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1.
Curr Transplant Rep ; : 1-10, 2022 Nov 12.
Article in English | MEDLINE | ID: covidwho-2122246

ABSTRACT

Purpose of Review: Certain immunocompromised individuals are at risk for protracted COVID-19, in which SARS-CoV-2 leads to a chronic viral infection. However, the pathogenesis, diagnosis, and management of this phenomenon remain ill-defined. Recent Findings: Herein, we review key aspects of protracted SARS-CoV-2 infection in immunocompromised individuals, or the so-called long persisters, and describe the clinical presentation, risk factors, diagnosis, and treatment modalities of this condition, as well as intra-host viral evolution. Based on the available data, we also propose a framework of criteria with which to approach this syndrome. Summary: Protracted COVID-19 is an uncharacterized syndrome affecting patients with B-cell depletion; our proposed diagnostic approach and definitions will inform much needed future research.

3.
Annu Rev Med ; 2022 Jul 18.
Article in English | MEDLINE | ID: covidwho-1950319

ABSTRACT

The COVID-19 pandemic has been accompanied by SARS-CoV-2 evolution and emergence of viral variants that have far exceeded initial expectations. Five major variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) have emerged, each having both unique and overlapping amino acid substitutions that have affected transmissibility, disease severity, and susceptibility to natural or vaccine-induced immune responses and monoclonal antibodies. Several of the more recent variants appear to have evolved properties of immune evasion, particularly in cases of prolonged infection. Tracking of existing variants and surveillance for new variants are critical for an effective pandemic response. Expected final online publication date for the Annual Review of Medicine, Volume 74 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

4.
JAMA Netw Open ; 5(7): e2220957, 2022 07 01.
Article in English | MEDLINE | ID: covidwho-1929711

ABSTRACT

Importance: The effectiveness of monoclonal antibodies (mAbs), casirivimab-imdevimab and sotrovimab, is unknown in patients with mild to moderate COVID-19 caused by the SARS-CoV-2 Delta variant. Objective: To evaluate the effectiveness of mAb against the Delta variant compared with no mAb treatment and to ascertain the comparative effectiveness of casirivimab-imdevimab and sotrovimab. Design, Setting, and Participants: This study comprised 2 parallel studies: (1) a propensity score-matched cohort study of mAb treatment vs no mAb treatment and (2) a randomized comparative effectiveness trial of casirivimab-imdevimab and sotrovimab. The cohort consisted of patients who received mAb treatment at the University of Pittsburgh Medical Center outpatient infusion centers and emergency departments from July 14 to September 29, 2021. Participants were patients with a positive SARS-CoV-2 test result who were eligible to receive mAbs according to emergency use authorization criteria. Exposure: For the trial, patients were randomized to either intravenous casirivimab-imdevimab or sotrovimab according to a system therapeutic interchange policy. Main Outcomes and Measures: For the cohort study, risk ratio (RR) estimates for the primary outcome of hospitalization or death by 28 days were compared between mAb treatment and no mAb treatment using propensity score-matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospitalization) within 28 days after mAb treatment, where patients who died were assigned -1 day in a bayesian cumulative logistic model adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio (OR) less than 1. Equivalence was defined as a 95% posterior probability that the OR was within a given bound. Results: A total of 3069 patients (1023 received mAb treatment: mean [SD] age, 53.2 [16.4] years; 569 women [56%]; 2046 had no mAb treatment: mean [SD] age, 52.8 [19.5] years; 1157 women [57%]) were included in the prospective cohort study, and 3558 patients (mean [SD] age, 54 [18] years; 1919 women [54%]) were included in the randomized comparative effectiveness trial. In propensity score-matched models, mAb treatment was associated with reduced risk of hospitalization or death (RR, 0.40; 95% CI, 0.28-0.57) compared with no treatment. Both casirivimab-imdevimab (RR, 0.31; 95% CI, 0.20-0.50) and sotrovimab (RR, 0.60; 95% CI, 0.37-1.00) were associated with reduced hospitalization or death compared with no mAb treatment. In the clinical trial, 2454 patients were randomized to receive casirivimab-imdevimab and 1104 patients were randomized to receive sotrovimab. The median (IQR) hospital-free days were 28 (28-28) for both mAb treatments, the 28-day mortality rate was less than 1% (n = 12) for casirivimab-imdevimab and less than 1% (n = 7) for sotrovimab, and the hospitalization rate by day 28 was 12% (n = 291) for casirivimab-imdevimab and 13% (n = 140) for sotrovimab. Compared with patients who received casirivimab-imdevimab, those who received sotrovimab had a median adjusted OR for hospital-free days of 0.88 (95% credible interval, 0.70-1.11). This OR yielded 86% probability of inferiority for sotrovimab vs casirivimab-imdevimab and 79% probability of equivalence. Conclusions and Relevance: In this propensity score-matched cohort study and randomized comparative effectiveness trial, the effectiveness of casirivimab-imdevimab and sotrovimab against the Delta variant was similar, although the prespecified criteria for statistical inferiority or equivalence were not met. Both mAb treatments were associated with a reduced risk of hospitalization or death in nonhospitalized patients with mild to moderate COVID-19 caused by the Delta variant. Trial Registration: ClinicalTrials.gov Identifier: NCT04790786.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Bayes Theorem , COVID-19/drug therapy , Cohort Studies , Female , Humans , Middle Aged , Prospective Studies
5.
Contemp Clin Trials ; 119: 106822, 2022 08.
Article in English | MEDLINE | ID: covidwho-1885667

