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Week Ending: October 24, 2009
Alan Franciscus
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This Issue:
October 19, 2009
Relapse Common in HIV/HCV Co-infected Patients after Treatment for HCV
www.aidsmap.com
Michael Carter
Relapse after apparently successful treatment for hepatitis C virus occurs in over a third of individuals who are co-infected with HIV and hepatitis C, Spanish investigators report in the November 1st edition of Clinical Infectious Diseases.
Relapses were more common in co-infected patients who carried the harder-to-treat hepatitis C 1 and 4 genotypes. Most relapses occurred within three months of the completion of hepatitis therapy, and re-infection with hepatitis C accounted for most of the apparent relapses seen after this time.
A significant proportion of HIV-positive individuals are co-infected with hepatitis C virus, and liver disease caused by this co-infection is now an important cause of illness and death in patients with HIV.
Treatment is available for hepatitis C and consists of pegylated interferon and ribavirin dosed by weight. The length of treatment depends on which hepatitis C genotype an individual is infected with: the harder-to-treat genotypes 1 and 4 require 48 weeks of therapy, whereas genotypes 2 and 3 are treated for 24 weeks.
The goal of hepatitis C treatment is an undetectable hepatitis C viral load 24 weeks after the completion of treatment. Only about a third of HIV-positive patients with chronic hepatitis C achieve this outcome, which is a significantly poorer treatment response rate to that seen in hepatitis C mono-infected individuals (approximately 50%).
It is generally assumed that once a patient had achieved a sustained response to hepatitis C therapy that they have been cured of their infection and that the chance of relapse is very low.
Investigators in Madrid wished to get a better understanding of the prevalence and timing of relapse to hepatitis C therapy. They hope that their findings will help inform the optimum time to use new hepatitis C drugs that are currently in development.
The investigators therefore undertook a retrospective study involving 604 patients who received hepatitis C treatment between 2001 and 2007. Approximately two-thirds of the study sample (64%) were HIV-positive.
A total of 275 (46%) patients had an undetectable hepatitis C viral load after completing therapy for the infection. But only 37% of co-infected patients achieved this outcome compared to 61% of those who were only infected with hepatitis C.
Moreover, co-infected patients were more likely to experience a relapse than mono-infected individuals (33% vs 22%).
Relapses were seen in 41% of co-infected patients who carried genotypes 1 and 4.
All but three of the relapses occurred within three months of treatment for hepatitis C being completed.
Of the three relapses that occurred after this time, two were thought to by the investigators to be cases of re-infection. Phylogenetic analysis revealed that these two patients were infected with a strain of hepatitis C that was distinct from the that for which they were treated.
“Hepatitis C relapse after successful peginterferon plus ribavirin therapy is more common in hepatitis C/HIV-coinfected patients than in hepatitis C-monoinfected patients,” conclude the investigators.
They add, “regardless of HIV infection status, hepatitis C relapse is more common in patients infected with hepatitis C genotypes 1 and 4…and almost always occurs within the first twelve weeks after discontinuation of treatment. Most occurrences beyond twelve weeks are reinfections.”
Reference
Medrano J et al. Rate and timing of hepatitis C virus relapse after a successful course of pegylated interferon plus ribavirin in HIV-infected and HIV-uninfected patients. Clin Infect Dis 49:1397-1401, 2009.
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U.S. to End War on Medical Marijuana in Legal States
www.reuters.com
By James Vicini and Dan Whitcomb
WASHINGTON/LOS ANGELES (Reuters) - In a sharp policy shift, the Obama administration told federal attorneys not to prosecute patients who use marijuana for medical reasons or dispensaries in states where it has been legalized.
A Justice Department official said the formal guidelines were issued Monday to reflect President Barack Obama's views. The Bush administration had said it could enforce the federal law against marijuana and that it trumped state laws.
The decision was praised by activists in California, the first state to legalize medical marijuana in 1996. But concern remains among some medical and law enforcement authorities about hundreds of clinics said to be selling pot under the protection of state law and without regard to health.
A spokesman for California Governor Arnold Schwarzenegger issued a brief statement in which Schwarzenegger appeared to support the policy change:
"The governor believes it is appropriate for the federal government to focus their resources on criminal activity and securing the border," the statement said.
As a candidate during his presidential bid last year, Obama said he intended to halt raids of medical marijuana facilities operating legally under state laws.
After he took office in January, a Drug Enforcement Administration raid on a dispensary in Lake Tahoe, California, raised questions about whether he would follow that pledge.
A White House spokesman repeated Obama's view that "federal resources should not be used to circumvent state laws."
Stephen Gutwillig, California head of the Drug Policy Alliance, called the move a good first step.
"There is a fundamental need of patients to access marijuana as medicine right now," he said. "While it's great to see the Obama administration radically de-escalate the Bush and Clinton administrations' war on medical marijuana patients, more needs to be done to protect sick people and their caregivers."
California Leads the Way
About a dozen states have followed California in adopting medical marijuana laws and a similar number have pending legislation or ballot measures planned on the issue.
Gutwillig called on the Obama administration to support a proposed by Massachusetts Democrat Barney Frank that would give states the right to adopt their own medical marijuana laws.
But the head of a California drug rehabilitation clinic criticized Monday's move as irresponsible.
"The Justice Department is required to enforce all federal laws that are on the books," said Jerrod Menz, president of A Better Tomorrow Treatment Center, said in a written statement.
"Imagine if the administration took a similar stance on immigration policy. Can you imagine the outrage?"
Attorney General Eric Holder said the Justice Department would continue to prosecute people who claim to comply with state or local law but were concealing illegal operations.
