Effectiveness of Nirmatrelvir-Ritonavir Against the Development of Post-COVID-19 Conditions Among U.S. Veterans : A Target Trial Emulation

Abstract

Background: COVID-19 has been linked to the development of many post-COVID-19 conditions (PCCs) after acute infection. Limited information is available on the effectiveness of oral antivirals used to treat acute COVID-19 in preventing the development of PCCs.

Objective: To measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir-ritonavir in preventing PCCs.

Design: Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir-ritonavir versus no treatment.

Setting: Veterans Health Administration (VHA).

Participants: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022.

Intervention: Nirmatrelvir-ritonavir treatment for acute COVID-19.

Measurements: Cumulative incidence of 31 potential PCCs at 31 to 180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions and symptoms.

Results: Eighty-six percent of the participants were male, with a median age of 66 years, and 17.5% were unvaccinated. Baseline characteristics were well balanced between participants treated with nirmatrelvir-ritonavir and matched untreated comparators. No differences were observed between participants treated with nirmatrelvir-ritonavir (n = 9593) and their matched untreated comparators in the incidence of most PCCs examined individually or grouped by organ system, except for lower combined risk for venous thromboembolism and pulmonary embolism (subhazard ratio, 0.65 [95% CI, 0.44 to 0.97]; cumulative incidence difference, -0.29 percentage points [CI, -0.52 to -0.05 percentage points]).

Limitations: Ascertainment of PCCs using International Classification of Diseases, 10th Revision, codes may be inaccurate. Evaluation of many outcomes could have resulted in spurious associations with combined thromboembolic events by chance.

Conclusion: Out of 31 potential PCCs, only combined thromboembolic events seemed to be reduced by nirmatrelvir-ritonavir.

Primary funding source: U.S. Department of Veterans Affairs.

Visual Abstract.. Effectiveness of Nirmatrelvir–Ritonavir Against the Development of Post–COVID-19 Conditions Among U.S. Veterans

Limited information is available on the effectiveness of oral antivirals used to treat acute COVID-19 in preventing the development of post–COVID-19 conditions (PCCs) after acute infection. This retrospective target trial emulation study sought to measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir–ritonavir in preventing PCCs.

Figure 1.. Study design and matching strategy for emulation of a target trial comparing the effectiveness of nirmatrelvir–ritonavir prescribed within 5 days of the test-positive date versus no treatment for acute COVID-19 with respect to incidence of post–COVID-19 conditions from days 31 to 180 after the index date: illustration of nested sequential trials from day 0/1 to day 5 after the test-positive date.

We executed 5 nested sequential trials corresponding to each of the 5 days following the test-positive date (day 0) on which persons would be eligible to participate in the nirmatrelvir–ritonavir or no-treatment group, as follows. 1) Persons treated on day 0/1 after the test-positive date were matched to persons who were untreated on day 0/1. Eligible persons were alive and not hospitalized on day 0 or 1, and the index date was the beginning of day 2. 2) Persons treated on day 2 after the test-positive date were matched to persons who were untreated on days 0 to 2. Eligible persons were alive and not hospitalized on days 0 to 2, and the index date was the beginning of day 3. 3) Persons treated on day 3 after the test-positive date were matched to persons who were untreated on days 0 to 3. Eligible persons were alive and not hospitalized on days 0 to 3, and the index date was the beginning of day 4. 4) Persons treated on day 4 after the test-positive date were matched to persons who were untreated on days 0 to 4. Eligible persons were alive and not hospitalized on days 0 to 4, and the index date was the beginning of day 5. 5) Persons treated on day 5 after the test-positive date were matched to persons who were untreated on days 0 to 5. Eligible persons were alive and not hospitalized on days 0 to 5, and the index date was the beginning of day 6. Participants who were treated on a given trial day were no longer eligible for a subsequent trial day. Persons who were untreated on a given day and remained eligible (alive, not hospitalized, and untreated) were eligible for subsequent trial days. Treatment assignment was based on observed treatment for a given trial day. To perform an intention-to-treat analysis, we kept persons in their assigned group (e.g., persons assigned to the no-treatment group for day 0/1 who received any outpatient COVID-19 treatment on day 2 or later were still analyzed in the no-treatment group). NIH = National Institutes of Health; VISN = Veterans Affairs Integrated Service Network.

Figure 2.. Identification of eligible veterans in the emulation of a target trial comparing the effectiveness of nirmatrelvir–ritonavir versus no treatment with respect to incidence of post–COVID-19 conditions from days 31 to 180 after the index date.

VHA = Veterans Health Administration. * Nirmatrelvir–ritonavir, molnupiravir, remdesivir, or any anti–SARS-CoV-2 monoclonal antibodies. † See the Supplement Methods for definitions of advanced renal impairment and advanced liver disease. ‡ See Supplement Table 4 for a list of medications with contraindications for nirmatrelvir–ritonavir.

Figure 3.. Comparison of matched groups in an emulated target trial of nirmatrelvir–ritonavir versus no treatment among veterans who tested positive for SARS-CoV-2 from 1 January to 31 July 2022 with respect to risk for incident PCCs from days 31 to 180 after the index date.

Cumulative incidence at 31 to 180 days is shown as a percentage, and the difference in cumulative incidence between groups is shown with the 95% CI (green bars with whiskers). This is an absolute comparison measure, such that a value <0 suggests lower risk for a PCC in the nirmatrelvir–ritonavir group compared with the matched untreated group. The figure also shows subhazard ratios and their 95% CIs (lines with whiskers). This is a relative comparison measure, such that a value <1 suggests lower risk for a PCC in the nirmatrelvir–ritonavir group compared with the matched untreated group. Effects are shown for individual PCCs and also with PCCs aggregated across organ systems (e.g., cardiac, pulmonary). COPD = chronic obstructive pulmonary disease; PCC = post–COVID-19 condition; PTSD = posttraumatic stress disorder.