March 31, 2012

Science Celebrates Cocoa and Chocolate’s Potential Health Benefits

Released:3/14/2012 11:45 PM EDT
Embargo expired: 3/28/2012 7:30 PM EDT
Source:American Chemical Society (ACS)

EMBARGOED FOR RELEASE: Wednesday, March 28, 2012, 7:30 p.m. Eastern Time
Note to journalists: Please report that this research was presented at a meeting of the American Chemical Society

A press conference on this topic will be held at 2:15 p.m. Eastern Time, March 28, 2012, in the ACS Press Center, Room 15A, in the San Diego Convention Center. Reporters can attend in person or access live audio and video of the event and ask questions at www.ustream.tv/channel/acslive.

Newswise — SAN DIEGO, March 28, 2012 — If eccentric candy-maker Willy Wonka could leap from the pages of Roald Dahl’s classic, Charlie and the Chocolate Factory, and walk these streets, he might make a bee-line for a festival of cocoa and chocolate on the menu today at the 243rd National Meeting & Exposition of the American Chemical Society (ACS).

As the world’s largest scientific society, ACS is hosting a celebration of scientific discoveries about the food that could lay claim to being the world’s favorite treat, comfort food and indulgence. The ACS symposium, titled “Cocoa: Science and Technology,” features 18 reports from international experts on the key ingredient in chocolate — cocoa — and the emerging health benefits and other aspects of the food that has delighted people for almost 2,000 years.

“Chocolate is one of the foods with the greatest appeal to the general population,” said Sunil Kochhar, Ph.D., one of the symposium participants. “The luscious aroma, taste and textures of chocolate have delighted the senses of people in many parts of the world for centuries and make it a well-known comfort food.”

Kochhar, who is with the Nestlé Research Center in Lausanne, Switzerland, is noted for landmark research that is helping to establish chocolate’s potential health benefits. He described one study, for instance, published in the Journal of Proteome Research, one of ACS’s 41 peer-reviewed scientific journals, detailing the biochemical basis for chocolate’s reputation as a comfort food. The study, which included 30 healthy adults, found that eating about an ounce and a half of dark chocolate per day reduced levels of stress hormones and other indicators of emotional anxiety in people who felt stressed-out.

“The flavonoids and other ingredients in chocolate with beneficial health effects originate in cocoa,” Kochhar explained. “In making chocolate, cocoa seeds undergo natural fermentation before being processed into key ingredients for making chocolate — namely cocoa fat and cocoa powder.”

Among other presentations at the symposium, scientists reported:

  • How the introduction of new varieties of the cacao tree that resist “witch’s broom,” a fungal disease that has decimated some crops, may affect the taste of cocoa and chocolate.
  • That chocolate may be useful in treating of diseases involving disorders of the trigeminal nerve, including migraine and temporomandibular joint (TMJ) disorder. The study found evidence that cocoa contains biologically active ingredients that soothe the nerve’s excitability, a probable cause of these disorders.
  • Findings about the biological basis of chocolate’s anti-inflammatory effects. Its rich content of polyphenols inhibit secretion of certain enzymes into the small intestine that cause inflammation.
  • How chocolate may be helpful in fighting cardiovascular problems for individuals with type 2 diabetes. Flavonoids in the chocolate strengthen mitochondria, the powerhouse of body cells, which are in a weakened condition in patients with cardiovascular problems.
  • On chocolate and high blood pressure. They found that flavonoids in chocolate lower blood pressure and thus might help in reducing heart disease risks.
  • A cocoa-rich diet may reduce the risk of colon cancer by preventing undesirable changes in the cells or destroying cells that form precancerous lesions.
  • That epicatechin, a beneficial antioxidant especially rich in dark chocolate, strengthens cell membranes and offers protection from some forms of cardiovascular disease.
  • Feeding chocolate to animals in laboratory experiments helped protect their livers from damage that can lead to liver disease.
  • Chocolate consumption may be especially beneficial for cigarette smokers. Polyphenols in the dark chocolate act on blood platelets to prevent clot formation.

The American Chemical Society is a non-profit organization chartered by the U.S. Congress. With more than 164,000 members, ACS is the world’s largest scientific society and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.

To automatically receive news releases from the American Chemical Society contact newsroom@acs.org.

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Selected abstracts from the symposium “Cocoa: Science and Technology” follow.

Abstracts

Cocoa and chocolate: The science of delightSunil Kochhar1, Nestle Research Center, P O Box 44, Lausanne-26, Vaud, Switzerland , 412 178 49336, sunil.kochhar@rdls.nestle.com
Chocolate is one of the foods with the greatest appeal to the general population. The attractive tastes and textures of chocolate and chocolate products delight the senses and make it a well-known comfort food. Cocoa seeds undergo natural fermentation before they are turned into a key ingredient for chocolate making namely cocoa fat and cocoa powder. The latter is indeed rich source of peptides and flavonoids, and produces the delectable taste and aroma of chocolate after roasting. In spite of a large body of literature on the cocoa flavor, there are very few studies devoted to the role of proteins/peptides in the flavor development of cocoa or chocolate. Cocoa storage proteins, which makes up to 10-15 % (w/w) dry weight, is made up of four predominant proteins of apparent molecular weight 14.5-, 31- and 47-kDa and 21-kDa representing 95 % (w/w) of total protein. We developed an in-vitro fermentation process of cocoa beans, mimicking the natural fermentation and identified a number short-chain peptides originating from storage proteins that are the key cocoa/chocolate flavor precursors. The presentation will cover the characterization of proteins and peptides and flavor precursors. Additionally, results from a recent study employing metabolomics approach to study the possible metabolic signatures linked to the regular intake of dark chocolate in healthy subjects will be presented. In summary, metabolic profiles of plasma and urine samples when combined with multivariate statistics show discrimination of subjects according to their chocolate liking as given by the scoring to the questionnaire on chocolate consumption. The class separation using plasma metabolic profiles was present even from samples collected before the chocolate intake, supporting most likely the occurrence of metabolic imprint or memory independent of the chocolate intake. Results indicate that subjects who do not like chocolate harbour statistically different lipoprotein profile in the postprandial phase.

Labels on chocolate bars: An accurate number for consumers to determine relative antioxidant contentJoe A Vinson1, Prof, PhD, University of Scranton, Department of Chemistry, Loyola Hall, University of Scranton, PA, 18510, United States , 570-941-7551, vinson@scranton.edu
There has been a dramatic increase in articles published about chocolate and health, especially related to heart disease and diabetes. Currently on the labels of many chocolate bars are % cacao solids (CS). But does this number have any relationship with the amount of polyphenol antioxidants in the product? Our group analyzed 31 commercial pure chocolate bars that have % CS on the label by Folin and FRAP. The catechin equivalents of the defatted extracts were corrected to determine polyphenols (µmol/g) in the chocolate bar. Foreign bars (milk and dark chocolate combined) have more antioxidants than domestic bars with the same % CS on the label. There is a significant linear relationship between % CS on the label and polyphenol content with both Folin and FRAP. Thus the consumer can know that 70% CS has about twice as much total antioxidants per serving as a bar with 35% CS.

Regulation of inflammatory proteins in trigeminal ganglion and trigeminal nucleus caudalis in response to cocoa enriched diets: Implications for migraine and TMJ disorderPaul L Durham1, Dr., PhD, 524 N Boonville, Springfield, MO, 65806, United States , 417-836-3026, pauldurham@missouristate.edu
The objective of our research was to investigate the cellular effects of a cocoa-enriched diet on neurons and glia in the trigeminal ganglia and trigeminal nucleus caudalis under basal conditions, and in response to acute or chronic inflammation. Sprague Dawley rats were fed a control diet or isocaloric diets enriched in cocoa for 14 days prior to injection of capsaicin or complete Freund's adjuvant (CFA). The stimulated expression of proteins associated with promoting and maintaining inflammatory and nociceptive responses were repressed in animals on a cocoa enriched diet. The inhibitory effects of cocoa are likely to be mediated via increased basal expression of the anti-inflammatory proteins MKP-1, MKP-3, and IL-10. Data from our study provide evidence that cocoa contains biologically active ingredients that modulate neuronal excitability, and thus, cocoa would be beneficial as a nutraceutical for the treatment of diseases involving trigeminal nerve activation such as migraine and TMJ disorder.