"It will not be a priority to use federal resources to prosecute patients with serious illnesses or their caregivers who are complying with state laws on medical marijuana," he said. "But we will not tolerate drug traffickers who hide behind claims of compliance with state law to mask activities that are clearly illegal."
In California, critics argue that lax regulation of the law has led to the mushrooming of dispensaries operating for profit, rather than for the public good.
Los Angeles County District Attorney Steve Cooley this month announced a crackdown on dispensaries that sell for profit and to people who do not qualify under law.
Cooley said in a statement that he welcomed the new policy as "clarifying the federal government's role in handling illegal medical marijuana dispensaries" and said it was consistent with the position taken by his office.
"The attorney general's announcement recognizes that those dispensaries operating in violation of state law are subject to prosecution by the state and federal governments," he said.
"A collaboration of numerous agencies, including federal, state and local police, county and city prosecutors, will combat the proliferation of illegal medical marijuana dispensaries in Los Angeles."
A Justice Department official said federal prosecutors will not hesitate to prosecute medical marijuana cases that involve unlawful use of firearms, violence, illegal sales to minors, money laundering or other violations of U.S. law.
(Editing by Mary Milliken and Eric Walsh)
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Human Genome to Seek Hepatitis Drug Approval in Q4
www.reuters.com
* Partner Novartis to pay $75 mln milestone payment
* Shares rise 2.7 percent in light premarket
NEW YORK, Oct 19 (Reuters) - Human Genome Sciences Inc (HGSI.O) and its partner Novartis (NOVN.VX) will seek approval for their experimental hepatitis C drug in the fourth quarter, Human Genome said on Monday.
Human Genome earned $75 million payment from Novartis for completing the Phase 3 development program for the drug, and for submitting applications seeking regulatory approval.
The companies selected Zalbin as the brand name for the drug, known chemically as albinterferon-alfa 2b, in the United States, and Joulferon as the brand name in the rest of the world.
Human Genome shares fell sharply in March after it said the drug met its main goal in a late-stage trial but did not show better efficacy than standard drugs.
Shares have rebounded, however, fueled by enthusiasm for the company's experimental drug for lupus.
Shares rose 2.7 percent to $20.50 in light premarket trading.
(Reporting by Lewis Krauskopf; Editing by Derek Caney)
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New Joint Statement Streamlines Definition of Metabolic Syndrome
www.medscape.com
Michael O'Riordan
October 12, 2009 — A new joint statement from a number of professional organizations has identified specific criteria for the clinical diagnosis of the metabolic syndrome, tightening up the definition, which previously differed from one organization to the next [1].
The statement, published online October 5, 2009, in Circulation, includes the participation of the International Diabetes Federation (IDF), the National Heart, Lung, and Blood Institute (NHLBI), the World Heart Federation, the International Atherosclerosis Society, and the American Heart Association (AHA) and is an attempt to eliminate some of the confusion regarding how to identify patients with the syndrome.
"This paper represents an attempt to make the definition global," Dr Robert Eckel (University of Colorado, Denver), one of the authors of the new report, told heartwire . "The IDF definition and the [National Cholesterol Education Program Adult Treatment Panel] ATP III definition have been the two that have been utilized most frequently, and now the different organizations--the IDF, the International Atherosclerosis Society, the NHLBI, and the AHA--have all signed on to a single definition. I think that's a step forward in terms of not continuing to confuse people who are working in this field."
Specifically, the new metabolic-syndrome definition streamlines previous differences related to abdominal obesity as defined by measurements in waist circumference. Substantial disparities existed between the previous IDF and the ATP III definitions of what constituted an excessively large waist circumference, by as much as 8 cm between the two groups, but these have been amended. Now, the criteria for elevated waist circumference are based on population- and country-specific definitions, which, although streamlined, do leave some work to be done, said Eckel.
"The problem that still exists is that regional differences around the world may be substantial in terms of what waist circumference confers additional risk for heart disease and diabetes," he said. "The new definition relies on different geographic regions, or different countries, to drill down into their own databases in terms of relating waist circumference to risk." Eckel noted that the IDF previously considered elevations in waist circumference mandatory when defining metabolic syndrome, although the ATP III did not. Now, waist circumference is just one of five criteria that physicians can use when diagnosing the metabolic syndrome. Patients with three of the five criteria--including elevated waist circumference, elevated triglycerides, reduced high-density lipoprotein (HDL)-cholesterol levels, elevated blood pressure, and elevated fasting-glucose levels--are considered to have the syndrome.
Criteria for Clinical Diagnosis of the Metabolic Syndrome
Measure |
Categorical cut points |
Elevated waist circumference |
Population- and country-specific definitions |
Elevated triglycerides (drug treatment for elevated triglycerides is an alternate indicator) |
>150 mg/dL |
Reduced HDL cholesterol (drug treatment for reduced HDL cholesterol is an alternate indicator) |
<40 mg/dL for males and <50 mg/dL for females |
Elevated blood pressure (drug treatment for elevated blood pressure is an alternate indicator) |
Systolic >130 mm Hg and/or diastolic >85 mm Hg |
Elevated fasting glucose (drug treatment for elevated glucose is an alternate indicator) |
>100 mg/dL |
Notably absent from the joint statement is the American Diabetes Association. As reported by heartwire , there are unresolved scientific issues between the ADA and other associations, including the AHA, regarding the metabolic syndrome. Specifically, the ADA, as well as the European Association for the Study of Diabetes (EASD), objected to the manner in which the metabolic syndrome was characterized as a risk factor for heart disease or diabetes, arguing that there was no need to diagnose a patient with the syndrome because emphasis should be placed on aggressively treating the individual risk factors. In 2005, the ADA and EASD issued their own joint statement calling for a critical appraisal of the metabolic syndrome, its designation as a syndrome, and its clinical utility.
