Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with COVID-19
The New England Journal of Medicine
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and illness with the associated coronavirus disease 2019 (Covid-19) continue to threaten global health.
Persons with particular characteristics such as older age, current smoking, or underlying clinical conditions such as cardiovascular disease, diabetes, obesity, and cancer are at high risk for severe Covid-19 and associated adverse outcomes.
In a meta-analysis, patients with prespecified coexisting conditions were approximately twice as likely to have progression to severe Covid-19 and five times as likely to die from Covid-19 as patients without those conditions. Mortality among older adults may be greater than that among persons with prespecified coexisting conditions.
TAKE-HOME MESSAGE
This phase II/III randomized trial evaluated the safety and efficacy of nirmatrelvir plus ritonavir in nonhospitalized adults with mild to moderate COVID-19. Participants received either nirmatrelvir plus ritonavir or placebo.
Treatment of symptomatic COVID-19 with nirmatrelvir plus ritonavir was associated with an 89% lower risk of progression to severe COVID-19 compared with placebo.
Nirmatrelvir plus ritonavir was associated with reduced risk of progression to severe COVID-19 among symptomatic, unvaccinated, nonhospitalized patients.
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BACKGROUND
Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro.
METHODS
Study conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated.
RESULTS
A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group, the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population. All 13 deaths occurred in the placebo group. The viral load was lower with nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo.
CONCLUSIONS
Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns.
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