Alterations in skeletal muscle indicators of mitochondrial structure and biogenesis in patients with type 2 diabetes and heart failure: Effects of epicatechin rich cocoaFrancisco Villarreal1, Dr., MD, PhD, UCSD, Medicine, 9500 Gilman Dr., La Jolla, CA, 92093, United States , 858-534-3630, fvillarr@ucsd.edu
(-)-Epicatechin (Epi), a flavanol in cacao stimulates mitochondrial volume and cristae density and protein markers of skeletal muscle (SkM) mitochondrial biogenesis in mice. Type 2 diabetes mellitus (DM2) and heart failure (HF) are diseases associated with defects in SkM mitochondrial structure/function. A study was implemented to assess perturbations and to determine the effects of Epi-rich chocolate in SkM mitochondrial structure and mediators of biogenesis. Five patients with DM2 and stage II/III HF consumed dark chocolate containing ~100 mg of Epi/day for 3 months. We assessed changes in protein and/or activity levels of oxidative phosphorylation proteins, porin, mitofilin, nNOS, nitric oxide , cGMP, SIRT1, PGC1α, Tfam and, mitochondria volume and cristae abundance by electron microscopy from SkM. Apparent major losses in mitochondria structure and mediators of biogenesis were observed prior to treatment. Epi-rich cocoa increased protein and/or activity of these molecules as well as cristae abundance while not changing mitochondria volume density. Epi-rich cocoa treatment improves SkM mitochondrial structure and in an orchestrated manner, increases molecular markers of mitochondrial biogenesis resulting in enhanced cristae density. Future controlled studies are warranted using Epi-rich cocoa (or pure Epi) to translate improved mitochondrial structure into enhanced cardiac and/or SkM muscle function.

Dark chocolate inhibits platelet isoprostanes via nox2 down-regulation in smokersPasquale Pignatelli1, Md, PhD, Sapienza, University of Rome, Internal Medicine and Medical Specialities, Viale del Policlinico, Rome, Rm, Italy , 0039-6-4997-7777, pasquale.pignatelli@uniroma1.it

Dark chocolate receptors: Epicatechin-induced cardiac protection is dependent on delta-opioid receptor stimulation and altered membrane dynamics
Hemal H. Patel1,2, PhD, University of California, San Diego, Anesthesiology, VA San Diego Healthcare System, #125, 3350 La Jolla Village Dr., San Diego, CA, 92161, United States , 619-534-4906, hepatel@ucsd.edu Epicatechin, a dark chocolate flavonol/antioxidant, is linked to cardiovascular cytoprotection. Low-dose epicatechin, with little antioxidant activity, is protective; however, the mechanism of this cytoprotection is unknown. We tested if epicatechin mediates cardiac protection via delta opioid receptor (DOR) activation and modulation of membrane ultrastructure. Myocardial infarct size was decreased in epicatechin-treated mice compared to controls, and this effect was blocked by a DOR antagonist. Epicatechin increased phosphorylation of Src, Akt, and IκBα and decreased expression of c-Jun NH(2)-terminal kinase expression and caspase-activated DNase. DOR attenuated these signaling effects. Lipid rafts are critical for cardiac protection. The effect of epicatechin on cardiac myocyte membrane dynamics was examined with electron paramagnetic resonance (EPR) spectroscopy. Epicatechin increased membrane order parameter (decreased membrane fluidity) when compared to vehicle treated myocytes, an effect blocked by naloxone. In conclusion, epicatechin alters membrane dynamics and acts via DOR to produce cardiac protection from ischemia-reperfusion injury.

Systemic absorption and metabolism of proanthocyanidins in pigs
Hans-Ulrich Humpf1, Prof. Dr., University of Muenster, Institute of Food Chemistry, Corrensstr. 45, Muenster, NRW, 48149, Germany , +49 251 83 33391, humpf@uni-muenster.de

Cocoa, blood pressure and cardiovascular risk
Davide Grassi1, Dr, MD, PhD, University of L'Aquila, Internal Medicine and Public Hear, Viale S. Salvatore, Building Delta 6, L'Aquila, Italia, 67100, Italy , 0039 0862 434749, 0039 0862 434749, davide.grassi@cc.univaq.it Flavonoids from cocoa might exert some beneficial vascular effects and reduce the risk of cardiovascular morbidity and mortality. We observed that flavanol-rich but not flavanol-free chocolate administration was able to significantly lower both SBP and DBP in healthy subjects and in hypertensive patients with and without glucose intolerance. Further, flavanol-rich chocolate administration significantly improved nitric oxide-dependent flow-mediated dilation (FMD). Accordingly, different meta-analysis, on the effectiveness of flavonoid-rich foods on cardiovascular disease, reported that chocolate and cocoa intake significantly reduced SBP (-5.88 mmHg) and DBP (-3.30 mmHg). The antihypertensive responses observed support the inclusion of moderate amounts of flavanol-rich cocoa in the daily diet to potentially delay the onset of hypertension or ameliorate its control. Practicability of cocoa products as part of a long-term treatment for hypertension has yet to be completely explained. Further investigation on the dose-dependent and long-term effects of cocoa products should clarify these critical points.

Storage induced changes in lipid polymorphism in dark chocolate
Nicki J Engeseth1, Professor, Ph.D., University of Illinois, Food Science & Human Nutrition, 905 S. Goodwin, 208 Bevier, Urbana, IL, 61801, United States , 217-244-6788, engeseth@illinois.edu Chocolate is cocoa mass and sugar suspended in a cocoa butter matrix. Cocoa butter can crystallize in six structures, called polymorphs. Triglycerides reorganize to polymorph VI during long-term storage. Structural changes occur that are magnified with improper storage. Impact of storage conditions on polymorph transition and relationship to perception of chocolate flavor and texture were studied. Long term storage significantly impacts polymorph transition and flavor and texture of chocolate. Rate of polymorphic transition is often exacerbated by temperature cycling, typically used in research. Temperature cycling using different cycling regimes was conducted. Key differences between regimes revealed issues related to emulsification, leading to chocolate formulation with 3 emulsifiers. Chocolate formulated with these emulsifiers was subject to temperature cycling and long term storage. Key differences between emulsifiers and conditions will be highlighted. Future studies are aimed at compositional and structural information about triglycerides with different emulsifiers and use of novel processing strategies.

Cocoa flavonoids and effects on cardiovascular risk factors: Meta-analysis of randomized controlled trials
Eric L Ding1, PhD, Harvard Medical School, Brigham & Women's Hospital, Harvard School of Public Health, 655 Huntington Ave, Building 2, Department of Nutrition, Boston, Massachusetts, 02115, United States , 617-466-9626, eding@jhu.edu A growing body of evidence suggests that the consumption of foods rich in polyphenolic compounds—particularly cocoa—may have cardioprotective effects. No review, however, has yet examined the effect of flavonoid-rich cocoa on all major cardiovascular risk factors or has examined potential dose-response relationships for these effects. A systematic review and meta-analysis of randomized, controlled trials was performed to evaluate the effect of flavonoid-rich cocoa (FRC) on cardiovascular risk factors and to assess a dose-response relationship. Inclusion and exclusion criteria, as well as dependent and independent variables, were determined a priori. Data were collected for: blood pressure, pulse, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, BMI, C-reactive protein, flow-mediated vascular dilation (FMD), fasting glucose, fasting insulin, serum isoprostane, and insulin sensitivity/resistance indices. Twenty-four papers, with 1106 participants, met criteria for final analysis. In response to FRC consumption, systolic blood pressure decreased by 1.63 mmHg (p=0.033), LDL cholesterol decreased by 0.077 mmol/L (p=0.038), and HDL cholesterol increased by 0.046 mmol/L (p=0.037), while total cholesterol, triglyceride, and CRP remained the same. Moreover, insulin resistance decreased (HOMA-IR: –0.94 points, p<0.001), while FMD increased (1.53%, p<0.001). A non-linear dose-response relationship was found between FRC and FMD (p=0.004), with maximum effect observed at a flavonoid dose of 500mg/day; a similar relationship may exist with HDL cholesterol levels (p=0.06). FRC consumption significantly improves blood pressure, insulin resistance, lipid profiles, and FMD. These short-term benefits warrant larger long-term investigations into the cardioprotective role of flavonoid-rich cocoa.

Dietary-feeding of cocoa prevents colonic preneoplastic lesions in azoxymethane-treated rats
Maria Angeles Martin1, ICTAN-CSIC, Department of Metabolism of Nutrition, C/ Jose Antonio Novais, 10, Madrid, Madrid, Spain , +34 915445607, amartina@ictan.csic.es Cocoa is a rich source of bioactive compounds with potential chemopreventive ability but up to date its effectiveness in animal models of colon carcinogenesis has not been addressed. Herein, we have used the well-defined azoxymethane (AOM)-induced colon cancer model in rats to investigate the ability of a cocoa enriched diet in preventing the early phase of chemically induced colorectal cancer. Our results showed that cocoa feeding significantly reduced AOM-induced colonic aberrant crypt foci formation and crypt multiplicity. Oxidative imbalance in colon tissues seems to be prevented by cocoa as indicated by reduced oxidation markers levels and increased enzymatic and non-enzymatic endogenous defences. Cocoa-rich diet also decreased the levels of proliferative and proinflammatory markers and induced pro-apoptotic effects. These findings provide evidences that a cocoa-rich diet may inhibit the early stage of colon carcinogenesis probably by preventing oxidative stress and cell proliferation and by inducing apoptosis.

