Effectiveness of Sotrovimab in Preventing COVID-19-related Hospitalizations or Deaths Among U.S. Veterans (preprint)

Background: Data on effectiveness of sotrovimab preventing COVID-19-related hospitalization or mortality, particularly after the emergence of the Omicron variant, are limited. Method: Determine the real-world clinical effectiveness of sotrovimab for prevention of 30-day COVID-19 related hospitalization or mortality using a retrospective cohort within the U.S. Department of Veterans Affairs (VA) healthcare system. Veterans aged [≥]18 years, diagnosed with COVID-19 between December 1, 2021, and April 4, 2022, were included. Sotrovimab recipients (n=2,816) were exactly matched to untreated controls (n=11,250) on date of diagnosis, vaccination status, and region. The primary outcome was COVID-19-related hospitalization or all-cause mortality within 30 days from diagnosis. Cox proportional hazards modeling estimated the hazard ratios (HR) and 95% Confidence Interval (CI) for the association between receipt of sotrovimab and outcomes. Results: During BA.1 dominance, compared to matched controls, sotrovimab-treated patients had a 70% lower risk hospitalization within 30 days or mortality (HR 0.30; 95%CI, 0.23-0.40), a 66% lower risk of 30-day hospitalization (HR 0.34; 95%CI, 0.25-0.46), and a 77% lower risk of 30-day all-cause mortality (HR 0.23; 95%CI, 0.14-0.38). During BA.2 dominance sotrovimab-treated patients had a 71% (HR .29; 95%CI, 0.08-0.98) lower risk of 30-day COVID-19-related- hospitalization, emergency, or urgent care. Limitations include confounding by indication. Conclusions: Using national real-world data from high risk and predominantly vaccinated Veterans, administration of sotrovimab, compared with no treatment, was associated with reduced risk of 30-day COVID-19-related hospitalization or all-cause mortality during the Omicron BA.1 period and reduced risk of progression to severe COVID-19 during the BA.2 dominant period.

Excess mortality in the general population versus Veterans Healthcare System during the first year of the COVID-19 pandemic in the United States (preprint)

Importance The COVID-19 pandemic had a substantial impact on the overall rate of death in the United States during the first year. It is unclear whether access to comprehensive medical care, such as through the VA healthcare system, altered death rates compared to the US population. Objective: Quantify the increase in death rates during the first year of the COVID-19 pandemic in the general US population and among individuals who receive comprehensive medical care through the Department of Veterans Affairs (VA). Design: Analysis of changes in all-cause death rates by quarter, stratified by age, sex race/ethnicity, and region, based on individual-level data. Hierarchical regression models were fit in a Bayesian setting. Standardized rates were used for comparison between populations. Setting and participants: General population of the United States, enrollees in the VA, and active users of VA healthcare. Exposure and main outcome: Changes in rates of death from any cause during the COVID-19 pandemic in 2020 compared to previous years. Results Sharp increases were apparent across all of the adult age groups (25 years and older) in both the general US population and the VA populations. Across all of 2020, the relative increase in death rates was similar in the general US population (RR: 1.20 (95% CI: 1.17, 1.22)), VA enrollees (RR: 1.20 (95% CI: 1.14, 1.29)), and VA active users (RR: 1.19 (95% CI: 1.14, 1.26)). Because the pre-pandemic standardized mortality rates were higher in the VA populations prior to the pandemic, the absolute rates of excess mortality were higher in the VA populations. Conclusions and Relevance: Despite access to comprehensive medical care, active users of the VA had similar relative mortality increases from all causes compared with the general US population. Factors that influenced baseline rates of death and that mitigated viral transmission in the community are more likely to have influenced the impact of the pandemic.