To heartwire , Eckel said the IDF, AHA, NHLBI, and others began working on the new metabolic syndrome definition in 2008 and that they simply went ahead without ADA participation. He stressed the metabolic syndrome is not a disease but simply a clustering of risk factors. The original intention of identifying the syndrome was simply to draw clinicians' and the public's attention to the importance of a high-quality lifestyle, and the metabolic syndrome is never meant to be used as a predictor of heart disease or diabetes risk.
References
1. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome. A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120:1640-1645. Abstract.
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October 20, 2009
Medivir AB Broadens Its Hepatitis C Collaboration with Tibotec, Entering a Partnership in the Field of HCV Polymerase
http://www.chiroeco.com
Medivir AB (STO:MVIRB) announced today a new Research, Development and License agreement in the field of hepatitis C virus (HCV). Under the agreement, executed with Ortho Biotech Products L.P. of Bridgewater, NJ (a wholly owned subsidiary of Johnson & Johnson), Medivir will partner with Tibotec BVBA of Mechelen, Belgium.
The goal of the HCV partnership is to identify and develop orally active inhibitors of the HCV polymerase NS5B. Activities will centre on screening new and existing libraries of nucleoside analogues, developed by Medivir, that show anti-HCV activity in vitro.
Medivir and Tibotec will together carry out the preclinical phase of the project with the aim of nominating drug candidates. Tibotec will thereafter have responsibility for clinical development and marketing of such compounds. Tibotec has been granted exclusive marketing rights in all countries except the Nordic countries where marketing rights are retained by Medivir.
According to the agreement, Medivir will receive an upfront payment of 5 million euros at signing. Medivir will receive further milestone payments up to a total of 142 million euros for one compound reaching the market and up to 272 million euros if two compounds reach the market and approved for two indications. Medivir will receive a royalty on product sales. The agreement also provides for research funding to Medivir.
It is gratifying that we can broaden our collaboration with Tibotec. Strategically it is crucial to evaluate further HCV drug targets “ such as the inhibition of polymerase NS5B “ when endeavoring to treat HCV. Collaborating with Tibotec makes good sense when we are already engaged in the development of a compound with a different point of attack, namely the protease enzyme. The compound, TMC435350, is in phase IIa clinical trials, says Medivir™s CEO Lars Adlersson.
For more on Medivir, please see the company website: www.medivir.se
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Asian Injecting Drug Users Unite to Form Regional Organization
http://www.citizen-news.org
Over twenty-five injecting drug users from nine different countries met in Bangkok on 16-17 October 2009 to finalize the Asian Network of People who Use Drugs (ANPUD) Constitution and elect a Steering Committee for the first regional network of people who use drugs. Based on the principles of Meaningful Involvement of People who Use Drugs (MIPUD), ANPUD has been setup by people who use drugs to advocate for the rights and unify the voices of their communities across Asia. ANPUD has over 150 members throughout the Asia region who are collaborating to influence decisions that affect their lives.
Despite being the region with the largest number of people using injecting drugs in the world, access to effective services such as needle and syringe exchange programs and opioid substitution therapy to prevent HIV and hepatitis C (Hep C or HCV) transmission, the Asia region, has the lowest coverage of harm reduction services across the globe. The lack of affordable HIV and HCV prevention, treatment, care and support services is largely driven by the stigma and discrimination associated with drug use.
The Director of the Joint United Nations Programme on HIV/AIDS (UNAIDS) Regional Support Team, Dr. Prasada Rao, spoke of the urgent need to engage with drug user networks and offered his support to ANPUD, saying that "for UNAIDS, HIV prevention among drug users is a key priority at the global level. I am very pleased today to be here to see ANPUD being shaped into an organization that will play a key role in Asia's HIV response. It is critical that we are able to more effectively involve the voices of Asian people who use drugs in the scaling up of HIV prevention services across Asia."
Jimmy Dorabjee, a key guiding figure in ANPUD’s development, explained the raison d’etre for ANPUD: "People who use drugs are stigmatized, criminalized and abused in every country in Asia. Our human rights are violated and we have little in the way of health services to stay alive. If governments do not see people who use drugs, hear us and talk to us, they will continue to ignore us."
By forming ANPUD, people who use drugs in Asia will be able to work together to engage organizations and policymakers involved in the Asian response to HIV and drug use. ANPUD's existence is critical to efforts to improve policies and services that affect the lives of drug using communities, and can contribute expertise, resources and peer support to strengthen national responses and build drug user networks. ANPUD will also focus its advocacy efforts on improving the quality of lives for people who use drugs, harmonization of policies, decriminalization, access to evidence-based, locally-driven harm reduction services, HIV prevention and treatment services and increased access to hepatitis C treatment for drug users in Asia.
By 31st December 2009, ANPUD will be officially registered as an organization. In the meantime, the constitution and governance documents have been approved. An interim Steering Committee composed of six representatives was formed, with Mohamad Firdaus (Apit) from Malaysia, Bun Bong from Cambodia, Ekta Thapa Mahat from Nepal, Hadi Yusfian from Indonesia, Myo Kyaw Lynn (Tom) from Myanmar and Yvonne Sibuea from Indonesia as elected representatives.
The Steering Committee is supported by a Technical Support Team who will mentor the members of the Steering Committee over the next few months.
At the end of the meeting, Ekta was proud to be taking back something concrete to Nepal: "When I go back home, I am now responsible for sharing the experiences with the 250 or so drug users who are actively advocating for better services at the national level. It will be a great way for us to work together and help build the capacity of people who use drugs in Asia."
