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BACKGROUND: Viral load (VL) surrogate endpoints transformed development of HIV and hepatitis C therapeutics. Surrogate endpoints for CMV-related morbidity and mortality could advance development of antiviral treatments. Although observational data support using CMV VL as a trial endpoint, randomized controlled trials (RCTs) demonstrating direct associations between virological markers and clinical endpoints are lacking. METHODS: We performed CMV DNA PCR on frozen serum samples from the only placebo-controlled RCT of ganciclovir for early treatment of CMV after hematopoietic cell transplantation (HCT). We used established criteria to assess VL kinetics as surrogates for CMV disease or death by weeks 8, 24, and 48 after randomization and quantified antiviral effects captured by each marker. We used ensemble-based machine learning to assess the predictive ability of VL kinetics and performed this analysis on a ganciclovir prophylaxis RCT for validation. RESULTS: VL suppression with ganciclovir reduced cumulative incidence of CMV disease and death for 20 years after HCT. Mean VL, peak VL, and change in VL during the first 5 weeks of treatment fulfilled the Prentice definition for surrogacy, capturing more than 95% of ganciclovir’s effect, and yielded highly sensitive and specific predictions by week 48. In the prophylaxis trial, the viral shedding rate satisfied the Prentice definition for CMV disease by week 24. CONCLUSIONS: Our results support using CMV VL kinetics as surrogates for CMV disease, provide a framework for developing CMV preventative and therapeutic agents, and support reductions in VL as the mechanism through which antivirals reduce CMV disease. FUNDING: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Introduction The paradigm for preventing clinically significant cytomegalovirus (CMV) infection and CMV disease after hematopoietic cell transplantation (HCT) has shifted from preemptive treatment to antiviral prophylaxis with the approval of letermovir. Previously, our group validated the use of quantitative CMV DNA viral load as a surrogate endpoint for tissue-invasive CMV disease (ASBMT 2018) in the pre-emptive treatment setting. Objectives To address whether CMV viral load kinetics could serve as valid surrogate endpoints for CMV disease in the prophylactic setting, we performed CMV viral load testing of frozen serum samples collected during a placebo-controlled randomized trial of ganciclovir (GCV) given at engraftment (Goodrich et al. Ann Intern Med 1993). Because this study pre-dated the approval of ganciclovir, CMV disease occurred in an extremely high proportion of patients, allowing us to link viral load kinetics with CMV disease, which would not be possible in the modern treatment environment. Methods We calculated each patient's CMV viral load kinetics (mean, peak, maximum change, percentage of positive viral loads) from samples collected during the first five weeks after randomization and analyzed their value as surrogates for CMV disease by 24 weeks after randomization. First, we tested each marker for fulfillment of the Prentice criteria for valid surrogate endpoints using multivariable logistic regression, including quantifying the degree to which each marker captured the effect of ganciclovir on CMV disease. Secondly, to determine the ability of the viral load markers to predict CMV disease, we developed a ‘SuperLearner' machine learning model and quantified prediction accuracy by cross-validated area under the receiver-operator characteristic curves (cv-AUCs). Results Mean, peak, change, and percentage of positive viral loads were significantly higher in the placebo group than in the ganciclovir group. See viral loads by group in Fig 1. Percentage of positive viral load satisfied Prentice criteria as a valid surrogate endpoint for CMV disease by week 24 after randomization (Fig 2). All kinetics explained greater than 80% of ganciclovir's reduction in CMV disease (mean: 86%, peak: 83%, maximum change: 95%, percent positive: 94%). We found that a SuperLearner model that included all four viral load kinetics, CMV donor serostatus, acute graft-versus-host disease, and baseline viral load predicted CMV disease with 91% cv-AUC in the placebo group, 78% in the ganciclovir group, and 82% in the combined groups (Fig 3). Conclusion We have shown for the first time in a clinical endpoint-rich, placebo-controlled antiviral prophylaxis trial that CMV viral load kinetics fulfill the Prentice criteria as valid surrogate endpoints and have high predictive value for CMV disease after HCT.

