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.

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.

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.

SARS-CoV-2 Convalescent Sera Binding and Neutralizing Antibody Concentrations Compared with COVID-19 Vaccine Efficacy Estimates against Symptomatic Infection.

Previous COVID-19 vaccine efficacy (VE) studies have estimated neutralizing and binding antibody concentrations that correlate with protection from symptomatic infection; how these estimates compare to those generated in response to SARS-CoV-2 infection is unclear. Here, we assessed quantitative neutralizing and binding antibody concentrations using standardized SARS-CoV-2 assays on 3,067 serum specimens collected during 27 July 2020 to 27 August 2020 from COVID-19-unvaccinated persons with detectable anti-SARS-CoV-2 antibodies. Neutralizing and binding antibody concentrations were severalfold lower in the unvaccinated study population compared to published concentrations at 28 days postvaccination. In this convenience sample, ~88% of neutralizing and ~63 to 86% of binding antibody concentrations met or exceeded concentrations associated with 70% COVID-19 VE against symptomatic infection; ~30% of neutralizing and 1 to 14% of binding antibody concentrations met or exceeded concentrations associated with 90% COVID-19 VE. Our study not only supports observations of infection-induced immunity and current recommendations for vaccination postinfection to maximize protection against COVID-19, but also provides a large data set of pre-COVID-19 vaccination anti-SARS-CoV-2 antibody concentrations that will serve as an important comparator in the current setting of vaccine-induced and hybrid immunity. As new SARS-CoV-2 variants emerge and displace circulating virus strains, we recommend that standardized binding antibody assays that include spike protein-based antigens be utilized to estimate antibody concentrations correlated with protection from COVID-19. These estimates will be helpful in informing public health guidance, such as the need for additional COVID-19 vaccine booster doses to prevent symptomatic infection. IMPORTANCE Although COVID-19 vaccine efficacy (VE) studies have estimated antibody concentrations that correlate with protection from COVID-19, how these estimates compare to those generated in response to SARS-CoV-2 infection is unclear. We assessed quantitative neutralizing and binding antibody concentrations using standardized assays on serum specimens collected from COVID-19-unvaccinated persons with detectable antibodies. We found that most unvaccinated persons with qualitative antibody evidence of prior infection had quantitative antibody concentrations that met or exceeded concentrations associated with 70% VE against COVID-19. However, only a small proportion had antibody concentrations that met or exceeded concentrations associated with 90% VE, suggesting that persons with prior COVID-19 would benefit from vaccination to maximize protective antibody concentrations against COVID-19.

Comparative Effectiveness and Antibody Responses to Moderna and Pfizer-BioNTech COVID-19 Vaccines among Hospitalized Veterans - Five Veterans Affairs Medical Centers, United States, February 1-September 30, 2021.

The mRNA COVID-19 vaccines (Moderna and Pfizer-BioNTech) provide strong protection against severe COVID-19, including hospitalization, for at least several months after receipt of the second dose (1,2). However, studies examining immune responses and differences in protection against COVID-19-associated hospitalization in real-world settings, including by vaccine product, are limited. To understand how vaccine effectiveness (VE) might change with time, CDC and collaborators assessed the comparative effectiveness of Moderna and Pfizer-BioNTech vaccines in preventing COVID-19-associated hospitalization at two periods (14-119 days and ≥120 days) after receipt of the second vaccine dose among 1,896 U.S. veterans at five Veterans Affairs medical centers (VAMCs) during February 1-September 30, 2021. Among 234 U.S. veterans fully vaccinated with an mRNA COVID-19 vaccine and without evidence of current or prior SARS-CoV-2 infection, serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2 were also compared. Adjusted VE 14-119 days following second Moderna vaccine dose was 89.6% (95% CI = 80.1%-94.5%) and after the second Pfizer-BioNTech dose was 86.0% (95% CI = 77.6%-91.3%); at ≥120 days VE was 86.1% (95% CI = 77.7%-91.3%) for Moderna and 75.1% (95% CI = 64.6%-82.4%) for Pfizer-BioNTech. Antibody levels were significantly higher among Moderna recipients than Pfizer-BioNTech recipients across all age groups and periods since vaccination; however, antibody levels among recipients of both products declined between 14-119 days and ≥120 days. These findings from a cohort of older, hospitalized veterans with high prevalences of underlying conditions suggest the importance of booster doses to help maintain long-term protection against severe COVID-19.†.

