Effectiveness of Nirmatrelvir/Ritonavir for Outpatients in the Era of Omicron, Vaccination, and Previous Infection: A Meta-analysis
Among outpatients in the Omicron period, nirmatrelvir plus ritonavir was linked to fewer hospitalizations and deaths, with the largest absolute benefit in moderate- and high-risk patients.
*Systematic review and meta-analysis of cohort studies; Level 2a (OCEBM).
*Systematic review and meta-analysis of cohort studies; Level 2a (OCEBM).
Citation
Ebell M, Kurotschka P. Effectiveness of Nirmatrelvir/Ritonavir for Outpatients in the Era of Omicron, Vaccination, and Previous Infection: A Meta-analysis. Journal of General Internal Medicine. 2026. doi:10.1007/s11606-026-10494-4
Background
Earlier trials of nirmatrelvir plus ritonavir (Paxlovid) occurred before widespread vaccination and prior infection. This review asked whether it still helps prevent hospitalization and death among contemporary outpatients.
Patients
Adults and adolescents (12 years or older) with COVID-19 managed as outpatients during the Omicron period (data collection started no earlier than December 2021). Excluded: initially hospitalized patients; studies without adjusted analyses; non–peer-reviewed reports; and special populations (such as pregnancy or specific diseases like cancer or transplant).
Intervention
Nirmatrelvir plus ritonavir.
Control
No antiviral treatment.
Outcome
30-day hospitalization (all-cause and COVID-19-related) and 30-day death (all-cause and COVID-19-related); also a combined outcome of hospitalization or death.
Follow-up Period
30 days.
Results
| Outcome (30-day) | Pooled adjusted relative risk (95% confidence interval) |
|---|---|
| All-cause hospitalization | 0.54 (0.43 to 0.68) |
| COVID-19 hospitalization (primary) | 0.45 (0.36 to 0.56) |
| All-cause death | 0.30 (0.23 to 0.39) |
Estimated number needed to treat to prevent one COVID-19 hospitalization (using external baseline-risk groups): low risk 1148; moderate risk 84; high risk 20.
Limitations
All included studies were observational, so unmeasured differences between treated and untreated groups may still explain part of the benefit. Results varied across studies, and definitions of “immunocompromised” and outcomes differed. For low-risk patients, the absolute benefit is very small despite favorable relative risk.
Funding
No project-specific funding reported.
Clinical Application
Use nirmatrelvir plus ritonavir mainly for moderate- and high-risk outpatients; expect minimal absolute benefit in low-risk patients and prioritize shared decision-making and drug–drug interaction review.
Discussion
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In this meta-analysis of adjusted cohort studies, nirmatrelvir/ritonavir was associated with lower 30-day COVID-19 hospitalization (pooled aRR 0.45, 95% CI 0.36–0.56) and mortality. Given the nonrandomized design and potential residual confounding, what would you need to see to change your prescribing for low-risk outpatients (e.g., NNT ≈1148)? The authors report a pooled RR for COVID-19 hospitalization of 0.45 and estimate NNTs of 1148 (baseline risk 0.16%), 84 (2.2%), and 20 (8.9%). Which concept best explains why the NNT changes so much across risk groups?