Showing papers by "James D. Neaton published in 2016"

A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection.

Abstract: BACKGROUND Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD) METHODS Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerase-chain-reaction (PCR) assay Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day) Patients were stratified according to baseline PCR cycle-threshold value for the virus (≤22 vs >22) and country of enrollment Oral favipiravir was part of the current standard of care in Guinea The primary end point was mortality at 28 days RESULTS A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30% Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 912%, falling short of the prespecified threshold of 975% Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, -15 percentage points; 95% confidence interval, -36 to 7) Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups CONCLUSIONS In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy (Funded by the National Institute of Allergy and Infectious Diseases and others; PREVAIL II ClinicalTrialsgov number, NCT02363322 )

Relevance of Interleukin-6 and D-Dimer for Serious Non-AIDS Morbidity and Death among HIV-Positive Adults on Suppressive Antiretroviral Therapy.

Abstract: Author(s): Grund, Birgit; Baker, Jason V; Deeks, Steven G; Wolfson, Julian; Wentworth, Deborah; Cozzi-Lepri, Alessandro; Cohen, Calvin J; Phillips, Andrew; Lundgren, Jens D; Neaton, James D; INSIGHT SMART/ESPRIT/SILCAAT Study Group | Abstract: BackgroundDespite effective antiretroviral treatment (ART), HIV-positive individuals are at increased risk of serious non-AIDS conditions (cardiovascular, liver and renal disease, and cancers), perhaps due in part to ongoing inflammation and/or coagulation. To estimate the potential risk reduction in serious non-AIDS conditions or death from any cause that might be achieved with treatments that reduce inflammation and/or coagulation, we examined associations of interleukin-6 (IL-6), D-dimer, and high-sensitivity C-reactive protein (hsCRP) levels with serious non-AIDS conditions or death in 3 large cohorts.MethodsIn HIV-positive adults on suppressive ART, associations of IL-6, D-dimer, and hsCRP levels at study entry with serious non-AIDS conditions or death were studied using Cox regression. Hazard ratios (HR) adjusted for age, gender, study, and regression dilution bias (due to within-person biomarker variability) were used to predict risk reductions in serious non-AIDS conditions or death associated with lower "usual" levels of IL-6 and D-dimer.ResultsOver 4.9 years of mean follow-up, 260 of the 3766 participants experienced serious non-AIDS conditions or death. IL-6, D-dimer and hsCRP were each individually associated with risk of serious non-AIDS conditions or death, HR = 1.45 (95% CI: 1.30 to 1.63), 1.28 (95% CI: 1.14 to 1.44), and 1.17 (95% CI: 1.09 to 1.26) per 2x higher biomarker levels, respectively. In joint models, IL-6 and D-dimer were independently associated with serious non-AIDS conditions or death, with consistent results across the 3 cohorts and across serious non-AIDS event types. The association of IL-6 and D-dimer with serious non-AIDS conditions or death was graded and persisted throughout follow-up. For 25% lower "usual" IL-6 and D-dimer levels, the joint biomarker model estimates a 37% reduction (95% CI: 28 to 46%) in the risk of serious non-AIDS conditions or death if the relationship is causal.ConclusionsBoth IL-6 and D-dimer are independently associated with serious non-AIDS conditions or death among HIV-positive adults with suppressed virus. This suggests that treatments that reduce IL-6 and D-dimer levels might substantially decrease morbidity and mortality in patients on suppressive ART. Clinical trials are needed to test this hypothesis.

Interleukin 6 Is a Stronger Predictor of Clinical Events Than High-Sensitivity C-Reactive Protein or D-Dimer During HIV Infection

Abstract: BACKGROUND: Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer levels are linked to adverse outcomes in human immunodeficiency virus (HIV) infection, but the strength of their associations with different clinical end points warrants investigation. METHODS: Participants receiving standard of care in 2 HIV trials with measured biomarker levels were followed to ascertain all-cause death, non–AIDS-related death, AIDS, cardiovascular disease (CVD), and non–AIDS-defining malignancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) of each end point for quartiles and log2-transformed IL-6, hsCRP, and D-dimer levels were calculated using Cox models. Marginal models modelling multiple events tested for equal effects of biomarker levels on different end points. RESULTS: Among 4304 participants, there were 157 all-cause deaths, 117 non–AIDS-related deaths, 101 AIDS cases, 121 CVD cases, and 99 non–AIDS-defining malignancies. IL-6 was more strongly associated with most end points, compared with hsCRP. IL-6 appeared to be a stronger predictor than D-dimer for CVD and non–AIDS-defining malignancies, but 95% CIs overlapped. Independent associations of IL-6 were stronger for non–AIDS-related death (HR, 1.71; 95% CI, 1.43–2.04) and all-cause death (HR, 1.56; 95% CI, 1.33–1.84) and similar for CVD (HR, 1.35; 95% CI, 1.12–1.62) and non–AIDS-defining malignancies (HR, 1.30; 95% CI, 1.06–1.61). There was heterogeneity of IL-6 (P < .001) but not hsCRP (P = .15) or D-dimer (P = .20) as a predictor for different end points. CONCLUSIONS: IL-6 is a stronger predictor of fatal events than of CVD and non–AIDS-defining malignancies. Adjuvant antiinflammatory and antithrombotic therapies should be tested in HIV-infected individuals.

