Showing papers by "James D. Neaton published in 2022"

The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19

Abstract: In a large cross-sectional study done in 114 centers in 10 countries, the authors assessed whether there was an association of an elevated SARS-CoV-2 plasma antigen level at presentation with a variety of patient characteristics, clinical outcomes, and viral factors.

RAGE has potential pathogenetic and prognostic value in nonintubated hospitalized patients with COVID-19

Abstract: Background The value of the soluble receptor for advanced glycation end-products (sRAGE) as a biomarker in COVID-19 is not well understood. We tested the association between plasma sRAGE and illness severity, viral burden, and clinical outcomes in hospitalized patients with COVID-19 who were not mechanically ventilated. Methods Baseline sRAGE was measured among participants enrolled in the ACTIV-3/TICO trial of bamlanivimab for hospitalized patients with COVID-19. Spearman’s rank correlation was used to assess the relationship between sRAGE and other plasma biomarkers, including viral nucleocapsid antigen. Fine-Gray models adjusted for baseline supplemental oxygen requirement, antigen level, positive endogenous anti-nucleocapsid antibody response, sex, age, BMI, diabetes mellitus, renal impairment, corticosteroid treatment, and log2-transformed IL-6 level were used to assess the association between baseline sRAGE and time to sustained recovery. Cox regression adjusted for the same factors was used to assess the association between sRAGE and mortality. Results Among 277 participants, baseline sRAGE was strongly correlated with viral plasma antigen concentration (ρ = 0.57). There was a weaker correlation between sRAGE and biomarkers of systemic inflammation, such as IL-6 (ρ = 0.36) and CRP (ρ = 0.20). Participants with plasma sRAGE in the highest quartile had a significantly lower rate of sustained recovery (adjusted recovery rate ratio, 0.64 [95% CI, 0.43–0.90]) and a higher unadjusted risk of death (HR, 4.70 [95% CI, 2.01–10.99]) compared with participants in the lower quartiles. Conclusion Elevated plasma sRAGE in hospitalized, nonventilated patients with COVID-19 was an indicator of both clinical illness severity and plasma viral load. Plasma sRAGE in the highest quartile was associated with a lower likelihood of sustained recovery and higher unadjusted risk of death. These findings, which we believe to be novel, indicate that plasma sRAGE may be a promising biomarker for COVID-19 prognostication and clinical trial enrichment. Trial Registration ClinicalTrials.gov NCT04501978. Funding NIH (5T32GM008440-24, 18X107CF6, HHSN261201500003I, R35HL140026, and OT2HL156812).

What drives willingness to receive a new vaccine that prevents an emerging infectious disease? A discrete choice experiment among university students in Uganda

Abstract: Background There is a critical need to identify the drivers of willingness to receive new vaccines against emerging and epidemic diseases. A discrete choice experiment is the ideal approach to evaluating how individuals weigh multiple attributes simultaneously. We assessed the degree to which six attributes were associated with willingness to be vaccinated among university students in Uganda. Methods We conducted a single-profile discrete choice experiment at Makerere University in 2019. Participants were asked whether or not they would be vaccinated in 8 unique scenarios where attributes varied by disease risk, disease severity, advice for or against vaccination from trusted individuals, recommendations from influential figures, whether the vaccine induced indirect protection, and side effects. We calculated predicted probabilities of vaccination willingness using mixed logistic regression models, comparing health professional students with all other disciplines. Findings Of the 1576 participants, 783 (49.8%) were health professional students and 685 (43.5%) were female. Vaccination willingness was high (78%), and higher among health students than other students. We observed the highest vaccination willingness for the most severe disease outcomes and the greatest exposure risks, along with the Minister of Health’s recommendation or a vaccine that extended secondary protection to others. Mild side effects and recommendations against vaccination diminished vaccination willingness. Interpretation Our results can be used to develop evidence-based messaging to encourage uptake for new vaccines. Future vaccination campaigns, such as for COVID-19 vaccines in development, should consider acknowledging individual risk of exposure and disease severity and incorporate recommendations from key health leaders.

