The goal of chronic hepatitis C treatment is to remove the virus to avoid progression of HCV-related disease. Sustained virologic response (SVR) is the most widely used efficacy endpoint in clinical ...studies of hepatitis C, and represents the eradication of HCV from the body. The aim of the current review was to examine the long-term clinical, economic and quality of life benefits associated with achieving SVR.
A systematic literature review was performed using the PubMed, EMBASE and Cochrane library databases to identify articles examining the clinical, economic and quality of life benefits associated with SVR, published in English language from 2002-2013. For inclusion studies were required to enroll ≥100 patients and to report clinical endpoints including hepatocellular carcinoma, overall- or liver-related mortality, or progression of disease/complications (e.g. portal hypertension, esophageal varices). Review of economic studies on cost/cost-effectiveness of achieving SVR were focused on studies assessing boceprevir/telaprevir plus pegIFN and ribavirin as this represents the current standard of care in several jurisdictions worldwide. Quality of life evidence was required to use validated quality of life instruments and provide a quantitative analysis of the impact of SVR versus no treatment or treatment failure.
SVR is durable with late relapse rates over 4-5 year periods being in the range of 1-2%. Patients who achieve SVR frequently demonstrate some regression of fibrosis/cirrhosis and have a substantially reduced risk for hepatocellular carcinoma (relative risk RR 0.1-0.25), liver-related mortality (RR 0.03-0.2) and overall mortality (RR 0.1-0.3) in comparison with no treatment or treatment failure. In the 5 years post-treatment, medical costs for patients achieving SVR are 13-fold lower than patients not achieving SVR. Patients who achieve SVR also have health state utility values that are 0.05 to 0.31 higher than non-responders to treatment.
SVR represents the fundamental goal of antiviral treatment for patients infected with chronic HCV, so as to reduce risk of liver disease progression. Achievement of SVR has implications beyond those of clearing viral infection; it is associated with improved long-term clinical outcomes, economic benefits and improved health-related quality of life.
Activated protein C resistance (APCR) reflects a hemostatic state defined by a reduced ability of activated protein C (APC) to affect an anticoagulant response. This state of hemostatic imbalance is ...characterized by a heightened risk of venous thromboembolism. Protein C is an endogenous anticoagulant that is produced by the hepatocytes and undergoes proteolysis-mediated activation to APC. APC in turn degrades activated Factors V and VIII. APCR describes a state of resistance by activated Factors V and VIII to APC-mediated cleavage of these factors, thereby promoting amplified thrombin production and a potentially procoagulant state. This resistance of APC may be inherited or acquired. Mutations in Factor V are responsible for the most frequent form hereditary APCR. The predominant mutation, a G1691A missense mutation at Arginine 506, the so-called Factor V Leiden FVL, causes a deletion of an APC-targeted cleavage site in Factor Va, thereby rendering it resistant to inactivation by APC. There are a variety of laboratory assays for APCR, but this chapter focuses on a procedure using a commercially available clotting assay that utilizes a snake venom and ACL TOP analyzers.
Enlarge! CH bond activation and β‐carbon elimination are combined in a net intramolecular hydroacylation of alkylidenecyclobutanes and alkylideneazetidines in the presence of rhodium catalysts, ...affording eight‐membered‐ring compounds in high yield (see scheme). This study demonstrates the possibility of exploiting the strain energy of azetidines through β‐carbon elimination in new transition‐metal‐catalyzed reactions.
Background. We determined temporal trends (1985–2011) in hepatitis C virus (HCV) incidence and associated behavioral exposures for people who inject drugs (PWID) from the United States (Boston, ...Baltimore, and San Francisco), Canada (Montreal), the Netherlands (Amsterdam), and Australia (Sydney and Melbourne). Methods. Using population-based cohort data from HCV-negative PWID, we calculated overall and within-city HCV incidence trends, HCV rates by study enrollment period (1985–2011), and temporal trends in exposure behaviors. Poisson regression models estimated trends in HCV incidence over calendar-time. Survival models identified risk factors for HCV incidence across cities and estimated independent effects of city and calendar period on HCV infection risk. Results. Among 1391 initially HCV-negative participants followed prospectively (1644.5 person-years of observation PYO), 371 HCV incident infections resulted in an overall incidence of22.6per 100 PYO (95% confidence interval CI, 20.4–25.0). Incidence was highest and remained elevated in Baltimore (32.6/100 PYO), San Francisco (24.7/100 PYO), and Montreal (23.5/100 PYO), lowest in Melbourne and Amsterdam (7.5/100 PYO and 13.1/100 PYO, respectively), and moderate (21.4/100 PYO) in Sydney. Higher rates of syringe and equipment sharing and lower prevalence of opioid agonist therapy were associated with HCV incidence in cities with the highest incidence. Risk for infection dropped by 18% for every 3-year increase in calendar-time (adjusted hazard ratio, 0.8 95% CI, .8–.9) in the multivariable model. Conclusions. Differences in prevention strategies and injecting contexts may explain the ongoing high HCV incidence in these North American cities and emphasize the need for scale-up of opioid agonist therapy and increased coverage of needle and syringe programs in North America.
