Trends in the Prevalence of Advanced Liver Disease Among Patients With Hepatitis C Virus in the Florida State Medicaid Program

Trends in the Prevalence of Advanced Liver Disease Among Patients With Hepatitis C Virus in the Florida State Medicaid Program

403 and AdvLD (decompensated cirrhosis, hepatocellular carcinoma, and liver transplant). The target population was US individuals born between 1946 a...

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and AdvLD (decompensated cirrhosis, hepatocellular carcinoma, and liver transplant). The target population was US individuals born between 1946 and 1964. To estimate the current HCV infection status and stage of disease progression in this population, a run-in period from 1964 to 2010 was modeled whereby incident cases and disease progression were estimated using published age- and gender-specific rates of infection, spontaneous clearance and progression. Screening of the eligible (i.e. no diagnosis of HCV) population was assumed to begin in 2010. Alternatives considered were either to continue current risk-based screening (RBS) or to implement BCS wherein all Baby-Boomer individuals would be targeted. Yearly probabilities of acceptance of RBS were estimated from observational studies and differed by HCV infection status, and gender (males: 0.62% for uninfected and 2.83% infected; females: 0.72% and 2.92%, respectively), with screening continuing until age 70. BCS was assumed to capture 100% of the eligible population over the first 5 years of implementation, with equal numbers screened each year. Model inputs, including genotype-specific (1 vs. 2&3) treatment response rates, and state-specific mortality were estimated from literature. Primary model outcomes were cumulative lifetime incidence of AdvLD and associated mortality. Results: Following the initial run-in period, a population of 80,626,900 was identified as eligible for HCV screening. Over the lifetime of the eligible cohort, the BCS strategy resulted in to 55,400 fewer cases of decompensated cirrhosis (234,800 vs. 290,200 with RBS), 31,100 fewer cases of hepatocellular carcinoma (135,400 vs. 165,500) and 6,200 fewer cases of liver transplant (28,300 vs. 34,500) compared to RBS. There were 50,300 fewer deaths associated with HCV infection and AdvLD with BCS than with RBS (229,900 vs. 280,200). Discussion: Model results demonstrate that implementation of a targeted agebased screening program in the Baby-Boomer population is likely to provide important health benefits versus current RBS by reducing lifetime cases of AdvLD, liver transplant and deaths due to liver disease.

AASLD Abstracts

Knockdown of DCAMKL-1 Results in Liver Cancer Tumor Growth Arrest Through Inhibition of c-MYC via Let-7a MicroRNA; Inhibits EMT via Mir-200a MicroRNA Dependent Mechanisms Sripathi M. Sureban, Dongfeng Qu, Randal May, Sima Asfa, Shrikant Anant, Courtney W. Houchen Background: MicroRNAs (miRNAs) are non-protein coding RNAs that regulate gene expression. Recent reports have demonstrated that several key primary miRNA transcripts (primiRNAs), are blocked post-transcriptionally in various human primary tumors including colon and pancreatic cancer. Nanoparticles (NP) are extremely small (<100 nanometers in size and can be used to create powerful interactions with biomolecules both on the surface of and inside of cancer cells. It has enormous potential in cancer biology by providing targeted therapeutic drug delivery. Here we demonstrate that NP-siRNA mediated blockade of the novel putative intestinal and pancreatic normal and cancer stem cell marker DCAMKL1 resulted in: tumor growth arrest of Huh7.5 human hepatoma tumor xenografts; decreased c-Myc expression via increased let-7a miRNA and decreased epithelial to mesenchymal transition (EMT) via increased miR-200a miRNA. Aim: To determine the role of DCAMKL1 on c-Myc, EMT and tumorigenesis in liver cancer. Methods: mRNA and miRNA expressions were determined by real-time RT PCR and protein by immunohistochemistry/western blot. siRNA-targeting DCAMKL-1 was encapsulated in Poly(lactide-co-glycolide) (PLGA)-based nanoparticles (NP-siDCAMKL-1) and direct injected into Huh7.5 tumor xenografts formed in nude mice with tumor volumes measured. Huh7.5 cells were transfected with plasmid encoding the firefly luciferase gene with a let-7a miRNA-binding site at the 3'UTR to measure let-7a expression following the knockdown of DCAMKL-1. Results: Increased expression of DCAMKL-1 was found in human liver tumors compared to uninvolved normal human liver. NP-siDCAMKL-1-mediated knockdown of DCAMKL-1 resulted in Huh7.5 tumor growth arrest, down regulated proto-oncogene c-Myc via increased let-7a miRNA. This increase was confirmed by a corresponding reduction in let-7a miRNA specific luciferase activity. Furthermore, knockdown of DCAMKL-1 also induced miR-200a, an EMT inhibitor, along with downregulation of EMT-associated transcription factors ZEB1, ZEB2, N-cadherin, Snail, Slug and Twist. Conclusion: DCAMKL-1 is a novel liver cancer stem cell marker that is involved in tumorigenesis and EMT. DCAMKL-1 is a negative regulator of let-7a and miR200a miRNA biogenesis. This may represent a novel target for anti-cancer stem cell based therapies for liver cancer and perhaps other solid tumors.

