years likely would have survived 5 years or more if they had avoided the infection. The reason for Paxlovid's decreased effectiveness isn't that the drug suddenly stopped working; it's that vaccine and infection-derived immunity have made the very worst outcomes of Covid-19 thankfully uncommon.

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A previous version of this post appeared on the AFP Community Blog.