Unraveling the cocoa bean fermentation process opens new perspectives for chocolate production
Luc De Vuyst1, Prof. Dr. ir., PhD, Vrije Universiteit Brussel, Research Group of Industrial Microbiology and Food Biotechnology, Pleinlaan 2, Brussels, Belgium, B-1050, Belgium , +32-2-6293245, ldvuyst@vub.ac.be Cocoa fermentations are still carried out spontaneously. Once cocoa pods are opened, cocoa pulp-bean mass is inoculated by surrounding microbiota, which develop fast and selectively and ferment it for six days. A correct succession of microbial activities guarantees a successful fermentation process. Investigations of this process in several countries unraveled that always the same species of yeast, lactic acid bacteria, and acetic acid bacteria dominate the fermentation, independent of fermentation method and cocoa population, provided that good agricultural, fermentation and drying practices are applied. Several strains were tested in appropriate cocoa pulp simulation media to unravel their functional roles as well as in plastic vessels containing fresh cocoa pulp-bean mass as to their capacity to dominate the cocoa fermentation process. This procedure allowed us to develop a starter culture composed of Saccharomyces cerevisiae, Lactobacillus fermentum, and Acetobacter pasteurianus to improve the cocoa fermentation process. Uniformly fermented cocoa beans were obtained after four days of fermentation resulting in chocolate with standard flavor profiles.

Functional foods and food security: Cocoa mass and chocolates produced from "Witch Broom Disease” resistant cultivars of Brazil
Leonardo Fonseca Maciel1, Federa University of Bahia, Department of Bromatological Analysis, Rua Barão de Jeremoabo S/N Campus Universitário de Ondina, Faculdade de Farmácia, Ondina, Salvador, Bahia, 40170115, Brazil , 557132836970, lfmaciel@ufba.br The chocolate flavor is composed by many compounds whose formation depends on the genetic background and environment where cocoa is grown, as well as processing operations that begin on the farm and continue in the industries that process cocoa and chocolate. Cocoa production in Brazil suffered a sharp decline in the last two decades, due to a disease knowing as “witch broom disease” (Moniliophtora perniciosa). Trying to overcome this problem, cultivars resistant to fungus were obtained. Thus this study was carried out to evaluate the antioxidant capacity, phenolic compounds profile and mycotoxins (aflatoxin and ochratoxin) content from new cacao cultivars resistant to "witch broom disease” that were monitored during fermentation. Fruits of the new cocoa cultivars (SR162 and PH16), both resistant to “witch broom disease”, were studied and compared to conventional cocoa.

Cocoa-rich diet attenuates N-nitrosodiethylamine-induced liver injury in rats
Sonia Ramos1, ICTAN-CSIC, Department of Metabolism and Nutrition, Jose Antonio Novais 10, Madrid, Madrid, 28040, Spain , +34915492300, s.ramos@ictan.csic.es Cocoa has increasingly attracted attention due to its biological properties. The objective was to investigate the effects of cocoa feeding against N-nitrosodiethylamine (DEN)-induced liver injury in rats. Male rats were divided into five groups. Groups 1 and 2 were fed with standard and cocoa diet, respectively. Groups 3 and 4 were injected with DEN at 2 and 4 weeks, and fed with standard and cocoa diet, respectively. Group 5 was treated with DEN, received the standard diet for 4 weeks and then it was replaced by the cocoa-diet. The cocoa-rich diet prevented the reduction of hepatic glutathione concentration and catalase and GPx activities in DEN-injected rats, and diminished protein carbonyl content, caspase-3 activity, p-AKT and p-JNK levels, and increased GST activity. Cocoa administration did not abrogate the DEN-induced body weight loss, the increased levels of hepatic-specific enzymes and LDH. These results suggested that cocoa-rich diet attenuates the DEN-induced liver injury.

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EEOC Sues AT&T for Disability Discrimination

Saturday, March 31, 2012 :: Staff infoZine

Employee With Hepatitis C Fired for Taking Approved Disability Leave, Federal Agency Charges

Indianapolis, IN - infoZine - The U.S. Equal Employment Opportunity Commission (EEOC) filed suit against AT&T Corp., a leader in telecommunication services, for failing to reasonably accommodate a long-term employee’s disability and then firing her because of that disability.

According to the EEOC’s suit, Lupe Cardona, who worked for AT&T Corp. as a customer service representative in Indianapolis from 1984, requested a reasonable accommodation in the form of a finite leave of absence in order to receive interferon treatment for Hepatitis C. Without the treatment, her disease could have eventually been fatal. Upon learning of Cardona’s disability and need for a leave of absence, AT&T granted her leave request. Thus, Cardona was on an approved, paid medical leave of absence from June 24 to Oct. 24, 2010, when her physician determined the treatment was successful and released her to return to work without restriction. Two days later, AT&T fired her, claiming her use of approved leave to receive life-saving treatment violated its attendance policy. AT&T refused to provide Cardona a reasonable accommodation by exempting her leave of absence from its no-fault attendance policy.

Such alleged conduct violates the Americans With Disabilities Act (ADA). The EEOC filed suit after first attempting to reach a pre-litigation settlement through its conciliation process. The EEOC filed its lawsuit in U.S. District Court for the Southern District of Indiana (EEOC v. AT&T Corp., Civil Case No.: 1:12-cv-0402-TWP-DKL) after first attempting to reach a pre-litigation settlement through its conciliation process. The EEOC’s lawsuit seeksback pay, compensatory and punitive damages and reinstatement or front pay for Cardona as well as injunctive relief, including a court order prohibiting AT&T from failing to provide reasonable accommodation to disabled employees by counting absences caused by their disability as “chargeable,” or unprotected, absences under its attendance policy.

“The refusal of AT&T to make a perfectly reasonable exception to its draconian attendance policy to accommodate the known disability of an employee violated federal law as well as common sense and common decency,” said EEOC trial attorney Patrick Holman.

Barbara A. Seely, regional attorney of the EEOC’s St. Louis District Office, added, “This employer’s conduct is precisely what Congress had in mind when enacting the ADA. The very essence of reasonable accommodation is making exceptions to hard-and-fast rules in circumstances like this when to do so causes no undue hardship to the employer – and failing to do so might cause grave harm. AT&T’s actions here were not only baffling, but downright cruel.”

The EEOC is responsible for enforcing federal laws against employment discrimination. Further information is available at www.eeoc.gov.

Source

Nurse lobbying for hep C treatment changes

By Jenn McGarrigle - Nanaimo News Bulletin
Published: March 31, 2012 1:00 PM

A Nanaimo nurse is part of a group lobbying for expanded PharmaCare coverage for patients suffering from hepatitis C.

Fran Falconer, the mid-Island's only hepatitis support nurse and a volunteer with the non-profit group HepCBC, chaired a public forum in Victoria earlier this month on new treatment guidelines developed by the Canadian Association for the Study of the Liver.

"We hosted the meeting to push the government to make changes," she said.

Hepatitis C is a disease of the liver caused by the hepatitis C virus (HCV). If left untreated or uncured, it can result in end-stage liver failure, leading to organ transplant or death.

Provincial statistics indicate there are about 64,000 British Columbians currently diagnosed with hepatitis C, of whom about 25 per cent have cleared their infection without treatment, much the way people get rid of a flu virus.

HepCBC, a non-profit organization run by and for people infected with or affected by hep C, estimates about 60 per cent of people with the virus will have a long-term infection that causes no problems or causes levels of liver damage ranging from mild to serious.

Falconer said the group already got one of the things it wants – the province announced this week it has approved PharmaCare coverage for a new drug for hep C genotype 1 patients, which is proven to enhance cure rates.

Without coverage, the drug cost patients about $1,000 per week.

Falconer said the next step is to expand PharmaCare coverage to all patients who want treatment and are unable to fight off the virus on their own.

An HCV patient must prove damage to the liver before the province will cover costs of treatment, she said.

"This is a virus that is attacking the liver," said Falconer. "Why are we waiting until there is significant damage? The earlier we treat, the less sick people are, so treatment is more effective."

Treating patients before damage occurs is more cost-effective because caring for patients with health issues resulting from hep C is much more costly, she said.

"An ounce of prevention is worth a pound of cure," said Falconer. "We want equal opportunity for all patients to access care. When people have diabetes, they get treated. Patients with hepatitis C have to qualify."

She also wants more people to get tested – advocates believe there are many people infected who don't know it because they do not have symptoms.

"We call this disease the silent epidemic," said Falconer.

She said intravenous drug users are not the only population at risk – the virus is spread through direct contact with the blood of an infected person and some baby boomers might have been exposed through blood transfusions, tattoos or piercings.

Dr. Paul Hasselback, medical health officer with the Vancouver Island Health Authority, said anyone who received a blood transfusion before 1990 should be tested, as that's when hep C screening began.

He said the health authority is not seeing as many "new" cases as it is finding people who were infected when they were younger – symptoms take years to develop – and in recent years, an average of 80 people per year in Nanaimo are diagnosed.

"There's still probably a significant number who are not aware," said Hasselback.

He said the Canadian Association for the Study of the Liver's new treatment guidelines are a reflection of a better understanding of the hep C virus and the health authority does look at these recommendations, although it is up to the province to make funding decisions.

