Modeling hepatitis C micro-elimination among people who inject drugs with direct-acting antivirals in metropolitan Chicago

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and mortality worldwide. Direct-acting antiviral (DAA) therapy leads to high cure rates. However, persons who inject drugs (PWID) are at risk for reinfection after cure and may require multiple DAA treatments to reach the World Health Organization’s (WHO) goal of HCV elimination by 2030. Using an agent-based model (ABM) that accounts for the complex interplay of demographic factors, risk behaviors, social networks, and geographic location for HCV transmission among PWID, we examined the combination(s) of DAA enrollment (2.5%, 5%, 7.5%, 10%), adherence (60%, 70%, 80%, 90%) and frequency of DAA treatment courses needed to achieve the WHO’s goal of reducing incident chronic infections by 90% by 2030 among a large population of PWID from Chicago, IL and surrounding suburbs. We also estimated the economic DAA costs associated with each scenario. Our results indicate that a DAA treatment rate of >7.5% per year with 90% adherence results in 75% of enrolled PWID requiring only a single DAA course; however 19% would require 2 courses, 5%, 3 courses and <2%, 4 courses, with an overall DAA cost of $325 million to achieve the WHO goal in metropolitan Chicago. We estimate a 28% increase in the overall DAA cost under low adherence (70%) compared to high adherence (90%). Our modeling results have important public health implications for HCV elimination among U.S. PWID. Using a range of feasible treatment enrollment and adherence rates, we report robust findings supporting the need to address re-exposure and reinfection among PWID to reduce HCV incidence

Vitamin D Levels are Associated with Liver Disease Severity in Patients with Cirrhosis

Vitamin D deficiency is common in advanced liver disease but its clinical significance remains controversial. The aim of this study was to examine the correlation of 25-hydryoxyvitamin D levels with liver disease severity and calcium levels in adults with cirrhosis. This cross-sectional study included 180 adults with cirrhosis enrolled in a clinical cohort study at a single university hospital. The mean age was 58.8 (±9.2) years, and cirrhosis was attributed to alcohol use in 27.2%, hepatitis C in 35.0%, non-alcoholic steatohepatitis in 27.2%, and both alcohol and hepatitis C in 10.6%. The median model for end-stage liver disease-sodium (MELD-Na) score was 12.0 (interquartile range 9.0–16.0), and mean serum albumin levels were 3.4 (±0.7) gm/dl. Median serum 25-hydroxyvitamin D levels were 28.0 (interquartile range 20–38) ng/mL, with 16 patients (8.9%) having levels <12 ng/ml and 43 (23.9%) with 25(OH)D levels <20 ng/ml. No correlation was noted between levels of 25-hydroxyvitamin D and albumin-corrected calcium in the total group and in groups stratified by vitamin D supplementation. In contrast, both serum albumin (r = 0.32; P < 0.001) and MELD-Na scores were significantly correlated with 25-hydroxyvitamin D levels (r = –0.29; P < 0.001). Correlations between 25-hydroxyvitamin D levels and serum albumin (r = −0.39; P < 0.001) and MELD-Na scores did not change substantially after excluding 67 patients receiving vitamin D supplementation (r = −0.33; P = 0.009). In conclusion, total 25-hydroxyvitamin D levels correlate inversely with liver disease severity in adults with cirrhosis

Physicians' preference values for hepatitis C health states and antiviral therapy: A survey

BACKGROUND: Physicians' perspectives regarding hepatitis C shape their approach to patient management. We used utility analysis to evaluate physicians' perceptions of hepatitis C-related health states (HS) and their threshold to recommend treatment. METHODS: A written questionnaire was administered to practicing physicians. They were asked to rate hepatitis C health states on a visual analog scale ranging from 0% (death) to 100% (health without hepatitis C). Physicians then judged quality of life associated with the side effects of antiviral therapy for hepatitis C and indicated the sustained virological response rate that they would require to recommend treatment. RESULTS: One hundred and thirteen physicians from five states were included. Median utility ratings for hepatitis C health states declined significantly with increasing severity of symptoms: HS1-No Symptoms, No Cirrhosis (88%; 12% reduction from good health), HS2-Mild Symptoms, No Cirrhosis (66%), HS3-Moderate Symptoms, No Cirrhosis (49%), HS4-Mild Symptoms, Cirrhosis (40%), HS5-Severe Symptoms, Cirrhosis (18%) [p < 0.001]. The median rating for life with side effects of antiviral therapy was 47%, suggesting a 53% reduction from good health. That was similar to the utility value for HS3-Moderate Symptoms, No Cirrhosis. The median threshold value for recommending treatment was a sustained response rate of 60%. CONCLUSIONS: 1) Physicians' utility ratings for hepatitis C health states were inversely related to the severity of disease manifestations described. 2) Physicians viewed side effects of therapy unfavorably and indicated that on average, they would require a 60% sustained response rate before recommending treatment, which far exceeds the efficacy of current antiviral therapy for hepatitis C in the majority of patients

Inhibition of Insulin‐Like Growth Factor 1 Receptor Enhances the Efficacy of Sorafenib in Inhibiting Hepatocellular Carcinoma Cell Growth and Survival