Evaluating Primary Endpoints for COVID-19 Therapeutic Trials to Assess Recovery

Abstract: Rationale Uncertainty regarding the natural history of coronavirus disease (COVID-19) led to difficulty in efficacy endpoint selection for therapeutic trials. Capturing outcomes that occur after hospital discharge may improve assessment of clinical recovery among hospitalized patients with COVID-19. Objectives Evaluate 90-day clinical course of patients hospitalized with COVID-19, comparing three distinct definitions of recovery. Methods We used pooled data from three clinical trials of neutralizing monoclonal antibodies to compare: 1) the hospital discharge approach; 2) the TICO (Therapeutics for Inpatients with COVID-19) trials sustained recovery approach; and 3) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-ICU setting without organ failure or major extrapulmonary manifestations of COVID-19. We defined discordance as a difference between time to recovery. Measurements and Main Results Discordance between the hospital discharge and comprehensive approaches occurred in 170 (20%) of 850 enrolled participants, including 126 hospital readmissions and 24 deaths after initial hospital discharge. Discordant participants were older (median age, 68 vs. 59 years; P < 0.001) and more had a comorbidity (84% vs. 70%; P < 0.001). Of 170 discordant participants, 106 (62%) had postdischarge events captured by the TICO approach. Conclusions Among patients hospitalized with COVID-19, 20% had clinically significant postdischarge events within 90 days after randomization in patients who would be considered “recovered” using the hospital discharge approach. Using the TICO approach balances length of follow-up with practical limitations. However, clinical trials of COVID-19 therapeutics should use follow-up times up to 90 days to assess clinical recovery more accurately.

Randomized Trial of Vaccines for Zaire Ebola Virus Disease.

Abstract: BACKGROUND Questions remain concerning the rapidity of immune responses and the durability and safety of vaccines used to prevent Zaire Ebola virus disease. METHODS We conducted two randomized, placebo-controlled trials - one involving adults and one involving children - to evaluate the safety and immune responses of three vaccine regimens against Zaire Ebola virus disease: Ad26.ZEBOV followed by MVA-BN-Filo 56 days later (the Ad26-MVA group), rVSVΔG-ZEBOV-GP followed by placebo 56 days later (the rVSV group), and rVSVΔG-ZEBOV-GP followed by rVSVΔG-ZEBOV-GP 56 days later (the rVSV-booster group). The primary end point was antibody response at 12 months, defined as having both a 12-month antibody concentration of at least 200 enzyme-linked immunosorbent assay units (EU) per milliliter and an increase from baseline in the antibody concentration by at least a factor of 4. RESULTS A total of 1400 adults and 1401 children underwent randomization. Among both adults and children, the incidence of injection-site reactions and symptoms (e.g., feverishness and headache) was higher in the week after receipt of the primary and second or booster vaccinations than after receipt of placebo but not at later time points. These events were largely low-grade. At month 12, a total of 41% of adults (titer, 401 EU per milliliter) and 78% of children (titer, 828 EU per milliliter) had a response in the Ad26-MVA group; 76% (titer, 992 EU per milliliter) and 87% (titer, 1415 EU per milliliter), respectively, had a response in the rVSV group; 81% (titer, 1037 EU per milliliter) and 93% (titer, 1745 EU per milliliter), respectively, had a response in the rVSV-booster group; and 3% (titer, 93 EU per milliliter) and 4% (titer, 67 EU per milliliter), respectively, had a response in the placebo group (P<0.001 for all comparisons of vaccine with placebo). In both adults and children, antibody responses with vaccine differed from those with placebo beginning on day 14. CONCLUSIONS No safety concerns were identified in this trial. With all three vaccine regimens, immune responses were seen from day 14 through month 12. (Funded by the National Institutes of Health and others; PREVAC ClinicalTrials.gov number, NCT02876328; EudraCT numbers, 2017-001798-18 and 2017-001798-18/3rd; and Pan African Clinical Trials Registry number, PACTR201712002760250.).