Tixagevimab/Cilgavimab for Prevention of COVID-19 during the Omicron Surge: Retrospective Analysis of National VA Electronic Data (preprint)

Background: Little is known regarding the effectiveness of tixagevimab/cilgavimab in preventing SARS-CoV-2 infection in this population, particularly after the emergence of the Omicron variant. Objective: To determine the effectiveness of tixagevimab/cilgavimab for prevention of SARS-CoV-2 infection and severe disease among immunocompromised patients. Design: Retrospective cohort study with propensity matching and difference-in-difference analyses. Setting: U.S. Department of Veterans Affairs (VA) healthcare system. Participants: Veterans age [≥]18 years as of January 1, 2022, receiving VA healthcare. We compared a cohort of 1,848 patients treated with at least one dose of intramuscular tixagevimab/cilgavimab to matched controls selected from 251,756 patients who were on immunocompromised or otherwise at high risk for COVID-19. Patients were followed through April 30, 2022, or until death, whichever occurred earlier. Main Outcomes: Composite of SARS-CoV-2 infection, COVID-19-related hospitalization, and all-cause mortality. We used cox proportional hazards modelling to estimate the hazard ratios (HR) and 95% CI for the association between receipt of tixagevimab/cilgavimab and outcomes. Results: Most (69%) tixagevimab/cilgavimab recipients were [≥]65 years old, 92% were identified as immunocompromised in electronic data, and 73% had [≥]3 mRNA vaccine doses or two doses of Ad26.COV2. Compared to propensity-matched controls, tixagevimab/cilgavimab-treated patients had a lower incidence of the composite COVID-19 outcome (17/1733 [1.0%] vs 206/6354 [3.2%]; HR 0.31; 95%CI, 0.18-0.53), and individually SARS-CoV-2 infection (HR 0.34; 95%CI, 0.13-0.87), COVID-19 hospitalization (HR 0.13; 95%CI, 0.02-0.99), and all-cause mortality (HR 0.36; 95%CI, 0.18-0.73). Limitations: Confounding by indication and immortal time bias. Conclusions: Using national real-world data from predominantly vaccinated, immunocompromised Veterans, administration of tixagevimab/cilgavimab was associated with lower rates of SARS-CoV-2 infection, COVID-19 hospitalization, and all-cause mortality during the Omicron surge.

Relative effectiveness of booster vs. 2-dose mRNA Covid-19 vaccination in the Veterans Health Administration: Self-controlled risk interval analysis (preprint)

ABSTRACT Importance Previous studies have analyzed effectiveness of booster mRNA Covid-19 vaccination and compared it with 2-dose primary series for both Delta and Omicron variants. Observational studies that estimate effectiveness by comparing outcomes among vaccinated and unvaccinated individuals may suffer from residual confounding and exposure misclassification. Objective To estimate relative effectiveness of booster vaccination versus the 2-dose primary series with self-controlled study design Design, Setting and Participants We used the Veterans Health Administration (VHA) Corporate Data Warehouse to identify U.S. Veterans enrolled in care ≥2 years who received the 2-dose primary mRNA Covid-19 vaccine series and a mRNA Covid-19 booster following expanded recommendation for booster vaccination, and who had a positive SARS-CoV-2 test during the Delta (9/23/2021-11/30/2021) or Omicron (1/1/22-3/1/22) predominant period. Among them, we conducted a self-controlled risk interval (SCRI) analysis to compare odds of SARS-CoV-2 infection during a booster exposure interval versus a control interval. Exposures control interval (days 4-6 post-booster vaccination, presumably prior to gain of booster immunity), and booster exposure interval (days 14-16 post-booster vaccination, presumably following gain of booster immunity) Outcomes and Measures Positive PCR or antigen SARS-CoV-2 test. Separately for Delta and Omicron periods, we used conditional logistic regression to calculate odds ratios (OR) of a positive test for the booster versus control interval and calculated relative effectiveness of booster versus 2-dose primary series as (1-OR)*100. The SCRI approach implicitly controlled for time-fixed confounders. Results We found 42 individuals with a positive SARS-CoV-2 test in the control interval and 14 in the booster exposure interval during Delta period, and 137 and 66, respectively, in Omicron period. For the booster versus 2-dose primary series, the odds of infection were 70% (95%CI: 42%, 84%) lower during the Delta period and 56% (95%CI: 38%, 67%) lower during Omicron. Results were similar for ages <65 and ≥65 years in the Omicron period. In sensitivity analyses among those with prior Covid-19 history, and age stratification, ORs were similar to the main analysis. Conclusions Booster vaccination was more effective relative to a 2-dose primary series, the relative effectiveness was consistent across age groups and was higher during the Delta predominant period than during the Omicron period.

