Effectiveness of COVID-19 Treatment With Nirmatrelvir-Ritonavir or Molnupiravir Among U.S. Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes.

BACKGROUND: Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes in the setting of Omicron variant transmission and COVID-19 vaccination is limited. OBJECTIVE: To measure the effectiveness of nirmatrelvir-ritonavir and molnupiravir for outpatient treatment of COVID-19. DESIGN: Three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir. 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 or molnupiravir pharmacotherapy. MEASUREMENTS: Incidence of any hospitalization or all-cause mortality at 30 days and from 31 to 180 days. RESULTS: Eighty-seven percent of participants were male; the median age was 66 years, and 18% were unvaccinated. Compared with matched untreated control participants, those treated with nirmatrelvir-ritonavir (n = 9607) had lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1000 participants; risk difference [RD], -8.25 [95% CI, -12.27 to -4.23] per 1000 participants) and death (1.25 vs. 5.47 per 1000 participants; RD, -4.22 [CI, -5.45 to -3.00] per 1000 participants). Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02]). Molnupiravir-treated participants (n = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1000 participants at 30 days; RD, -10.42 [CI, -13.49 to -7.35] per 1000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization. A difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. LIMITATION: The date of COVID-19 symptom onset for most veterans was unknown. CONCLUSION: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death. Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Adverse outcomes of SARS-CoV-2 infection with delta and omicron variants in vaccinated versus unvaccinated US veterans: retrospective cohort study.

OBJECTIVES: To determine the association between covid-19 vaccination types and doses with adverse outcomes of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection during the periods of delta (B.1.617.2) and omicron (B.1.1.529) variant predominance. DESIGN: Retrospective cohort. SETTING: US Veterans Affairs healthcare system. PARTICIPANTS: Adults (≥18 years) who are affiliated to Veterans Affairs with a first documented SARS-CoV-2 infection during the periods of delta (1 July-30 November 2021) or omicron (1 January-30 June 2022) variant predominance. The combined cohorts had a mean age of 59.4 (standard deviation 16.3) and 87% were male. INTERVENTIONS: Covid-19 vaccination with mRNA vaccines (BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)) and adenovirus vector vaccine (Ad26.COV2.S (Janssen/Johnson & Johnson)). MAIN OUTCOME MEASURES: Stay in hospital, intensive care unit admission, use of ventilation, and mortality measured 30 days after a positive test result for SARS-CoV-2. RESULTS: In the delta period, 95 336 patients had infections with 47.6% having at least one vaccine dose, compared with 184 653 patients in the omicron period, with 72.6% vaccinated. After adjustment for patient demographic and clinical characteristics, in the delta period, two doses of the mRNA vaccines were associated with lower odds of hospital admission (adjusted odds ratio 0.41 (95% confidence interval 0.39 to 0.43)), intensive care unit admission (0.33 (0.31 to 0.36)), ventilation (0.27 (0.24 to 0.30)), and death (0.21 (0.19 to 0.23)), compared with no vaccination. In the omicron period, receipt of two mRNA doses were associated with lower odds of hospital admission (0.60 (0.57 to 0.63)), intensive care unit admission (0.57 (0.53 to 0.62)), ventilation (0.59 (0.51 to 0.67)), and death (0.43 (0.39 to 0.48)). Additionally, a third mRNA dose was associated with lower odds of all outcomes compared with two doses: hospital admission (0.65 (0.63 to 0.69)), intensive care unit admission (0.65 (0.59 to 0.70)), ventilation (0.70 (0.61 to 0.80)), and death (0.51 (0.46 to 0.57)). The Ad26.COV2.S vaccination was associated with better outcomes relative to no vaccination, but higher odds of hospital stay and intensive care unit admission than with two mRNA doses. BNT162b2 was generally associated with worse outcomes than mRNA-1273 (adjusted odds ratios between 0.97 and 1.42). CONCLUSIONS: In veterans with recent healthcare use and high occurrence of multimorbidity, vaccination was robustly associated with lower odds of 30 day morbidity and mortality compared with no vaccination among patients infected with covid-19. The vaccination type and number of doses had a significant association with outcomes.

Design and analysis of outcomes following SARS-CoV-2 infection in veterans.

BACKGROUND: Understanding how SARS-CoV-2 infection impacts long-term patient outcomes requires identification of comparable persons with and without infection. We report the design and implementation of a matching strategy employed by the Department of Veterans Affairs' (VA) COVID-19 Observational Research Collaboratory (CORC) to develop comparable cohorts of SARS-CoV-2 infected and uninfected persons for the purpose of inferring potential causative long-term adverse effects of SARS-CoV-2 infection in the Veteran population. METHODS: In a retrospective cohort study, we identified VA health care system patients who were and were not infected with SARS-CoV-2 on a rolling monthly basis. We generated matched cohorts within each month utilizing a combination of exact and time-varying propensity score matching based on electronic health record (EHR)-derived covariates that can be confounders or risk factors across a range of outcomes. RESULTS: From an initial pool of 126,689,864 person-months of observation, we generated final matched cohorts of 208,536 Veterans infected between March 2020-April 2021 and 3,014,091 uninfected Veterans. Matched cohorts were well-balanced on all 39 covariates used in matching after excluding patients for: no VA health care utilization; implausible age, weight, or height; living outside of the 50 states or Washington, D.C.; prior SARS-CoV-2 diagnosis per Medicare claims; or lack of a suitable match. Most Veterans in the matched cohort were male (88.3%), non-Hispanic (87.1%), white (67.2%), and living in urban areas (71.5%), with a mean age of 60.6, BMI of 31.3, Gagne comorbidity score of 1.4 and a mean of 2.3 CDC high-risk conditions. The most common diagnoses were hypertension (61.4%), diabetes (34.3%), major depression (32.2%), coronary heart disease (28.5%), PTSD (25.5%), anxiety (22.5%), and chronic kidney disease (22.5%). CONCLUSION: This successful creation of matched SARS-CoV-2 infected and uninfected patient cohorts from the largest integrated health system in the United States will support cohort studies of outcomes derived from EHRs and sample selection for qualitative interviews and patient surveys. These studies will increase our understanding of the long-term outcomes of Veterans who were infected with SARS-CoV-2.

