Nirmatrelvir Plus Ritonavir Improves Outcomes of COVID-19 Breakthrough Infection

Nirmatrelvir plus ritonavir decreased the risk for hospitalization and COVID-19-related complications in vaccinated individuals with breakthrough infection.

Nirmatrelvir plus ritonavir decreased the rate of emergency department (ED) visits, hospitalizations, and death among vaccinated individuals with breakthrough COVID-19 infection. These findings were published in Clinical Infectious Diseases.

Investigators from Lahey Hospital and Medical Center in the United States sourced data for this retrospective cohort study from the TriNetX Analytics Network database, which includes electronic health records from more than 120 health care organizations. The analysis included vaccinated individuals (N=111,588) diagnosed with COVID-19 breakthrough infection between December 2021 and April 2022. The investigators aimed to evaluate outcomes among patients who did and did not (controls) receive nirmatrelvir plus ritonavir within 5 days of testing positive for COVID-19. Propensity-score matching was used to balance differences between the 2 patient groups. The primary composite outcome was all-cause hospitalizations, ED visits, and death within a follow-up period of 30 days.

Among patients included in the treatment (n=1131) and control (n=110,457) groups, the mean age was 57.6±16.3 and 49.3±17.6 years, 63.0% and 64.3% were women, and 21% and 25% had a BMI of at least 30 kg/m2, respectively. A total of 1130 patients from each group were then evaluated after propensity-score matching.

At 30 days, the primary composite outcome occurred among 89 (7.9%) patients in the treatment group and 163 (14.4%) in the control group (odds ratio [OR], 0.5; 95% CI, 0.39-0.67; P <.001). Similar results were noted on analysis of individual outcomes, with the number of all-cause ER visits (82 vs 142; OR, 0.5; 95% CI, 0.41-0.73; P <.001) and hospitalizations (10 vs 23; OR, 0.45; 95% CI, 0.2-0.9; P =.02) significantly decreased among patients in the treatment vs control groups. In addition, none of the patients in the treatment group died, with all 10 reported deaths occurring among those in the control group.

antiviral agents may play an increasingly important role in reducing the severity of illness.

Further analysis showed a significant decrease in the occurrence of constitutional (6.3% vs 12.9%; P <.001), cardiopulmonary (13.5% vs 27.3%; P <.001), gastrointestinal (3.3% vs 7.87%; P <.001), and nervous system and musculoskeletal (0.8% vs 2.2%; P <.001) symptoms among patients in the treatment vs control groups. Treatment with nirmatrelvir plus ritonavir also was associated with lower rates of respiratory tract infection (2.38% vs 8.14%; P =.000), arrhythmia (1.9% vs 3.8%; P =.008), and diagnoses of anxiety or mood disorders (5.6% vs 10%; P =.000).

Similar results were noted in an exploratory analysis that assessed outcomes between 10 and 30 days, with overall rates of symptoms and complications decreased among patients in the treatment vs control groups.

Limitations include potential misclassification bias as some patients may have sought care outside the health care networks that shared information with the TriNetX database.

For patients with breakthrough COVID-19 infection, “antiviral agents may play an increasingly important role in reducing the severity of illness,” the investigators noted. In regard to patients at increased for COVID-19-related complications, the investigators concluded that “these data support administering antiviral therapy to this vulnerable group, vaccination status notwithstanding.”

Disclosure: Multiple authors declared affiliations with industry. Please see the original reference for a full list of disclosures.


Ganatra S, Dani SS, Ahmad J, et al. Oral nirmatrelvir and ritonavir in non-hospitalized vaccinated patients with covid-19. Clin Infect Dis. 2022;ciac673. doi:10.1093/cid/ciac673