Ele Morrison, Program Manager, Regional Partnership project, of Australian Illicit and Injecting Drug Users League (AIVL), said that "the results of the meeting exceeded my expectations. The participants set ambitious goals for themselves and they have achieved a lot in just two days to setup this new organization. The building blocks for genuine ownership by people who use drugs is definitely there." This meeting was organized by drug users, for drug users, with financial support from the World Health Organisation (WHO), the United Nations Regional Task Force and AIVL.
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Investigators at Erasmus University Release New Data on Hepatitis B Virus
www.newsrx.com
The potential impact of long-term antiviral therapy on the burden of chronic hepatitis B has hardly been documented. The aim of this study was to estimate the effects of prolonged antiviral therapy and antiviral resistance on the mortality and morbidity of active chronic hepatitis B patients, researchers in Netherlands report.
A population cohort of chronic hepatitis B patients in the Netherlands was constructed and stratified according to 10-year age groups, prevalence of hepatitis B surface antigen, hepatitis B virus DNA level, alanine aminotransferase level, hepatitis B e antigen status, and presence of cirrhosis. A Markov model was created to mathematically simulate the cohort's progression through a finite series of health states.
The analysis was performed on the basis of four scenarios: natural history, long-term therapy with a high-resistance profile drug without or with salvage, and therapy with a low-resistance profile drug. It has been estimated that there were 64,000 people (0.4%) suffering from chronic hepatitis B infection in the Netherlands in 2005, with 6521 (10%) of them having high viremia and elevated alanine aminotransferase levels.
Within a 20-year period, 1725 (26%) of the 6521 patients in the active chronic hepatitis B cohort will die because of liver-related causes. Of the 5685 without cirrhosis at entry, 1671 (29%) will develop cirrhosis. Of those 836 with cirrhosis at entry, 619 (74%) will die within a 20-year period.
If this active chronic hepatitis B cohort is fully detected and treated, mortality related to liver disease can be reduced by 80% if a low-resistance profile drug is chosen from the start. The effect is due to both the reduction in complications of cirrhosis and the prevention of the development of cirrhosis.
The researchers concluded: "Long-term antiviral therapy with a strategy that minimizes or controls resistance will have a major preventive effect on liver-related mortality and morbidity.
Toy and colleagues published their study in Hepatology (Potential Impact of Long-Term Nucleoside Therapy on the Mortality and Morbidity of Active Chronic Hepatitis B. Hepatology, 2009;50(3):743-751).
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Drinking Coffee Slows Progression of Liver Disease in Chronic Hepatitis C Sufferers
http://www.healthnewsdigest.com
(HealthNewsDigest.com) - Patients with chronic hepatitis C and advanced liver disease who drink three or more cups of coffee per day have a 53% lower risk of liver disease progression than non-coffee drinkers according to a new study led by Neal Freedman, Ph.D., MPH, from the National Cancer Institute (NCI). The study found that patients with hepatitis C-related bridging fibrosis or cirrhosis who did not respond to standard disease treatment benefited from increased coffee intake. An effect on liver disease was not observed in patients who drank black or green tea. Findings of the study appear in the November issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.
Hepatitis C virus (HCV) infects approximately 2.2% of the world’s population with more than 3 million Americans infected. The Centers for Disease Control and Prevention (CDC) cites HCV as the leading cause of liver transplantation in the U.S. and accounts for 8,000 to 10,000 deaths in the country annually. Globally, the World Health Organization (WHO) estimates 3 to 4 million persons contract HCV each year with 70% becoming chronic cases that can lead to cirrhosis of the liver and liver cancer.
This study included 766 participants enrolled in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had hepatitis C-related bridging fibrosis or cirrhosis and failed to respond to standard treatment of the anti-viral drugs peginterferon and ribavirin. At the onset of the study, HALT-C patients were asked to report their typical frequency of coffee intake and portion size over the past year, using 9 frequency categories ranging from ‘never’ to ‘every day’ and 4 categories of portion size (1 cup, 2 cups, 3-4 cups, and 5+ cups). A similar question was asked for black and green tea intake. “This study is the first to address the association between liver disease progression related to hepatitis C and coffee intake,” stated Dr. Freedman.
Participants were seen every 3 months during the 3.8-year study period to assess clinical outcomes which included: ascites (abnormal accumulation of fluid in the abdomen), prognosis of chronic liver disease, death related to liver disease, hepatic encephalopathy (brain and nervous system damage), hepatocellular carcinoma (liver cancer), spontaneous bacterial peritonitis, variceal hemorrhage, or increase in fibrosis. Liver biopsies were also taken at 1.5 and 3.5 five years to determine the progression of liver disease.
Results showed that participants who drank 3 or more cups of coffee per day had a relative risk of .47 for reaching one of the clinical outcomes. Researchers did not observe any association between tea intake and liver disease progression, though tea consumption was low in the study. “Given the large number of people affected by HCV it is important to identify modifiable risk factors associated with the progression of liver disease,” said Dr. Freedman. “Although we cannot rule out a possible role for other factors that go along with drinking coffee, results from our study suggest that patients with high coffee intake had a lower risk of disease progression.” Results from this study should not be generalized to healthier populations cautioned the authors.
Article: “Coffee Intake Is Associated with Lower Rates of Liver Disease Progression in Chronic Hepatitis C,” Neal D. Freedman, James E. Everhart, Karen L. Lindsay , Marc G. Ghany, Teresa M. Curto, Mitchell L. Shiffman, William M. Lee, Anna S. Lok, Adrian M. Di Bisceglie, Herbert L. Bonkovsky, John C. Hoefs, Jules L. Dienstag, Chihiro Morishima, Christian C. Abnet, Rashmi Sinha1, and the HALT-C Trial Group. Hepatology; Published Online: July 13, 2009 (DOI: 10.1002/hep.23162); Print Issue Date: November 2009.
http://www3.interscience.wiley.com/journal/
122511224/abstract
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Beach Boy Spreads Hep C Message
http://www.eveningstar.co.uk
IPSWICH: A member of one of the world's most famous bands, The Beach Boys, visited an Ipswich man who is recovering from a deadly virus.
