Bezlotoxumab for prevention of recurrent Clostridium difficile infection in patients at increased risk for recurrence

Background: Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B indicated to prevent C. difficile infection (CDI) recurrence (rCDI) in adults at high risk for rCDI. This post hoc analysis of pooled monocolonal antibodies for C.difficile therapy (MODIFY) I/II data assessed bezlotoxumab efficacy in participants with characteristics associated with increased risk for rCDI. Methods: The analysis population was the modified intent-to-treat population who received bezlotoxumab or placebo (n = 1554) by risk factors for rCDI that were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion of participants with rCDI in 12 weeks, fecal microbiota transplant procedures, 30-day all cause and CDI-associated hospital readmissions, and mortality at 30 and 90 days after randomization were presented. Results: The majority of enrolled participants (75.6%) had ≥1 risk factor; these participants were older and a higher proportion had comorbidities compared with participants with no risk factors. The proportion of placebo participants who experienced rCDI exceeded 30% for each risk factor compared with 20.9% among those without a risk factor, and the rCDI rate increased with the number of risk factors (1 risk factor: 31.3%; ≥3 risk factors: 46.1%). Bezlotoxumab reduced rCDI, fecal microbiota transplants, and CDI-associated 30-day readmissions in participants with risk factors for rCDI. Conclusions: The risk factors prespecified in the MODIFY statistical analysis plan are appropriate to identify patients at high risk for rCDI. While participants with ≥3 risk factors had the greatest reduction of rCDI with bezlotoxumab, those with 1 or 2 risk factors may also benefit. Clinical Trials Registration: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II)

Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency

Patients who have common variable immunodeficiency (CVID) and granulomatous/lymphocytic interstitial lung disease (GLILD) are at high risk for early mortality and B cell lymphomas. Infection with human herpes virus type 8 (HHV8), a B cell lymphotrophic virus, is linked to lymphoproliferative disorders in people who have secondary immunodeficiencies. Therefore, we determined the prevalence of HHV8 infection in CVID patients with GLILD. Genomic DNA isolated from peripheral blood mononuclear cells was screened by nested- and real time-quantitative PCR (QRT-PCR) for the presence of HHV8 genome. It was positive in 6/9 CVID patients with GLILD (CVID-GLILD), 1/21 CVID patients without GLILD (CVID-control), and no patients receiving intravenous gamma globulin (n = 13) or normal blood donors (n = 20). Immunohistochemistry (IHC) demonstrated expression of the latency-associated nuclear antigen-1 (LANA-1) in the biopsies of the lung, liver, and bone marrow of four patients with CVID-GLILD. One CVID-GLILD patient developed a B cell lymphoma during the course of the study. QRT-PCR demonstrated high copy number of HHV8 genome and IHC showed diffuse staining for LANA-1 in the malignant lymph node. HHV8 infection may be an important factor in the pathogenesis of the interstitial lung disease and lymphoproliferative disorders in patients with CVID

Part C Early Intervention for Infants and Toddlers: Percentage Eligible Versus Served

OBJECTIVE: Part C early intervention is a nationwide program that serves infants and toddlers who have developmental delays. Previous research has revealed that large numbers of candidates for Part C services do not receive early intervention. Current eligibility criteria for Part C services vary from state to state. This article compares estimates of the percentage of children who are likely to be eligible for early intervention in each state and Washington, DC, with the proportion of children who are served in each of those jurisdictions. METHODS: Data for this study were obtained from the Early Childhood Longitudinal Survey–Birth Cohort. Using these data, we computed the proportion of children who would be eligible based on the numerical eligibility definitions currently in use across the United States. RESULTS: This study revealed the proportion of infants and toddlers likely to be eligible for Part C services ranges from 2% to 78% across the United States. The proportion of children enrolled in Part C ranges from 1.48% to 6.96%. CONCLUSIONS: This research documented substantial variability in the proportion of children who are likely to be eligible for Part C services. Most states have adopted eligibility definitions that make many more children candidates for Part C early intervention than they serve. However, current rates of enrollment are insufficient to serve all children with delays that fall under 2 SDs below the mean on any of the 5 developmental domains that are required to be evaluated by Part C regulations. </jats:sec