ABSTRACT

BACKGROUND: Monoclonal antibodies (mAb) that neutralize SARS-CoV-2 decrease hospitalization and death compared to placebo in patients with mild to moderate COVID-19; however, comparative effectiveness is unknown. We report the comparative effectiveness of bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab. METHODS: A learning health system platform trial in a U.S. health system enrolled patients meeting mAb Emergency Use Authorization criteria. An electronic health record-embedded application linked local mAb inventory to patient encounters and provided random mAb allocation. Primary outcome was hospital-free days to day 28. Primary analysis was a Bayesian model adjusting for treatment location, age, sex, and time. Inferiority was defined as 99% posterior probability of an odds ratio < 1. Equivalence was defined as 95% posterior probability the odds ratio is within a given bound. FINDINGS: Between March 10 and June 25, 2021, 1935 patients received treatment. Median hospital-free days were 28 (IQR 28, 28) for each mAb. Mortality was 0.8% (1/128), 0.8% (7/885), and 0.7% (6/922) for bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. Relative to casirivimab-imdevimab (n = 922), median adjusted odds ratios were 0.58 (95% credible interval [CI] 0.30-1.16) and 0.94 (95% CI 0.72-1.24) for bamlanivimab (n = 128) and bamlanivimab-etesevimab (n = 885), respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab. INTERPRETATION: Among patients with mild to moderate COVID-19, bamlanivimab-etesevimab or casirivimab-imdevimab treatment resulted in 86% probability of equivalence. No treatment met prespecified criteria for statistical equivalence. Median hospital-free days to day 28 were 28 (IQR 28, 28) for each mAb. FUNDING AND REGISTRATION: This work received no external funding. The U.S. government provided the reported mAb. This trial is registered at ClinicalTrials.gov, NCT04790786.


Subject(s)
COVID-19 , Learning Health System , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Bayes Theorem , Humans , SARS-CoV-2
6.
Clin Infect Dis ; 75(1): e630-e644, 2022 08 24.
Article in English | MEDLINE | ID: covidwho-1886372

ABSTRACT

BACKGROUND: We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency. METHODS: Prospective study of fully vaccinated immunocompromised adults (solid organ transplant [SOT], hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus [HIV]) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity. RESULTS: A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r = 0.89, P < .0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW. CONCLUSIONS: Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency.