David Marks, the guitarist from the 60s rock band, met Geoffrey Cleghorn at his home in Highfield Road, to help launch a government campaign, Get Tested. Get Treated, to raise awareness of hepatitis C.
Hepatitis C is a virus that is carried in the blood and can lead to liver failure. As there are no symptoms, many people do not know they are carrying the virus.
Mr Marks, who is from Los Angeles, discovered he had the virus in 1999 when he went to hospital with a broken rib. Following treatment, he has now been virus-free for five years.
He said: “I don't know exactly how I contracted hepatitis C, having been exposed to multiple risk factors in my past including experimentation with drugs. It was frightening when they told me I had it. I did not know what it was.”
Mr Cleghorn, 61, believes he contracted the virus after dallying with some dangerous drugs in the 70s when he was a graphic artist. He only discovered he had it two years ago after some tests when he started volunteering with the Iceni Project in Ipswich.
He said: “It was an awful shock. I did not realise I had anything wrong with me. I now feel better than I have for the last five years.”
His treatment is due to finish in the next fortnight.
If you think you have contracted the virus, visit www.nhs.uk/hepc or call the free information line on 0800 1814114.
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October 21, 2009
First Time Production of Liver Cells from Adult Skin Cells Using Induced Pluripotent Stem Cell Technology
www.medicalnewstoday.com
Scientists have for the first time produced liver cells from adult skin cells using the induced pluripotent stem cell (iPSC) technology.
The study, led by the University of Edinburgh's MRC Centre for Regenerative Medicine, paves the way for the creation of a stem cell library that can be used for in vitro hepatic disease models.
Presently primary human hepatocytes (PHHs) are the 'gold standard' cell type used in predictive drug toxicology. These cells are derived from dead or donor tissue. The cells can only survive for three to five days and do not have the ability to multiply. PHH cells are therefore a scarce and expensive resource.
This study shows an alternative way of sourcing hepatocytes, by creating hepatic endoderm using the iPSC technology and then differentiating it into hepatocytes.
The in vitro derived hepatocytes showed similar attributes to PHH cells used for predictive drug toxicology assays, including CYP3A4 and CYP1A2 metabolism.
The method was successfully carried out with a variety of polymorphic variants, with cells derived from males and females of different ethnic origins.
Drug development is a long and cost-intensive business. Each new drug takes many years to develop and pre-approval costs are in the region of $ 1,3 billion per approved drug. Often drugs have to be withdrawn at this stage because of unwanted side-effects.
The new method has the potential to supply an unlimited and reliable source of hepatocytes. These hepatocytes are highly characterised and reproducible and should therefore enable earlier use in the screening cascade used by industry for drug discovery.
Gareth Sullivan, of the University's MRC Centre for Regenerative Medicine, said: "What we have been able to do will help drug discovery because it means we are able to test drugs for adverse reactions at a much earlier stage."
Prof Sir Ian Wilmut, Director of the University's MRC Centre for Regenerative Medicine, said: 'We are now looking for ways to bring this technology into routine use for drug testing. This is an exciting opportunity and it gives me great pleasure to be able to turn the first recommendation of the UK Stem Cell Initiative into a reality.'
The UK Stem Cell Initiative was an advisory board of the Government. It was set up in 2005 to formulate a ten-year vision of stem cell research in the UK. The board came up with a list of recommendations, the first one being: the UK Government should establish a public-private partnership to develop predictive toxicology tools from stem cell lines.
The research, which was carried out in collaboration with Harvard Medical School, is published by the journal Hepatology. As well as using liver cells created from stem cell lines to test drugs, it is hoped the cells could eventually be used in therapy for patients suffering from liver disease. They could also play a role to aid research into liver disease.
Source: Tara Womersley, University of Edinburgh
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Scientists Identify Specific Markers That Trigger Aggressiveness of Liver Cancer
www.medicalnewstoday.com
Patients with Positive Epithelial-Mesenchymal Transition Markers Have Lowest Survival Rate
Hepatocellular carcinoma (HCC) or primary liver cancer forms in the epithelial tissue of the liver and is most commonly caused by the hepatitis B virus (HBV) or hepatitis C virus (HCV). In the U.S., the National Cancer Institute (NCI) estimates that 15,000 men and 6,000 women are diagnosed with HCC each year. Worldwide, HCC accounts for 632,000 cases with the highest regions being Western Pacific and Africa according to a 2004 World Health Organization (WHO) report.
Researchers from Taipei Veterans General Hospital investigated the molecular mechanisms of HCC, one of the most common tumors found in Taiwan and largely caused by the high prevalence (15%-20%) of HBV in the country. The study, funded in part by a grant from the National Science Council, is the first to provide a comprehensive profile of multiple Epithelial-Mesenchymal Transition (EMT) markers and to demonstrate that Snail and Twist, but not Slug, are the major inducers of EMT in HCC. Results of the study are published in the November issue of Hepatology, a journal of the American Association for the Study of Liver Diseases.
EMT is critical in the development of invasiveness and metastatic potential of human cancers, and described as process where epithelial cells no longer adhere to one another, taking on fibroblastic properties. The EMT process is initiated by suppression of E-cadherin function through the major EMT regulators (Snail, Slug, and Twist). E-cadherin (calcium dependent adhesion molecules) is a type of protein found in the epithelial cells that ensure tissue cells bind together. When E-cadherin function is lost, cancer is able to progress and metastasize.