Background and Aim
Chronic hepatitis C virus (HCV), particularly genotype 1, is associated with insulin resistance (IR) and diabetes. This study evaluated the impact of HCV clearance by all‐oral ...direct‐acting antiviral treatments on IR and glycemic control.
Methods
Included in this prospective case–control study were 133 consecutive HCV‐genotype 1 patients with advance liver fibrosis (F3–F4) without type 2 diabetes. Sixty eight were treated with direct‐acting antiviral and 65 were untreated. Liver fibrosis was assessed by transient elastography. Pre‐treatment, end‐treatment, and 3 months post‐treatment withdrawal IR homeostasis was assessed by homeostatic model assessment (HOMA)‐IR, HOMA‐S, and HOMA‐B.
Results
At baseline, treated, and untreated patients showed similar liver fibrosis levels, HOMA‐IR was 4.90 ± 4.62 and 4.64 ± 5.62, respectively. HOMA‐IR correlated with HCV RNA levels. At the end of treatment, all patients cleared HCV RNA, regardless of liver fibrosis and body mass index, and a reduction in HOMA‐IR at 2.42 ± 1.85 was showed (P < 0.001); in addition, increased insulin sensitivity, decreased insulin secretion, reduction of serum glucose, and insulin levels were observed. Data were confirmed 3 months after treatment withdrawal in the 65 patients who cleared HCV. No variation occurred in untreated patients. Overall, 76.5% of sustained virologic response patients showed IR improvements, of which 41.2% normalized IR. Improvement of IR was strictly associated with HCV clearance; however, patients with the highest levels of fibrosis remain associated with some degree of IR.
Conclusions
The data underline a role of HCV in development of IR and that viral eradication reverses IR and improves glycemic control and this could prevent IR‐related clinical manifestations and complications.
Give me five: Pd‐catalyzed intramolecular C sp 3H arylations have been successfully extended to alkenylations. This method shows remarkable selectivity and gives synthetically useful ...hexahydroindoles, as illustrated with the synthesis of the octahydroindole core of the aeruginosin family of natural products (see picture).
Carbon fibers as key component in short carbon fiber reinforced ceramic matrix composites (CMCs) have obvious influence on their tribological behavior. In this work, we creatively design CMCs with ...five different fiber orientations, namely, randomly oriented fibers, fibers oriented parallel to the friction surface and angled at 0°, 45°, and 90° toward the sliding direction, and standing fibers that are vertical to the friction surface, to investigate fiber orientation dependence of tribological behavior of short carbon fiber reinforced ceramic matrix composites. Tribological tests of CMC brake pads mated with steel disk on a laboratory‐scale dynamometer indicate that short carbon fiber reinforced carbon−silicon carbide (C/C‐SiC) brake pads with fibers orientated at 45° show the best tribological performance among the pads with fibers unidirectionally aligned. C/C‐SiC composites with short carbon fibers randomly distributed, exhibiting excellent tribological properties, are still ideal candidates for manufacturing high performance friction materials.