Cytomegalovirus viremia and risk of disease progression and death in HIV-positive patients starting antiretroviral therapy

Abstract: Objective: The aim of this study was to assess the prevalence of cytomegalovirus (CMV) viremia in HIV-positive patients starting antiretroviral therapy (ART) and to evaluate its impact on clinical outcomes. Design: A retrospective analysis of four clinical trials (INSIGHT FIRST, SMART, START, and ANRS REFLATE TB). Methods: Stored plasma samples from participants were used to measure CMV viremia at baseline prior to initiating ART and at visits through 1 year of follow-up after ART initiation. CMV viremia was measured centrally using a quantitative PCR assay. Within FIRST, associations of CMV viremia at baseline and through 8 months of ART were examined with a composite clinical outcome of AIDS, serious non-AIDS events, or death using Cox proportional hazards regression. Results: Samples from a total of 3176 participants, 1169 from FIRST, 137 from ANRS REFLATE TB, 54 from SMART, and 1816 from START were available with baseline CMV viremia prevalence of 17, 26, 0, and 1%, respectively. Pooled across trials, baseline CMV viremia was associated with low CD4+ T-cell counts and high HIV RNA levels. In FIRST, CMV viremia was detected in only 5% of participants between baseline and month 8. After adjustment for CD4+ T-cell count and HIV RNA levels, hazard ratios for risk of clinical outcomes was 1.15 (0.86–1.54) and 2.58 (1.68–3.98) in FIRST participants with baseline and follow-up CMV viremia, respectively. Conclusion: Baseline CMV viremia in HIV-positive patients starting ART is associated with advanced infection and only persistent CMV viremia after ART initiation is associated with a higher risk of morbidity and mortality.

Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19

Abstract: Novel therapies for SARS-CoV-2 infection have been a focus of research and enquiry, and many promising compounds tested in phase 1 and 2 trials have emerged. In this multinational clinical trial, one such compound—a designed ankyrin repeat protein, ensovibep—was compared with standard of care to determine whether it improved outcomes among patients hospitalized with COVID-19. After randomly assigning 485 patients, the trial was stopped for early futility because the odds of a more favorable pulmonary outcome were no different in those randomized to treatment versus control. This study highlights that effective antiviral therapies for patients hospitalized with COVID-19 remain an unmet need. Even though this trial was negative, important lessons regarding how to conduct such trials and test promising compounds can be gleaned from this study.

LB2305. Long Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection: Findings from the Extended Follow-up of the START Trial