Implementation of an Ebola virus disease vaccine clinical trial during the Ebola epidemic in Liberia: Design, procedures, and challenges

Abstract: The index case of the Ebola virus disease epidemic in West Africa is believed to have originated in Guinea. By June 2014, Guinea, Liberia, and Sierra Leone were in the midst of a full-blown and complex global health emergency. The devastating effects of this Ebola epidemic in West Africa put the global health response in acute focus for urgent international interventions. Accordingly, in October 2014, a World Health Organization high-level meeting endorsed the concept of a phase 2/3 clinical trial in Liberia to study Ebola vaccines. As a follow-up to the global response, in November 2014, the Government of Liberia and the US Government signed an agreement to form a research partnership to investigate Ebola and to assess intervention strategies for treating, controlling, and preventing the disease in Liberia. This agreement led to the establishment of the Joint Liberia–US Partnership for Research on Ebola Virus in Liberia as the beginning of a long-term collaborative partnership in clinical research betwee...

Design of a Randomized Controlled Trial for Ebola Virus Disease Medical Countermeasures: PREVAIL II, the Ebola MCM Study

Abstract: Background Unique challenges posed by emerging infectious diseases often expose inadequacies in the conventional phased investigational therapeutic development paradigm. The recent Ebola outbreak in West Africa presents a critical case-study highlighting barriers to faster development. During the outbreak, clinical trials were implemented with unprecedented speed. Yet, in most cases, this fast-tracked approach proved too slow for the rapidly evolving epidemic. Controversy abounded as to the most appropriate study designs to yield safety and efficacy data, potentially causing delays in pivotal studies. Preparation for research during future outbreaks may require acceptance of a paradigm that circumvents, accelerates, or reorders traditional phases, without losing sight of the traditional benchmarks by which drug candidates must be assessed for activity, safety and efficacy. Methods We present the design of an adaptive, parent protocol, ongoing in West Africa until January 2016. The exigent circumstances of the outbreak and limited prior clinical experience with experimental treatments, led to more direct bridging from preclinical studies to human trials than the conventional paradigm would typically have sanctioned, and required considerable design flexibility. Results Preliminary evaluation of the "barely Bayesian" design was provided through computer simulation studies. The understanding and public discussion of the study design will help its future implementation.

INSIGHT FLU005: An Anti–Influenza Virus Hyperimmune Intravenous Immunoglobulin Pilot Study

Abstract: UNLABELLED Hemagglutination inhibition (HAI) antibody responses to anti-influenza virus hyperimmune intravenous immunoglobulin (hIVIG) were characterized. Thirty-one patients with influenza during the 2013-2014 season were randomly assigned to receive 0.25 g/kg of hIVIG (n = 16) or placebo (n = 15). For hIVIG recipients, the ratio of geometric mean titers (1 hour after infusion/before infusion) was 4.00 (95% confidence interval [CI], 2.61-6.13) for 2009 pandemic influenza A(H1N1) and 1.76 (95% CI, 1.33-2.32) for influenza A(H3N2) and influenza B. Among patients with 2009 pandemic influenza A(H1N1), ratios for hIVIG (n = 9) versus placebo (n = 8) were higher 1 hour after infusion (3.9 [95% CI, 2.3-6.7]) and sustained through day 3 (2.0 [95% CI, 1.0-4.0]). hIVIG administration significantly increases HAI titer levels among patients with influenza, supporting the need to perform a clinical outcomes study. CLINICAL TRIALS REGISTRATION NCT02008578.

The per-protocol effect of immediate versus deferred antiretroviral therapy initiation.

Abstract: Objective The Strategic Timing of AntiRetroviral Treatment (START) trial found a lower risk of a composite clinical outcome in HIV-positive individuals assigned to immediate initiation of antiretroviral therapy (ART) compared with those assigned to deferred initiation However, 30% of those assigned to deferred initiation started ART earlier than the protocol specified To supplement the published intention-to-treat (ITT) effect estimates, here we estimate the per-protocol effect of immediate versus deferred ART initiation in START Design The START trial randomized 4685 HIV-positive participants with CD4 cell counts more than 500 cells/μl to start ART immediately after randomization (immediate initiation group) or to wait until the CD4 cell count dropped below 350 cells/μl or an AIDS diagnosis (deferred initiation group) Methods We used the parametric g-formula to estimate and compare the cumulative 5-year risk of the composite clinical outcome in the immediate initiation group, and deferred initiation groups had all the trial participants adhered to the protocol Results We estimated that the 5-year risk of the composite outcome would have been 32% under immediate ART initiation and 70% under deferred initiation The difference of 38% (95% confidence interval 15, 65) was larger than the ITT effect estimate of 31%, corresponding to a difference in effect estimates of 072% (-035, 235) Conclusion The ITT effect estimate may underestimate the benefit of immediate ART initiation by 23% This estimate can be used by patients and policy-makers who need to understand the full extent of the benefit of changes in ART initiation policies

Letter by Kuller and Neaton Regarding Article, "Association of Race With Mortality and Cardiovascular Events in a Large Cohort of US Veterans".

Abstract: Kovesdy et al1 conclude that among veterans receiving health care through the US Veterans Health Administration, event rates among blacks compared with whites are lower or similar for all-cause mortality, coronary heart disease incidence, and stroke. Their Table 2 shows a slightly higher age-adjusted all-cause rate for black compared with white men, a higher incidence of coronary heart disease among white compared with black men, a much higher rate of stroke in black compared with white men, and similar rates of acute myocardial infarction. We previously reported that for the 300 647 white and 20 223 black men screened for the Multiple Risk …