Characteristics of the study population
Among 558,037 patients with their first SARS-CoV-2 infection between March 1, 2022, and February 1, 2023, 497,499 were eligible for the study (Fig. 1). Among eligible adult patients, 165,256 received Paxlovid within 5 days of infection and 307,922 did not. The baseline characteristics of the two groups are presented in Table 1.
Table 1
Population characteristics of adult SARS-CoV-2 infected patients for evaluating the effectiveness of the acute prescription of Paxlovid on the PASC conditions, during the period from March 1, 2022, to February 1, 2023
| Paxlovid treated SARS-CoV-2 Infected Patients. (N = 165,256) | No treated SARS-CoV-2 Infected Patients (N = 307,922) | SMD |
Characteristic | | | |
Sex — no. (%) | | | |
Female | 100,931 (61.1) | 196,527 (63.8) | -0.06 |
Male | 64,300 (38.9) | 111,224 (36.1) | 0.06 |
Other/Missing | 25 (0.0) | 171 (0.1) | -0.02 |
Median age (IQR) — yr | 61 (48—71) | 50 (35—65) | 0.49 |
Age group — no. (%) | | | |
18–24 | 3,649 (2.2) | 26,292 (8.5) | -0.28 |
25–34 | 12,128 (7.3) | 53,258 (17.3) | -0.31 |
35–49 | 30,936 (18.7) | 74,274 (24.1) | -0.13 |
50–64 | 50,522 (30.6) | 74,914 (24.3) | 0.14 |
65+ | 68,021 (41.2) | 79,184 (25.7) | 0.33 |
Race/Ethnicity — no. (%) | | | |
Asian Non-Hispanic | 6,453 (3.9) | 17,258 (5.6) | -0.08 |
Black or African American Non-Hispanic | 15,125 (9.2) | 43,307 (14.1) | -0.15 |
Hispanic or Latino Any Race | 9,848 (6.0) | 37,630 (12.2) | -0.22 |
White Non-Hispanic | 116,020 (70.2) | 175,712 (57.1) | 0.28 |
Other Non-Hispanic | 3,545 (2.1) | 9,772 (3.2) | -0.06 |
Unknown | 14,265 (8.6) | 24,243 (7.9) | 0.03 |
No. of hospital visits in the past 3 year — no. (%) | | | |
Inpatient 0 | 138,148 (83.6) | 261,619 (85.0) | -0.04 |
Inpatient 1–2 | 19,765 (12.0) | 35,296 (11.5) | 0.02 |
Inpatient > = 3 | 7,343 (4.4) | 11,007 (3.6) | 0.04 |
Outpatient 0 | 1,544 (0.9) | 11,394 (3.7) | -0.18 |
Outpatient 1–2 | 7,899 (4.8) | 26,481 (8.6) | -0.15 |
Outpatient > = 3 | 155,813 (94.3) | 270,047 (87.7) | 0.23 |
Emergency 0 | 130,061 (78.7) | 223,574 (72.6) | 0.14 |
Emergency 1–2 | 27,353 (16.6) | 58,644 (19.0) | -0.07 |
Emergency > = 3 | 7,842 (4.7) | 25,704 (8.3) | -0.15 |
Median Area Deprivation Index (IQR) — rank | 30 (12—54) | 37 (16—61) | -0.20 |
BMI (IQR) | 29 (25—35) | 29 (24—35) | 0.03 |
Documented Vaccination Status | | | |
Fully vaccinated | 67,718 (41.0) | 111,921 (36.3) | 0.10 |
Partially vaccinated | 26,333 (15.9) | 41,717 (13.5) | 0.07 |
No evidence | 72,282 (43.7) | 156,552 (50.8) | -0.14 |
Patients in different Index time — no. (%) | | | |
03/22 − 06/22 | 48,541 (29.4) | 117,644 (38.2) | -0.19 |
07/22 − 10/22 | 68,535 (41.5) | 127,243 (41.3) | 0.00 |
11/22 − 02/23 | 48,180 (29.2) | 63,035 (20.5) | 0.20 |
Patient w/o documented risks— no. (%) | 5,597 (3.4) | 35,874 (11.7) | -0.32 |
Pregnant— no. (%) | 822 (0.5) | 4,368 (1.4) | -0.09 |
Patient with at least one risk factor— no. (%) | 158,837 (96.1) | 267,680 (86.9) | 0.33 |
Individual Risk Factors — no. (%) | | | |
Cancer | 20,016 (12.1) | 23,277 (7.6) | 0.15 |
Chronic kidney disease | 10,709 (6.5) | 20,746 (6.7) | -0.01 |
Chronic liver disease | 11,232 (6.8) | 17,398 (5.7) | 0.05 |
Chronic lung disease | 33,140 (20.1) | 55,918 (18.2) | 0.05 |
Cystic fibrosis | 224 (0.1) | 225 (0.1) | 0.02 |
Dementia or other neurological conditions | 4,897 (3.0) | 7,272 (2.4) | 0.04 |
Diabetes | 25,877 (15.7) | 41,410 (13.4) | 0.06 |
Disabilities | 1,340 (0.8) | 3,045 (1.0) | -0.02 |
Heart conditions | 33,471 (20.3) | 50,986 (16.6) | 0.10 |
Hypertension | 68,942 (41.7) | 101,995 (33.1) | 0.18 |
HIV infection | 1,173 (0.7) | 1,839 (0.6) | 0.01 |
Immune dysfunction | 62,773 (38.0) | 81,236 (26.4) | 0.25 |
Mental health conditions | 27,472 (16.6) | 56,395 (18.3) | -0.04 |
Overweight and obesity | 108,679 (65.8) | 185,509 (60.2) | 0.11 |
Sickle cell disease or thalassemia | 18,546 (11.2) | 34,254 (11.1) | 0.00 |
Smoking current or former | 32,814 (19.9) | 59,393 (19.3) | 0.01 |
Stroke or cerebrovascular disease | 9,363 (5.7) | 14,048 (4.6) | 0.05 |
Substance use disorders | 11,894 (7.2) | 33,630 (10.9) | -0.13 |
Tuberculosis | 77 (0.0) | 199 (0.1) | -0.01 |
a. The SARS-CoV-2 positive patients were identified by a) positive SARS-CoV-2 polymerase-chain-reaction (PCR) or antigen laboratory tests; b) the ICD-10-CMdiagnosis code U07.1 representing COVIID-19 diagnosis; or c) Paxlovid (nirmatrelvir/ritonavir) or Remdesivir prescriptions. The first documented evidence was defined as the index event. IQR denotes the interquartile range. The percentage may not sum up to 100 because of rounding. ADI, the Area Deprivation Index. BMI, Body Mass Index. b. A standardized mean difference (SMD) of > 0.10 or <-0.10 indicates an important effect size difference between the two samples, otherwise, no significant difference is assumed. c. Pregnant patients were included when SARS-CoV-2 infection occurred during pregnancy. |