Abstract: Abstract Background Deferral of antiretroviral therapy (ART) initiation until CD4 count < 350 cells/μL in people with CD4 > 500 increases risk of AIDS and serious non-AIDS (SNA) conditions. Evidence from randomized trials is lacking to assess the extent to which ongoing excess risk due to having deferred initiation is reduced once ART is initiated and viral load suppressed. Methods START randomized 4684 ART-naïve HIV+ adults with CD4 > 500 cells/μL to start ART immediately (IMM, n=2325) or defer ART until CD4 < 350 cells/μL or AIDS developed (DEF, n= 2359). In 2015 the study demonstrated a 57% reduction in the risk of the primary endpoint (AIDS, SNA or death) for IMM ART; all assigned to DEF were recommended to start ART. Follow up continued to 31Dec2021. To determine whether the benefit of IMM compared to DEF was maintained, increased, or reduced, Cox models were used to estimate and compare hazard ratios (HR, IMM:DEF), for the primary endpoint and its components from randomization through 31Dec2015 (Pre 2016) with the period 1Jan2016 through 31Dec2021 (Post 2016). HRs for all follow-up, randomization through 31Dec2021, were also estimated. Results Pre 2016, median CD4 was 648 cells/μL in IMM and 460 cells/μL in DEF at ART initiation, a difference of 188 cells/μL (95% CI: 180-197); at the end of 2015, 98.9% of IMM and 84.8% of DEF were prescribed ART. The percentage of follow-up time spent on ART pre 2016 was 94.5% for IMM and 35.5% for DEF; and the average difference in CD4 count was 199 cells/μL. This contrasts with post 2016 during which the percentage of follow-up time on ART was 99.5% for IMM and 95.6% for DEF; and the average difference in CD4 was 155 cells/mL (Figure 1). During both time periods, initiation of ART led to rapid declines in HIV RNA to ≤ 200 copies/mL. For the primary endpoint and each component, the benefit of IMM compared to DEF in Post 2016 was reduced compared to Pre 2016 (Figure 2). Overall follow-up, from randomization to 2021 (median 9.3 years), the HR for the primary endpoint was 0.61 (95%CI: 0.49, 0.76; p< 0.001).Figure 1: ART Use, HIV RNA ≤ 200 cp/mL, and CD4 Cell Count, Pre 2016 and Post 2016Figure 2: Hazard Ratios Comparing Event Rates Within Treatment Groups, by Time Period Conclusion Among people with CD4 > 500, the excess risk of AIDS and SNA conditions associated with delaying ART initiation is substantially diminished soon after ART is initiated, but persistent excess risk remains. The results reinforce the importance of early diagnosis of HIV and prompt initiation of ART. Disclosures Gail Matthews, MBChB, PhD, Abbvie Inc: Grant/Research Support|Astra Zeneca: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support.

A Safety Monitoring Framework for Critical Care Trials of Agents with Potential to Lower Blood Pressure

Abstract: RATIONALE: Based on encouraging preliminary data, we undertook a randomized, placebo-controlled trial of synthetic vasoactive intestinal peptide (aviptadil) for treatment of COVID-19 acute respiratory distress syndrome (ARDS). Aviptadil may cause vasodilation and resultant hypotension. Given the high background incidence of hypotension from many causes (e.g., sedatives, sepsis, positive pressure ventilation) in critically ill patients, an ascertainment and grading strategy for postrandomization hypotension capable of distinguishing “signal” from “noise” is essential to the trial's conduct and interpretation. METHODS: We evaluated whether existing adverse event (AE) severity frameworks were adequate to characterize hypotension occurring in critically ill patients. Based on these findings, we developed and implemented a customized framework for hypotension-related safety monitoring and outcome collection during the Therapeutics for Severely Ill Inpatients with COVID-19 (TESICO) trial of aviptadil for COVID-19 ARDS (NCT04843761). RESULTS: Hypotension severity assigned to COVID-19 ARDS patients by existing AE frameworks - largely developed for outpatients - appeared misaligned with the frameworks' own generic/conceptual severity criteria. Existing frameworks' hypotension-specific AE grading tables lacked necessary detail and reporting guidance, over-graded mild hypotension, and missed safety signals suggested by increasing vasopressor requirements. We therefore developed a novel hypotension AE grading table aligned with conceptual AE severity criteria for critically ill patients (Figure). In addition to general severity criteria, the table adds criteria specific to the investigational agent's peri-infusion period and provides guidance for evaluating the “seriousness” of a hypotensive event in the context of subjects' preexisting critical illness. In combination with detailed reporting on the components of AE events, the study's protocol committee, sponsor, and data safety monitoring board approved the customized table for use in outcome measurement as well as real-time safety monitoring and AE reporting. We implemented a strategy to efficiently collect the hypotension-related data required for safety monitoring and allow automated hypotension AE grading according to both the adopted schema and existing AE frameworks. CONCLUSIONS: We developed a framework acceptable to diverse stakeholders for hypotension safety monitoring in COVID-19 ARDS patients receiving aviptadil or placebo. The monitoring framework will be validated in the ongoing TESICO trial and could be adapted for other trials of vasoactive investigational agents targeting critically ill patients. Comprehensive AE grading criteria designed specifically for critically ill patients could improve trials' ability to meaningfully monitor and report safety outcomes in this population.