OBJECTIVE To estimate binge eating disorder (BED) prevalence according to DSM-5 and DSM-IV-TR criteria in US adults and to estimate the proportion of individuals meeting DSM-5 BED criteria who reported being formally diagnosed. METHODS A representative sample of US adults who participated in the National Health and Wellness Survey were asked to respond to an Internet survey (conducted in October 2013). Assessments included 3-month, 12-month, and lifetime BED prevalence based on DSM-5 and DSM-IV-TR criteria and demographics, psychiatric comorbidities, and self-esteem (Rosenberg Self-Esteem Scale). Descriptive statistics are provided. Prevalence estimates were calculated using poststratification sampling weights. RESULTS Of 22,397 respondents, 344 (women, n = 242; men, n = 102) self-reported symptoms consistent with DSM-5 BED symptom criteria. The 3-month, 12-month, and lifetime DSM-5 prevalence estimates (95% CIs) projected to the US population were 1.19% (1.04%-1.37%), 1.64% (1.45%-1.85%), and 2.03% (1.83%-2.26%), respectively. The 12-month and lifetime projected DSM-IV-TR prevalence estimates were 1.15% (1.00%-1.32%) and 1.52% (1.35%-1.70%), respectively. Of respondents meeting DSM-5 BED criteria in the past 12 months, 3.2% (11/344) reported receiving a formal diagnosis. Compared with non-BED respondents, respondents meeting DSM-5 BED criteria in the past 12 months were younger (mean ± SD age = 46.01 ± 14.32 vs 51.59 ± 15.80 years; P < .001), had a higher body mass index (mean ± SD = 33.71 ± 9.36 vs 27.96 ± 6.68 kg/m²; P < .001), and had lower self-esteem (mean ± SD score = 16.47 ± 6.99 vs 23.33 ± 6.06; P < .001). CONCLUSIONS DSM-5 BED criteria resulted in higher BED prevalence estimates than with DSM-IV-TR criteria. Most BED respondents did not report being formally diagnosed, indicating an unmet need in BED recognition and diagnosis.

Background Rare invasive fungal infections (IFIs) such as chromoblastomycosis (CBM), fungal mycetoma (mycetoma), hyalohyphomycosis/phaeohyphomycosis (hyalo/phaeo), and mucormycosis (mucor) cause significant morbidity and mortality in immunocompromised patients. Few effective treatment options are available for these IFIs, therefore we assessed the clinical efficacy of posaconazole, a broad-spectrum triazole antifungal compound with demonstrated activity against IFIs. Methods We performed a systemic literature review of Medline and EMBASE to identify studies published from 2005 (year of posaconazole approval) to October 30, 2019, reporting the efficacy/effectiveness of posaconazole monotherapy or combination therapy for treating CBM, mycetoma, hyalo/phaeo, and mucor. Two reviewers screened and extracted data based on predefined PICOS criteria. Effectiveness outcomes included cure, response, relapse, radiologic improvement; mortality and any other effectiveness measures reported. Study quality was assessed using National Institute for Health and Care Excellence-recommended checklists. A narrative descriptive summary was used to summarize study findings. Results Of 2612 articles identified, 351 articles (mostly case reports) were included. Positive clinical outcomes with posaconazole therapy were observed in most patients with CBM (73.9%, 17/23), mycetoma (100%, 2/2), hyalo/phaeo (53.3%, 49/92), and mucor (66.7%, 564/845). The population for mycetoma was small; only 2 positive cases (Figure). Overall survival was ~70% or greater across the IFIs examined. Posaconazole efficacy and mortality differed by line of therapy as well as for monotherapy versus combination therapy. Positive response was higher in second line monotherapy than first line monotherapy in CBM and mucor. Higher mortality was observed with combination therapy than monotherapy in hyalo/phaeo and mucor infections (except for first line use in mucor). Figure. Overall Results of Posaconazole Treatment Conclusion Despite the rarity of these IFIs, substantial data have been published since posaconazole’s initial approval in the year 2005, and the evidence demonstrates that posaconazole is an effective therapeutic option alone or in combination for the treatment of these rare IFIs. Disclosures Mark Bernauer, BPharm, RPh, Merck & Co, Inc. (Consultant) Hetty Waskin, MD/MPH, Merck & Co, Inc. (Employee) Nicole Cossrow, PhD, Merck & Co, Inc. (Employee) Allysen Kaminski, BA, Merck & Co, Inc. (Consultant) Havilland Campbell, BS, Merck & Co, Inc. (Employee) Dipen Patel, BPharm, PhD, Merck & Co, Inc. (Consultant)