478 Trends in the Prevalence of Advanced Liver Disease Among Patients With Hepatitis C Virus in the Florida State Medicaid Program Joseph Menzin, Leigh Ann White, Christine Nichols, Baris Deniz Background: Much of the clinical burden of hepatitis C virus (HCV) stems from the onset of advanced liver diseases (ALD), including hepatocellular carcinoma (HCC). There are limited data on trends in the prevalence of ALD among HCV patients in Medicaid populations. Aim: The aim of this research was to investigate current epidemiologic trends in the prevalence of ALD among Medicaid patients with HCV. Methods: Data on healthcare utilization, enrollment, and demographics were collected from the Florida Medicaid database (fiscal years [FY] 1998-2008). Patients with either a HCV diagnosis on an inpatient or outpatient claim or with prescription therapy for HCV were included in the analysis. Next, we identified which of these patients had an ALD-related diagnosis, including HCC, decompensated cirrhosis, and/or diagnosis or procedure codes indicating a liver transplant. Patients were required to have at least 1 month of Medicaid eligibility, and were excluded if they were eligible for Medicare or an HMO at any time during the year of analysis. Prevalence of HCV and ALD were analyzed annually. Results: The prevalence of HCV rose from approximately 2.2 to 4.4 per 1,000 eligible Medicaid patients from FY ‘98-‘99 to FY ‘04-‘05, and then declined to 3.3 per 1,000 patients in FY ‘07-‘08. Despite this recent decline in the prevalence of HCV between FY '04-'05 and '07-‘08, the prevalence of ALD in the overall Medicaid population as well as the percentage of HCV patients with an ALD-related diagnosis increased in the same period (15% and 28% respectively) (Figure). Decompensated cirrhosis was the most prevalent ALD condition among HCV patients in all years, accounting for 77-85% of ALD-related diagnoses. HCC represented a growing portion of ALD-related diagnoses among HCV patients, increasing from 5% to 12% of ALD-related diagnoses in the study period. Conclusion: Although HCV prevalence in the Florida Medicaid database declined after peaking in fiscal year ‘04-‘05, the percentage and absolute number of hepatitis C patients with advanced liver disease rose. Increases in the prevalence of decompensated cirrhosis and hepatocellular carcinoma are likely the main source of increased advanced liver disease prevalence in hepatitis C patients.

