Researchers have suggested that for people who are fully vaccinated but have at least one risk factor for severe Covid, the antiviral drug Paxlovid did little to reduce symptom duration – however, experts have cautioned that the findings might not apply to older patients, and that further studies are needed.
The phase 2/3 trial of 1 296 participants, led by Pfizer scientists, were randomly assigned in a 1:1 ratio to receive nirmatrelvir–ritonavir (Paxlovid) or placebo every 12 hours for five days within five days of Covid-19 symptom onset.
CIDRAP reports that a total of 654 participants took Paxlovid, and 634 participants took the placebo during the trial, conducted from July 2021 to July 2022.
Included in the study were patients who were fully vaccinated and who had at least one risk factor for severe disease, as well as patients without such risk factors who had never been vaccinated against Covid-19, or had not been vaccinated within the previous year.
No significant between-group difference
The most common risk factors noted were obesity, smoking, and high blood pressure, and only 2% of participants had heart or lung conditions that predisposed them for severe Covid-19 infections.
Participants recorded daily symptom severity on a 4-point scale (0, absent; 1, mild; 2, moderate; 3, severe), and the included symptoms were cough, shortness of breath or difficulty breathing, feeling feverish, chills or shivering, muscle or body aches, diarrhoea, nausea, vomiting, headache, sore throat, and stuffy or runny nose.
The primary end point was sustained symptom alleviation, defined as the first of four consecutive days during which all symptoms that had been scored as moderate or severe and as mild or absent at baseline were scored as mild or absent and as absent, respectively, the authors said.
“The median time to sustained alleviation of all targeted signs and symptoms of Covid-19 was 12 days in the nirmatrelvir–ritonavir group and 13 days in the placebo group (P=0.60),” the authors wrote in The New England Journal of Medicine.
A secondary end point was Covid-19–related hospitalisation or death from any cause until day 28 of the trial. Five participants (0.8%) in the nirmatrelvir–ritonavir group and 10 (1.6%) in the placebo group were admitted to hospital for Covid, or died from any cause by day 28.
“The results regarding the numbers of Covid-19–related hospitalisations and deaths from any cause in this trial, although not significant, are consistent with and supported by recent real-world data,” the authors wrote.
Findings might not apply to older patients
The trial was notable for including younger participants: The median age was 42, and only 5% were 65 or older.
Michael Osterholm, PhD, MPH, director of the University of Minnesota’s Centre for Infectious Disease Research and Policy (CIDRAP), publisher of CIDRAP News, cautioned that the young participant population changed how risk was defined in the study.
“Can we really say an unvaccinated 18-year-old has the same risk factor as a vaccinated 89-year-old? I don’t think so.
“We need to avoid over-generalising the findings to older, high-risk populations,” he added. said. “For those people, Paxlovid is still a useful first-line treatment.”
In an editorial on the study, Rajesh Gandhi, MD, and Martin Hirsch, MD, wrote: “As with many medical interventions, there is likely to be a gradient of benefit for nirmatrelvir–ritonavir, with the patients at highest risk for progression most likely to derive the greatest benefit.”
They said longer-term studies on Paxlovid are warranted, to see the extent to which the drug offers protection against long Covid.
Study details
Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19
Jennifer Hammond, Robert Fountaine, James Rusnak et al.
Published in the NEJM on 3 April 2024
Abstract
Background
Nirmatrelvir in combination with ritonavir is an antiviral treatment for mild-to-moderate coronavirus disease 2019 (Covid-19). The efficacy of this treatment in patients who are at standard risk for severe Covid-19 or who are fully vaccinated and have at least one risk factor for severe Covid-19 has not been established.
Methods
In this phase 2–3 trial, we randomly assigned adults who had confirmed Covid-19 with symptom onset within the past 5 days in a 1:1 ratio to receive nirmatrelvir–ritonavir or placebo every 12 hours for 5 days. Patients who were fully vaccinated against Covid-19 and who had at least one risk factor for severe disease, as well as patients without such risk factors who had never been vaccinated against Covid-19 or had not been vaccinated within the previous year, were eligible for participation. Participants logged the presence and severity of pre-specified Covid-19 signs and symptoms daily from day 1 to day 28. The primary end point was the time to sustained alleviation of all targeted Covid-19 signs and symptoms. Covid-19–related hospitalisation and death from any cause were also assessed to day 28.
Results
Among the 1296 participants who underwent randomisation and were included in the full analysis population, 1 288 received at least one dose of nirmatrelvir–ritonavir (654 participants) or placebo (634 participants) and had at least one postbaseline visit. The median time to sustained alleviation of all targeted signs and symptoms of Covid-19 was 12 days in the nirmatrelvir–ritonavir group and 13 days in the placebo group (P=0.60). Five participants (0.8%) in the nirmatrelvir–ritonavir group and 10 (1.6%) in the placebo group were hospitalized for Covid-19 or died from any cause (difference, −0.8 percentage points; 95% confidence interval, −2.0 to 0.4). The percentages of participants with adverse events were similar in the two groups (25.8% with nirmatrelvir–ritonavir and 24.1% with placebo). In the nirmatrelvir–ritonavir group, the most commonly reported treatment-related adverse events were dysgeusia (in 5.8% of the participants) and diarrhoea (in 2.1%).
Conclusions
The time to sustained alleviation of all signs and symptoms of Covid-19 did not differ significantly between participants who received nirmatrelvir–ritonavir and those who received placebo.
The NEJM editorial article – Treating Acute Covid-19 — Final Chapters Still Unwritten (Open access)
See more from MedicalBrief archives:
UK regulatory body warns about Paxlovid risks
Pfizer: Paxlovid fails to prevent Covid in members of same household