BACKGROUNDPredicting recurrentClostridium difficileinfection (rCDI) remains difficult. METHODS. We employed a retrospective cohort design. Granular electronic medical record (EMR) data had been collected from patients hospitalized at 21 Kaiser Permanente Northern California hospitals. The derivation dataset (2007–2013) included data from 9,386 patients who experienced incident CDI (iCDI) and 1,311 who experienced their first CDI recurrences (rCDI). The validation dataset (2014) included data from 1,865 patients who experienced incident CDI and 144 who experienced rCDI. Using multiple techniques, including machine learning, we evaluated more than 150 potential predictors. Our final analyses evaluated 3 models with varying degrees of complexity and 1 previously published model.RESULTSDespite having a large multicenter cohort and access to granular EMR data (eg, vital signs, and laboratory test results), none of the models discriminated well (c statistics, 0.591–0.605), had good calibration, or had good explanatory power.CONCLUSIONSOur ability to predict rCDI remains limited. Given currently available EMR technology, improvements in prediction will require incorporating new variables because currently available data elements lack adequate explanatory power.Infect Control Hosp Epidemiol2017;38:1196–1203

Background Clostridium difficile infection (CDI) is the most commonly recognized cause of recurrent diarrhea. Bezlotoxumab, administered concurrently with antibiotics directed against C. difficile (standard of care [SoC]), has been shown to reduce the recurrence of CDI, compared with SoC alone. This study aimed to assess the cost-effectiveness of bezlotoxumab administered concurrently with SoC, compared with SoC alone, in subgroups of patients at risk of recurrence of CDI. Methods A computer-based Markov health state transition model was designed to track the natural history of patients infected with CDI. A cohort of patients entered the model with either a mild/moderate or severe CDI episode, and were treated with SoC antibiotics together with either bezlotoxumab or placebo. The cohort was followed over a lifetime horizon, and costs and utilities for the various health states were used to estimate incremental cost-effectiveness ratios (ICERs). Both deterministic and probabilistic sensitivity analyses were used to test the robustness of the results. Results The cost-effectiveness model showed that, compared with placebo, bezlotoxumab was associated with 0.12 quality-adjusted life-years (QALYs) gained and was cost-effective in preventing CDI recurrences in the entire trial population, with an ICER of $19824/QALY gained. Compared with placebo, bezlotoxumab was also cost-effective in the subgroups of patients aged ≥65 years (ICER of $15298/QALY), immunocompromised patients (ICER of $12597/QALY), and patients with severe CDI (ICER of $21430/QALY). Conclusions Model-based results demonstrated that bezlotoxumab was cost-effective in the prevention of recurrent CDI compared with placebo, among patients receiving SoC antibiotics for treatment of CDI.