Subject(s)
COVID-19 , HIV Infections , Adult , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , HIV Infections/complications , Humans , Immunocompromised Host , Prospective Studies , SARS-CoV-2 , Vaccination
7.
Clin Infect Dis ; 74(9): 1525-1533, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-1831036

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA) is detected in the bloodstream of some patients with coronavirus disease 2019 (COVID-19), but it is not clear whether this RNAemia reflects viremia (ie, virus particles) and how it relates to host immune responses and outcomes. METHODS: SARS-CoV-2 vRNA was quantified in plasma samples from observational cohorts of 51 COVID-19 patients including 9 outpatients, 19 hospitalized (non-intensive care unit [ICU]), and 23 ICU patients. vRNA levels were compared with cross-sectional indices of COVID-19 severity and prospective clinical outcomes. We used multiple imaging methods to visualize virions in plasma. RESULTS: SARS-CoV-2 vRNA was detected in plasma of 100%, 52.6%, and 11.1% of ICU, non-ICU, and outpatients, respectively. Virions were detected in plasma pellets using electron tomography and immunostaining. Plasma vRNA levels were significantly higher in ICU > non-ICU > outpatients (P < .0001); for inpatients, plasma vRNA levels were strongly associated with higher World Health Organization (WHO) score at admission (P = .01), maximum WHO score (P = .002), and discharge disposition (P = .004). A plasma vRNA level >6000 copies/mL was strongly associated with mortality (hazard ratio, 10.7). Levels of vRNA were significantly associated with several inflammatory biomarkers (P < .01) but not with plasma neutralizing antibody titers (P = .8). CONCLUSIONS: Visualization of virus particles in plasma indicates that SARS-CoV-2 RNAemia is due, at least in part, to viremia. The levels of SARS-CoV-2 RNAemia correlate strongly with disease severity, patient outcome, and specific inflammatory biomarkers but not with neutralizing antibody titers.


Subject(s)
COVID-19 , Antibodies, Neutralizing , Biomarkers , COVID-19/diagnosis , Cross-Sectional Studies , Humans , Prospective Studies , RNA, Viral , SARS-CoV-2 , Viremia
9.
Open forum infectious diseases ; 8(Suppl 1):S539-S539, 2021.
Article in English | EuropePMC | ID: covidwho-1565056

ABSTRACT

Background We sought to characterize the impact of the COVID-19 pandemic on HIV-related outcomes in a cohort of patients by examining rates of viral load (VL) suppression, retention-in-care, PrEP access, and STIs. Methods This was a single center, retrospective study of adults receiving HIV treatment or HIV/STI prevention services from 01/2019 - 12/2020. HIV outpatient visits were identified through HRSA’s CareWARE. Visits (in-person, telehealth) only included HIV primary care. HRSA core performance measures were utilized (Table 1). STI positivity rates and descriptive characteristics were calculated. New and refill PrEP prescriptions were tabulated. Chi-square tests compared unmatched non-parametric variables;McNemar’s test matched non-parametric variables. Multivariable logistic regression identified variables associated with retention in care and viral suppression. Results 1721 patients received care;1234 were seen in both years, 334 only in 2019, 153 only in 2020. The number of telehealth visits increased significantly: video (0% to 31%, < 0.001), phone (0% to 0.4%, p < 0.001). Though the proportion of kept appointments increased (57.2% vs 61.2%), the annual retention in care rate decreased from 74.5% to 70.9% (p = 0.002). Overall, 9.7% of patients had detectable VLs at any point. Compared to 2019, a lower proportion of patients maintained VL suppression in 2020, (91.6% vs 83.5% p = 0.075). More patients did not have a VL drawn in 2020 than in 2019 (10.3% vs 2.0 %, p < 0.001). Patients with detectable VLs in 2019 were more likely than those who were undetectable to have detectable VLs in 2020 (OR 18.2, 95% CI 9.91-33.42). Black race was associated with higher likelihood of lack of VL suppression (OR = 2.0;95% CI 1.10-3.66). There were no significant differences between gender or age groups in rates of viral suppression, number screened for bacterial STIs or positive results. Visits for new and refill PrEP prescriptions decreased by 59% and 7%, respectively. Conclusion Rates of viral load suppression and retention in care decreased in 2020 compared to 2019. The proportion of clinic visits attended increased after the integration of telemedicine in 2020. These data may be used to inform evidence-based interventions to improve the HIV continuum of care through telehealth. Disclosures Ghady Haidar, MD, Karuys (Grant/Research Support)

