Nirmatrelvir for Nonhospitalized Adults with Covid-19

To the Editor

Hammond et al. (April 14 issue)1 report that the administration of nirmatrelvir (plus ritonavir) in patients with SARS-CoV-2 infection within 3 days after symptom onset resulted in a better prognosis than administration within 5 days. However, according to Figure 2C of their article, the subgroup analysis according to time since symptom onset (≤3 days or >3 days) did not show significant results with nirmatrelvir as compared with placebo. On the basis of all the information provided, we are concerned about the sufficiency of evidence supporting the conclusion drawn.

Moreover, we recommend a further analysis involving patients who received monoclonal antibodies or other drugs in order to evaluate whether there could be potential cross interactions between treatments. Finally, the treatment that was assessed in this trial ought to be considered in the current omicron (B.1.1.529) variant era and in a fully vaccinated population.2 To date, more than half the population worldwide has had SARS-CoV-2 infection or has been vaccinated3; their situations differ from those in this trial population.

Brian S. Chen
Chung Shan Medical University School of Medicine, Taichung City, Taiwan

Cheng-Hsien Hung, B.Sc.
Chang Bing Show Chwan Memorial Hospital, Changhua City, Taiwan

James C.-C. Wei, M.D., Ph.D.
China Medical University, Taichung City, Taiwan

No potential conflict of interest relevant to this letter was reported.

This letter was published on July 20, 2022, at

Mr. Chen and Dr. Wei contributed equally to this letter.

  1. 1. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med 2022;386:1397-1408.

  2. 2. Nyberg T, Ferguson NM, Nash SG, et al. Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study. Lancet 2022;399:1303-1312.

  3. 3. World Health Organization. WHO coronavirus (COVID-19) dashboard. 2022 (

To the Editor

Nirmatrelvir is a promising orally administered antiviral agent against SARS-CoV-2. The Biden administration and other governments internationally have made access to nirmatrelvir treatment foundational to their Covid-19 strategy.1 Ideally, early treatment with nirmatrelvir (plus ritonavir) would reduce symptoms and improve overall health outcomes, including hospitalization.

From the data from the Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients (EPIC-HR) trial conducted by Hammond et al., which exclusively included high-risk unvaccinated patients, we calculated that the incidence of Covid-19–related hospitalization or death from any cause was approximately 5.5 percentage points (95% confidence interval, 4.0 to 7.1) lower in the nirmatrelvir group than in the placebo group (8 of 1039 patients [0.77%] vs. 66 of 1046 [6.31%]). However, the current debate surrounding hospital admissions “with” Covid-19 and “because of” Covid-19 shows the subjectivity of assigning cause of hospitalization. Moreover, this outcome discounts hospitalizations that were potentially related to the drug or to unexpected drug–drug interactions that may have been misinterpreted as being due to a patient’s underlying medical conditions. Furthermore, symptom relief was a prespecified secondary outcome in the trial ( number, NCT04960202) but was not reported. To help inform shared decision making, could the authors report the duration and severity of symptoms as well as the incidence of hospitalization for any cause or death from any cause?

Andrew M. Morris, M.D.
University of Toronto, Toronto, ON, Canada

Todd C. Lee, M.D., M.P.H.
McGill University, Montreal, QC, Canada

Dr. Lee reports receiving research salary support from Fonds de Recherche du Québec–Santé and peer-reviewed operating grants for Covid-19–related research from the Canadian Institutes of Health Research and being an investigator for several investigator-initiated trials involving outpatients with Covid-19. No other potential conflict of interest relevant to this letter was reported.

This letter was published on July 20, 2022, at

  1. 1. Department of Health and Human Services. Fact sheet: Biden administration launches nationwide test-to-treat initiative ensuring rapid “on the spot” access to lifesaving COVID treatments. March 8, 2022 (,taken%20soon%20after%20symptom%20onset).