Adapting the Surveillance Platform for Enteric and Respiratory Infectious Organisms at United States Veterans Affairs Medical Centers (SUPERNOVA) for COVID-19 Among Hospitalized Adults: Surveillance Protocol.

Introduction: Early in the COVID-19 pandemic, the Centers for Disease Control and Prevention (CDC) rapidly initiated COVID-19 surveillance by leveraging existing hospital networks to assess disease burden among hospitalized inpatients and inform prevention efforts. Materials and Methods: The Surveillance Platform for Enteric and Respiratory Infectious Organisms at Veterans Affairs Medical Centers (SUPERNOVA) is a network of five United States Veterans Affairs Medical Centers which serves nearly 400,000 Veterans annually and conducts laboratory-based passive and active monitoring for pathogens associated with acute gastroenteritis and acute respiratory illness among hospitalized Veterans. This paper presents surveillance methods for adapting the SUPERNOVA surveillance platform to prospectively evaluate COVID-19 epidemiology during a public health emergency, including detecting, characterizing, and monitoring patients with and without COVID-19 beginning in March 2020. To allow for case-control analyses, patients with COVID-19 and patients with non-COVID-19 acute respiratory illness were included. Results: SUPERNOVA included 1,235 participants with COVID-19 and 707 participants with other acute respiratory illnesses hospitalized during February through December 2020. Most participants were male (93.1%), with a median age of 70 years, and 45.8% non-Hispanic Black and 32.6% non-Hispanic White. Among those with COVID-19, 28.2% were transferred to an intensive care unit, 9.4% received invasive mechanical ventilation, and 13.9% died. Compared with controls, after adjusting for age, sex, and race/ethnicity, COVID-19 case-patients had significantly higher risk of mortality, respiratory failure, and invasive mechanical ventilation, and longer hospital stays. Discussion: Strengths of the SUPERNOVA platform for COVID-19 surveillance include the ability to collect and integrate multiple types of data, including clinical and illness outcome information, and SARS-CoV-2 laboratory test results from respiratory and serum specimens. Analysis of data from this platform also enables formal comparisons of participants with and without COVID-19. Surveillance data collected during a public health emergency from this key U.S. population of Veterans will be useful for epidemiologic investigations of COVID-19 spectrum of disease, underlying medical conditions, virus variants, and vaccine effectiveness, according to public health priorities and needs.

Comparison of Estimated Severe Acute Respiratory Syndrome Coronavirus 2 Seroprevalence Through Commercial Laboratory Residual Sera Testing and a Community Survey.

We compared severe acute respiratory syndrome coronavirus 2 seroprevalence estimated from commercial laboratory residual sera and a community household survey in metropolitan Atlanta during April and May 2020 and found these 2 estimates to be similar (4.94% vs 3.18%). Compared with more representative surveys, commercial sera can provide an approximate measure of seroprevalence.

Effectiveness of COVID-19 mRNA Vaccines Against COVID-19-Associated Hospitalization - Five Veterans Affairs Medical Centers, United States, February 1-August 6, 2021.