11.
Contemp Clin Trials ; 113: 106652, 2022 02.
Article in English | MEDLINE | ID: covidwho-1560571

ABSTRACT

Outpatient treatments that limit progression to severe coronavirus disease 2019 (COVID-19) are of vital importance to optimise patient outcomes and public health. Monoclonal antibodies (mAb) demonstrated ability to decrease hospitalizations in randomized, clinical trials. However, there are many barriers to mAb treatment such as patient access and clinician education. There are no data comparing efficacy or safety of available mAbs. We sought to rapidly launch an adaptive platform trial with the goals of enhancing access to treatment, regardless of geography and socioeconomic status, and evaluating comparative efficacy and safety of available mAbs. Within 21 days from idea genesis, we allocated mAb treatment to all patients within the context of this clinical trial. Within 2 months, we closed the gap of the likelihood of receiving mAb, conditional on background positivity rate, between Black and White patients (Black patients 0.238; White patients 0.241). We describe trial infrastructure, lessons learned, and future directions for a culture of learning while doing.


Subject(s)
Antineoplastic Agents, Immunological , COVID-19 , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Humans , SARS-CoV-2
12.
Clin Infect Dis ; 73(6): e1397-e1401, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1412539

ABSTRACT

Recent case studies have highlighted the fact that certain immunocompromised individuals are at risk for prolonged SARS-CoV-2 replication, intrahost viral evolution of multiply-mutated variants, and poor clinical outcomes. The immunologic determinants of this risk, the duration of infectiousness, and optimal treatment and prevention strategies in immunocompromised hosts are ill defined. Of additional concern is the widespread use of immunosuppressive medications to treat COVID-19, which may enhance and prolong viral replication in the context of immunodeficiency. We outline the rationale for 4 interrelated approaches to usher in an era of evidence-based medicine for optimal management of immunocompromised patients with COVID-19: multicenter pathogenesis and outcomes studies to relate the risk of severe disease to the type and degree of immunodeficiency, studies to evaluate immunologic responses to SARS-CoV-2 vaccines, studies to evaluate the efficacy of monoclonal antibodies for primary prophylaxis, and clinical trials of novel antiviral agents for the treatment of COVID-19.


Subject(s)
COVID-19 , Antiviral Agents/therapeutic use , COVID-19 Vaccines , Humans , Immunocompromised Host , SARS-CoV-2
13.
J Clin Virol Plus ; 1(3): 100026, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1385874

ABSTRACT

Background: Children infected with SARS-CoV-2 are often asymptomatic or have only mild symptoms, leading to underestimation of disease prevalence in symptom-based testing strategies. Objectives: This study sought to determine pediatric SARS-CoV-2 disease burden during local mitigation efforts by using antibody testing to compare seroprevalence estimates to cumulative PCR prevalence estimates. Study design: In this cross-sectional study, we collected 1142 strict phase and 1196 relaxed phase remnant blood specimens from patients less than 19-years-old in southwestern Pennsylvania (SWPA). Patients were excluded if their residential zip code was outside the region of interest, if they were under 6-months-old, or they had recently received antibody-modifying treatments. Demographic, encounter, and laboratory electronic medical record information was extracted. Samples were tested for SARS-CoV-2 spike protein IgG using an EUA ELISA, and PCR results were recorded from county health department data. Seroprevalence and Clopper-Pearson exact 95% confidence intervals were calculated. Results: The observed seroprevalence of SARS-CoV-2 spike protein antibodies in children during strictest mitigation was 0.53% (95% CI 0.19, 1.14) and 0.92% (95% CI 0.46,1.64) during moderately relaxed. Strict and relaxed phase PCR-based prevalence were significantly higher, 2.87% (95% CI 1.95, 4.08) and 3.64 (95% CI 3.01, 4.38), respectively. Conclusions: Estimates of pediatric seroprevalence were significantly lower than cumulative PCR prevalence estimates, and less than adult seroprevalence estimates, potentially due to biological, population, or sampling differences. Biological differences in pediatric immune responses to SARS-CoV-2 may make serosurvey interpretation challenging and these differences warrant further study.

