Oral Nirmatrelvir and Severe Covid-19 Outcomes During the Omicron Surge

Abstract Background Nirmatrelvir, an inhibitor of the main protease of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has demonstrated a significant decrease in the risk of progression to severe disease in symptomatic high-risk patients infected with the B.1.617.2 (delta) variant of SARS-CoV-2. The effectiveness of nirmatrelvir against the B.1.1.529 variant (omicron) is unknown. Methods The study included all Clalit Health Services members, 40 years of age and older, with confirmed infection of SARS-CoV-2 during the omicron surge that were defined as high-risk for severe disease. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association between nirmatrelvir treatment and hospitalizations and deaths due to Covid-19, with adjustment for individual sociodemographic factors, coexisting conditions, and prior Covid-19 immunity status. Results 109,213 participants were eligible for nirmatrelvir therapy during the two-month study period. Among the 42,819 eligible patients aged 65 years and above, 2,504 were treated with nirmatrelvir. Hospitalizations due to Covid-19 occurred in 14 out of the treated and 762 of the untreated patients: adjusted HR 0.33 (95% CI, 0.19 to 0.55). Death due to Covid-19 occurred in 2 treated and 151 untreated patients; adjusted HR: 0.19 (95% CI, 0.05 to 0.76). Among the 66,394 eligible patients 40 to 64 years of age, 1,435 were treated with nirmatrelvir. Hospitalizations due to Covid-19 occurred in 9 treated and 334 untreated patients: adjusted HR 0.78 (95% CI, 0.40 to 1.53). Death due to Covid-19 occurred in 1 treated and 13 untreated patients; adjusted HR: 1.64 (95% CI, 0.40 to 12.95). Conclusions Nirmatrelvir therapy was associated with a 67% reduction in Covid-19 hospitalizations and an 81% reduction in Covid-19 mortality in patients 65 years and above. However, no significant benefit in avoidance of severe Covid-19 outcomes was shown in younger adults.