Rates of and Factors Associated With Primary and Booster COVID-19 Vaccine Receipt by US Veterans, December 2020 to June 2022.

Importance: COVID-19 vaccination rates remain suboptimal in the US. Identifying factors associated with vaccination can highlight existing gaps and guide targeted interventions to improve vaccination access and uptake. Objective: To describe incidence and patient characteristics associated with primary, first booster, and second booster COVID-19 vaccination in the Veterans Health Administration (VHA). Design, Setting, and Participants: This retrospective cohort study assessed US veterans receiving care in VHA medical centers and outpatient clinics as of December 1, 2020. All VHA enrollees with an inpatient, outpatient, or telehealth encounter in VHA as well as a primary care physician appointment in the preceding 24 months were included. Exposures: Demographic characteristics, place of residence, prior SARS-CoV-2 infection, and underlying medical conditions. Main Outcomes and Measures: Cumulative incidence of primary, first booster, and second booster COVID-19 vaccination through June 2022. Cox proportional hazards regression was used to identify factors independently associated with COVID-19 vaccination. Results: Among 5 632 413 veterans included in the study, 5 094 392 (90.4%) were male, the median (IQR) age was 66 (51-74) years, 1 032 334 (18.3%) were Black, 448 714 (8.0%) were Hispanic, and 4 202 173 (74.6%) were White. Through June 2022, cumulative incidences were 69.0% for primary vaccination, 42.9% for first booster, and 9.3% for second booster. Cumulative incidence for primary vaccination increased with increasing age, from 46.9% (95% CI, 46.8%-47.0%) among veterans aged 18 to 49 years to 82.9% (95% CI, 82.8%-83.0%) among veterans aged 80 to 84 years. More Black veterans completed primary vaccination (71.7%; 95% CI, 71.6%-71.8%) compared with White veterans (68.9%; 95% CI, 68.9%-69.0%), and more urban-dwelling veterans completed primary vaccination (70.9%; 95% CI, 70.9%-71.0%) compared with highly rural-dwelling veterans (63.8%; 95% CI, 63.4%-64.1%). Factors independently associated with higher likelihood of both primary and booster vaccination included older age, female sex, Asian or Black race, Hispanic ethnicity, urban residence, and lack of prior SARS-CoV-2 infection. Conclusions and Relevance: In this cohort study of US veterans, COVID-19 vaccination coverage through June 2022 was suboptimal. Primary vaccination can be improved among younger, rural-dwelling veterans. Greater uptake of booster vaccination among all veterans is needed.

Consensus elements for observational research on COVID-19-related long-term outcomes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its long-term outcomes may be jointly caused by a wide range of clinical, social, and economic characteristics. Studies aiming to identify mechanisms for SARS-CoV-2 morbidity and mortality must measure and account for these characteristics to arrive at unbiased, accurate conclusions. We sought to inform the design, measurement, and analysis of longitudinal studies of long-term outcomes among people infected with SARS-CoV-2. We fielded a survey to an interprofessional group of clinicians and scientists to identify factors associated with SARS-CoV-2 infection and subsequent outcomes. Using an iterative process, we refined the resulting list of factors into a consensus causal diagram relating infection and 12-month mortality. Finally, we operationalized concepts from the causal diagram into minimally sufficient adjustment sets using common medical record data elements. Total 31 investigators identified 49 potential risk factors for and 72 potential consequences of SARS-CoV-2 infection. Risk factors for infection with SARS-CoV-2 were grouped into five domains: demographics, physical health, mental health, personal social, and economic factors, and external social and economic factors. Consequences of coronavirus disease 2019 (COVID-19) were grouped into clinical consequences, social consequences, and economic consequences. Risk factors for SARS-CoV-2 infection were developed into a consensus directed acyclic graph for mortality that included two minimally sufficient adjustment sets. We present a collectively developed and iteratively refined list of data elements for observational research in SARS-CoV-2 infection and disease. By accounting for these elements, studies aimed at identifying causal pathways for long-term outcomes of SARS-CoV-2 infection can be made more informative.

Effectiveness of mRNA COVID-19 Vaccine Boosters Against Infection, Hospitalization, and Death: A Target Trial Emulation in the Omicron (B.1.1.529) Variant Era.