14.
Clin Infect Dis ; 73(3): e815-e821, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1338685

ABSTRACT

A chimeric antigen receptor-modified T-cell therapy recipient developed severe coronavirus disease 2019, intractable RNAemia, and viral replication lasting >2 months. Premortem endotracheal aspirate contained >2 × 1010 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA copies/mL and infectious virus. Deep sequencing revealed multiple sequence variants consistent with intrahost virus evolution. SARS-CoV-2 humoral and cell-mediated immunity were minimal. Prolonged transmission from immunosuppressed patients is possible.


Subject(s)
COVID-19 , Receptors, Chimeric Antigen , Cell- and Tissue-Based Therapy , Humans , SARS-CoV-2 , Virus Replication
15.
Open Forum Infect Dis ; 8(7): ofab353, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1337282

ABSTRACT

We measured severe acute respiratory syndrome coronavirus 2 immunoglobulin G responses in 67 patients with hematological malignancies after 2 messenger RNA vaccine doses. Forty-six percent were nonresponders; patients with B-cell chronic lymphocytic leukemia were at highest risk (77% nonresponders). Patients with hematological malignancies should continue wearing masks and socially distancing. Studies of revaccination, boosters, and humoral immune correlates of protection are needed.

16.
Open Forum Infect Dis ; 8(7): ofab254, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1305436

ABSTRACT

BACKGROUND: Monoclonal antibody treatment may prevent complications of coronavirus disease 2019 (COVID-19). We sought to quantify the impact of bamlanivimab monoclonal antibody monotherapy on hospitalization and mortality among outpatients at high risk of COVID-19 complications. METHODS: In this observational study we compared outpatients who received bamlanivimab monoclonal antibody from December 9, 2020 to March 3, 2021 to nontreated patients with a positive polymerase chain reaction or antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the same period who were eligible for monoclonal antibody treatment. The primary outcome was 28-day hospitalization or all-cause mortality, and the secondary outcome was hospitalization or emergency department visit without hospitalization. The risk-adjusted odds of study outcomes comparing bamlanivimab treated and untreated patients was determined using 1:5 propensity matching and multivariable logistic regression. RESULTS: Among 232 patients receiving bamlanivimab matched with 1160 comparator patients, the mean age was 67 years, 56% were female, and 196 (14%) of patients experienced hospitalization or mortality. After adjustment for propensity to receive treatment, bamlanivimab treatment was associated with a significantly reduced risk-adjusted odds of hospitalization or mortality within 28 days (odds ratio [OR], 0.40; 95% confidence interval [95% CI], 0.24-0.69; P < .001). Bamlanivimab treatment was also associated with a significantly lower risk adjusted odds of hospitalization or emergency department visit without hospitalization (OR, 0.54; 95% CI, 0.35-0.82; P = .004). The results were most strongly associated with patients age 65 years and older. CONCLUSIONS: Bamlanivimab monoclonal antibody monotherapy was associated with reduced hospitalizations and mortality within 28 days among outpatients with mild to moderate COVID-19.Use of bamlanivimab monotherapy for outpatients with mild to moderate COVID-19 infection was associated with reductions in hospitalizations and mortality within 28 days. Benefit was strongest in those age 65 years or older.