In an e-mail, the Ministry of Health said the province spends more than $100 million per year on prevention, education and treatment of hepatitis C and because many patients will recover from hepatitis on their own, providing pharmaceutical interventions to all who contract it would result in spending millions more unnecessarily.

Source

Complex answer: Finding hepatitis C antivirals

SN79a_X_hep

A benzimidazole prompts the RNA of hepatitis C to open up a portion of its hinge-like structure and encapsulate the inhibitor

[April 1, 2012]

Attacking hepatitis

Hepatitis C is a chronic infectious disease that afflicts some 170 million people worldwide, causing chronic liver disease and liver cancer. Chemists at the University of California, San Diego have finally obtained the first high- resolution crystal structure of a compound that binds to the genetic material of the hepatitis C virus and blocks its replication.

Hepatitis C, according to the US Centers for Disease Control and Prevention, now kills more Americans each year than HIV/AIDS. Finding antiviral agents is thus an important quarry. Until early in 2011, with the approval of two protease inhibitors against HCV infection, there were no small molecule pharmaceuticals for attacking the virus. Indeed, the conventional therapy consisted of an immunostimulatory regimen of interferon and ribavirin, but this is not particularly effective and has several side effects. Moreover, the virus mutates rapidly with low RNA fidelity of certain enzymes from generation to generation and so there are already pre-existing drug-resistance mutations in HCV. Combination therapy with novel antiviral agents is the way forward.

Now, Thomas Hermann and colleagues Sergey Dibrov, Kejia Ding, Nicholas Brunn, Matthew Parker, Mikael Bergdahl and David Wyles at UCSD and San Diego State University, explain how the internal ribosome entry site (IRES) in the hepatitis C virus (HCV) RNA genome is "essential for the initiation of viral protein synthesis". They point out that the IRES domains adopt well-defined structures, or folds, that are could be targeted with antiviral agents that block translation. As such, the team has now determined the three-dimensional structure of the IRES subdomain IIa complexed to which is a benzimidazole translation inhibitor.

The 2.2 Å resolution structure has allowed the team to compare the unbound RNA in conjunction with solutions studies of the inhibitor bound to the target and so reveal that the ligand causes the RNA to undergo a dramatic conformational change. This adaptation leads to the formation of a deep pocket resembling the substrate binding sites in riboswitches, the team explains. "The presence of a well-defined ligand-binding pocket within the highly conserved IRES subdomain IIa holds promise for the development of unique anti-HCV drugs with a high barrier to resistance," the team explains.

Lethal inhibitions

Hermann and colleagues describe details of the complex structure in the journal Proceedings of the National Academy of Sciences and suggest that the research could provide a useful model for the design of pharmaceuticals to inhibit hepatitis C virus. This is a particularly critical avenue of investigation as there are currently no available vaccines against this potentially lethal virus.

"The lack of detailed information on how inhibitors lock onto the viral genome target has hampered the development of better drugs," explains Hermann. "This structure will guide approaches to rationally design better drug candidates and improve the known benzimidazole inhibitors," he adds. "Also, the crystal structure demonstrates that the binding pocket for the inhibitors in the hepatitis C virus RNA resembles drug-binding pockets in proteins." This, Hermann points out, is an important aspect of the research as it could help scientists to overcome the perceived notion that RNA targets are too unlike traditional protein targets to be a useful focus for the discovery of small molecule inhibitors.

The discovery of a deep solvent-excluding inhibitor binding pocket in the highly conserved subdomain IIa of the HCV IRES adds, what the team refers to as "a unique dimension to the repertoire of targets for anti-HCV therapy". The architecture of the well-defined benzimidazole binding site will be a valuable starting point for the structure-based design of HCV inhibitors, supported by the notion of viral translation as an attractive therapeutic target," the team concludes.

Related links

  • Proc Natl Acad Sci, 2012, Online: "Structure of a hepatitis C virus RNA domain in complex with a translation inhibitor reveals a binding mode reminiscent of riboswitches"

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Public release date: 31-Mar-2012

Contact: Karen Warmkessel
kwarmkessel@umm.edu
410-328-8919
University of Maryland Medical Center

Researchers find metformin inhibits fatty acid synthesis, ability of cancer cells to reproduce

Baltimore, MD – March 31, 2012. Metformin, a drug widely used to treat Type II diabetes, may help to prevent primary liver cancer, researchers at the University of Maryland Marlene and Stewart Greenebaum Cancer Center report in the April 2012 issue of Cancer Prevention Research. Primary liver cancer, or hepatocellular carcinoma, is an often-deadly form of cancer that is on the rise worldwide and is the fastest-growing cause of cancer-related deaths among American men.

Patients with Type II diabetes have a two- to three-fold increased relative risk of developing primary liver cancer. Also at risk are people who are obese, have hepatitis or non-alcoholic fatty liver disease (NAFLD). Metformin, which is derived from the French lilac, is used to treat NAFLD as well as diabetes, and currently is being studied in connection with the prevention of a variety of cancers. This pre-clinical study is the first to focus on liver cancer.

"Our research demonstrated that metformin prevents primary liver cancer in animal models. Mice treated with metformin had significantly smaller and fewer tumors than those who did not receive the medication," says the study's senior author, Geoffrey D. Girnun, Ph.D., assistant professor of biochemistry and molecular biology at the University of Maryland School of Medicine and a research scientist at the University of Maryland Greenebaum Cancer Center. "Based on these findings, we believe metformin should be evaluated as a preventive agent in people who are at high risk. Many patients with diabetes already are taking this medication, with few side effects."

Dr. Girnun adds, "There have been several retrospective epidemiological studies linking metformin with reduced risk of liver cancer, but our study is the first to formally test whether metformin can protect against carcinogenesis – not just tumor growth and development, but actual tumor formation in the liver." He says he will seek federal funding for a clinical trial to study the anti-cancer effects of metformin in patients who have Type II diabetes.

E. Albert Reece, M.D., Ph.D., M.B.A., vice president of medical affairs at the University of Maryland and dean of the University of Maryland School of Medicine, says, "Hepatocellular carcinoma represents a serious public health threat worldwide. With the alarming increases in obesity, Type II diabetes and hepatitis B and C, an even greater number of people will be at risk of developing this cancer in the future. Not only do we need to find more effective treatments, we must also find ways to prevent it. This study conducted by Dr. Girnun and his colleagues is an excellent first step that may ultimately help us to prevent liver cancer in targeted populations."

Kevin J. Cullen, M.D., professor of medicine at the University of Maryland School of Medicine and director of the University of Maryland Greenebaum Cancer Center, says, "This study increases our knowledge of cancer cell metabolism and offers new insights into a possible mechanism for preventing a difficult-to-treat cancer. Translational research is an important focus of our cancer center, and we plan to continue this important area of research as part of a clinical study to determine if there is a possible benefit to patients."

The study is featured on the cover of Cancer Prevention Research, a journal published by the American Association for Cancer Research. Kavita Bhalla, Ph.D., a postdoctoral fellow at the University of Maryland School of Medicine and a Greenebaum Cancer Center research scientist, is the lead author.

Glucose is converted into fatty acids in the liver through a process called lipogenesis. This process is increased in people who have diabetes, hepatitis, fatty liver disease as well as cancer. Dr. Girnun says metformin reduces the level of glucose and inhibits this fatty acid synthesis. "When you block this process, you prevent the cells from making more building blocks to make more cells. There is also no energy to put the building blocks together, and the cells are not able to proliferate, thereby preventing tumors from developing," he explains.

In the study, researchers found that mice treated with metformin in their food developed 57 percent fewer liver tumors than the mice that did not receive the drug; the size of the tumors was reduced by about 37 percent.

###

About the University of Maryland School of Medicine

Established in 1807, the University of Maryland School of Medicine is the first public medical school in the United States, and the first to institute a residency-training program. The School of Medicine was the founding school of the University of Maryland and today is an integral part of thSourcee 11-campus University System of Maryland. On the University of Maryland's Baltimore campus, the School of Medicine serves as the anchor for a large academic health center which aims to provide the best medical education, conduct the most innovative biomedical research and provide the best patient care and community service to Maryland and beyond. www.medschool.umaryland.edu.

About the University of Maryland Marlene and Stewart Greenebaum Cancer Center

The University of Maryland Marlene and Stewart Greenebaum Cancer Center is a National Cancer Institute-designated cancer center, which is part of the University of Maryland Medical Center and the University of Maryland School of Medicine. The center is recognized for its active clinical and basic science research program. It has comprehensive programs to treat all types of cancer and is a major referral center for patients throughout Maryland and the region. It is recognized as one of the top 25 cancer centers in the nation by U.S. News and World Report. For more information about the center, go to www.umgcc.org.