Hepatocellular carcinoma (HCC) is the fifth most common primary cancer and second largest cause of cancer‐related death worldwide. The first‐line oral chemotherapeutic agent sorafenib only increases survival in patients with advanced HCC by less than 3 months. Most patients with advanced HCC have shown limited response rates and survival benefits with sorafenib. Although sorafenib is an inhibitor of multiple kinases, including serine/threonine‐protein kinase c‐Raf, serine/threonine‐protein kinase B‐Raf, vascular endothelial growth factor receptor (VEGFR)‐1, VEGFR‐2, VEGFR‐3, and platelet‐derived growth factor receptor β, HCC cells are able to escape from sorafenib treatment using other pathways that the drug insufficiently inhibits. The aim of this study was to identify and target survival and proliferation pathways that enable HCC to escape the antitumor activity of sorafenib. We found that insulin‐like growth factor 1 receptor (IGF1R) remains activated in HCC cells treated with sorafenib. Knockdown of IGF1R sensitizes HCC cells to sorafenib treatment and decreases protein kinase B (AKT) activation. Overexpression of constitutively activated AKT reverses the effect of knockdown of IGF1R in sensitizing HCC cells to treatment with sorafenib. Further, we found that ceritinib, a drug approved by the U.S. Food and Drug Administration for treatment of non‐small cell lung cancer, effectively inhibits the IGF1R/AKT pathway and enhances the inhibitory efficacy of sorafenib in human HCC cell growth and survival in vitro, in a xenograft mouse model and in the c‐Met/β‐catenin‐driven HCC mouse model. Conclusion: Our study provides a biochemical basis for evaluation of a new combination treatment that includes IGF1R inhibitors, such as ceritinib and sorafenib, in patients with HCC

ABL1, Overexpressed in Hepatocellular Carcinomas, Regulates Expression of NOTCH1 and Promotes Development of Liver Tumors in Mice

Background & Aims We investigated whether ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1) is involved in development of hepatocellular carcinoma (HCC). Methods We analyzed clinical and gene expression data from The Cancer Genome Atlas. Albumin-Cre (HepWT) mice and mice with hepatocyte-specific disruption of Abl1 (HepAbl–/– mice) were given hydrodynamic injections of plasmids encoding the Sleeping Beauty transposase and transposons with the MET gene and a catenin β1 gene with an N-terminal truncation, which induces development of liver tumors. Some mice were then gavaged with the ABL1 inhibitor nilotinib or vehicle (control) daily for 4 weeks. We knocked down ABL1 with short hairpin RNAs in Hep3B and Huh7 HCC cells and analyzed their proliferation and growth as xenograft tumors in mice. We performed RNA sequencing and gene set enrichment analysis of tumors. We knocked down or overexpressed NOTCH1 and MYC in HCC cells and analyzed proliferation. We measured levels of phosphorylated ABL1, MYC, and NOTCH1 by immunohistochemical analysis of an HCC tissue microarray. Results HCC tissues had higher levels of ABL1 than non-tumor liver tissues, which correlated with shorter survival times of patients. HepWT mice with the MET and catenin β1 transposons developed liver tumors and survived a median 64 days; HepAbl–/– mice with these transposons developed tumors that were 50% smaller and survived a median 81 days. Knockdown of ABL1 in human HCC cells reduced proliferation, growth as xenograft tumors in mice, and expression of MYC, which reduced expression of NOTCH1. Knockdown of NOTCH1 or MYC in HCC cells significantly reduced cell growth. NOTCH1 or MYC overexpression in human HCC cells promoted proliferation and rescued the phenotype caused by ABL1 knockdown. The level of phosphorylated (activated) ABL1 correlated with levels of MYC and NOTCH1 in human HCC specimens. Nilotinib decreased expression of MYC and NOTCH1 in HCC cell lines, reduced the growth of xenograft tumors in mice, and slowed growth of liver tumors in mice with MET and catenin β1 transposons, reducing tumor levels of MYC and NOTCH1. Conclusions HCC samples have increased levels of ABL1 compared with nontumor liver tissues, and increased levels of ABL1 correlate with shorter survival times of patients. Loss or inhibition of ABL1 reduces proliferation of HCC cells and slows growth of liver tumors in mice. Inhibitors of ABL1 might be used for treatment of HCC

Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry

Background : It is unclear whether mild to moderate iron overload in liver diseases other than hereditary haemochromatosis (HH) contributes to hepatocellular carcinoma. This study examined the association between hepatic iron grade and hepatocellular carcinoma in patients with end-stage liver disease of diverse aetiologies. Methods : The prevalence of hepatic iron overload and hepatocellular carcinoma was examined in 5224 patients undergoing liver transplantation. Explant pathology reports were reviewed for the underlying pathological diagnosis, presence of hepatocellular carcinoma and degree of iron staining. The distribution of categorical variables was studied using Χ 2 tests. Results : Both iron overload and hepatocellular carcinoma were the least common with biliary cirrhosis (1.8 and 2.8% respectively). Hepatocellular carcinoma was the most common in patients with hepatitis B (16.7%), followed by those with hepatitis C (15.1%) and HH (14.9%). In the overall cohort, any iron overload was significantly associated with hepatocellular carcinoma ( P =0.001), even after adjustment for the underlying aetiology of liver disease. The association between hepatic iron content and hepatocellular carcinoma was the strongest in patients with biliary cirrhosis ( P <0.001) and hepatitis C ( P <0.001). Conclusions : Iron overload is associated with hepatocellular carcinoma in patients with end-stage liver disease, suggesting a possible carcinogenic or cocarcinogenic role for iron in chronic liver disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75573/1/j.1478-3231.2007.01596.x.pd