BACKGROUND: The effectiveness of a third mRNA COVID-19 vaccine dose (booster dose) against the Omicron (B.1.1.529) variant is uncertain, especially in older, high-risk populations. OBJECTIVE: To determine mRNA booster vaccine effectiveness (VE) against SARS-CoV-2 infection, hospitalization, and death in the Omicron era by booster type, primary vaccine type, time since primary vaccination, age, and comorbidity burden. DESIGN: Retrospective matched cohort study designed to emulate a target trial of booster vaccination versus no booster, conducted from 1 December 2021 to 31 March 2022. SETTING: U.S. Department of Veterans Affairs health care system. PARTICIPANTS: Persons who had received 2 mRNA COVID-19 vaccine doses at least 5 months earlier. INTERVENTION: Booster monovalent mRNA vaccination (Pfizer-BioNTech's BNT162b2 or Moderna's mRNA-1273) versus no booster. MEASUREMENTS: Booster VE. RESULTS: Each group included 490 838 well-matched persons, who were predominantly male (88%), had a mean age of 63.0 years (SD, 14.0), and were followed for up to 121 days (mean, 79.8 days). Booster VE more than 10 days after a booster dose was 42.3% (95% CI, 40.6% to 43.9%) against SARS-CoV-2 infection, 53.3% (CI, 48.1% to 58.0%) against SARS-CoV-2-related hospitalization, and 79.1% (CI, 71.2% to 84.9%) against SARS-CoV-2-related death. Booster VE was similar for different booster types (BNT162b2 or mRNA-1273), age groups, and primary vaccination regimens but was significantly higher with longer time since primary vaccination and higher comorbidity burden. LIMITATION: Predominantly male population. CONCLUSION: Booster mRNA vaccination was highly effective in preventing death and moderately effective in preventing infection and hospitalization for up to 4 months after administration in the Omicron era. Increased uptake of booster vaccination, which is currently suboptimal, should be pursued to limit the morbidity and mortality of SARS-CoV-2 infection, especially in persons with high comorbidity burden. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Early Adoption of Anti-SARS-CoV-2 Pharmacotherapies Among US Veterans With Mild to Moderate COVID-19, January and February 2022.

Importance: Older adults and individuals with medical comorbidities are at increased risk for severe COVID-19. Several pharmacotherapies demonstrated to reduce the risk of COVID-19-related hospitalization and death have been authorized for use. Objective: To describe factors associated with receipt of outpatient COVID-19 pharmacotherapies in the Veterans Affairs (VA) health care system. Design, Settings, and Participants: This cohort study assessed outpatient veterans with risk factors for severe COVID-19 who tested positive for SARS-CoV-2 during January and February 2022. The setting was the VA health care system, the largest integrated health care system in the US. Exposures: Demographic characteristics, place of residence, underlying medical conditions, and COVID-19 vaccination. Main Outcomes and Measures: The odds of receipt of any COVID-19 pharmacotherapy, including sotrovimab, nirmatrelvir boosted with ritonavir, molnupiravir, or remdesivir were estimated using multivariable logistic regression. Results: Among 111 717 veterans included in this study (median [IQR] age, 60 [46-72] years; 96 482 [86.4%] male, 23 362 [20.9%] Black, 10 740 [9.6%] Hispanic, 75 973 [68.0%] White) who tested positive for SARS-CoV-2 during January to February 2022, 4233 (3.8%) received any COVID-19 pharmacotherapy, including 2870 of 92 396 (3.1%) in January and 1363 of 19 321 (7.1%) in February. Among a subset of 56 285 veterans with documented COVID-19-related symptoms in the 30 days preceding a positive SARS-CoV-2 test, 3079 (5.5%) received any COVID-19 pharmacotherapy. Untreated veterans had a median (IQR) age of 60 (46-71) years and a median (IQR) of 3 (2-5) underlying medical conditions. Veterans receiving any treatment were more likely to be older (aged 65 to 74 years vs 50 to 64 years: adjusted odds ratio [aOR], 1.66 [95% CI, 1.52-1.80]; aged at least 75 years vs 50 to 64 years: aOR, 1.67 [95% CI, 1.53-1.84]) and have a higher number of underlying conditions (at least 5 conditions vs 1 to 2 conditions: aOR, 2.17 [95% CI, 1.98-2.39]). Compared with White veterans, Black veterans (aOR, 0.65 [95% CI, 0.60-0.72]) were less likely to receive treatment; and compared with non-Hispanic veterans, Hispanic veterans (aOR, 0.88 [95% CI, 0.77-0.99]) were less likely to receive treatment. There were 16 546 courses of sotrovimab, nirmatrelvir, and molnupiravir allocated across the VA during this period. Conclusions and Relevance: In this cohort study of veterans who tested positive for SARS-CoV-2 during January and February when supply of outpatient COVID-19 pharmacotherapies was limited, prescription of these pharmacotherapies was underused, and many veterans with risk factors for severe COVID-19 did not receive treatment. Veterans from minority racial and ethnic groups were less likely to receive any pharmacotherapy.

Complexity and Challenges of the Clinical Diagnosis and Management of Long COVID.