Source

Hepatocellular carcinoma

The Lancet, Volume 379, Issue 9822, Pages 1245 - 1255, 31 March 2012

doi:10.1016/S0140-6736(11)61347-0

Published Online: 20 February 2012

Original TextAlejandro Forner MD a b, Josep M Llovet MD a b c d, Dr Jordi Bruix MD a b

Summary

Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. Patients with cirrhosis are at highest risk of developing this malignant disease, and ultrasonography every 6 months is recommended. Surveillance with ultrasonography allows diagnosis at early stages when the tumour might be curable by resection, liver transplantation, or ablation, and 5-year survival higher than 50% can be achieved. Patients with small solitary tumours and very well preserved liver function are the best candidates for surgical resection. Liver transplantation is most beneficial for individuals who are not good candidates for resection, especially those within Milano criteria (solitary tumour ≤5 cm and up to three nodules ≤3 cm). Donor shortage greatly limits its applicability. Percutaneous ablation is the most frequently used treatment but its effectiveness is limited by tumour size and localisation. In asymptomatic patients with multifocal disease without vascular invasion or extrahepatic spread not amenable to curative treatments, chemoembolisation can provide survival benefit. Findings of randomised trials of sorafenib have shown survival benefits for individuals with advanced hepatocellular carcinoma, suggesting that molecular-targeted therapies could be effective in this chemoresistant cancer. Research is active in the area of pathogenesis and treatment of hepatocellular carcinoma.

Source

March 30, 2012

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The bacterium, Bacillus cereus as cultivated on sheep blood agar 

Credits: CDC/ Courtesy of Larry Stauffer, Oregon State Public Health Laboratory

March 30, 2012

Pharmaceutical giant, Bristol Myers-Squibb (BMS) announced Thursday a global recall of the sterile organ storage fluid, Viaspan after bacterial contamination was discovered on the production line at a manufacturing facility in Austria.

The bacterium, Bacillus cereus was found in fluid used to test the sterility of the Viaspan production line. Batches of Viaspan are now being tested for contamination.

Viaspan is a fluid used to preserve organs, primarily the liver, pancreas and bowel, after removal from the donor until transplant into the organ recipient.

The recall applies to 10 countries where there are alternative storage solutions: Australia, Italy, Estonia, Slovenia, Argentina, Chile, Germany, France, Ireland, and the United Kingdom.

BMS is also working with health officials in 11 other European countries and New Zealand that use Viaspan but do not have alternative solutions.

Viaspan is not sold in the United States or Asia.

The Belfast Telegraph reports that BMS is performing tests to determine where the leak in the production line is located. A faulty pressure gauge is thought to be the problem.

In the UK, where there are about 800 liver, 250 pancreas and 30 to 40 bowel transplants each year, they will continue to use Viaspan as there is currently no evidence of any problems in patients who have recently had transplants where Viaspan has been used according to Chief Medical Officer Professor Dame Sally Davies.

Patients that did present with an infection with Bacillus cereus could be treated with antibiotics.

Bacillus cereus is an aerobic, spore-forming bacterium found in the soil and the environment worldwide.

The organism is a well-recognized and common cause of food poisoning worldwide.

Bacillus cereus made the news last year when alcohol pads produced by the Triad Group were found to be contaminated with the spore-forming bacteria. The contaminated pads were implicated in the death of a 2-year-old boy.

Source

From Medscape Medical News > Conference News

Neil Canavan

March 30, 2012 (New York, New York) — Peginterferon alfa-2a, in combination with the protease inhibitor boceprevir and ribavirin (R), was shown to have efficacy equivalent or superior to that seen with historical use of the same regimen with peginterferon alfa-2a — the standard of care — for treating hepatitis C virus (HVC) infection, according to data reported here at the International Conference on Viral Hepatitis (ICVH) 2012.

These results provide a definitive rationale for the inclusion of the alfa-2a interferon variant in the treatment regimen, allowing for greater ease of administration by the patient infected with HCV.

"This is the first trial in which peginterferon alfa-2a was used as a backbone instead of alfa-2b," said study investigator John Howe, PhD, senior principal scientist, Merck & Co., Inc, Whitehouse, New Jersey.

In a previous study of the combination with alfa-2b, the RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) trial, patients who were previously nonresponders or had relapsed after treatment with ribavirin and interferon alfa-2b showed significant improvement in sustained viral response (SVR) with the addition of boceprevir (66% vs 21% for controls).

The current investigation was a double-blind, placebo-controlled study that randomly assigned 201 HCV genotype-1 relapsers and nonresponders in a 1:2 fashion to 1 of 2 treatment groups. Treatment group 1 received 4 weeks of peginterferon alfa-2a and ribavirin followed by 44 weeks of placebo plus ribavirin plus peginterferon alfa-2a (standard of care). Treatment group 2 received 4 weeks of ribavirin plus peginterferon alfa-2a followed by boceprevir plus ribavirin plus peginterferon alfa-2a for 44 weeks.

Therapy was discontinued in both treatment groups if HCV RNA was undetectable at week 12 (defined as HCV RNA level of 9.3 IU/mL).

Results showed a superior efficacy for the boceprevir combination; 64% of patients achieved an SVR as compared with 21% in the control group (P < .0001).

The rate of relapse with the protease inhibitor combination, 12%, was lower than that with the standard of care, 33% (P value not reported).

"These results are consistent with RESPOND-2," said Dr. Howe.

Reasons for a non-SRV outcome in the boceprevir/peginterferon alfa-2a/ribavirin treatment group for a total of 44 patients were as follows: viral breakthrough on treatment after initially being undetectable for 1 patient; incomplete virologic response for 4 patients; relapse after treatment for 11 patients; and nonresponse for the remaining 28 non-SVR patients (this figure includes patients who discontinued treatment for any reason).

Samples from 33 of 44 patients who received boceprevir/peginterferon alfa-2a/ribavirin who did not achieve SVR were subjected to sequence analysis of postbaseline resistance-associated variants (RAVs). This analysis revealed that 8 of the 33 patients had RAVs; the total included 1 patient with viral breakthrough, 3 patients who had incomplete responses, 2 patients who relapsed, and 2 nonresponders.

By resistance locus, overall RAV profiles were similar to those in all other studies in which peginterferon alfa-2b was used as part of an HCV treatment combination. "The resistance data collected in this trial are consistent with results reported in SPRINT-2 and RESPOND-2," said Dr. Howe.

Treatment Choices With HCV

"I believe that these two interferons [alfa-2a, alfa-2b] are similar," commented Ayse Aytaman, MD, chief of gastroenterology and hepatology, Veterans Affairs New York Harbor Health Care System, Brooklyn, New York. "But we use the alfa-2a more commonly because it's easier for the patient. It is a prepared syringe, you don't have to give weight-based dosing, and it comes in different dosages. It is much simpler. It's particularly good for patients who have trouble understanding instructions."

As for choosing between the 2 new protease inhibitors now at her disposal (boceprevir and telaprevir), "We are trying to learn how to deal with them," she said. "Yes, they are very potent, but they have a lot of side effects."

Before adding interferon on top of a protease inhibitor, Dr. Aytaman cautioned that there are some patients for whom the physician may want to wait for better pharmacologic options before treating.

"When I look at a patient who is 60 years old, I have to consider that I'm going to take a year out of this person's life with them coming to me weekly, or biweekly, injecting himself, being miserable with flu-like symptoms… Why?" Even if the patient has early-stage cirrhotic disease, Dr. Aytaman is willing to wait for an all-oral HCV treatment combination with fewer side effects.

If she has to choose between the protease inhibitors available now, side effect profile is one consideration; cost is another.

"There is a huge cost difference. Telaprevir, even though it's only [given] for 3 months, is much more expensive than boceprevir. If it wasn't for that, every hepatologist I know would go for telaprevir because it's so much simpler, with a much shorter duration of treatment."

"The reality is, I'm given a budget to treat patients. If I can treat more patients for fewer dollars, I will," said Dr. Aytaman, "That said, I do use both. Most of my patients get boceprevir, but for previous null responders, or if I'm anticipating significant anemia or cytopenia, I go for telaprevir."

Dr. Howe is an employee of Merck & Co. Dr. Aytaman has disclosed no relevant financial relationships, and her opinions are expressed as a physician, not as an employee of the US government.

International Conference on Viral Hepatitis (ICVH) 2012. Abstract # 79317. Presented March 26, 2012.

Source

Increasing Routine Viral Hepatitis Testing

March 30, 2012

By Ronald Valdiserri, M.D., M.P.H., Deputy Assistant Secretary for Health, Infectious Diseases, and Director, Office of HIV/AIDS and Infectious Disease Policy, U.S. Department of Health and Human Services

ron_valdiserri_headshot1

Dr. Ronald Valdiserri

The Viral Hepatitis Action Plan spells out the importance of identifying persons infected with viral hepatitis early in the course of their disease as an important component of national efforts to improve diagnosis, care and treatment to prevent liver disease and liver cancer. As awareness of viral hepatitis increases and treatment options become more effective and better tolerated, it is vital that we implement best practices to improve the frequency, availability, and acceptability of viral hepatitis testing.