The United States Food and Drug Administration recently issued guidance that CMV DNAemia (quantitative CMV viral load as measured by PCR) could be used in a composite endpoint along with tissue-invasive CMV disease as the primary endpoint in allogeneic HCT CMV prophylaxis trials. However, the specific time points after antiviral treatment initiation at which to measure viral load and the viral load thresholds that most accurately predict clinical CMV disease have not been identified. In order to estimate the treatment effect of an antiviral agent on CMV clinical outcomes, placebo-controlled, randomized trial data with accompanying viral load measurements are needed. Unfortunately, in the modern era of PCR and early preemptive treatment, ethically, placebo-controlled, randomized trials that allow for the development of CMV disease after HCT can no longer be performed. To overcome this limitation, we performed CMV DNA PCR testing on frozen plasma samples collected during the first 100 days post-HCT in the only placebo-controlled, double-blind RCT of ganciclovir for the early treatment of CMV infection after HCT (Goodrich et al. NEJM 1991). We used three analytic methods (Cox proportional hazards models, machine learning, and a novel non-parametric method) to determine which of 14 viral load markers, measured in the first four weeks of treatment, are the most useful surrogates of antiviral treatment for the prevention of CMV disease. All methods identified peak viral load and percentage of positive samples by week 4 as highly associated with or predictive of tissue-invasive CMV disease by week 8 post-randomization. Cox proportional hazards models (Figure 1) yielded significant associations for peak viral load measured by week 4 (HR 1.4, 95% CI 1.1-1.9) and percentage of positive samples by week 4 (HR 1.6, CI 1.1-2.3). The machine-learning ensemble algorithm SuperLearner implemented in R (Figure 2) demonstrated cross-validated area under the receiver-operator curves of at least 75% for peak viral load (75%, CI 62-87%) and percentage of positive plasma samples (77%, CI 63-90%) measured by week 4. Using a novel statistical technique that allows direct estimation of biomarker surrogacy (Parast et al. Stat Med 2017), we estimated that the percentage of ganciclovir treatment effect explained by peak viral load and percentage of positive samples measured by week 4 was greater than 85%—peak viral load 89%, CI 56-100%; percent positive samples 91%, CI 60-100% (Figure 3). Peak viral load and percentage of positive samples by week 4 are highly predictive of CMV disease and the treatment effect of ganciclovir. Our analysis suggests that these may be the best surrogate markers of ganciclovir treatment and introduces novel methods for identifying optimal candidate biomarkers as surrogates for clinical endpoints.

To estimate binge eating disorder (BED) prevalence according to DSM-5 and DSM-IV-TR criteria in US adults and to estimate the proportion of individuals meeting DSM-5 BED criteria who reported being formally diagnosed.A representative sample of US adults who participated in the National Health and Wellness Survey were asked to respond to an Internet survey (conducted in October 2013). Assessments included 3-month, 12-month, and lifetime BED prevalence based on DSM-5 and DSM-IV-TR criteria and demographics, psychiatric comorbidities, and self-esteem (Rosenberg Self-Esteem Scale). Descriptive statistics are provided. Prevalence estimates were calculated using poststratification sampling weights.Of 22,397 respondents, 344 (women, n = 242; men, n = 102) self-reported symptoms consistent with DSM-5 BED symptom criteria. The 3-month, 12-month, and lifetime DSM-5 prevalence estimates (95% CIs) projected to the US population were 1.19% (1.04%-1.37%), 1.64% (1.45%-1.85%), and 2.03% (1.83%-2.26%), respectively. The 12-month and lifetime projected DSM-IV-TR prevalence estimates were 1.15% (1.00%-1.32%) and 1.52% (1.35%-1.70%), respectively. Of respondents meeting DSM-5 BED criteria in the past 12 months, 3.2% (11/344) reported receiving a formal diagnosis. Compared with non-BED respondents, respondents meeting DSM-5 BED criteria in the past 12 months were younger (mean ± SD age = 46.01 ± 14.32 vs 51.59 ± 15.80 years; P.001), had a higher body mass index (mean ± SD = 33.71 ± 9.36 vs 27.96 ± 6.68 kg/m²; P.001), and had lower self-esteem (mean ± SD score = 16.47 ± 6.99 vs 23.33 ± 6.06; P.001).DSM-5 BED criteria resulted in higher BED prevalence estimates than with DSM-IV-TR criteria. Most BED respondents did not report being formally diagnosed, indicating an unmet need in BED recognition and diagnosis.

The prevalence of obesity is increasing among all age and racial groups in the United States. There is, however, a disproportionate rise in the prevalence of obesity among African-Americans and Hispanic/Mexican Americans. Obesity is a major contributor to the insulin resistant syndrome (IRS), a condition of multiple metabolic abnormalities that is a precursor to type 2 diabetes, and confers a high risk for cardiovascular events. The estimated prevalence of IRS is also greater in Mexican Americans and African-Americans than in Caucasians. The IRS is identifiable in children, and as with adults, there are racial differences in its expression even at a young age. The obesity-associated diseases, including diabetes and hypertension, are found at higher rates within the minority races compared with Caucasians. However, there are differences, in that obesity-related hypertension occurs at higher rates among African-Americans, and obesity-related diabetes occurs at higher rates among Mexican Americans. Race/ethnic differences in lifestyle behaviors and economic disadvantage may account for some of the race disparity in obesity-related diseases and disease outcomes. Environmental factors, however, do not explain all of the race disparity in disease expression, indicating that there are genetic/molecular factors that are operational as well.