COVID-19 mRNA vaccines (Pfizer-BioNTech and Moderna) have been shown to be highly protective against COVID-19-associated hospitalizations (1-3). Data are limited on the level of protection against hospitalization among disproportionately affected populations in the United States, particularly during periods in which the B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, predominates (2). U.S. veterans are older, more racially diverse, and have higher prevalences of underlying medical conditions than persons in the general U.S. population (2,4). CDC assessed the effectiveness of mRNA vaccines against COVID-19-associated hospitalization among 1,175 U.S. veterans aged ≥18 years hospitalized at five Veterans Affairs Medical Centers (VAMCs) during February 1-August 6, 2021. Among these hospitalized persons, 1,093 (93.0%) were men, the median age was 68 years, 574 (48.9%) were non-Hispanic Black (Black), 475 were non-Hispanic White (White), and 522 (44.4%) had a Charlson comorbidity index score of ≥3 (5). Overall adjusted vaccine effectiveness against COVID-19-associated hospitalization was 86.8% (95% confidence interval [CI] = 80.4%-91.1%) and was similar before (February 1-June 30) and during (July 1-August 6) SARS-CoV-2 Delta variant predominance (84.1% versus 89.3%, respectively). Vaccine effectiveness was 79.8% (95% CI = 67.7%-87.4%) among adults aged ≥65 years and 95.1% (95% CI = 89.1%-97.8%) among those aged 18-64 years. COVID-19 mRNA vaccines are highly effective in preventing COVID-19-associated hospitalization in this older, racially diverse population of predominately male U.S. veterans. Additional evaluations of vaccine effectiveness among various age groups are warranted. To prevent COVID-19-related hospitalizations, all eligible persons should receive COVID-19 vaccination.

Epidemiologic Findings from Case Investigations and Contact Tracing for First 200 Cases of Coronavirus Disease, Santa Clara County, California, USA.

In January 2020, Santa Clara County, California, USA, began identifying laboratory-confirmed coronavirus disease among residents. County staff conducted case and contact investigations focused on households and collected detailed case demographic, occupation, exposure, and outcome information. We describe the first 200 test-positive cases during January 31-March 20, 2020, to inform future case and contact investigations. Probable infection sources included community transmission (104 cases), known close contact with a confirmed case-patient (66 cases), and travel (30 cases). Disease patterns across race and ethnicity, occupational, and household factors suggested multiple infection risk factors. Disproportionately high percentages of case-patients from racial and ethnic subgroups worked outside the home (Hispanic [86%] and Filipino [100%]); household transmission was more common among persons from Vietnam (53%). Even with the few initial cases, detailed case and contact investigations of household contacts capturing occupational and disaggregated race and ethnicity data helped identify at-risk groups and focused solutions for disease control.

Demographic, clinical, and epidemiologic characteristics of persons under investigation for Coronavirus Disease 2019-United States, January 17-February 29, 2020.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), evolved rapidly in the United States. This report describes the demographic, clinical, and epidemiologic characteristics of 544 U.S. persons under investigation (PUI) for COVID-19 with complete SARS-CoV-2 testing in the beginning stages of the pandemic from January 17 through February 29, 2020. METHODS: In this surveillance cohort, the U.S. Centers for Disease Control and Prevention (CDC) provided consultation to public health and healthcare professionals to identify PUI for SARS-CoV-2 testing by quantitative real-time reverse-transcription PCR. Demographic, clinical, and epidemiologic characteristics of PUI were reported by public health and healthcare professionals during consultation with on-call CDC clinicians and subsequent submission of a CDC PUI Report Form. Characteristics of laboratory-negative and laboratory-positive persons were summarized as proportions for the period of January 17-February 29, and characteristics of all PUI were compared before and after February 12 using prevalence ratios. RESULTS: A total of 36 PUI tested positive for SARS-CoV-2 and were classified as confirmed cases. Confirmed cases and PUI testing negative for SARS-CoV-2 had similar demographic, clinical, and epidemiologic characteristics. Consistent with changes in PUI evaluation criteria, 88% (13/15) of confirmed cases detected before February 12, 2020, reported travel from China. After February 12, 57% (12/21) of confirmed cases reported no known travel- or contact-related exposures. CONCLUSIONS: These findings can inform preparedness for future pandemics, including capacity for rapid expansion of novel diagnostic tests to accommodate broad surveillance strategies to assess community transmission, including potential contributions from asymptomatic and presymptomatic infections.

Estimated SARS-CoV-2 Seroprevalence in the US as of September 2020.