Effectiveness of mRNA COVID-19 Booster Vaccines against Omicron and Delta Variants among US Veterans (preprint)

Background We estimated vaccine effectiveness (VE) of mRNA vaccines among US Veterans during periods of Delta and Omicron variant dominance. Patients included in this study were largely 65 years or older (62,834, 55%), male (101,259, 88%), and non-Hispanic white (66,986, 58%). Methods We used SARS-CoV-2 laboratory test results to conduct a matched test-negative case-control study to estimate VE of three and two doses of mRNA vaccines against infection (regardless of symptoms), and a matched case-control study to estimate VE against COVID-19-related hospitalization and death. We estimated VE as (1-odds ratio) x 100%. Severity of disease was measured using hospital length of stay (LOS) and admission to an intensive care unit (ICU). Results Against infection, booster doses had 7-times higher VE - 59% (95% confidence interval [CI], 57 to 61) - than 2-dose VE (7%; 95% CI, 3 to 10) during the Omicron period. For the Delta period, estimated VE against infection was 90% (95% CI, 88 to 92) among boosted vaccinees, 64% higher than VE among 2-dose vaccinees [55% (95% CI, 51 to 58)]. Against hospitalization, booster dose VE was 87% (95% CI, 80 to 91) during Omicron and 95% (95% CI, 91 to 97) during Delta; the 2-dose VE was 44% (95% CI, 26 to 58) during Omicron and 75% (95% CI, 70 to 80) during Delta. Against death, estimated VE with a booster dose was 94% (95% CI, 85 to 98) during Omicron and 96% (95% CI, 88 to 99) during Delta, while the 2-dose VE was 75% (95% CI, 52 to 87) during Omicron and 93% (95% CI, 85 to 97) during Delta. During the Omicron period, average hospital LOS was 4 days shorter [3 days (95%CI, 3 to 4 days)] than during the Delta period. Conclusions A mRNA vaccine booster is more effective against infection, hospitalization, and death than 2-dose vaccination among an older male population with comorbidities.

SARS-Cov-2 Infection versus Vaccine-Induced Immunity among Veterans (preprint)

BackgroundWith over 40 million cases of SARS-CoV-2 infection reported in the US and discussion of both vaccine mandates as well as boosters ongoing, we aim to examine protection conferred by previous infection compared with vaccination so that citizens and policy makers can make informed decisions. ObjectivesTo compare mRNA COVID-19 vaccine-induced immunity against immunity induced by previous infection with SARS-CoV-2 between June and August 2021 when the Delta variant became dominant in the US. We conducted a retrospective observational study comparing two groups whose incident vaccination or infection occurred within the first two months of 2021: (1) SARS-CoV-2-naive individuals who received a full mRNA vaccination - 2 doses of either Pfizer or Moderna vaccine, (2) newly infected individuals who were subdivided into those have not been vaccinated and those have been vaccinated after their infection. Matched multivariable Cox proportional hazards model was applied. We evaluated laboratory (RT-PCR) confirmed SARS-CoV-2 infection during follow-up, COVID-related hospitalization, and deaths. SettingVeterans Health Administration (VHA). Main outcomesPositive SARS-CoV-2 PCR test, COVID-related hospitalization, and deaths. Protection was estimated from hazard ratios with 95% confidence intervals (CI). ResultsA total of 9,539 patients with SARS-CoV-2 infection during the first two months of 2021 were matched to 14,458 and 23,105 patients fully vaccinated with Moderna and Pfizer mRNA vaccines, during the same two months. 3,917 (41%) of patients with SARS-CoV-2 infection were subsequently vaccinated. We plan to study this group separately. Consequently, protections were estimated among those with infection but were not subsequently vaccinated and those vaccinated with a mRNA vaccine. Among seniors, Moderna and Pfizer mRNA vaccines offered stronger protection against infection, lowering the risk by an additional 66% [HR: 0.34 (95% CI, 0.14-0.78)] and 68% [HR: 0.32 (95% CI, 0.14-0.70)]; stronger protection against hospitalization, lowering the risk by an additional 61% [HR: 0.34 (95% CI, 0.14-0.78)] and 45% [HR: 0.34 (95% CI, 0.14-0.78)]; and stronger protection against deaths lowering the risk by an additional 95% [HR: 0.05 (95% CI, 0.004-0.62)] and 99% [HR: 0.01 (95% CI, 0.001-0.44)]. Among young adults (age < 65), the protections offered by vaccines were statistically equivalent to that provided by previous infection, especially in terms of absolute incidence rate. ConclusionsAmong the elderly (age 65 or older), two-dose mRNA vaccines provided stronger protection against infection, hospitalization, and death, compared to natural immunity. Among young adults (age < 65), the protections offered between natural immunity and vaccine-induced immunity were similar.