Metabolic syndrome (MetS) is a clinical condition that includes multiple cardiovascular disease risk factors including obesity, high blood pressure or hypertension, dyslipidemia, and abnormal glucose metabolism. The core metabolic abnormality in MetS is insulin resistance, or impaired insulin mediated glucose regulation that results in elevated plasma insulin concentration. MetS, or multiple cardiovascular risk factors, markedly increase risk for diabetes, atherosclerosis, and adverse metabolic and cardiovascular outcomes. Although commonly associated with adult diseases and aging, MetS is also identifiable in childhood. Because obesity is a key component of the syndrome, the prevalence of MetS in U.S. adults is over 25%, with higher rates among race/ethnic minority groups. The population prevalence of MetS is much less in childhood at approximately 4 to 5%. However, due to the childhood obesity epidemic the prevalence of MetS among obese children and adolescents is approximately 30% with similar race/ethnic disparity among race/minority groups.

Context Treatment Resistant Depression (TRD) is a significant and burdensome health concern. Objective To characterize, compare and understand the difference between TRD and non-TRD patients and episodes in respect of their episode duration, treatment patterns and healthcare resource utilization. Design and Setting Patients between 18 and 64 years with a new diagnosis of major depressive disorder (MDD) and without a previous or comorbid diagnosis of schizophrenia or bipolar disease were included from PharMetrics Integrated Database, a claims database of commercial insurers in the US. Episodes of these patients in which there were at least two distinct failed regimens involving antidepressants and antipsychotics were classified as TRD. Patients 82,742 MDD patients were included in the analysis; of these patients, 125,172 episodes were identified (47,654 of these were drug-treated episodes). Main Outcome Measures Comparison between TRD and non-TRD episodes in terms of their duration, number and duration of lines of treatment, comorbidities, and medical resource utilization. Results Of the treated episodes, 6.6% (N = 3,134) met the criteria for TRD. The median time to an episode becoming TRD was approximately one year. The mean duration of a TRD episode was 1,004 days (vs. 452 days for a non-TRD episode). More than 75% of TRD episodes had at least four lines of therapy; half of the treatment regimens included a combination of drugs. Average hospitalization costs were higher for TRD than non-TRD episodes: $6,464 vs. $1,734, as were all other health care utilization costs. Conclusions While this study was limited to relatively young and commercially covered patients, used a rigorous definition of TRD and did not analyze for cause or consequence, the results highlight high unmet medical need and burden of TRD on patients and health care resources.

An association of plasma homocysteine concentration ([Hcy]) with cardiovascular events has been described, but the role of [Hcy] in the early phase of cardiovascular disease is uncertain. The purpose of this study was to determine whether [Hcy] is related to blood pressure (BP) or other risk factors in African Americans, a population at high risk for cardiovascular disease.This cross-sectional study was conducted on a sample of premenopausal African American women (N = 119) and men (N = 56), 30 to 40 years of age. Each subject was classified as normotensive or hypertensive. Fasting blood samples were obtained for serum lipids, insulin, glucose, Hcy, folate, and B-12, followed by an oral glucose tolerance test.Mean [Hcy] was higher in hypertensives compared to normotensives, but the difference was statistically significant only in women (10.5 +/- 5.3 v 8.2 +/- 2.3; P.01). In women, the simple correlation analysis revealed a statistically significant relationship of [Hcy] with systolic BP (r = 0.22, P =.02) and diastolic BP (r = 0.240, P =.01). However, after adjusting for age and body mass index (BMI), the correlations were attenuated and no longer significant. There was a significant inverse relationship of [Hcy] with plasma folate (r = -0.35, P.001) and B-12 (r = -0.29, P.01) in women.Although the simple correlation coefficient suggests a significant relationship of [Hcy] with BP in women, this relationship was no longer statistically significant after adjustment for age and BMI. The significant inverse relationship of plasma folate and B-12 with [Hcy] suggest that diet factors may affect the crude [Hcy]-BP relationship identified in this sample.