Importance: There is increasing recognition of the long-term health effects of SARS-CoV-2 infection (sometimes called long COVID). However, little is yet known about the clinical diagnosis and management of long COVID within health systems. Objective: To describe dominant themes pertaining to the clinical diagnosis and management of long COVID in the electronic health records (EHRs) of patients with a diagnostic code for this condition (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code U09.9). Design, Setting, and Participants: This qualitative analysis used data from EHRs of a national random sample of 200 patients receiving care in the Department of Veterans Affairs (VA) with documentation of a positive result on a polymerase chain reaction (PCR) test for SARS-CoV-2 between February 27, 2020, and December 31, 2021, and an ICD-10 diagnostic code for long COVID between October 1, 2021, when the code was implemented, and March 1, 2022. Data were analyzed from February 5 to May 31, 2022. Main Outcomes and Measures: A text word search and qualitative analysis of patients' VA-wide EHRs was performed to identify dominant themes pertaining to the clinical diagnosis and management of long COVID. Results: In this qualitative analysis of documentation in the VA-wide EHR, the mean (SD) age of the 200 sampled patients at the time of their first positive PCR test result for SARS-CoV-2 in VA records was 60 (14.5) years. The sample included 173 (86.5%) men; 45 individuals (22.5%) were identified as Black and 136 individuals (68.0%) were identified as White. In qualitative analysis of documentation pertaining to long COVID in patients' EHRs 2 dominant themes were identified: (1) clinical uncertainty, in that it was often unclear whether particular symptoms could be attributed to long COVID, given the medical complexity and functional limitations of many patients and absence of specific markers for this condition, which could lead to ongoing monitoring, diagnostic testing, and specialist referral; and (2) care fragmentation, describing how post-COVID-19 care processes were often siloed from and poorly coordinated with other aspects of care and could be burdensome to patients. Conclusions and Relevance: This qualitative study of documentation in the VA EHR highlights the complexity of diagnosing long COVID in clinical settings and the challenges of caring for patients who have or are suspected of having this condition.

Rates and Factors Associated With Documentation of Diagnostic Codes for Long COVID in the National Veterans Affairs Health Care System.

Importance: Some persons infected with SARS-CoV-2 experience symptoms or impairments many months after acute infection. Objectives: To determine the rates, clinical setting, and factors associated with documented receipt of COVID-19-related care 3 or more months after acute infection. Design, Setting, and Participants: This retrospective cohort study used data from the US Department of Veterans Affairs health care system. Participants included persons with a positive SARS-CoV-2 test between February 1, 2020, and April 30, 2021, who were still alive 3 months after infection and did not have evidence of reinfection. Data analysis was performed from February 2020 to December 2021. Exposures: Positive SARS-CoV-2 test. Main Outcomes and Measures: Rates and factors associated with documentation of COVID-19-related International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes (U07.1, Z86.16, U09.9, and J12.82) 3 or more months after acute infection (hereafter, long-COVID care), with follow-up extending to December 31, 2021. Results: Among 198 601 SARS-CoV-2-positive persons included in the study, the mean (SD) age was 60.4 (17.7) years, 176 942 individuals (89.1%) were male, 133 924 (67.4%) were White, 44 733 (22.5%) were Black, and 19 735 (9.9%) were Hispanic. During a mean (SD) follow-up of 13.5 (3.6) months, long-COVID care was documented in a wide variety of clinics, most commonly primary care and general internal medicine (18 634 of 56 310 encounters [33.1%]), pulmonary (7360 of 56 310 encounters [13.1%]), and geriatrics (5454 of 56 310 encounters [9.7%]). Long-COVID care was documented in 26 745 cohort members (13.5%), with great variability across geographical regions (range, 10.8%-18.1%) and medical centers (range, 3.0%-41.0%). Factors significantly associated with documented long-COVID care included older age, Black or American Indian/Alaska Native race, Hispanic ethnicity, geographical region, high Charlson Comorbidity Index score, having documented symptoms at the time of acute infection (adjusted odds ratio [AOR], 1.71; 95% CI, 1.65-1.78) and requiring hospitalization (AOR, 2.60; 95% CI, 2.51-2.69) or mechanical ventilation (AOR, 2.46; 95% CI, 2.26-2.69). Patients who were fully vaccinated at the time of infection were less likely to receive long-COVID care (AOR, 0.78; 95% CI, 0.68-0.90). Conclusions and Relevance: Long-COVID care was documented in a variety of clinical settings, with great variability across regions and medical centers and was documented more commonly in older persons, those with higher comorbidity burden, those with more severe acute COVID-19 presentation and those who were unvaccinated at the time of infection. These findings provide support and guidance for health care systems to develop systematic approaches to the evaluation and management of patients who may be experiencing long COVID.

Comparison of Moderna versus Pfizer-BioNTech COVID-19 vaccine outcomes: A target trial emulation study in the U.S. Veterans Affairs healthcare system.