To inform and advance these efforts, my office hosted a day-long consultation last month. Sharing their perspectives with us were representatives from state and local health departments, community health centers, drug treatment and correctional health programs, local and national advocacy organizations, the American Association for the Study of Liver Disease, the National Medical Association and other partners. Also participating in the discussion were experts from various federal agencies including the Centers for Disease Control, Agency for Healthcare Research and Quality, Centers for Medicaid and Medicare Services, HRSA’s Bureau of Primary Health Care and HIV/AIDS Bureau, Indian Health Service, National Institutes of Health, Office of Minority Health, and Substance Abuse and Mental Health Services Administration, as well as Federal Bureau of Prisons and the Department of Veterans Affairs.

Among the many examples of promising practices shared from diverse settings were:

  • Targeting patient education and outreach – Tamara Brickham, M.P.H., Houston Department of Health and Human Services, shared details of a successful community partnership model the agency used to increase hepatitis B awareness, screening, testing and vaccination among Asian Americans. To more effectively reach the communities with a higher prevalence of HBV infection, the health department partnered with numerous community-based organizations already working with the Vietnamese, Chinese, Korean, and Asian Indian communities. Ms. Brickham noted that this enabled the health department to take the education, screening, vaccination and testing activities directly to higher risk adults in community settings rather than waiting for them to come to the health department or a healthcare provider. As a result of the first year of this population-specific outreach, more than 1,000 people were screened. Three percent were identified as having chronic HBV infection and were referred for care. One-third of those screened were vaccinated.
  • Using rapid testing – Several participants highlighted the challenge of getting those who do ultimately get tested to return for their results. Colleen Flanigan, R.N., M.S., Director of the Viral Hepatitis Section at the New York State Department of Health, discussed how a 12-site state-supported demonstration project will use rapid HCV testing to overcome this hurdle. The demonstration project will target higher risk populations and use rapid HCV tests to eliminate the need for clients to return for a second visit for test results. Clients with a reactive test result will receive a written referral to a provider that can perform a confirmatory PCR test. Through the demonstration project, they will study how this approach improves diagnosis and linkage to care for chronic HCV.
  • Adapting systems to support viral hepatitis testing – A number of participants noted that inadequate fiscal resources are an impediment in many settings but that even when resources are available, improving viral hepatitis screening and testing requires the development of processes and systems that make it easier for providers to implement the recommended protocols. Kenneth Tai, M.D., discussed the efforts he led at North East Medical Services (NEMS) in San Francisco to address high rates of HBV among its patient population who are primarily people of Asian heritage. NEMS started by setting a goal to increase HBV testing and vaccination among patients from 60% to 70% in one year. In addition to enhancing patient education, the community health center undertook critical systems changes including: adding an HBV module to the electronic health record (EHR) used at the clinic, improving the workflow in the clinic to make testing and vaccination more efficient, and mining EHR data to generate a list of patients being seen each day who need an HBV test. Finally, the health center also added HBV testing as a measure to its physician report card. Janet Durfee, R.N., M.S.N, A.P.R.N., Deputy Chief Consultant, Clinical Public Health at the Department of Veterans Affairs (VA) noted that systems changes have also helped the VA health system to improve and enhance their HCV screening efforts. Among the changes implemented in recent years has been adding a clinical reminder to the electronic health record prompting healthcare providers to screen and test if indicated. VA has distributed responsibility for screening among nurses and other personnel, so this does not fall to physicians alone. To address both provider and patient discomfort with discussing risks, VA revised its approach so that providers ask the patient whether he/she has any of a list of risks, thereby avoiding the need to admit to any particular stigmatizing risk factor and increasing the likelihood of candid responses.

“The promising practices shared by consultation participants and the lively discussion that followed underscored that it is possible to improve the frequency, availability, and acceptability of viral hepatitis testing in a variety settings, in some cases by only making minor changes to processes, in others through partnerships and coordination of services,” observed my colleague Corinna Dan, R.N., M.P.H., Viral Hepatitis Policy Advisor, Office of HIV/AIDS and Infectious Disease Policy, who organized the consultation.

As Corinna notes, the consultation clearly illustrated that numerous successful approaches to improving viral hepatitis testing exist in very diverse settings. A key to our success in scaling up these efforts will be better documenting, disseminating and encouraging the adoption of these model programs.

Source

Treatment of Hepatitis C Virus in Liver Transplant Recipients

Hepatology - Hepatitis C Management in Special Populations

Authors: Mark S. Sulkowski, MD (More Info)

Last Reviewed: 3/1/12

The decision to initiate hepatitis C virus (HCV) therapy must weigh the benefits of achieving a sustained virologic response (SVR) vs the risks of triggering graft rejection and the side effects associated with immunosuppressive therapy. Although a preemptive antiviral approach intuitively seems to offer the best chance for liver transplant recipients, several reasons prevent the American Association for the Study of Liver Diseases (Management Guidelines)[Ghany 2009] and the European Association for the Study of the Liver (Management Guidelines) from recommending this approach:[EASL 2011]

  • Postoperative increases in human leukocyte antigen and major histocompatibility complex elevate the risk of acute rejection in the presence of immunomodulators such as interferon-based therapy
  • Patients have a reduced clinical status while recovering from surgery
  • Between 30% and 50% of patients will not develop chronic liver disease
  • 40% to 60% of patients are not candidates for this therapy because of cytopenias, renal disease, or other underlying conditions
  • Early therapy has been associated with high rates of adverse effects, an increased risk of graft rejection, and higher proportions of patients requiring dose reductions

Thus, the recommended standard of care is the treatment of histologically confirmed recurrent disease, either by persistent, unexplained elevated alanine aminotransferase levels or by histologically confirmed fibrosis once rejection, biliary obstruction, and vascular damage have been ruled out.[Ghany 2009; Ponziani 2011]

Peginterferon alfa alone or in combination with ribavirin are recommended for the treatment of recurrent HCV infection in posttransplanted patients.[EASL 2011; Ghany 2009] However, severe adverse effects, including anemia, thrombocytopenia, and leukopenia, contribute to the low adherence to the recommended dose of ribavirin, which may lead to the low response rates of transplant recipients (Figure), even when hematopoietic growth factors are administered.[Ponziani 2011]

Figure. Response rates with peginterferon plus ribavirin for the treatment of recurrent HCV postliver transplantation.

HCV_SpecialPops_Figure

The HCV protease inhibitors boceprevir and telaprevir have not been studied and therefore are not approved in patients with liver transplants. However, a study of telaprevir plus peginterferon alfa-2a and ribavirin is planned for stable liver transplant patients (Clinical Trial: NCT01467505). Because this and other studies are completed with HCV protease inhibitors in the transplantation setting, drug-drug interactions will become an important consideration. Indeed, since both boceprevir and telaprevir inhibit CYP3A4, coadministration with any medication that is known to be metabolized by CYP3A4 should be done under close clinical supervision and monitoring.[Ghany 2011] Unfortunately, 2 drugs commonly used to prevent allograft rejection, cyclosporine and tacrolimus, are metabolized via the CYP3A4 pathway. In a phase I, nonrandomized pharmacokinetic study involving 10 healthy volunteers, coadministration of cyclosporine and telaprevir increased the elimination half-life of cyclosporine from 12 ± 1.67 hours to 42.1 ± 11.3 hours; tacrolimus and telaprevir coadministration increased the half-life of tacrolimus from 40.7 ± 5.85 hours to 196 ± 159 hours.[Garg 2011] A comparable study of the impact of boceprevir on the pharmacokinetics of cyclosporine and tacrolimus was also conducted.[Hulskotte 2011] In contrast to telaprevir, boceprevir is primarily metabolized by aldo-keto reductase with a lesser contribution from CYP3A4. In a study of 10 healthy volunteers, coadministration of boceprevir with cyclosporine induced a 2.01-fold increase in Cmax and a 2.70-fold increase in the area under the concentration time curve (AUC) from time 0 to infinity after single dosing (AUCinf) of cyclosporine. By contrast, coadministration of boceprevir and tacrolimus caused a 9.9-fold increase in Cmax and a 17.1-fold increase in AUCinf of tacrolimus. These data indicate that coadministration of boceprevir with either cyclosporine or tacrolimus would require significant dose adjustments of the calcineurin inhibitors and attentive monitoring of their trough concentrations, of renal function, and of potential adverse effects; in particular, coadministration with tacrolimus would likely require significant dose reduction and/or prolonged dosing. When considering the results of these studies, it is important to emphasize that the populations assessed involved healthy participants. In the context of liver transplant recipients with HCV recurrence, the pharmacokinetic effects of boceprevir or telaprevir on elimination of these immunosuppressive agents may be greater.[Charlton 2011] Thus, these protease inhibitors should not be used in combination with the calcineurin inhibitors cyclosporine and tacrolimus until the appropriate dose reductions are understood.[Garg 2011] Finally, many other agents that require cytochrome P450 enzymes for their metabolism are often administered in the transplantation setting, including mycophenolate mofetil, macrolides, calcium channel blockers, and others.[Charlton 2011] As a result, pharmacokinetic interactions with cyclosporine or tacrolimus provide only a partial view of potential protease inhibitor effects that may be relevant to liver transplant recipients.

A summary of recommendations for the management of recurrent HCV in liver transplant recipients is shown in Table 10.

