Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. METHODS: Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). RESULTS: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. CONCLUSIONS: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. IMPACT AND IMPLICATIONS: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. CLINICAL TRIAL NUMBER: NCT03065699.

Characterizing patients with asthma who received Global Initiative for Asthma steps 4-5 therapy and managed in a specialty care setting.

BACKGROUND: Severe asthma is recognized in the European Respiratory Society/American Thoracic Society guidelines as a major unmet need in the management of asthma. OBJECTIVE: The study objective was to describe the clinical burden of Global Initiative for Asthma (GINA) steps 4-5 asthma for patients treated by specialists in the U.S. community setting. METHODS: Patients, ages ≥12 years, with asthma who received GINA step 4 or 5 treatment and were treated at a large U.S. allergy practice network between January 1, 2010, and April 30, 2016, were retrospectively identified by using electronic health records. Clinical outcomes included lung function (forced expiratory volume in one second of expiration [FEV1] and FEV1% predicted), symptom control (Asthma Control Test [ACT]), the fractional exhaled nitric oxide (FeNO) value (FeNO ≥25 ppb indicates airway inflammation), and asthma medication use. The change in outcomes from baseline to 12 and 24 months after the index date was calculated. RESULTS: Of 120,116 patients with asthma, 12,922 (10.8%) had severe asthma, 68% (n = 8751) while on step 4 therapy. The mean baseline prebronchodilation FEV1% predicted was 79.7%, and the mean baseline ACT score was 17.0. With uncontrolled asthma defined as an ACT score of ≤19 and/or an FEV1 value of <80% predicted and/or oral corticosteroid use of ≥2 bursts, 52.5% and 57.7% of patients on step 4 and step 5 therapy, respectively, had uncontrolled asthma at baseline. Of a subset of patients, 40.9% had an eosinophil count of ≥300 cells/mm3 and 44% had an FeNO concentration of ≥25 ppb. Small increases in the FEV1 value were observed from baseline to 12 months (n = 4022) and 24 months (n = 2326) postindex (0.07 and 0.04 L, respectively). CONCLUSION: A considerable proportion of patients had uncontrolled asthma while on current GINA steps 4-5 treatment, which indicated that additional therapies may be required to reduce the clinical burden of severe asthma.

Relative importance of PSA in prostate cancer treatment.

METHODS AND MATERIALS: A retrospective study was conducted to (1) determine the relationship between baseline prostate-specific antigen (PSA) levels and initial treatment decisions for prostate cancer (surgery, hormone therapy, radiation, or watchful waiting) and (2) estimate the impact of PSA progression (doubling or three consecutive rises) on subsequent treatment decisions. Patient records (n=1116) from three community urology practices and a large academic health system were reviewed. Multivariate models were fitted to assess the relationship between initial treatment and baseline PSA, Gleason score, race, number of comorbid conditions and age and between PSA progression and time to subsequent therapy (adjusted for other factors). RESULTS: Baseline PSA was a significant predictor of initial treatment among men with localized disease with the likelihood of hormone therapy increasing with higher PSA levels and the likelihood of surgery decreasing steadily with higher PSA levels. PSA was the strongest predictor of hormone therapy as first choice followed by age. Age followed by PSA was the strongest predictor of surgery as first treatment as well as radiation therapy. Initial PSA levels did not predict the choice of watchful waiting. Patients with PSA progression were eight times (95% CI: 5.3-12.1) more likely to initiate a subsequent therapy than patients who did not have PSA progression when controlling for other predictors. CONCLUSIONS: In clinical practice, PSA significantly impacts the urologist's primary therapy choice and determines when they introduce subsequent treatments.

Prevalence and clinical correlates of HIV viremia ('blips') in patients with previous suppression below the limits of quantification.

OBJECTIVE: To examine the prevalence and clinical correlates of subsequently measurable viremia in HIV-infected patients who have achieved viral suppression below the limits of quantification (< 50 copies/ml). DESIGN: Non-randomized dynamic cohort study of ambulatory HIV patients in nine HIV clinics in eight cities. PATIENTS: Patients had two consecutive HIV-1 RNA levels < 50 copies/ml (minimum, 2 months apart) that were followed by at least two more viral level determinations while remaining on the same antiretroviral therapy (ART) between January 1997 and June 2000 (median 485 days). Transiently viremic patients were defined having a subsequently measurable viremia but again achieved suppression < 50 copies/ml. RESULTS: Of the 448 patients, 122 (27.2%) had transient viremia, 19 (4.2%) had lasting low-level viremia and 33 (7.4%) had lasting high-level viremia (defined as 50-400 and > 400 copies/ml, respectively). Only 16 (13.1%) of those who had transient viremia later had persistent viremia > 50 copies/ml. The occurrence of transient viremia did not vary with whether the patient was ART-naive or experienced (P = 0.31), or currently taking protease inhibitors or not (P = 0.08). On consistent ART, the median percentage increase in CD4 cell count was statistically different between subgroups of our cohort (Kruskal-Wallis, P = 0.002). CONCLUSIONS: Transiently detectable viremia, usually 50-400 copies/ml, was frequent among patients who had two consecutive HIV-1 RNA levels below the limits of quantification. In this analysis, such viremia did not appear to affect the risk of developing lasting viremia. Caution is warranted before considering a regimen as 'failing' and changing medications.