404 25-Hydroxycholesterol-3-Sulfate (25HC3S): A Physiological Ligand of PPARγ? Shanwei Shen, Douglas M. Heuman, William M. Pandak, Shunlin Ren Background: PPARγ is ligand-activated nuclear receptor that regulates expression of many genes involved in metabolism, cellular proliferation, differentiation, and immune response. Activation of PPARγ by binding to a ligand is followed by translocation from cytosol to nucleus, where active PPARγ forms heterodimers with the retinoid X receptor (RXR), and activates target gene expression by binding to PPAR response element (PPRE). 25HC3S is an oxysterol sulfate regulatory molecule, produced endogenously in hepatocytes in response to overexpression of the mitochondrial cholesterol transporter StARD1. We found that 25HC3S decreases lipid biosynthesis and inhibits inflammatory responses in hepatocytes. Our preliminary data also showed that 25HC3S increases nuclear PPARγ levels. Hypothesis: 25HC3S serves as a novel endogenous physiological ligand of PPARγ. Methods: To evaluate binding of 25HC3S with PPARγ: 1. Molecular dynamic simulation was carried out by software NAMD2.6, 2. Molecular docking, by software eHiTS 9.0 (SimBioSys Inc.), 3. Binding affinity was determined by PolarscreenTM PPARγ competitor assay, 4. To determine the ability of 25HC3S to induce PPARγ activation, HEK293 cells were co-transfected with recombinant plasmids encoding PPARγ and PPRE-luciferase, or plasmids encoding GAL4-PPARγLBD, and GAL4-responsive promoter-luciferase. Induction of luciferease activity by 25HC3S and other known or potential ligands was determined. Results: Molecular dynamic study using NAMD2.6 program shows that the binding of 25HC3S to PPARγ closes the pocket door by turning the C-terminal fragment and changes the three dimensional structure of PPARγ molecule. This subsequently activates its DNA binding domain by twisting 45o. Docking data shows that the boat form of 25HC3S fits the binding pocket with high scoring. The hydrophilic residue Arg288 is critical for docking. IC50 and Ki were calculated from competition binding assay. Binding of 25HC3S was compared to rosiglitazone, a known potent PPARγ agonist (Ki=52nM) and to 15-deoxy-Δ12,14-Prostaglandin J2, a known physiological PPARγ ligand (Ki=0.56μM). 25HC3S had a Ki of 1.1μM, well within physiological range. 25-hydroxycholesterol, cholesterol, and cholesterol-3-sulfate failed to bind PPARγ (Ki >1 mM). 25HC3S induced luciferase expression, consistent with activation of PPARγ. In the presence of the PPARγ antagonist T0070907, 25HC3S failed to increase PPARγ reporter gene activities (p<0.01). Using chimeric receptor/reporter system, 25HC3S was found to induce transcriptional activity of luciferase, while other oxysterols could not. Conclusion: Our results indicate that 25HC3S is an endogenous PPARγ ligand. 477 The Impact of Birth-Cohort Screening for Hepatitis C Virus (HCV) Compared With Current Risk-Based Screening on Lifetime Incidence of and Mortality From Advanced Liver Disease (AdvLD) in the United States (U.S.) Lisa McGarry, Gary L. Davis, Zobair M. Younossi, Vivek Pawar, Jaime Rubin, Hemangi Parekh, Milton Weinstein

479 HIV-Viral Hepatitis Coinfection is Associated With Risk for Increasing APRI Despite Mitigating Effect of HAART Jennifer Price, Eric C. Seaberg, Sheila Badri, Mallory D. Witt, Kristin D'Acunto, Chloe Thio

Objective: Current HCV screening practices that target high-risk populations such as injection drug users have had limited success. Recent research has identified high HCV prevalence among Baby Boomers (born between 1946 and 1964) who may have contracted HCV decades ago and are no longer identified as high-risk. The study objective was to assess the health impact of HCV screening in the US Baby-Boomer birth cohort (“birth-cohort screening” or BCS). Methods: A Markov model of the natural history of HCV and subsequent liver disease was developed with health states for HCV uninfected, mild through advanced fibrosis stages,

AASLD Abstracts

BACKGROUND: Coinfection with HIV and viral hepatitis is common. HIV accelerates liver fibrosis in both chronic HBV and HCV infections. In HIV-viral hepatitis coinfected subjects, the AST to platelet ratio index (APRI) has been validated as a noninvasive marker of hepatic fibrosis. The purpose of this study was to determine factors associated with increased APRI both before and after initiating HAART in a cohort of men at-risk for or infected with HIV and viral hepatitis infections. METHODS: Men from the Multicenter AIDS Cohort Study

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