Abstract 4253 Background: Castleman's Disease (CD), first described in 1956 by Benjamin Castleman and also known as angiofollicular or giant lymph node hyperplasia, is characterized by lymphadenopathy resulting from abnormal proliferation of B lymphocytes and plasma cells. The clinical manifestations of the disease range from asymptomatic discrete lymphadenopathy, Unicentric Castleman's Disease (UCD), to a more severe form with recurrent episodes of diffuse lymphadenopathy and multi-organ involvement, Multicentric Castleman's Disease (MCD). In a discrete subpopulation, MCD is associated with HIV and Human herpesvirus-8 (HHV-8) infection. Incidence and prevalence of this rare disease is generally unknown but the hypothesized prevalence of CD ranges between 30,000 and 100,000 in the US. There are no codes to accurately identify CD, UCD or MCD in national databases. Objective: The objective of this effort is to propose an algorithm identifying and characterizing potential CD patients to estimate related incidences based on available information and patient characteristics from a national claims database. Methods: The diagnostic and procedure codes that are used in diagnosing lymphadenopathy patients in a longitudinal commercial claims database were used to define and characterize a cohort of likely CD patients. Included patients were required to be continuously enrolled in the database for at least three years. Patients with a history of rheumatoid arthritis (RA), Lupus, Hodgkin's disease (HD), Non-Hodgkin's Lymphoma (NHL) or other malignancies were excluded. Patients must have a diagnosis code of ICD-9 = 785.6 indicating lymphadenopathy followed by a lymph node biopsy (procedure code = 38505) on or within two years after the initial ICD-9 diagnosis date. Patients who had a diagnosis, within 1 year after the initial ICD-9 diagnosis date, of RA, Lupus, HD, NHL or other malignancies were excluded. Once the pool of potential CD patients was identified, it was further characterized according to age, gender, prescription medication use and comorbidities, particularly the development of NHL. To estimate incidence of the disease in the US, the number of patients identified in the pool adjusted for the total patient-time in the database was applied to US census population. Results: In a claims database of nearly 27 million patients (N=26,982,399), 16,967 patients were identified with an ICD-9 diagnosis of 785.6 and a biopsy code of 38505. After the additional exclusion criteria based on a three year continuous enrollment and a biopsy code on of within two years after the index diagnosis date and excluding patients with prior RA, Lupus, HD, NHL or other malignancies, there were 2,094 patients. After further excluding patients who developed RA, Lupus, HD, NHL other malignancies or HIV within one year after the diagnosis date, 1,153 patients remained with potential diagnosis of CD. These patients were mostly female (64.4%, N=742) and the mean and median age of this cohort were 43 and 45 years, respectively. The most common comorbid conditions were swelling in head/neck, followed by malaise and fatigue and pain in limb. Among these patients, only a quarter were taking a steroid or chemotherapy. Steroid use (dexamethasone and prednisone) was the more common treatment; rituxan usage was documented for less than 1% of the cohort. Based on this sample the incidence rate of CD is 21 cases per million person-years. Applying this rate to the 25 years and older US population, assumed to be 207,301,600 in 2011, the incidence of CD in the US is 4,353 patients. Discussion: To date, a thorough investigation of the incidence of CD in the US has not been done. Within the limitations of this effort, a plausible strategy using a US claims database to identify and characterize patients with CD was developed and confirms the very low incidence of CD. Furthermore this effort characterizes potential CD patients as young adults, and only very few of them receive treatment with steroids or chemotherapy. The low chemotherapy usage may suggest that there are very few MCD patients in this cohort. The value of this effort is to demonstrate a relatively quick and cost-effective strategy to characterize the epidemiology and medical need for a rare disorder. Disclosures: Mehra: Janssen Global Services, LLC: Employment. Cossrow:Janssen Global Services, LLC: Employment. Stellhorn:Janssen Global Services, LLC: Employment. Vermeulen:Janssen Biologics Europe: Employment. Desai:Janssen Global Services, LLC: Employment. Munshi:Janssen Global Services, LLC: Consultancy.