Background: mRNA COVID-19 vaccines manufactured by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) have been shown to be efficacious but have not been compared in head-to-head clinical trials. Methods: We designed this observational study to emulate a target trial of COVID-19 vaccination by BNT162b2 versus mRNA-1273 among persons who underwent vaccination in the national U.S. Veterans Affairs (VA) healthcare system from 11/12/2020 to 25/03/2021 using combined VA and Medicare electronic health records. We identified the best matching mRNA-1273 recipient(s) for each BNT162b2 recipient, using exact/coarsened-exact matching (calendar week, VA integrated service network, age buckets and Charlson comorbidity index buckets) followed by propensity score matching. Vaccine recipients were followed from the date of first vaccine dose until 25/08/2021 for the development of SARS-CoV-2 infection, SARS-CoV-2-related hospitalization or SARS-CoV-2-related death. Findings: Each group included 902,235 well-matched vaccine recipients, followed for a mean of 192 days, during which 16,890 SARS-CoV-2 infections, 3591 SARS-CoV-2-related hospitalizations and 381 SARS-CoV-2-related deaths were documented. Compared to BNT162b2, mRNA-1273 recipients had significantly lower risk of SARS-CoV-2 infection (adjusted hazard ratio [aHR] 0.736, 95% CI 0.696-0.779) and SARS-CoV-2-related hospitalization (aHR 0.633, 95% CI 0.562-0.713), which persisted across all age groups, comorbidity burden categories and black/white race. The differences between mRNA-1273 and BNT162b2 in risk of infection or hospitalization were progressively greater when the follow-up period was longer, i.e. extending to March 31, June 30 or August 25, 2021. These differences were more pronounced when we analyzed separately the outcomes that occurred during the follow-up period from July 1 to August 25, 2021 when the Delta variant became predominant in the U.S. (aHR for infection 0.584, 95% CI 0.533-0.639 and aHR for hospitalization 0.387, 95% 0.311-0.482). SARS-CoV-2-related deaths were less common in mRNA-1273 versus BNT162b2 recipients (168 versus 213) but this difference was not statistically significant (aHR 0.808, 95% CI 0.592-1.103). Interpretation: In conclusion, although absolute rates of infection, hospitalization and death in both vaccine groups were low regardless of the vaccine received, our data suggests that compared to BNT162b2, vaccination with mRNA-1273 resulted in significantly lower rates of SARS-CoV-2-infection and SARS-CoV-2-related hospitalization. These differences were greater with longer follow-up time since vaccination and even more pronounced in the Delta variant era. Funding: U.S. Department of Veterans Affairs, grant numbers COVID19-8900-11 and C19 21-278.

COVID-19 Vaccination Effectiveness Against Infection or Death in a National U.S. Health Care System : A Target Trial Emulation Study.

BACKGROUND: Little is known about real-world COVID-19 vaccine effectiveness (VE) in racially and ethnically diverse, elderly populations with high comorbidity burden. OBJECTIVE: To determine the effectiveness of messenger RNA COVID-19 vaccines. DESIGN: Target trial emulation study comparing newly vaccinated persons with matched unvaccinated controls. SETTING: U.S. Department of Veterans Affairs health care system. PARTICIPANTS: Among persons receiving care in the Veterans Affairs health care system (n = 5 766 638), those who received at least 1 dose of the Moderna or Pfizer-BioNTech COVID-19 vaccine from 11 December 2020 to 25 March 2021 (n = 2 099 871) were matched to unvaccinated controls in a 1:1 ratio according to demographic, clinical, and geographic characteristics. INTERVENTION: Follow-up for SARS-CoV-2 infection or SARS-CoV-2-related death, defined as death within 30 days of infection, began after the vaccination date or an identical index date for the matched unvaccinated controls and continued until up to 30 June 2021. MEASUREMENTS: Vaccine effectiveness against SARS-CoV-2 infection or SARS-CoV-2-related death. RESULTS: Vaccinated and unvaccinated groups were well matched; both were predominantly male (92.9% vs. 93.4%), had advanced age (mean, 68.7 years in both groups), had diverse racial and ethnic distribution (for example, Black: 17.3% vs. 17.0%, Hispanic: 6.5% vs. 6.1%), and had substantial comorbidity burden. Vaccine effectiveness 7 or more days after the second vaccine dose was 69% (95% CI, 67% to 70%) against SARS-CoV-2 infection and 86% (CI, 82% to 89%) against SARS-CoV-2-related death and was similar when follow-up was extended to 31 March versus 30 June. Vaccine effectiveness against infection decreased with increasing age and comorbidity burden. LIMITATION: Predominantly male population and lack of data on SARS-CoV-2 variants. CONCLUSION: In an elderly, diverse, high-comorbidity population, COVID-19 VE against infection was substantially lower than previously reported, but VE against death was high. Complementary infection mitigation efforts remain important for pandemic control, even with vaccination. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Trends Over Time in the Risk of Adverse Outcomes Among Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: We aimed to describe trends in adverse outcomes among patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between February and September 2020 within a national healthcare system. METHODS: We identified enrollees in the national United States Veterans Affairs healthcare system who tested positive for SARS-CoV-2 between 28 February 2020 and 30 September 2020 (n = 55 952), with follow-up extending to 19 November 2020. We determined trends over time in incidence of the following outcomes that occurred within 30 days of testing positive: hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and death. RESULTS: Between February and July 2020, there were marked downward trends in the 30-day incidence of hospitalization (44.2% to 15.8%), ICU admission (20.3% to 5.3%), mechanical ventilation (12.7% to 2.2%), and death (12.5% to 4.4%), which subsequently plateaued between July and September 2020. These trends persisted after adjustment for sociodemographic characteristics, comorbid conditions, documented symptoms, and laboratory tests, including among subgroups of patients hospitalized, admitted to the ICU, or treated with mechanical ventilation. From February to September, there were decreases in the use of hydroxychloroquine (56.5% to 0%), azithromycin (48.3% to 16.6%), vasopressors (20.6% to 8.7%), and dialysis (11.6% to 3.8%) and increases in the use of dexamethasone (3.4% to 53.1%), other corticosteroids (4.9% to 29.0%), and remdesivir (1.7% to 45.4%) among hospitalized patients. CONCLUSIONS: The risk of adverse outcomes in SARS-CoV-2-positive patients decreased markedly between February and July, with subsequent stabilization from July to September. These trends were not explained by changes in measured baseline patient characteristics and may reflect changing treatment practices or viral pathogenicity.