17.
Trials ; 22(1): 363, 2021 May 25.
Article in English | MEDLINE | ID: covidwho-1243818

ABSTRACT

OBJECTIVES: The primary objective is to evaluate the comparative effectiveness of COVID-19 specific monoclonal antibodies (mABs) with US Food and Drug Administration (FDA) Emergency Use Authorization (EUA), alongside UPMC Health System efforts to increase patient access to these mABs. TRIAL DESIGN: Open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization PARTICIPANTS: We will evaluate patients who meet the eligibility criteria stipulated by the COVID-19 mAB EUAs who receive mABs within the UPMC Health System, including infusion centers and emergency departments. EUA eligibility criteria include patients with mild to moderate COVID-19, <10 days of symptoms, and who are at high risk for progressing to severe COVID-19 and/or hospitalization (elderly, obese, and/or with specific comorbidities). The EUA criteria exclude patients who require oxygen for the treatment of COVID-19 and patients already hospitalized for the treatment of COVID-19. We will use data collected for routine clinical care, including data entered into the electronic medical record and from follow-up calls. INTERVENTION AND COMPARATOR: The interventions are the COVID-19 specific mABs authorized by the EUAs. All aspects of mAB treatment, including eligibility criteria, dosing, and post-infusion monitoring, are as per the EUAs. As a comparative effectiveness trial, all patients receive mAB treatment, and the interventions are compared against each other. When U.S. government mAB policies change (e.g., FDA grants or revokes EUAs), UPMC Health System policies and the evaluated mAB interventions will accordingly change. From November 2020 to February 2021, FDA issued EUAs for three mAB treatments (bamlanivimab; bamlanivimab and etesevimab; and casirivimab and imdevimab), and at trial launch on March 10, 2021 we evaluated all three. Due to a sustained increase in SARS-CoV-2 variants in the United States resistant to bamlanivimab administered alone, on March 24, 2021 the U.S. Government halted distribution of bamlanivimab alone, and UPMC accordingly halted bamlanivimab monotherapy on March 31, 2021. On April 16, 2021, FDA revoked the EUA for bamlanivimab monotherapy. At the time of manuscript submission, we are therefore evaluating the two mAB treatments authorized by EUAs (bamlanivimab and etesevimab; and casirivimab and imdevimab). MAIN OUTCOMES: The primary outcome is total hospital free days (HFD) at 28 days after mAB administration, calculated as 28 minus the number of days during the index stay (if applicable - e.g., for patients admitted to hospital after mAB administration in the emergency department) minus the number of days readmitted during the 28 days after treatment. This composite endpoint captures the number of days from the day of mAB administration to the 28 days thereafter, during which the patient is alive and free of hospitalization. Death within 28 days is recorded as -1 HFD, as the worst outcome. RANDOMISATION: We will start with equal allocation. Due to uncertainty in sample size, we will use a Bayesian adaptive design and response adaptive randomization to ensure ability to provide statistical inference despite variable sample size. When mABs are ordered by UPMC physicians as a generic referral order, the order is filled by UPMC pharmacy via therapeutic interchange. OPTIMISE-C19 provides the therapeutic interchange via random allocation. Infusion center operations teams and pharmacists use a mAB assignment application embedded in the electronic medical record to determine the random allocation. BLINDING (MASKING): This trial is open-label. However, outcome assessors conducting follow-up calls at day 28 are blinded to mAB assignment, and investigators are blinded to by-mAB aggregate outcome data until a statistical platform trial conclusion is reached. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Sample size will be determined by case volume throughout the course of the pandemic, supply of FDA authorized mABs, and by that needed to reach a platform trial conclusion of inferiority, superiority, or futility of a given mAB. The trial will continue as long as more than one mAB type is available under EUA, and their comparative effectiveness is uncertain. TRIAL STATUS: Protocol Version 1.0, February 24, 2021. Recruitment began March 10, 2021 and is ongoing at the time of manuscript submission. The estimated recruitment end date is February 22, 2022, though the final end date is dependent on how the pandemic evolves, mAB availability, and when final platform trial conclusions are reached. As noted above, due to U.S. Government decisions, UPMC Health System halted bamlanivimab monotherapy on March 31, 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04790786 . Registered March 10, 2021 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
COVID-19 , Aged , Antibodies, Monoclonal/adverse effects , Bayes Theorem , Humans , Random Allocation , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
18.
Open Forum Infect Dis ; 8(2): ofab022, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1091225