Quantitative morphometric analysis of hepatocellular carcinoma: development of a programmed algorithm and preliminary application

PURPOSEThe quantitative relationship between tumor morphology and malignant potential has not been explored in liver tumors. We designed a computer algorithm to analyze shape features of hepatocellular carcinoma (HCC) and tested feasibility of morphologic analysis. MATERIALS AND METHODSCross-sectional images from 118 patients diagnosed with HCC between 2007 and 2010 were extracted at the widest index tumor diameter. The tumor margins were outlined, and point coordinates were input into a MATLAB (MathWorks Inc., Natick, Massachusetts, USA) algorithm. Twelve shape descriptors were calculated per tumor: the compactness, the mean radial distance (MRD), the RD standard deviation (RDSD), the RD area ratio (RDAR), the zero crossings, entropy, the mean Feret diameter (MFD), the Feret ratio, the convex hull area (CHA) and perimeter (CHP) ratios, the elliptic compactness (EC), and the elliptic irregularity (EI). The parameters were correlated with the levels of alpha-fetoprotein (AFP) as an indicator of tumor aggressiveness. RESULTSThe quantitative morphometric analysis was technically successful in all cases. The mean parameters were as follows: compactness 0.88±0.086, MRD 0.83±0.056, RDSD 0.087±0.037, RDAR 0.045±0.023, zero crossings 6±2.2, entropy 1.43±0.16, MFD 4.40±3.14 cm, Feret ratio 0.78±0.089, CHA 0.98±0.027, CHP 0.98±0.030, EC 0.95±0.043, and EI 0.95±0.023. MFD and RDAR provided the widest value range for the best shape discrimination. The larger tumors were less compact, more concave, and less ellipsoid than the smaller tumors (P < 0.0001). AFP-producing tumors displayed greater morphologic irregularity based on several parameters, including compactness, MRD, RDSD, RDAR, entropy, and EI (P < 0.05 for all). CONCLUSIONComputerized HCC image analysis using shape descriptors is technically feasible. Aggressively growing tumors have wider diameters and more irregular margins. Future studies will determine further clinical applications for this morphologic analysis

Genome-wide association study of iron traits and relation to diabetes in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL): potential genomic intersection of iron and glucose regulation?

Genetic variants contribute to normal variation of iron-related traits and may also cause clinical syndromes of iron deficiency or excess. Iron overload and deficiency can adversely affect human health. For example, elevated iron storage is associated with increased diabetes risk, although mechanisms are still being investigated. We conducted the first genome-wide association study of serum iron, total iron binding capacity (TIBC), transferrin saturation, and ferritin in a Hispanic/Latino cohort, the Hispanic Community Health Study/Study of Latinos (>12 000 participants) and also assessed the generalization of previously known loci to this population. We then evaluated whether iron-associated variants were associated with diabetes and glycemic traits. We found evidence for a novel association between TIBC and a variant near the gene for protein phosphatase 1, regulatory subunit 3B (PPP1R3B; rs4841132, β = -0.116, P = 7.44 × 10-8). The effect strengthened when iron deficient individuals were excluded (β = -0.121, P = 4.78 × 10-9). Ten of sixteen variants previously associated with iron traits generalized to HCHS/SOL, including variants at the transferrin (TF), hemochromatosis (HFE), fatty acid desaturase 2 (FADS2)/myelin regulatory factor (MYRF), transmembrane protease, serine 6 (TMPRSS6), transferrin receptor (TFR2), N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2), ABO blood group (ABO), and GRB2 associated binding protein 3 (GAB3) loci. In examining iron variant associations with glucose homeostasis, an iron-raising variant of TMPRSS6 was associated with lower HbA1c levels (P = 8.66 × 10-10). This association was attenuated upon adjustment for iron measures. In contrast, the iron-raising allele of PPP1R3B was associated with higher levels of fasting glucose (P = 7.70 × 10-7) and fasting insulin (P = 4.79 × 10-6), but these associations were not attenuated upon adjustment for TIBC-so iron is not likely a mediator. These results provide new genetic information on iron traits and their connection with glucose homeostasis

Prevalence of Suspected Nonalcoholic Fatty Liver Disease in Hispanic/Latino Individuals Differs by Heritage

Non-alcoholic fatty liver disease (NAFLD) was shown to disproportionally affect Hispanic persons. We examined the prevalence of suspected NAFLD in Hispanic/Latino persons with diverse backgrounds