Macrophages Kill Human Papillomavirus Type 16 E6-Expressing Tumor Cells by Tumor Necrosis Factor Alpha- and Nitric Oxide-Dependent Mechanisms

The expression of adenovirus serotype 2 or 5 (Ad2/5) E1A sensitizes cells to killing by NK cells and activated macrophages, a property that correlates with the ability of E1A to bind the transcriptional coadaptor proteins p300-CBP. The E6 oncoproteins derived from the high-risk human papillomaviruses (HPV) interact with p300 and can complement mutant forms of E1A that cannot interact with p300 to induce cellular immortalization. Therefore, we determined if HPV type 16 (HPV16) E6 could sensitize cells to killing by macrophages and NK cells. HPV16 E6 expression sensitized human (H4 and C33A) and murine (MCA-102) cell lines to lysis by macrophages but not by NK cells. The lysis of cells that expressed E6 by macrophages was p53 independent but dependent on the production of tumor necrosis factor alpha (TNF-α) or nitric oxide (NO) by macrophages. Unlike cytolysis assays with macrophages, E6 expression did not significantly sensitize cells to lysis by the direct addition of NO or TNF-α. Like E1A, E6 has been reported to sensitize cells to lysis by TNF-α by inhibiting the TNF-α-induced activation of NF-κB. We found that E1A, but not E6, blocked the TNF-α-induced activation of NF-κB, an activity that correlated with E1A-p300 binding. In summary, Ad5 E1A and HPV16 E6 sensitized cells to lysis by macrophages. Unlike E1A, E6 did not block the ability of TNF-α to activate NF-κB or sensitize cells to lysis by NK cells, TNF-α, or NO. Thus, there appears to be a spectrum of common and unique biological activities that result as a consequence of the interaction of E6 or E1A with p300-CBP

1232-P: Predictors of ß-Cell Function Changes: Pooled Analysis from Phase 3 Ertugliflozin Studies

Improving glycemic control generally improves β-cell function in T2DM but the predictors for this effect are unclear. SGLT2 inhibitors improve glycemia and have no known direct effects on β-cell function. Therefore, we aimed to identify predictors of β-cell function changes by treatment with the SGLT2 inhibitor ertugliflozin (ERTU). Data of patients (pts) randomized to ERTU (5 or 15 mg) only or placebo (PBO) only from four phase 3 ERTU studies of the VERTIS clinical program were pooled and analyzed. Change from baseline in β-cell function (fasting homeostatic model assessment beta [HOMA-β] and C-peptide Insulinogenic Index [IGI] at 30 min of a mixed meal tolerance test) at Week 26 was assessed, followed by linear regression analyses to examine the relationship between change in β-cell function versus metabolic and demographic characteristics. ERTU compared with PBO improved β-cell function when assessed by the changes from baseline (95% CIs) in HOMA-β (14.7 [12.3,17.1] versus −0.4 [−3.4, 2.5]) but not IGI. Change in HOMA-β correlated negatively and similarly with change in A1C in both groups (ERTU: r=−0.29; PBO: r=−0.36, both P&amp;lt;0.001). In the ERTU group, change in HOMA-β correlated positively with baseline fasting plasma glucose (FPG; r=0.23, P&amp;lt;0.001) and baseline A1C (r=0.14, P&amp;lt;0.001) but negatively with baseline HOMA-β (r=−0.32, P&amp;lt;0.001) in simple linear regression analyses; no significant correlations were found with age, sex, ethnicity, diabetes duration, baseline serum triglycerides, creatinine, weight or systolic blood pressure. Correlations between change in HOMA-β and baseline FPG, A1C and HOMA-β remained significant in multiple regression analyses. ERTU improves fasting HOMA-β but not the postprandial IGI in pts with T2DM. Pts with high baseline FPG and A1C values but low baseline HOMA-β may derive greater benefit than those with low baseline FPG, A1C and high HOMA-β with ertugliflozin treatment in terms of fasting HOMA-β. Disclosure S. Gallo: Employee; Self; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. A. Raji: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. R.A. Calle: Employee; Self; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. M.C. Ellison: Employee; Self; Merck &amp; Co., Inc. C. Meyer: Employee; Self; Merck &amp; Co., Inc. Funding Merck Sharp &amp; Dohme Corp; Pfizer Inc. </jats:sec