Table 10. Summary of Recommendations for the Management of Recurrent HCV in Liver Transplant Recipients

  • Prophylactic HCV therapy in liver graft recipients is not recommended.
  • Histologically confirmed recurrent disease, either by persistent, unexplained elevated alanine aminotransferase levels or by histologically confirmed fibrosis once rejection, biliary obstruction, and vascular damage have been ruled out, should be treated.
  • Peginterferon alfa alone or in combination with ribavirin are recommended for the treatment of recurrent HCV infection in posttransplanted patients.
  • The HCV protease inhibitors boceprevir and telaprevir have not been studied and therefore are not approved in liver transplant patients.

Source

Also See: An Open Label Study of the Effect of Telaprevir in Combination With Ribavirin and Peginterferon on HCV Infection in Stable Liver Transplant Patients

Conditions: Hepatitis C

Interventions: Drug: Telaprevir
1125 mg bid for 12 weeks
Drug: ribavirin
Initial dose of 600 mg total daily dose with goal of up to 1000mg-1200mg total daily dose based on body weight for 48 weeks
Drug: peginterferon alfa-2a
180 mcg/week for 48 weeks

Study Phase: Phase 2

Status: Recruiting

Study IDs: VX11-950-117 NCT01467505

To assess efficacy of telaprevir, peginterferon alfa-2a (Peg-IFN), and ribavirin (RBV) for HCV in a 48-week total treatment duration regimen following liver transplantation.

Study Description | Recruitment Information | Tracking Information | Administrative Information

ClinicalTrials.gov processed this record on 3/30/2012

Source: U.S. National Library of Medicine (NLM) and ClinicalTrials.gov.

March 28, 2012

ICVH 2012: Next-Generation HCV Protease Inhibitor Shows Promise

From Medscape Medical News

Megan Brooks

March 28, 2012 (New York, New York) — In vitro data on a next-generation hepatitis C virus (HCV) NS3/4A protease inhibitor garnered considerable interest here at the International Conference on Viral Hepatitis 2012.

MK-5172, being developed by Merck & Co, demonstrated "potent activity" against the majority of primary first-generation protease inhibitor resistance-associated variants (RAVs) in biochemical and cell-based phenotype assays, reported Richard J. Barnard, PhD, from Merck & Co.

MK-5172 also inhibited patient-derived NS3 proteases across HCV genotypes and retained activity against HCV proteases isolated from 5 patients with vaniprevir RAVs.

In his presentation, Dr. Barnard noted that virologic failure with first-generation protease inhibitors is often associated with the emergence of RAVs; it is important that next-generation molecules are pangenotypic and active against first-generation protease inhibitor RAVs. "MK-5172 fulfills the profile expected of a next-generation" HCV protease inhibitor, he said.

Douglas T. Dieterich, MD, professor of medicine from the division of liver diseases at Mount Sinai School of Medicine in New York City, who was not involved in the study, told Medscape Medical News that "MK-5172 represents a promising potential best-in-class second-generation protease inhibitor."

"MK-5172 is a truly second-generation protease inhibitor," he explained. "This is really good news for the people who have already failed treatment with a first-generation protease inhibitor."

MK-5172, Dr. Dieterich said, "has activity against the most common resistance mutations caused by telaprevir and boceprevir. Even more encouraging for global use, it is active against genotypes 1, 2, 4, 5, and 6."

Dr. Barnard reports being an employee of Merck & Co and owning stock in the company. Dr. Dieterich reports financial relationships with Bristol-Myers Squibb, Gilead Sciences, Roche Laboratories, and Boehringer Ingelheim.

International Conference on Viral Hepatitis (ICVH) 2012: Oral Abstract: 79340. Presented March 26, 2012.

Source

March 28, 2012 4:37 pm

Tumor response assessment to sorafenib in patients with advanced hepatocellular carcinoma: do we need new criteria?

By Dr Mohmed Bouattour

Sorafenib, an oral multi-tyrosine kinase inhibitor, is the first and so far the only drug that has shown overall survival benefit in patients with advanced hepatocellular carcinoma (HCC) in two large multicenter, double-blind, placebo-controlled randomized phase III trials [1-2]. Despite the survival benefit in this population, sorafenib has been infrequently associated with changes in tumors dimensions, challenging standard RECIST criteria [3]. Tumor shrinkage and dimensional change, usually assessed to define tumor response of cytotoxic drugs based on the morphological RECIST criteria, was observed in less than 5% of patients. Furthermore, changes in tumor angiogenesis are observed such as decrease in the number of vessels in tumor masses and the appearance of large areas of intratumor necrosis (Figure 2). This feature is acknowledged to reflect the antitumor activity of antiangiogenic drugs that does not always translate into changes in the diameter of the tumor, making the radiological evaluation of efficacy using standard RECIST criteria often inappropriate [4].

In the phase II study evaluating sorafenib [5], among 11 patients strictly evaluated for intratumor necrosis appearance in addition to RECIST criteria, several tumors had size increasing and as well as increasing tumor necrosis. Before treatment, the mean diameter of these tumors was 6.4 cm (interval 2.5 to 14.2 cm) and the mean proportion of tumor necrosis was 9.8% (interval 0.4% to 33.5%). After treatment, the mean diameter of these tumors was 7.2 cm (interval 1.7 to 16.0 cm) and the mean proportion of tumor necrosis was 27% (interval 0.7 to 75%) [5]. Similar observations were shown with sunitinib [6] and bevacizumab [7].

Given this context, experts have suggested new response criteria based on changes in tumor vascularization and density. The modified RECIST criteria (mRECIST) were an amendment of the RECIST criteria; they take into account dimension changes in the tumor arterial enhancement [8]. Choi criteria [9] where composite criteria, covering tumor size and tumor density in CT scan, have been proposed to evaluate response to sunitinib, another potent antiangiogenic agent, in HCC patients [10].

We recently showed in the American Association for the Study of Liver Disease meeting (AASLD) 2011 at San Francisco, interesting results about the relevance of theses criteria in patients with advanced HCC and treated with sorafenib [11]. In our study, 60 patients were evaluated according to those criteria by CT-scan performed within 3 months of treatment. At the first tumor evaluation,we observed that only 2 patients (3.3%) experienced a decrease ≥ 30% of the largest diameter. The majority of patients (51.6%) had no significant changes in tumor size. This confirms the low response rates by RECIST criteria observed with sorafenib. According to mRECIST, 12 patients (21.4%) were categorized as early responder with 2 complete response (3.3%) and 10 partial response (16.7%). When we apply the Choi criteria, we noticed that 27 patients (45%) were considered as partial responders and 14 patients (23.3%) had tumor stabilization. Interestingly, these new criteria were able to identify responders with better overall survival. In fact, responder patients according to mRECIST had better OS than progressive patients (> 14.4 months vs. 5.8 months, respectively, p = 0.0008). Moreover, Choi criteria can predict overall survival in patients with HCC treated by sorafenib since the median OS in the group of responder patients was > 14.4 months compared to the median OS of 6 months in the group of progressive patients (p= 0.0012) [11]. Our results were comparable to another published study [12] in which the best tumor response rates of 53 patients were assessed by RECIST and mRECIST. In this cohort, the rates of objective response, stable disease were 2% and 79% respectively according to RECIST and 23% and 57% respectively by mRECIST. Similar to our results, response according mRECIST criteria can predict survival, since the median OS in the group of responder patients was 18 months compared to the median OS of 8 months in the group non-responder patients (p= 0.013) [12].

Taken together, those results stress the need to evaluate behind tumor size changes, vascular modification and disturbance observed with sorafenib and other antiangiogenic agents in patients with HCC. Further robust studies should take into account those criteria to validate them clinical practice.

References

1. Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-90.
2. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10: 25-34.
3. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, el al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-16.
4. Bouattour M, Dreyer C, Faivre S, Raymond E. Evaluation of antiangiogenic effects: biomarkers and functional imaging. International Oncology Updates: Present and future for antiangiogenic therapies in cancer. Permalyer Barcelona, 2010: 63-84.
5. Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24: 4293-300.
6. Faivre S, Bouattour M, Dreyer C, Raymond E. Sunitinib in hepatocellular carcinoma: redefining appropriate dosing, schedule, and activity endpoints. J Clin Oncol 2009; 27: 248-50.
7. Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008;26:2992-98.
8. Lencioni, R. & Llovet, J. M. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 30, 52–60 (2010).
9. Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007 ;25:1753-9.
10. Faivre S, Zappa M, Vilgrain V, Boucher E, Douillard JY, Lim HY, et al. Changes in tumor density in patients with advanced hepatocellular carcinoma treated with sunitinib. Clin. Cancer Res. 2011; 17, 4504–12.
11. Bouattour M, Wassermann J, Bruno O, et al. Blinded independent centralresponse assessment using RECIST, modified RECIST, and Choi criteria in patients treated with sorafenib for advanced advanced hepatocellular carcinoma. Oral communication presented at ILCA 2011 in Hong Kong and at AASLD 2011 in San Francisco. Hepatology; 2011 54(S1) (A 270).
12. Edeline J, Boucher E, Rolland Y, Vauléon E, Pracht M, Perrin C,et al. Comparison of tumor response by Response Evaluation Criteria in Solid Tumors(RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma. Cancer. 2012;118(1):147-56.