The COVID-19 Pandemic Highlights Opportunities to Improve Hepatocellular Carcinoma Screening and Diagnosis in a National Health System.

INTRODUCTION: We evaluated the coronavirus disease 2019 (COVID-19) pandemic's impact on hepatocellular carcinoma (HCC) screening and diagnosis among patients with cirrhosis in the Veterans Health Administration. METHODS: Rates and predictors of screening and diagnosis were reviewed September 1, 2019-February 29, 2020 ("pre-COVID-19," N = 94,612) and April 1, 2020-September 30, 2020 ("post-COVID-19," N = 88,073). RESULTS: Screening and diagnosis rates declined by 44% and 13%, respectively, after the COVID-19 pandemic. Screening declined irrespective of liver disease severity, but diagnosis declined only in Model for End Stage Liver Disease-Sodium score <20 or Fibrosis-4 score <3.25. Fibrosis-4 score ≥3.25 and HCC risk ≥1.5%/year strongly predicted HCC diagnosis but only moderately predicted receipt of screening. DISCUSSION: Screening and diagnosis rates declined after the COVID-19 pandemic. Prioritizing screening for patients at greatest risk for HCC may reduce delays in diagnosis.

Factors associated with early receipt of COVID-19 vaccination and adherence to second dose in the Veterans Affairs healthcare system.

BACKGROUND: We aimed to determine factors independently associated with early COVID-19 vaccination and adherence to two-dose regimens. METHODS: Among persons receiving care in the Veterans Affairs (VA) healthcare system (n = 5,766,638), we identified those who received at least one dose of COVID-19 vaccination through the VA, during the first ~3months following emergency use authorization, from December 11, 2020 to March 9, 2021 (n = 1,569,099, or 27.2%, including 880,200 (56.1%) Moderna, 676,279 (43.1%) Pfizer-BioNTech and 12,620 (0.8%) Janssen vaccines). RESULTS: Follow-up for receipt of vaccination began on December 11, 2020. After adjustment for baseline characteristics ascertained as of December 11, 2020, factors significantly associated with vaccination included older age, higher comorbidity burden, higher body mass index category, Black (vs. White) race (adjusted hazard ratio [AHR] 1.19, 95% CI 1.19-1.20), Hispanic (vs. non-Hispanic) ethnicity (AHR 1.12, 95% CI 1.11-1.13), urban (vs. rural) residence (AHR 1.31, 95% CI 1.31-1.31), and geographical region, while AI/AN race (vs. White), was associated with lower vaccination rate (AHR 0.85, 95% CI 0.84-0.87). Among persons who received both doses of Moderna or Pfizer-BioNTech vaccines, 95.3% received the second dose within ±4 days of the recommended date. Among persons who received the first vaccine dose, only 3.2% did not receive the second dose within 42 days for Pfizer versus 4.0% for Moderna (p<0.001). Factors independently associated with higher likelihood of missing the second dose included younger age (10.83% in 18-50 yo vs. 2.72% in 70-75 yo), AI/AN race, female sex, rural location, geographical region and prior positive test for SARS-CoV-2. CONCLUSIONS: We identified sociodemographic and clinical factors that may be used to target vaccination efforts and to further improve adherence to second vaccine dosing.

Risk Factors for Testing Positive for Severe Acute Respiratory Syndrome Coronavirus 2 in a National United States Healthcare System.

BACKGROUND: Identifying risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection could help health systems improve testing and screening strategies. The aim of this study was to identify demographic factors, comorbid conditions, and symptoms independently associated with testing positive for SARS-CoV-2. METHODS: This was an observational cross-sectional study at the Veterans Health Administration, including persons tested for SARS-CoV-2 nucleic acid by polymerase chain reaction (PCR) between 28 February and 14 May 2020. Associations between demographic characteristics, diagnosed comorbid conditions, and documented symptoms with testing positive for SARS-CoV-2 were measured. RESULTS: Of 88 747 persons tested, 10 131 (11.4%) were SARS-CoV-2 PCR positive. Positivity was associated with older age (≥80 vs <50 years: adjusted odds ratio [aOR], 2.16 [95% confidence interval {CI}, 1.97-2.37]), male sex (aOR, 1.45 [95% CI, 1.34-1.57]), regional SARS-CoV-2 burden (≥2000 vs <400 cases/million: aOR, 5.43 [95% CI, 4.97-5.93]), urban residence (aOR, 1.78 [95% CI, 1.70-1.87]), black (aOR, 2.15 [95% CI, 2.05-2.26]) or American Indian/Alaska Native Hawaiian/Pacific Islander (aOR, 1.26 [95% CI, 1.05-1.52]) vs white race, and Hispanic ethnicity (aOR, 1.52 [95% CI, 1.40-1.65]). Obesity and diabetes were the only 2 medical conditions associated with testing positive. Documented fevers, chills, cough, and diarrhea were also associated with testing positive. The population attributable fraction of positive tests was highest for geographic location (35.3%), followed by demographic variables (27.1%), symptoms (12.0%), obesity (10.5%), and diabetes (0.4%). CONCLUSIONS: The majority of positive SARS-CoV-2 tests were attributed to geographic location, demographic characteristics, and obesity, with a minor contribution of chronic comorbid conditions.