The median age in the Paxlovid-treated group was older than the non-treated group (61 [interquartile range (IQR), 48–71 vs 50 [IQR 35–65]). Paxlovid-treated patients were more likely to be (self-reported) White than non-treated patients, and more likely to have a risk factor (e.g., cancer, hypertension, immune dysfunction, overweight, and obesity) for developing severe COVID-19 illness. They were less likely to be (self-reported) Black or Hispanic, or have substance use disorders.
Comparisons were conducted for the Paxlovid-treated group and non-treated group and all measured variables were well-balanced between corresponding comparisons as summarized in Figures S1 and S2 in the Supplementary Appendix. In addition, significant associations of exposure were not observed with negative outcomes, as summarized in Figures S3 and S4 in the Supplementary Appendix, suggesting little residual confounding.
Paxlovid effectiveness
At 180 days of follow-up, the estimated risk of Long COVID was 30.51 events per 100 persons (95% confidence interval (CI), 30.25 to 30.77) in the Paxlovid-treated group and 33.50 (95% CI, 33.28 to 33.71) in the non-treated group (Fig. 2). Compared to patients in the non-treatment group, Paxlovid-treated patients had a reduced risk of Long COVID, with a Hazard Ratio (HR) of 0.88 (95% CI, 0.87 to 0.89) and risk reduction of 2.99 events per 100 persons (95% CI, 2.65 to 3.32). Paxlovid treatment was also associated with a lower risk of all-cause hospitalization (HR, 0.70, 95% CI, 0.68–0.73; risk reduction of 2.37 events per 100 persons, 95% CI, 2.19 to 2.56), and all-cause death (HR, 0.53, 95% CI, 0.46 to 0.60; risk reduction of 0.23 events per 100 persons, 95% CI, 0.19 to 0.28) in the post-acute 180 days.
Paxlovid treatment was associated with a lower risk of incident Long COVID across systems as shown in Fig. 2D, including post-acute neurological conditions (sleep disorders, cognitive problems, headache, encephalopathy, dementia), post-acute pulmonary conditions (pulmonary fibrosis, acute pharyngitis, shortness of breath), post-acute blood conditions (anemia), post-acute metabolic conditions (edema, diabetes, malnutrition), post-acute digestive conditions (abdominal pain, constipation), post-acute musculoskeletal conditions (joint pain), and some general conditions in the post-acute phase (e.g., malaise and fatigue, fever, smell, and taste). There were no conclusive associations between Paxlovid and hair loss (HR, 1.04, 95% CI 0.95 to 1.14), or ICD-10 codes U0.99 or B94.8 representing unspecified Post COVID-19 conditions or sequelae of infectious illness (HR, 0.97, 95% CI 0.89 to 1.05).
Paxlovid treatment was also associated with a lower risk of incident Long COVID in different subpopulations stratified by sex, race, age, baseline risk conditions (except for pregnant females), infection time, and different rural-urban commuting areas as shown in Fig. 3. Relatively greater risk reductions were observed in males (3.53 events per 100 persons, 95% CI, 2.98 to 4.08) compared to females (2.61, 95% 2.18 to 3.04) and for individuals aged \(\ge\) 65 (3.27, 95% CI, 2.74 to 3.81) compared to those under 65 (2.73, 95% CI, 2.29 to 3.17). Regarding the rural and urban areas, the greatest risk reduction was found in small towns (6.90 events per 100 persons, 95% CI, 4.28 to 9.52), followed by micropolitan (5.69, 95% CI, 3.96 to 7.42) and metropolitan patients (2.19, 95% CI, 1.83 to 2.56). The subgroup analyses for post-acute all-cause hospitalization or death are in Fig. S6 and S7 in the Supplementary Appendix. Results were broadly similar in sensitivity analyses that considered a secondary Long COVID definition with a focus on cognitive, fatigue, and respiratory conditions, and in a population with demographics similar to the Veteran Affairs study (87.8% male patients aged \(\ge\)60 years old or having any risk factors) (Fig. 3 and Fig. S8 in the Supplementary Appendix for the subgroup analyses).
However, in low-risk patients who didn’t have documented risk factors for severe COVID-19 illness or who were younger than 50, the association between Paxlovid treatment and incident Long COVID was inconclusive (HR, 1.03; 95% CI, 0.95–1.11).