Coverage and Effectiveness of mRNA COVID-19 Vaccines among Veterans (preprint)

Importance The effectiveness of mRNA vaccination in a large and diverse American population, with older age and higher co-morbidity has not been assessed. Objective To describe the scope of the mRNA vaccination rollout among the diverse U.S. Veterans population, and to study the mRNA COVID-19 vaccine effectiveness (VE) against infection, symptomatic disease, hospitalization, and death. Methods Vaccination histories were obtained from medical records to determine if patients tested for SARS-CoV-2 were unvaccinated, partially vaccinated (first dose of mRNA COVID-19 vaccine), or fully vaccinated (two doses) at time of testing. First, coverage with any COVID-19 vaccination was described for all Veterans enrolled in Veterans Health Administration (VHA). Second, to evaluate VE, a matched test-negative case-control evaluation was conducted utilizing SARS-CoV-2 positive (cases [n=16,690]) and SARS-CoV-2 negative (controls [n=61,610]) tests from Veterans aged ≥18 years old who routinely sought care at a VHA facility and were tested from December 14, 2020, through March 14, 2021. VE was calculated from odds ratios (ORs) with 95% confidence intervals (CI). Results By March 7, 2021, among 6,170,750 Veterans, 1,547,045 (23%) received at least one COVID-19 vaccination. mRNA COVID-19 VE against infection, regardless of symptoms, was 94% (95% CI 92-95) and 58% (95%CI 54-62) for full and partial vaccination (vs. no vaccination), respectively. VE against infection was similar across subpopulations, and it was not significantly different from VE against symptomatic disease. VE against COVID-19-related hospitalization and death for full vs. no vaccination was 89% (95%CI 81-93) and 99% (95%CI 87-100), respectively. Conclusions and Relevance The VHA’s efficient and equitable distribution of effective vaccines decreased COVID-19 infections, hospitalization, and mortality similarly for all Veterans, including Veterans with low income, homeless Veterans, immunocompromised, the elderly, minorities, and rural Veterans thus reducing health inequalities.

A national analysis of trends in COVID-19 infection and clinical management in Veterans Health Administration medical facilities (preprint)

OBJECTIVE We explored longitudinal trends in sociodemographic characteristics, reported symptoms, laboratory findings, pharmacological and non-pharmacological treatment, comorbidities, and 30-day in-hospital mortality among hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS This retrospective cohort study included 43,267 patients diagnosed with COVID-19 in the Veterans Health Administration between 03/01/20 and 08/31/20 and followed until 09/30/20. We focused our analysis on patients that were subsequently hospitalized, and categorized them into groups based on the month of hospitalization. We summarized our findings through descriptive statistics. We used a nonparametric rank-sum test for trend to examine any differences in the distribution of our study variables across the six months. RESULTS During our study period, 8,240 patients were hospitalized, and 1,081 (13.1%) died within 30 days of admission. Hospitalizations increased over time, but the proportion of patients that died consistently declined from March (N=221/890, 24.8%) to August (N=111/1,396, 8.0%). Patients hospitalized in March compared to August were younger on average, mostly black, and symptomatic. They also had a higher frequency of baseline comorbidities, including hypertension and diabetes, and were more likely to present with abnormal laboratory findings including low lymphocyte counts and elevated creatinine. Lastly, receipt of mechanical ventilation and Hydroxychloroquine declined from March to August, while treatment with Dexamethasone and Remdesivir increased. CONCLUSION We found evidence of declining COVID-19 severity and fatality over time within a national health care system.