The New England Journal of MedicineOral Nirmatrelvir–Ritonavir as Postexposure Prophylaxis for COVID-19

Nirmatrelvir-Ritonavir Shows No Significant Benefit as COVID-19 Postexposure Prophylaxis

A recent phase 2-3 double-blind trial evaluated the efficacy and safety of nirmatrelvir-ritonavir as postexposure prophylaxis for COVID-19 in asymptomatic adult household contacts. The study found that neither 5-day nor 10-day regimens of nirmatrelvir-ritonavir significantly reduced the risk of symptomatic SARS-CoV-2 infection compared to placebo. The trial was conducted primarily during the omicron variant predominance period and included a high proportion of seropositive participants at baseline.

Key Points:

• Study design: Randomized, placebo-controlled trial with 2,736 participants assigned to 5-day nirmatrelvir-ritonavir, 10-day nirmatrelvir-ritonavir, or placebo groups.
• Primary endpoint: Development of symptomatic SARS-CoV-2 infection, confirmed by RT-PCR or rapid antigen testing, through day 14.
• Results: Symptomatic, confirmed SARS-CoV-2 infection developed in 2.6% of the 5-day group, 2.4% of the 10-day group, and 3.9% of the placebo group.
• Risk reductions: 29.8% for the 5-day group (95% CI, -16.7 to 57.8; P=0.17) and 35.5% for the 10-day group (95% CI, -11.5 to 62.7; P=0.12) relative to placebo.
• High-risk subgroup: No significant difference in infection rates between nirmatrelvir-ritonavir groups and placebo among participants at high risk for severe COVID-19.
• Variant analysis: No obvious difference in efficacy between delta and omicron predominance periods.
• Baseline seropositivity: Approximately 91% of participants were seropositive for SARS-CoV-2 at baseline.
• Safety profile: Similar incidence of adverse events across groups (21.7% to 23.9%).
• Most common adverse events: Dysgeusia (5.9% in 5-day group, 6.8% in 10-day group, 0.7% in placebo group), COVID-19, and diarrhea.
• Viral load: Among participants positive at baseline, mean viral loads were lower in nirmatrelvir-ritonavir groups compared to placebo at days 5 and 7.
• Viral rebound: Observed in 2.6% of the 5-day group, 2.1% of the 10-day group, and 0% of the placebo group.
• Study limitations: High baseline seropositivity, potential unblinding due to distinctive taste of nirmatrelvir-ritonavir, and lack of detailed data on index patients.

HCN Medical Memo
Although nirmatrelvir-ritonavir has shown efficacy in treating early COVID-19 in high-risk patients, this study suggests its use as postexposure prophylaxis may not significantly reduce symptomatic infections in household contacts. Clinicians should consider these findings when making decisions about postexposure management, particularly in populations with high baseline seropositivity.

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