About the Author

Dr-Mohamed-Bouattour-150x150

Dr Mohamed Bouattour

Mohmed Bouattour is a Clinical physician in the department of Oncology and Hepatology at Beuajon Hospital in France. Dr. Mohamed Bouattour received his Gastroenterology Hepatology training at the Faculty of medicine of Sfax and Tunis in Tunisia. He completed and achieved his fellow at the department of Hepatology and Oncology in Beaujon Hospital in Paris France. He is currently a practitioner in Beaujon Hospital at these departments.

His interests go toward the field of Hepatology to study liver disease, hepatic malignancies and clinical trials to evaluate new agents in hepatocellular carcinoma.

Dr. Mohamed Bouattour is a peer reviewer for several scientific journals and has authored and co-authored more than 20 publications as well as book chapters. He is an active member of the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver (AASLD) and The American Society of Clinical Oncology (ASCO).

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The Journal of Sexual Medicine

Early View (Online Version of Record published before inclusion in an issue)

Shiu-Dong Chung MD1,2,3, Joseph J. Keller MPH4, Yu-Chih Liang PhD4, Herng-Ching Lin PhD3,*

Article first published online: 29 FEB 2012

DOI: 10.1111/j.1743-6109.2012.02663.x

© 2012 International Society for Sexual Medicine

Keywords:
  • Chronic Liver Diseases;
  • Erectile Dysfunction;
  • Hepatitis
ABSTRACT

Introduction. Chronic liver diseases are often accompanied by hypogonadism, testicular atrophy, and a reduction in libido, all of which are factors that may contribute to the development of erectile dysfunction (ED). However, large-scaled studies investigating the association between ED and viral hepatitis are still sparse.

Aim. This study aimed to estimate the association between ED and a prior diagnosis of viral hepatitis using a population-based dataset with a case-control design in Taiwan.

Methods. We identified 6,429 patients with ED as cases and randomly selected 32,145 subjects as controls. We used conditional logistic regression to compute the odds ratio (OR) for having previously received a diagnosis of viral hepatitis between cases and controls.

Main Outcome Measure. The prevalence and odds of having been previously diagnosed with hepatitis B, hepatitis C, a coinfection with hepatitis B and C, and viral hepatitis of other etiology were calculated between cases and controls.

Results. Of the 38,574 sampled subjects, 3,930 (10.2%) had viral hepatitis before the index date; viral hepatitis was found in 900 (14.0%) cases and in 3,030 (9.4%) controls. After adjusting for monthly income, geographic location, hypertension, diabetes, hyperlipidemia, hepatic steatosis, coronary heart disease, obesity, and alcohol abuse/alcohol dependence syndrome, cases were found to be more likely to have prior viral hepatitis than controls (OR = 1.51, 95% confidence interval [CI] = 1.39–1.64, P < 0.001). A much higher proportion of coinfection with viral hepatitis B and C was additionally found among cases (OR = 1.84, 95% CI = 1.72–1.97) than controls.

Conclusions. We conclude that ED was associated with prior viral hepatitis, especially with a coinfection of hepatitis B and C, after adjusting for potential confounders. Chung S-D, Keller JJ, Liang YC, and Lin HC. Association between viral hepatitis and erectile dysfunction: A population-based case-control analysis. J Sex Med **;**:**–**.

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Screening for HCV Infection in Jails - Viewpoint

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JAMA. 2012 March 26

Anne C. Spaulding, MD, MPH
David L. Thomas, MD, MPH

Jails are an ideal setting for routine hepatitis C virus (HCV) screening. At the turn of this century, the Centers for Disease Control and Prevention estimated that 16% to 41% of US inmates had serological evidence of prior HCV exposure and 12% to 35% had chronic infection.1 This high prevalence of hepatitis C, coupled with the fact that more than 7 million individuals passed through jails and prisons each year in the late 1990s, suggested that persons released from the criminal justice system may account for up to 29% to 43% of the 2.7 million to 3.9 million persons infected with hepatitis C in the United States.1,2

Most inmates with chronic hepatitis C are not aware of their infection. Although exact data on recognition of infection are not available, even in the US general population, only 25% to 35% of persons infected with HCV are aware of their condition.2 In recent years, 9 million unique individuals enter and leave jails yearly and an additional 1.5 million persons spent an entire year in prison.3 If, conservatively, 12% are infected with HCV, and because in marginalized populations those who are unaware of infection would likely be closer to 75% rather than 65%, then it is possible that as many as 1.0 million persons with undiagnosed HCV infection might come in contact with the correctional system each year.

According to US Supreme Court case law in Estelle v Gamble (429 US 97 [1976]), correctional facilities cannot display deliberate indifference to the health care needs of their residents. Thus, some HCV care has been provided in the correctional systems. However, because HCV therapy may last for up to 48 weeks, the infection could realistically only be treated in approximately 1% of incarcerated persons, according to modeling using parameters derived from a combined jail-prison correctional system.4 Finding hepatitis C among convicted persons with long sentences carries ethical obligations to treat appropriate candidates once the diagnosis is confirmed. The difference between those who could be potentially treated compared with those infected occurs because in short-term correctional facilities the median length of stay is 48 hours and jail detainees account for 95% of the persons incarcerated in and released from correctional facilities.3 The majority of persons entering a correctional facility during a given year stay for less than 12 months. Because treatment could not realistically be provided for short-term inmates, HCV screening has not been routinely conducted in jails, an omission that may represent a missed opportunity to identify persons with undiagnosed HCV infection.

Recognition of HCV infection matters. In May 2011, the US Food and Drug Administration approved 2 new, direct acting agents for treatment of genotype 1 chronic HCV infection. When used with the former standard of care (peginterferon and ribavirin), boceprevir or telaprevir increases cure rates by 20% to 30%. In addition, 40% to 60% of individuals will be able to abbreviate treatment substantially with the new drugs.5 A recent study suggested that HCV treatment can be effectively provided in community settings. Project ECHO (Extension for Community Health Care Outcomes) offers a model to increase availability of hepatitis treatment not just in prisons but also in publicly funded community health centers so that the incarcerated setting is not the only place in which an indigent person can access care.6 With the advent of "all oral" HCV treatments in the future, treatment feasibility and effectiveness will increase further, thus amplifying the public health importance of expanded HCV detection in jails.7

Recognition of HCV infection in a rapidly changing environment is possible. In February 2011, the US Food and Drug Administration approved a rapid fingerstick HCV test; a waiver that would allow its use in jails and other facilities without laboratory licensure was granted in November 2011. Thus, the HCV assay can be performed in 20 minutes on jail entrants, using point of care, opt-out testing strategies, that have been proven successful for HIV testing among inmates.8 Following opt-out hepatitis C screening in jails, downstream health care can be coordinated between jails, prisons, and the community. In a demonstration project designed to integrate opt-out HIV screening with other medical services, including hepatitis C testing, at the Fulton County, Georgia, jail, persons with positive test results were referred to a public hepatitis clinic integrated into the primary care services of Atlanta's Grady Memorial Hospital. This project is consistent with the Department of Health and Human Services Action Plan for the Prevention, Care, and Treatment of Viral Hepatitis,9 which calls for improved access to hepatitis treatment in primary care settings. In addition, the Affordable Care Act will eventually provide a mechanism for funding the care of persons whose HCV infection is identified in jails and who are released subsequently.

There are challenges to widespread implementation of HCV screening in short-term and long-term correctional facilities. Provision of medical screening and treatment is not the primary mission of correctional facilities. Jails are challenged with high throughput and entrants may have insufficient time for the counseling and confirmatory testing that are optimal in HCV screening programs. HCV screening and the coordination of care with existing health care facilities will require funding, although the economic benefits of HCV screening are long-term and may be realized by different state or federal agencies than those asked to fund the programs.

These challenges can be overcome and HCV screening could be implemented routinely in jails. Focusing efforts on detainees with a high pretest probability of having hepatitis C can decrease the number of tests that would need to be performed to find these infected persons.1 Directing HCV testing to persons born between 1945 and 1965, the birth cohort that includes an estimated two-thirds of those individuals currently infected with HCV in the United States, and following diagnosis with treatment using direct acting agents, has been shown to be cost-effective in community clinical settings.10 Concentrating on the 1945-1965 birth cohort in the correctional setting should likewise optimize the yield of HCV screening programs.

Thus, implementation of opt-out HCV screening should be considered for persons incarcerated in jails. If 70% of the approximately 1 million persons with hepatitis C who are in correctional facilities are offered the opportunity to have HCV testing, and if 70% accept such an offer, HCV screening in detainees may lead to the identification of as many as a half million new cases of hepatitis C in the first year of the program. Coupled with counseling and referral for treatment if released, such programs could have enormous effects on the HCV epidemic in the United States. With new treatments and new diagnostics, local public health agencies should invite jails to partner in hepatitis C screening.

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