Research Summary

Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients
with Covid-19
Hammond J et al. DOI: 10.1056/NEJMoa2309003

Clinical Problem
Effective oral treatments for Covid-19 are needed that can
shorten the time to symptom resolution and reduce the
risk of progression to severe illness. The oral antiviral
nirmatrelvir, in combination with ritonavir, has been
shown to reduce the risk of Covid-19–related hospitalization or death from any cause in unvaccinated adults
at high risk for severe Covid-19, but whether it can reduce
the duration of symptoms in a broader group is unknown.

Clinical Trial
Design: A phase 2–3, double-blind, randomized, controlled
trial assessed the efficacy and safety of nirmatrelvir–ritonavir in adult outpatients (either unvaccinated or not vaccinated within the previous year) without risk factors for
severe Covid-19 and fully vaccinated adults with at least
one risk factor for severe disease.
Intervention: 1296 adults with confirmed Covid-19 and
symptom onset within the previous 5 days were assigned
to receive either 300 mg of nirmatrelvir plus 100 mg of
ritonavir or placebo every 12 hours for 5 days. The primary end point was the time to sustained alleviation of
all targeted signs and symptoms of Covid-19.

Results
Efficacy: The time to sustained alleviation of symptoms
did not differ significantly between the two groups.
Safety: The percentages of participants with adverse
events through day 34 were similar in the two groups;
the most common adverse events in the nirmatrelvir–
ritonavir group were dysgeusia, diarrhea, and nausea.

Limitations and Remaining Questions
∎ The participants in the vaccinated high-risk subgroup
were enrolled regardless of the time since their last administered vaccine dose.
∎ Nirmatrelvir–ritonavir has a distinctive taste, so participants may have suspected that they were taking that
medication.
∎ The trial was started during the period of delta-variant
predominance, and therefore the efficacy of the treatment against other variants is unknown.

CONCLUSIONS
Among outpatients with Covid-19 who were at standard
risk or high risk for progression to severe Covid-19,
nirmatrelvir and ritonavir did not significantly shorten
the time to symptom alleviation.

Links: Full Article | NEJM Quick Take | Editorial