Professor Jaw-Ching Wu and colleagues obtained samples of primary HCC with adjacent non-tumorous liver tissues from 123 patients who had hepatic resection surgery between 1990 and 2002 at Taipei Veterans General Hospital. Reduced E-cadherin function was observed in 60.2% of patients. "We found a significant decrease in cancer-free intervals and overall survival for those patients who had a reduction in E-cadherin function," explained Dr. Wu. A downregulated expression of E-cadherin was also associated with large tumor size and multi-nodular tumors.
Results show that co-expression Snail and Twist (transcription factors or proteins that control when genes are switched on or off) indicates the worst prognosis for HCC patients. "Our research is the first to prove that the two proteins (Snail and Twist) work independently, but together promote EMT," noted Dr. Wu.
According to the study, overexpression of Twist is correlated with HCV-related HCC, partially explaining the highly invasive behavior and poor prognosis for patients with this form of liver cancer. Dr Wu added, "Our results provide essential information for determining HCC prognosis in patients and identifies possible new treatments for future HCC management."
Source: Wiley - Blackwell
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SciClone Announces Enrollment of First Patient in Its Phase 2 Trial of SCV-07 in Hepatitis C
http://www.sys-con.com
By: Marketwire
FOSTER CITY, CA -- (Marketwire) -- 10/21/09 -- SciClone Pharmaceuticals, Inc. (NASDAQ: SCLN) today announced the enrollment of its first patient at the Atlanta Gastroenterology Associates in Atlanta, GA, in a phase 2 trial of SCV-07 for the treatment of hepatitis C (also known as HCV). This multicenter, multidose, open-label study is designed to evaluate the safety and immunomodulatory effects of SCV-07 as a monotherapy or in combination with ribavirin in non-cirrhotic patients with genotype 1 chronic HCV who have relapsed after at least 44 weeks of treatment with pegylated interferon and ribavirin.
"During our previous phase 2A clinical trial of SCV-07 as a monotherapy to treat patients with chronic hepatitis C infections, we were pleased by the safety data and were very encouraged by the efficacy signal, namely, a reduction of viral loads and a corresponding increase in neopterin concentration in some patients after only seven days of SCV-07 administration," said Friedhelm Blobel, Ph.D., President and Chief Executive Officer of SciClone. "SciClone is eager to investigate further SCV-07's potential to enhance the immune response against hepatitis C and to determine whether the compound is capable of improving the current standard of care treatment."
"Currently approved therapies for the treatment of HCV can have significant side effects and often fall short of providing the most important treatment outcome, sustained viral response," said Kenneth Sherman, MD, PhD, Gould Professor of Medicine, Department of Internal Medicine at the University of Cincinnati, and a principal investigator in SciClone's study. "We are very excited by what appears to be SCV-07's ability to enhance patients' immune function without adding significant toxicity. Should ongoing clinical trials show the benefits of adding SCV-07 to ribavirin, it has the potential to become incorporated into standard treatment practices in the future."
The study, which will monitor biomarkers of immune activation and HCV viral load dynamics, will include two treatment cohorts of 20 patients each, who will receive SCV-07 at a dose of either 0.1 mg/kg or 1.0 mg/kg. The treatment period will be approximately eight weeks long, including four weeks of SCV-07 monotherapy followed by four weeks of SCV-07 in combination with ribavirin. In addition, there will be three follow-up visits within seven weeks after the completion of treatment.
For more information on SciClone's phase 2 trial of SCV-07 in the treatment of HCV, please visit www.clinicaltrials.gov.
About SCV-07
SCV-07 is a small molecule which stimulates the immune system through inhibition of STAT3-dependant signaling and the resulting effects on T-helper 1 cells, which are essential for clearance of viral infections. SCV-07 has shown a good safety profile in several early stage clinical trials in healthy volunteers and subjects with HCV at various doses. SciClone is also carrying out a phase-2, randomized, double-blinded, placebo-controlled trial of SCV-07 for the treatment of oral mucositis in patients with head and neck cancers undergoing chemo-radiation. The topline results from this trial are expected to be announced in the first half of 2010.
SCV-07 is protected by composition of matter patents as well as multiple method of treatment patents. SciClone has exclusive worldwide rights to SCV-07 outside of Russia, where the molecule has recently been approved for stimulation of depressed immune systems.
For additional information, please visit www.sciclone.com.
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I’ll Help You Beat ‘Hidden’ Disease
http://www.oldhamadvertiser.co.uk
A RECOVERING drug addict with hepatitis C has set up a support group to help others with the disease.
The group, the first of its kind in the borough, offers a place for those with the liver infection a place to go.
It was set up by Phil Drayton who spent 20 years addicted to heroin and contracted hep C from an infected needle while injecting drugs.
He was inspired to set up the group after his experience with a similar service in Manchester.
"Talking to someone about my disease and knowing there was someone supporting me was invaluable and has helped me in my journey to beat this disease," said the 48-year-old from Greenacres. Oldham, like many places in the country, has a hidden problem with hep C, but there is very little help out there. That is why I decided to stop waiting for someone to step in, but to help myself and hopefully help others. People living with the virus don’t need to deal with it on their own."
Until the late 1980s, life was good for Phil. Married with children and living in Lees, he ran his own kitchen fitting business.
However, one night he seriously injured another man in a drunken brawl and was jailed. His world came crashing down. His wife and kids left and when he was released he started using drugs such as cannabis, cocaine and heroin to cope with his crisis. Phil became caught in a vicious cycle, committing crimes to chase the next score.
In 15 years he was jailed 15 times and every attempt to kick drugs failed. Then last year he pledged to break the circle and has been clean for 11 months.
"I looked myself in the mirror and said, ‘you can't keep doing this’," he said. "I was doing anything for that warm glow. Drugs was my only concern and drugs and crime go hand in hand. It was a total waste of life."