Changes in the associations of race and rurality with SARS-CoV-2 infection, mortality, and case fatality in the United States from February 2020 to March 2021: A population-based cohort study.

BACKGROUND: We examined whether key sociodemographic and clinical risk factors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and mortality changed over time in a population-based cohort study. METHODS AND FINDINGS: In a cohort of 9,127,673 persons enrolled in the United States Veterans Affairs (VA) healthcare system, we evaluated the independent associations of sociodemographic and clinical characteristics with SARS-CoV-2 infection (n = 216,046), SARS-CoV-2-related mortality (n = 10,230), and case fatality at monthly intervals between February 1, 2020 and March 31, 2021. VA enrollees had a mean age of 61 years (SD 17.7) and were predominantly male (90.9%) and White (64.5%), with 14.6% of Black race and 6.3% of Hispanic ethnicity. Black (versus White) race was strongly associated with SARS-CoV-2 infection (adjusted odds ratio [AOR] 5.10, [95% CI 4.65 to 5.59], p-value <0.001), mortality (AOR 3.85 [95% CI 3.30 to 4.50], p-value < 0.001), and case fatality (AOR 2.56, 95% CI 2.23 to 2.93, p-value < 0.001) in February to March 2020, but these associations were attenuated and not statistically significant by November 2020 for infection (AOR 1.03 [95% CI 1.00 to 1.07] p-value = 0.05) and mortality (AOR 1.08 [95% CI 0.96 to 1.20], p-value = 0.21) and were reversed for case fatality (AOR 0.86, 95% CI 0.78 to 0.95, p-value = 0.005). American Indian/Alaska Native (AI/AN versus White) race was associated with higher risk of SARS-CoV-2 infection in April and May 2020; this association declined over time and reversed by March 2021 (AOR 0.66 [95% CI 0.51 to 0.85] p-value = 0.004). Hispanic (versus non-Hispanic) ethnicity was associated with higher risk of SARS-CoV-2 infection and mortality during almost every time period, with no evidence of attenuation over time. Urban (versus rural) residence was associated with higher risk of infection (AOR 2.02, [95% CI 1.83 to 2.22], p-value < 0.001), mortality (AOR 2.48 [95% CI 2.08 to 2.96], p-value < 0.001), and case fatality (AOR 2.24, 95% CI 1.93 to 2.60, p-value < 0.001) in February to April 2020, but these associations attenuated over time and reversed by September 2020 (AOR 0.85, 95% CI 0.81 to 0.89, p-value < 0.001 for infection, AOR 0.72, 95% CI 0.62 to 0.83, p-value < 0.001 for mortality and AOR 0.81, 95% CI 0.71 to 0.93, p-value = 0.006 for case fatality). Throughout the observation period, high comorbidity burden, younger age, and obesity were consistently associated with infection, while high comorbidity burden, older age, and male sex were consistently associated with mortality. Limitations of the study include that changes over time in the associations of some risk factors may be affected by changes in the likelihood of testing for SARS-CoV-2 according to those risk factors; also, study results apply directly to VA enrollees who are predominantly male and have comprehensive healthcare and need to be confirmed in other populations. CONCLUSIONS: In this study, we found that strongly positive associations of Black and AI/AN (versus White) race and urban (versus rural) residence with SARS-CoV-2 infection, mortality, and case fatality observed early in the pandemic were ameliorated or reversed by March 2021.

Cirrhosis and Severe Acute Respiratory Syndrome Coronavirus 2 Infection in US Veterans: Risk of Infection, Hospitalization, Ventilation, and Mortality.

BACKGROUND AND AIMS: Whether patients with cirrhosis have increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the extent to which infection and cirrhosis increase the risk of adverse patient outcomes remain unclear. APPROACH AND RESULTS: We identified 88,747 patients tested for SARS-CoV-2 between March 1, 2020, and May 14, 2020, in the Veterans Affairs (VA) national health care system, including 75,315 with no cirrhosis-SARS-CoV-2-negative (C0-S0), 9,826 with no cirrhosis-SARS-CoV-2-positive (C0-S1), 3,301 with cirrhosis-SARS-CoV-2-negative (C1-S0), and 305 with cirrhosis-SARS-CoV-2-positive (C1-S1). Patients were followed through June 22, 2020. Hospitalization, mechanical ventilation, and death were modeled in time-to-event analyses using Cox proportional hazards regression. Patients with cirrhosis were less likely to test positive than patients without cirrhosis (8.5% vs. 11.5%; adjusted odds ratio, 0.83; 95% CI, 0.69-0.99). Thirty-day mortality and ventilation rates increased progressively from C0-S0 (2.3% and 1.6%) to C1-S0 (5.2% and 3.6%) to C0-S1 (10.6% and 6.5%) and to C1-S1 (17.1% and 13.0%). Among patients with cirrhosis, those who tested positive for SARS-CoV-2 were 4.1 times more likely to undergo mechanical ventilation (adjusted hazard ratio [aHR], 4.12; 95% CI, 2.79-6.10) and 3.5 times more likely to die (aHR, 3.54; 95% CI, 2.55-4.90) than those who tested negative. Among patients with SARS-CoV-2 infection, those with cirrhosis were more likely to be hospitalized (aHR, 1.37; 95% CI, 1.12-1.66), undergo ventilation (aHR, 1.61; 95% CI, 1.05-2.46) or die (aHR, 1.65; 95% CI, 1.18-2.30) than patients without cirrhosis. Among patients with cirrhosis and SARS-CoV-2 infection, the most important predictors of mortality were advanced age, cirrhosis decompensation, and high Model for End-Stage Liver Disease score. CONCLUSIONS: SARS-CoV-2 infection was associated with a 3.5-fold increase in mortality in patients with cirrhosis. Cirrhosis was associated with a 1.7-fold increase in mortality in patients with SARS-CoV-2 infection.