The authors reply: In response to Chen et al.: the incidence of Covid-19–related hospitalization or death from any cause was significantly lower with nirmatrelvir (plus ritonavir) than with placebo, regardless of whether treatment was initiated within 3 days (relative risk reduction, 88.9%) or within 5 days (relative risk reduction, 87.8%) after symptom onset. The EPIC-HR trial was not designed to compare treatment started within 3 days with treatment started within 4 to 5 days. However, a treatment effect within the former group decreased by just 1.1 percentage point (from 88.9% to 87.8%) after all the patients were included in the analysis together, regardless of the time of symptom onset — a finding that suggests no clinically meaningful difference between the two. We conclude that treatment that is started within 5 days after symptom onset can lower the risk of progression to severe disease.

Only 42 patients (1.9%) in the EPIC-HR trial received monoclonal antibodies or other antiviral agents for the treatment of Covid-19; of those patients, 1 (in the placebo group) had a primary end-point event. Among patients receiving favipiravir, the only antiviral agent that was administered in at least 1% of the patients (61 [2.7%]), there were six primary end-point events (one in the nirmatrelvir group and five in the placebo group). The numbers were small yet showed no evidence of cross interactions between treatments.

We acknowledge that trial enrollment was completed before the omicron era. However, in vitro studies show that the omicron variant is as susceptible as the delta (B.1.617.2) variant to nirmatrelvir.1,2 Seropositive patients (i.e., those who have been vaccinated, previously infected, or both) typically present with lower baseline viral loads and a lower risk of severe disease. Nevertheless, in the seropositive subgroup, treatment with nirmatrelvir and ritonavir significantly reduced both the viral load and the risk of Covid-19–related hospitalization or death, although the absolute reduction was smaller than that in the seronegative subgroup. The relative risk reduction among patients treated within 5 days after symptom onset was 87.8% in the seropositive subgroup and 87.4% in the seronegative subgroup. These data support the generalization of results to the treatment of patients in locations where the omicron variant and vaccinations are more prevalent. The EPIC–Standard Risk trial ( number, NCT05011513), which involved vaccinated patients with at least one risk factor for severe Covid-19, did not show a significant difference in the incidence of hospitalization or death between patients treated with nirmatrelvir and ritonavir and those who received placebo.3

In response to Morris and Lee: Covid-19–related hospitalization and death from any cause were primary events. Hospitalization was defined as more than 24 hours in a hospital or similar acute care facility for the purpose of treatment for Covid-19. Investigators were responsible for confirming that hospitalization was required for the treatment of Covid-19. All the primary events were confirmed as hospitalizations for the treatment of worsening Covid-19. All the hospitalizations through day 34 were reported as serious adverse events (in 1.6% of the patients in the nirmatrelvir–ritonavir group and in 6.6% of those in the placebo group). None of the hospitalizations were thought to be related to nirmatrelvir treatment. Moreover, as an objective end point, there were no deaths in the nirmatrelvir group and 12 deaths in the placebo group.

We agree that symptom duration and severity are supporting data for efficacy. We are reviewing data regarding presence and severity of prespecified symptoms of Covid-19 from day 1 to day 28 in our trial.

Jennifer Hammond, Ph.D.
Pfizer, Collegeville, PA

Weihang Bao, Ph.D.
Pfizer, New York, NY

Abraham Simón-Campos, M.D.
Köhler and Milstein Research, Mérida, Mexico

Since publication of their article, the authors report no further potential conflict of interest.

This letter was published on July 20, 2022, at

  1. 1. Greasley SE, Noell S, Plotnikova O, et al. Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants. J Biol Chem 2022;298:101972-101972.

  2. 2. Rai DK, Yurgelonis I, McMonagle P, et al. Nirmatrelvir, an orally active Mpro inhibitor, is a potent inhibitor of SARS-CoV-2 variants of concern. January 19, 2022 ( preprint.

  3. 3. Pfizer reports additional data on Paxlovid supporting upcoming new drug application submission to U.S. FDA. June 14, 2022 (