Phil says contracting hep C was a big shock to him after spending 20 years being careful using needles.
"I never shared apart from one day by accident with a mate I knew had hep C," he said.
"The only time I was unsafe I got the virus. It was a like I had been kicked in the ribs when I found out, but this is the tightrope you walk using drugs."
Phil is undergoing treatment which includes injection therapy. The peer group meet every fortnight. For the next meeting date ring 0161 621 9101.
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Needle Exchanges Prevented 32,000 HIV Cases: Report
http://www.abc.net.au
By Brendan Trembath for AM
A new report has found needle and syringe exchange programs have directly prevented tens of thousands of cases of HIV and hepatitis C.
There are nearly 1,000 sites around the country where clean needles and syringes are handed out to drug users.
Researchers from the University of New South Wales, who authored the report, say it is also saving on health costs. For every $1 spent on needle and syringe exchange programs, state and federal governments save $4.
In the heart of Sydney's Kings Cross there are two spots where clean needles and syringes are handed out.
The director of the Kirketon Road centre, Dr Ingrid van Beek, says the range of people who come to needle syringe programs is quite surprising.
"Of course [there's] the more drug-dependent person that you see on the streets, and I think most people assume that's the only sort of person that injects drugs," she said.
"But we see people from tradesmen through to professionals, people from the arts. It's really very wide."
The report has found the 30 million needles and syringes distributed every year in Australia since 2000 have directly prevented more than 32,000 cases of HIV infection and close to 100,000 cases of hepatitis C, representing a saving in healthcare costs of more than $1 billion.
Associate Professor David Wilson led the team which completed the report.
"Not only do these programs save people from dying, but they also save Australians a load of money," he said.
"Hepatitis C can lead to cirrhosis of the liver, can lead to cancer and so forth, and eventually one might require a liver transplant. A liver transplant costs between $110,000 and $120,000 just for a single transplant."
Professor Wilson says the findings should provide good evidence and strong support for needle and syringe programs.
"We've also shown that these programs can extend further and there should be a demand for that," he said.
"We will actually get greater health outcomes and more economic return if we can expand the programs even further, by another 50 per cent or so."
Dr Van Beek says the report will help the work at Kirketon Road.
"I think it's really important evidence for us at the community coalface," she said.
"It's important for us to be able to explain to the community the benefits to them that these sorts of programs have."
The report was commissioned by the Federal Government and it will not please everyone.
The Christian Democratic Party opposes needle and syringe exchange programs.
The party's leader, Fred Nile, did not return several phone calls but in the past the party has said exchange programs have contributed to an increase in the number of addicts and facilitated the spread of Hepatitis C.
But Dr van Beek says the people they see would be injecting any way. She is convinced it is better to give them clean needles and syringes.
"Before, you know, we just didn't see these people necessarily because they might have been in back lanes or squats, or other sorts of situations," she said.
"Now ... they're coming to a health service and by being able to engage with them of course we are able to also talk to them about their drug dependency, that's a problem, and to refer them to drug-treatment programs.
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October 22, 2009
Discovery of Trigger for Deadly Food Toxin
www.medicalnewstoday.com
A toxin produced by mold on nuts and grains can cause liver cancer if consumed in large quantities. UC Irvine researchers for the first time have discovered what triggers the toxin to form, which could lead to methods of limiting its production.
Because of lax or nonexistent regulation, 4.5 billion people in developing countries are chronically exposed to vast amounts of this toxin, called aflatoxin - often hundreds of times higher than safe levels. In places such as China, Vietnam and South Africa, the combination of aflatoxin and hepatitis B virus exposure increases the likelihood of liver cancer occurrence by 60 times, and toxin-related cancer causes up to 10 percent of all deaths in those nations.
"It's shocking how profoundly these molds can affect public health," said Sheryl Tsai, UCI molecular biology & biochemistry, chemistry, and pharmaceutical sciences associate professor and lead author of a study appearing Thursday, Oct. 22, in the journal Nature that reports the finding.
Aflatoxin can colonize and contaminate nuts and grains before harvest or during storage. The U.S. Food & Drug Administration considers it an unavoidable food contaminant but sets maximum allowable limits.
The toxin wreaks havoc on a cancer-preventing gene in humans called p53. Without p53 protecting the body, aflatoxin can compromise immunity, interfere with metabolism, and cause severe malnutrition and cancer.
Tsai, graduate student Tyler Korman and undergraduate Oliver Kamari-Bidkorpeh, along with Johns Hopkins University researchers, found that a protein called PT is critical for aflatoxin to form in fungi. Previously, scientists didn't know what prompted the toxin's growth.
"The protein PT is the key to making the poison," Tsai said. "With this knowledge, perhaps we could kill the PT with drugs, inhibiting the mold's ability to make aflatoxin."
Destroying the mold - rather than just the PT - is the traditional method of decontamination, but it's expensive, costing hundreds of millions of dollars worldwide.
"This finding will lead to an increased understanding of how aflatoxin causes liver cancer in humans," said Dr. Frank Meyskens, Daniel G. Aldrich Jr. Endowed Chair and director of UCI's Chao Family Comprehensive Cancer Center. "It should allow for the development of inhibitors and, hopefully, a new chemoprevention approach to this deadly cancer."
Aflatoxin belongs to a class of organic compounds called polyketides. "Because polyketides provide the building blocks for both carcinogens and some of our most significant drugs, the importance of this study cannot be overemphasized," said Christopher Hughes, molecular biology & biochemistry professor and chair.
"This discovery provides insight into the mechanism of carcinogen production as well as an Achilles' heel that can be targeted by new generations of inhibitors. The basic understanding of polyketide synthesis that this work provides will be invaluable in the design of new polyketide-derived drugs."