Background & Aims Inflammation regulated by interleukin (IL) 8 promotes metastasis of hepatocellular carcinoma (HCC). The transcription factor forkhead box C1 (FOXC1) promotes metastasis by ...activating the epithelial to mesenchymal transition; its levels in liver tumors have been associated with shorter survival times of patients. We investigated whether FOXC1 activates inflammation signaling pathways in HCC cell lines. Methods We performed studies in the human HCC cell lines Huh-7 and SMMC7721, as well as the metastatic cell lines MHCC97H and HCCLM3. Cell lines were incubated with IL8 and transcription of reporter genes was measured; cells were also incubated with kinase inhibitors. Levels of FOXC1 or IL8 were knocked down with small interfering messenger RNAs in Huh7 cells; cells were analyzed in vitro in migration and invasion assays. To study metastasis, HCC cells were injected into flanks of BALB/C nude mice; 4 weeks later, the subcutaneous tumor fragments were collected and implanted into livers of the nude mice, and number and size tumors formed were measured. Chromatin immunoprecipitation assays were used to measure binding of transcription factors promoter regions of genes. We measured levels of FOXC1, IL8, CXCR1, and CCL2 in 2 groups of human HCC tissues collected from the Xijing or Tongji Hospitals in China (n = 690 and n = 312 samples, respectively) using immunohistochemistry. Results Incubation of HCC cells with IL8 led to increased expression of FOXC1, via activation of phosphoinositide 3-kinase signaling to AKT and hypoxia-inducible factor 1α. Knockdown of FOXC1 in HCC cells that overexpressed IL8 reduced the numbers of metastases formed in mice, compared with cells without FOXC1 knockdown. Transgenic overexpression of FOXC1 in HCC cells with IL8 knockdown increased the numbers of metastases formed in mice compared with cells without FOXC1 overexpression. CXCR1 and CCL2 were direct transcriptional targets of FOXC1. Knockdown of the combination of CXCR1 and CCL2 reduced the invasive activities of HCC cells that overexpress FOXC1 and formation of lung metastases in mice, and transgenic overexpression of CXCR1 increased cell’s invasive and metastatic abilities after knockdown of FOXC1. Liver metastases grown from cells that overexpressed FOXC1 were infiltrated by tumor-associated macrophages, and CCL2 knockdown decreased tumor-associated macrophage infiltration; depletion of macrophages from mice significantly reduced growth of metastases by cells that overexpressed FOXC1. In human HCC tissues, level of FOXC1 correlated with levels of IL8 and CXCR1 and CCL2 and infiltration of tumors by macrophage. In multivariate analysis, detection of FOXC1 and CCL2 were independent predictors for postoperative recurrence of HCC and overall survival. Conclusions In HCC cell lines, IL8 activates expression of FOXC1 via the phosphoinositide 3-kinase signaling to AKT and hypoxia-inducible factor 1α. FOXC1 expression leads to transactivation of CXCR1 and CCL2, promoting inflammation and the invasive and metastatic abilities of HCC cells.
Summary
Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and ...disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6 358 000 cases in 2008 and Brazil with 2 106 000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV‐infected populations are critical for addressing HCV‐related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.
Sorafenib displays a limited efficacy for advanced hepatocellular carcinoma (HCC). Some patients with HCC initially respond to sorafenib, but eventually succumb to the disease, indicating that the ...acquired resistance to sorafenib reduces its beneficial effects. No alternative drugs are available after the failure of sorafenib therapy. Therefore, investigation of the mechanisms underlying the acquired resistance and development of second‐line treatments for sorafenib‐resistant HCC are urgently required. In this study, sorafenib‐resistant HCC cells generated from sorafenib‐sensitive human HCC cells were shown to overproduce hepatocyte growth factor (HGF) and overexpress c‐Met kinase and its phosphorylated form, leading to the activation of Akt and ERK (extracellular signaling‐regulated kinase) pathways. Use of specific c‐Met inhibitors enhanced the effects of sorafenib by inhibiting the growth of sorafenib‐resistant HCC cells. Akt inhibitors, a class of second‐line therapeutic drugs under investigation for treating HCC in clinical trials, enhanced the effects of sorafenib, but also activated the c‐Met pathway in sorafenib‐resistant cells. Dual inhibition of Akt and c‐Met by their respective inhibitors, MK2206 and capmatinib, additively or synergistically suppressed sorafenib‐resistant HCC cells in vitro and sorafenib‐resistant HCC xenografts in mice. The anticancer activities of MK2206 mainly rely on its ability to induce cell apoptosis and autophagic death, while capmatinib treatment leads to cell cycle arrest at phase G1. These results provide strong evidence for further investigation on the clinical utility of dual inhibition of Akt and c‐Met, particularly MK2206 and capmatinib, as a second‐line therapy for advanced HCC that has acquired resistance to sorafenib.
The activation of HGF/c‐Met pathway contributes to the acquired resistance to sorafenib in hepatocellular carcinoma (HCC) cells. Inhibition of Akt activates the c‐Met pathway via compensatory feedback mechanisms, contributing to the resistance to Akt inhibitors in sorafenib‐resistant HCC cells. Dual inhibition of Akt and c‐Met suppresses sorafenib‐resistant HCC cells and tumors, representing a potential second‐line therapy for HCC that has acquired resistance to sorafenib.
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