Development of COVIDVax Model to Estimate the Risk of SARS-CoV-2-Related Death Among 7.6 Million US Veterans for Use in Vaccination Prioritization.

Importance: A strategy that prioritizes individuals for SARS-CoV-2 vaccination according to their risk of SARS-CoV-2-related mortality would help minimize deaths during vaccine rollout. Objective: To develop a model that estimates the risk of SARS-CoV-2-related mortality among all enrollees of the US Department of Veterans Affairs (VA) health care system. Design, Setting, and Participants: This prognostic study used data from 7 635 064 individuals enrolled in the VA health care system as of May 21, 2020, to develop and internally validate a logistic regression model (COVIDVax) that predicted SARS-CoV-2-related death (n = 2422) during the observation period (May 21 to November 2, 2020) using baseline characteristics known to be associated with SARS-CoV-2-related mortality, extracted from the VA electronic health records (EHRs). The cohort was split into a training period (May 21 to September 30) and testing period (October 1 to November 2). Main Outcomes and Measures: SARS-CoV-2-related death, defined as death within 30 days of testing positive for SARS-CoV-2. VA EHR data streams were imported on a data integration platform to demonstrate that the model could be executed in real-time to produce dashboards with risk scores for all current VA enrollees. Results: Of 7 635 064 individuals, the mean (SD) age was 66.2 (13.8) years, and most were men (7 051 912 [92.4%]) and White individuals (4 887 338 [64.0%]), with 1 116 435 (14.6%) Black individuals and 399 634 (5.2%) Hispanic individuals. From a starting pool of 16 potential predictors, 10 were included in the final COVIDVax model, as follows: sex, age, race, ethnicity, body mass index, Charlson Comorbidity Index, diabetes, chronic kidney disease, congestive heart failure, and Care Assessment Need score. The model exhibited excellent discrimination with area under the receiver operating characteristic curve (AUROC) of 85.3% (95% CI, 84.6%-86.1%), superior to the AUROC of using age alone to stratify risk (72.6%; 95% CI, 71.6%-73.6%). Assuming vaccination is 90% effective at preventing SARS-CoV-2-related death, using this model to prioritize vaccination was estimated to prevent 63.5% of deaths that would occur by the time 50% of VA enrollees are vaccinated, significantly higher than the estimate for prioritizing vaccination based on age (45.6%) or the US Centers for Disease Control and Prevention phases of vaccine allocation (41.1%). Conclusions and Relevance: In this prognostic study of all VA enrollees, prioritizing vaccination based on the COVIDVax model was estimated to prevent a large proportion of deaths expected to occur during vaccine rollout before sufficient herd immunity is achieved.

BMI and Outcomes of SARS-CoV-2 Among US Veterans.

OBJECTIVE: The purpose of this study is to examine the associations of BMI with testing positive for severe acute respiratory coronavirus 2 (SARS-CoV-2) and risk of adverse outcomes in a cohort of Veterans Affairs enrollees. METHOD: Adjusted relative risks/hazard ratios (HRs) were calculated for the associations between BMI category (underweight, normal weight, overweight, class 1 obesity, class 2 obesity, and class 3 obesity) and testing positive for SARS-CoV-2 or experiencing hospitalization, intensive care unit admission, mechanical ventilation, and death among those testing positive. RESULTS: Higher BMI categories were associated with higher risk of a positive SARS-CoV-2 test compared with the normal weight category (class 3 obesity adjusted relative risk: 1.34, 95% CI: 1.28-1.42). Among 25,952 patients who tested positive for SARS-CoV-2, class 3 obesity was associated with higher risk of mechanical ventilation (adjusted HR [aHR]: 1.77, 95% CI: 1.35-2.32) and mortality (aHR: 1.42, 95% CI: 1.12-1.78) compared with normal weight individuals. These associations were present primarily in patients younger than 65 and were attenuated or absent in older age groups (interaction P < 0.05). CONCLUSION: Veterans Affairs enrollees with higher BMI were more likely to test positive for SARS-CoV-2 and were more likely to be mechanically ventilated or die if infected with SARS-CoV-2. Higher BMI contributed relatively more to the risk of death in those younger than 65 years of age as compared with other age categories.