The study was supported by the National Institutes of Health, the Pew Charitable Trusts, the U.S. Department of Energy, and the Damon Runyon Cancer Research Foundation.
Source: Jennifer Fitzenberger, University of California - Irvine
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October 23, 2009
Hepatitis Deaths Will Triple
http://www.sciencealert.com.au
Australian National University
The number of people in Australia with chronic hepatitis B infection (HBV) is predicted to increase markedly over the next decade, according to a new report released by the Australian Centre for Economic Research on Health (ACERH) at the Australian National University (ANU).
The Impact of Chronic Hepatitis B in Australia: Projecting Mortality, Morbidity and Economic Impact, co-authored by Professor Jim Butler and Dr Rosemary Korda at ANU, and two clinicians, suggests that a national strategy involving a coordinated approach to screening, vaccination, and treatment of the disease is warranted.
“There appears to be a lack of appreciation of the potential benefits of identifying and treating those infected,” said Dr Korda. “Although Australia has adopted universal hepatitis B vaccination for infants, there are many people already infected for whom vaccination offers no benefit.
“Immigration patterns, the ageing of the infected pool of individuals and the small number of people receiving HBV drug therapy, together imply that the long-term pathology of HBV infection can be expected to become increasingly evident over the next decade.”
According to the report, under current levels of medical management and treatment:
- The number of people living with chronic hepatitis B infection will increase from 187 000 to 276 000
- The number of deaths attributable to chronic hepatitis B each year will increase from 450 in 2008 to 1550 in 2017
- There will be a three-fold increase in the number of people living with liver cancer directly caused by hepatitis B.
The researchers say that increases in the rate of infection could be mitigated through the development of a national strategy for Hepatitis B, which would increase awareness of the disease and encourage those infected to seek treatment.
“Our cost-effectiveness analyses indicate investment in such a strategy is economically justified given the looming increase in the numbers of people infected and the drug therapies that are available to treat those infected,” said Professor Butler.
Editor's Note: Original news release can be found here. The full report is available here.
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October 24, 2009
Judge Orders Release of Hepatitis Case Records
http://www.lasvegassun.com
By Jeff German
The public could soon learn a lot more about how last year’s hepatitis C outbreak occurred and health authorities’ role in it.
After a hearing this week, District Judge Allan Earl ruled that key records and the answers that witnesses and defendants gave to questions under oath must be made public as some of the cases move to trial. The records and depositions had been kept secret for the past 18 months.
Robert Cottle, the plaintiffs lawyer who persuaded Earl to make his decision Thursday, hailed it as the “biggest day” yet for about 300 former patients who allege they were infected with the potentially deadly hepatitis C virus at three clinics owned by Dr. Dipak Desai.
But Cottle said it was also a big day for the public because he expects these documents will highlight how little government oversight there was of the clinics before the outbreak.
“The public will discover that the clinics did not have any on-site inspections with any regularity other than every four to six years,” he said. “The depositions will show that the government isn’t putting enough effort into protecting the quality of the health care we receive.”
Cottle estimated that about 20 sworn depositions will have to be made public under Earl’s order. The depositions include those of several defendants, including doctors and nurses who did not take the Fifth Amendment. Depositions of witnesses such as pharmaceutical company employees and county and state health officials will also be released.
Plaintiffs lawyers think the depositions contain plenty of information — especially from county and state health officials — that will shed new light on the hepatitis C outbreak.
There are catches to Earl’s lifting of the confidentiality order — the documents won’t immediately be disclosed, and lawyers for the clinics and others involved in the litigation have 45 days to lodge objections to the release of any documents.
Attorneys for Brian Labus, the Southern Nevada Health District’s senior epidemiologist, and Dr. Lawrence Sands, the county’s chief health officer, have asked the Nevada Supreme Court to keep their depositions secret, arguing that as investigators they have a right under state law not to disclose their testimony. The Health District has yet to release a report of its own investigation into the hepatitis scare.
If the Supreme Court orders the depositions of Labus and Sands to remain confidential, it would override Earl’s ruling.
Cottle said a series of reports on inspections done last year by the then-Nevada Bureau of Licensure and Certification would have to be disclosed under Earl’s order. Those reports allege that Desai’s clinics were dispensing multiple doses out of vials of propofol, an anesthetic the clinics used in routine colonoscopies and other medical procedures.
Cottle said the public will be able to determine from the reports “how easily large vials of propofol can be abused and how the risks can be spread among the patients.”
Among the documents Earl deemed public are about 5,000 pages of financial records of the clinics previously turned over to plaintiffs lawyers. Included in the records are 18 months of pages from the general ledger, from early 2007 to mid-2008, showing all the money going in and out of the clinics, Cottle said.
“These records tell us the financial story of the clinics and will provide a basis to show the greed that was rampant there — the cutting of corners and cost containment and the reusing of vials and flushing fluids,” Cottle alleged.
Cottle and the other plaintiffs lawyers are operating under the theory that the infections occurred because the clinics squeezed multiple doses out of vials of propofol.
Other records could help the plaintiffs establish that the clinics were buying larger than normal vials of propofol and that they were shipped to the clinics with little or no reminders to physicians and nurses that the drug was to be used in single doses only, Cottle said.
The plaintiffs also expect to benefit from still other records Earl ordered turned over. Those are records of the “source patients,” hepatitis C carriers whose blood infected the propofol.
Although Earl ordered the identities of the source patients to remain confidential, other information in the records, such as the times those patients were treated and what size vials of propofol were used during their procedures, will provide the plaintiffs with crucial evidence they hope will prove their cases.
“It’s a shame that it took us 18 months to get these records,” said Ed Bernstein, another plaintiffs lawyer. “In any other case it would have been automatic to get these documents at the beginning of the case.”
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