ABSTRACT

BACKGROUND: We implemented a preprocedural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening initiative designed to sustain health care during a time when the extent of SARS-CoV-2 infection was unknown. METHODS: This was a prospective study of patients undergoing procedures at 3 academic hospitals in Pittsburgh, Pennsylvania (April 21-June 11), and 19 community hospitals across Middle/Western Pennsylvania and Southwestern New York (May 1-June 11). Patients at academic hospitals underwent symptom screening ≤7 days preprocedure, then SARS-CoV-2 nasopharyngeal polymerase chain reaction (PCR) testing 1-4 days preprocedure. A subset also underwent day-of-procedure testing. Community hospital patients underwent testing per local protocols. We report SARS-CoV-2 PCR positivity rates, impact, and barriers to testing encountered through June 11. PCR positivity rates of optional preprocedural SARS-CoV-2 testing for 2 consecutive periods following the screening initiative are also reported. RESULTS: Of 5881 eligible academic hospital patients, 2415 (41.1%) were tested (April 21-June 11). Lack of interest, distance, self-isolation, and nursing home/incarceration status were barriers. There were 11 PCR-positive patients (10 asymptomatic) among 10 539 patients tested (0.10%; 95% CI, 0.05%-0.19%): 3/2415 (0.12%; 95% CI, 0.02%-0.36%) and 8/8124 (0.10%; 95% CI, 0.04%-0.19%) at academic and community hospitals, respectively. Procedures were performed as scheduled in 40% (4/10) of asymptomatic PCR-positive patients. Positivity increased during subsequent coronavirus disease 2019 (COVID-19) surges: 54/34 948 (0.15%; 95% CI, 0.12%-0.20%) and 101/24 741 (0.41%; 95% CI, 0.33%-0.50%) PCR-positive patients from June 12-September 10 and September 11-December 15, respectively (P < .0001). CONCLUSIONS: Implementing preprocedural PCR testing was complex and revealed low infection rates (0.24% overall), which increased during COVID-19 surges. Additional studies are needed to define the COVID-19 prevalence threshold at which universal preprocedural screening is warranted.

19.
Science ; 371(6534): 1139-1142, 2021 03 12.
Article in English | MEDLINE | ID: covidwho-1063045

ABSTRACT

Zoonotic pandemics, such as that caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can follow the spillover of animal viruses into highly susceptible human populations. The descendants of these viruses have adapted to the human host and evolved to evade immune pressure. Coronaviruses acquire substitutions more slowly than other RNA viruses. In the spike glycoprotein, we found that recurrent deletions overcome this slow substitution rate. Deletion variants arise in diverse genetic and geographic backgrounds, transmit efficiently, and are present in novel lineages, including those of current global concern. They frequently occupy recurrent deletion regions (RDRs), which map to defined antibody epitopes. Deletions in RDRs confer resistance to neutralizing antibodies. By altering stretches of amino acids, deletions appear to accelerate SARS-CoV-2 antigenic evolution and may, more generally, drive adaptive evolution.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antigens, Viral/genetics , COVID-19/virology , Immune Evasion , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Sequence , Amino Acid Substitution , Antigens, Viral/chemistry , Evolution, Molecular , Genetic Drift , Humans , Protein Conformation , Sequence Deletion , Spike Glycoprotein, Coronavirus/chemistry
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