Influence of coinfection with hepatitis C virus on morbidity and mortality due to human immunodeficiency virus infection in the era of highly active antiretroviral therapy.

To ascertain the impact of hepatitis C virus (HCV) infection on human immunodeficiency virus (HIV) disease progression and associated death in the era of highly active antiretroviral therapy (HAART), we examined mortality rates, the presence of other diseases, and antiretroviral use in an observational cohort of 823 HIV-infected patients with and without HCV coinfection during the period of January 1996 through June 2001. Analyses were used to compare patient characteristics, comorbid conditions, and survival durations in HIV-infected and HIV-HCV-coinfected patients. HIV-HCV-coinfected persons did not have a statistically greater rate of acquired immunodeficiency syndrome or of renal or cardiovascular disease, but they did have more cases of cirrhosis and transaminase elevations. There were proportionately more deaths in the HIV-HCV-coinfected group. Age, baseline CD4+ cell count, and duration of HAART were significantly associated with survival, but HCV infection was not. HAART use was a strong predictor of increased duration of survival, suggesting that treatment is more important to survival than is HCV coinfection status.

A multicenter description of intermediate-care patients: comparison with ICU low-risk monitor patients.

STUDY OBJECTIVES: To describe the characteristics and outcomes of patients admitted to intermediate-care areas (ICAs) and to compare them with those of ICU patients who receive monitoring only on day 1 and are at a low risk (i.e., < 10%) for receiving subsequent active life-supporting therapy (i.e., low-risk monitor patients). DESIGN: Nonrandomized, retrospective, cohort study. SETTING: Thirteen US teaching hospitals and 19 nonteaching hospitals. PATIENTS: A consecutive sample of 8,971 patients at 37 ICAs and 5,116 low-risk (i.e., < 10%) monitor patients at 59 ICUs in 32 US hospitals. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We recorded demographic and clinical characteristics, resource use, and outcomes for the ICA and ICU low-risk monitor patients. Patient data and outcomes for this study were collected concurrently or retrospectively. ICA and ICU low-risk monitor patients were similar in regard to gender, race, and frequency of comorbitities, but ICA patients were significantly (p < 0.001) older, had fewer physiologic abnormalities (mean acute physiology score, 16.7 vs 19.8, respectively), and were more frequently admitted due to nonoperative diagnoses. The mean length of stay for ICA patients was significantly longer (3.9 days) than for ICU low-risk monitor patients (2.6 days; p < 0.001). The hospital mortality rate was significantly higher for ICA patients (3.1%) compared to ICU low-risk monitor patients (2.3%; p = 0.002). CONCLUSIONS: The clinical features of ICA patients are similar, but not identical to, those of less severely ill ICU monitor patients. Comparisons of hospital death rates and lengths of stay for these patients should be adjusted for characteristics that previously have been shown to influence these outcomes.

The use of benchmarking to identify top performing critical care units: a preliminary assessment of their policies and practices.

PURPOSE: To describe the policies and practices of intensive care units (ICUs) with good patient survival and highly efficient resource use and to identify relevant variables for future investigation. MATERIALS AND METHODS: We used clinical data for 359,715 patients from 108 ICUs to compare the ratios of actual with Acute Physiology and Chronic Health Evaluation (APACHE) III predicted hospital mortality, ICU and hospital stay, and the proportion of low-risk monitor patients. The best performing ICUs (top 10%) were defined by a mortality ratio of 1.0 or less, and either the lowest ratio for ICU stay, hospital stay, or percentage of low-risk monitor patients. The medical and nursing directors of top performing ICUs completed a questionnaire to describe their unit's structure policies and practices. RESULTS: Among the 108 ICUs, 61 (56%) had a ratio of actual to predicted hospital mortality of 1.0 or less and the best performing units had ICU stay ratios of 0.62 to 0.79, hospital stay ratios of 0.73 to 0.77, and admitted 10% to 38% low-risk monitor patients. ICU structure varied among the best performing ICUs. Units with the shortest ICU and hospital stay had alternatives to intensive care, methods to facilitate patient throughput, used multiple protocols for high-volume diagnoses and care processes, and continuously monitored resource use. Units with the fewest low-risk monitor patients screened potential admissions, had intermediate care areas, extended-stay recovery rooms, and care pathways for high-volume diagnoses. CONCLUSIONS: Benchmarking can be used to identify ICUs with good patient survival and highly efficient resource use. The combination of policies and practices used by these units might improve resource use in other ICUs.