Importance: Case-based surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely underestimates the true prevalence of infections. Large-scale seroprevalence surveys can better estimate infection across many geographic regions. Objective: To estimate the prevalence of persons with SARS-CoV-2 antibodies using residual sera from commercial laboratories across the US and assess changes over time. Design, Setting, and Participants: This repeated, cross-sectional study conducted across all 50 states, the District of Columbia, and Puerto Rico used a convenience sample of residual serum specimens provided by persons of all ages that were originally submitted for routine screening or clinical management from 2 private clinical commercial laboratories. Samples were obtained during 4 collection periods: July 27 to August 13, August 10 to August 27, August 24 to September 10, and September 7 to September 24, 2020. Exposures: Infection with SARS-CoV-2. Main Outcomes and Measures: The proportion of persons previously infected with SARS-CoV-2 as measured by the presence of antibodies to SARS-CoV-2 by 1 of 3 chemiluminescent immunoassays. Iterative poststratification was used to adjust seroprevalence estimates to the demographic profile and urbanicity of each jurisdiction. Seroprevalence was estimated by jurisdiction, sex, age group (0-17, 18-49, 50-64, and ≥65 years), and metropolitan/nonmetropolitan status. Results: Of 177 919 serum samples tested, 103 771 (58.3%) were from women, 26 716 (15.0%) from persons 17 years or younger, 47 513 (26.7%) from persons 65 years or older, and 26 290 (14.8%) from individuals living in nonmetropolitan areas. Jurisdiction-level seroprevalence over 4 collection periods ranged from less than 1% to 23%. In 42 of 49 jurisdictions with sufficient samples to estimate seroprevalence across all periods, fewer than 10% of people had detectable SARS-CoV-2 antibodies. Seroprevalence estimates varied between sexes, across age groups, and between metropolitan/nonmetropolitan areas. Changes from period 1 to 4 were less than 7 percentage points in all jurisdictions and varied across sites. Conclusions and Relevance: This cross-sectional study found that as of September 2020, most persons in the US did not have serologic evidence of previous SARS-CoV-2 infection, although prevalence varied widely by jurisdiction. Biweekly nationwide testing of commercial clinical laboratory sera can play an important role in helping track the spread of SARS-CoV-2 in the US.

Persons Evaluated for 2019 Novel Coronavirus - United States, January 2020.

In December 2019, a cluster of cases of pneumonia emerged in Wuhan City in central China's Hubei Province. Genetic sequencing of isolates obtained from patients with pneumonia identified a novel coronavirus (2019-nCoV) as the etiology (1). As of February 4, 2020, approximately 20,000 confirmed cases had been identified in China and an additional 159 confirmed cases in 23 other countries, including 11 in the United States (2,3). On January 17, CDC and the U.S. Department of Homeland Security's Customs and Border Protection began health screenings at U.S. airports to identify ill travelers returning from Wuhan City (4). CDC activated its Emergency Operations Center on January 21 and formalized a process for inquiries regarding persons suspected of having 2019-nCoV infection (2). As of January 31, 2020, CDC had responded to clinical inquiries from public health officials and health care providers to assist in evaluating approximately 650 persons thought to be at risk for 2019-nCoV infection. Guided by CDC criteria for the evaluation of persons under investigation (PUIs) (5), 210 symptomatic persons were tested for 2019-nCoV; among these persons, 148 (70%) had travel-related risk only, 42 (20%) had close contact with an ill laboratory-confirmed 2019-nCoV patient or PUI, and 18 (9%) had both travel- and contact-related risks. Eleven of these persons had laboratory-confirmed 2019-nCoV infection. Recognizing persons at risk for 2019-nCoV is critical to identifying cases and preventing further transmission. Health care providers should remain vigilant and adhere to recommended infection prevention and control practices when evaluating patients for possible 2019-nCoV infection (6). Providers should consult with their local and state health departments when assessing not only ill travelers from 2019-nCoV-affected countries but also ill persons who have been in close contact with patients with laboratory-confirmed 2019-nCoV infection in the United States.