Optimal timing of nirmatrelvir/ritonavir treatment after COVID-19 symptom onset or diagnosis: target trial emulation

Carlos K. H. Wong, Jonathan J. Lau, Ivan C. H. Au, Kristy T. K. Lau, Ivan F. N. Hung, Malik Peiris, Gabriel M. Leung and Joseph T. Wu ()
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Carlos K. H. Wong: Laboratory of Data Discovery for Health (D24H)
Jonathan J. Lau: Laboratory of Data Discovery for Health (D24H)
Ivan C. H. Au: The University of Hong Kong
Kristy T. K. Lau: The University of Hong Kong
Ivan F. N. Hung: The University of Hong Kong
Malik Peiris: The University of Hong Kong
Gabriel M. Leung: Laboratory of Data Discovery for Health (D24H)
Joseph T. Wu: Laboratory of Data Discovery for Health (D24H)

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Reports of symptomatic rebound and/or test re-positivity among COVID-19 patients following the standard five-day treatment course of nirmatrelvir/ritonavir have sparked debates regarding optimal treatment timing and dosage. It is unclear whether initiating nirmatrelvir/ritonavir immediately after symptom onset would improve clinical outcomes and/or lead to post-treatment viral burden rebound due to inadequate viral clearance during treatment. Here we show that, by emulating a randomized target trial using real-world electronic medical record data from all 87,070 adult users of nirmatrelvir/ritonavir in Hong Kong between 16th March 2022 and 15th January 2023, early initiation of nirmatrelvir/ritonavir treatment (0 to 1 days after symptom onset or diagnosis) significantly reduced the incidence of 28-day all-cause mortality and hospitalization compared to delayed initiation (2 or more days) (absolute risk reduction [ARR]: 1.50% (95% confidence interval 1.17-1.80%); relative risk [RR]: 0.77 (0.73, 0.82)), but may be associated with a significant elevated risk of viral burden rebound (ARR: −1.08% (−1.55%, −0.46%)), although the latter estimates were associated with high uncertainty due to limited sample sizes. As such, patients should continue to initiate nirmatrelvir/ritonavir early after symptom onset or diagnosis to better protect against the more serious outcomes of hospitalization and mortality.

Date: 2023
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DOI: 10.1038/s41467-023-43706-0

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