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Week Ending: August 29, 2009
Alan Franciscus
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This Issue:
August 23, 2009
Novel Targets for specific therapy of hepatitis C
http://www.pipelinereview.com/
Most hepatitis C virus (HCV) infected individuals seeking treatment are chronically infected. Treatment goal is to achieve a sustained virological response (SVR), which is the absence of serum HCV RNA up to 6 months after therapy is concluded. To increase efficiency of interferon treatment, pegylated interferon alpha (peg-IFN-alpha) therapy has been supplemented with ribavirin. Combination therapy with peg-IFN-alpha and ribavirin has resulted in a further increase in treatment efficiency with 54% of HCV infected patients achieving SVR. The response and rate of SVR is dependent on the genotype of HCV with only 30% of genotype 1 infected individuals achieving SVR, whereas greater than 80% of genotype 2 or 3 achieve SVR with combination therapy. Combination therapy treatment regiments are genotype dependent and the amount of peg-IFN-α administered is dependent on the type used.
The suboptimal response has led to a shift in the investigational focus for treatment of HCV toward specifically targeted antiviral therapy for HCV agents. Moreover, pegylated IFN alpha and/or ribavirin are associated with frequent side effects and have a negative impact on the patient's quality of life. Among the first wave of targeted HCV therapeutics are the NS3a protease and NS5B RNA polymerase inhibitors with 25 different compounds in clinical development and further 8 in the IND enabling study phase. Development of HCV protease inhibitors is slightly ahead of polymerase inhibitors. The first study combining HCV protease and polymerase inhibitors was successfully completed.
At least 17 further distinct molecules are in early clinical development and another five close to enter clinical investigation which have novel mechanisms of action. Among the targets are cyclophilin inhibitors, NS5A protein inhibitors, NS4B-RNA binding inhibitors, viral entry and replication inhibitors. Specific therapeutic vaccines and antibodies are included in those novel targeted HCV treatment modalities. Other novel mechanism of action agents are directed against host cell or viral structures.
Related report:
Competitor Analysis: Targeted Therapy of Hepatitis C
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August 24, 2009
U.S. probes Roche, Glaxo diet drug over liver injury
www.reuters.com
By Lisa Richwine
WASHINGTON (Reuters) - U.S. health officials are reviewing reports of liver injury in people who took Roche Holding AG's weight loss drug Xenical or the over-the-counter version sold by GlaxoSmithKline.
The Food and Drug Administration said on Monday it had received 32 reports between 1999 and 2008 of serious liver injury in patients taking the drug, which is known generically as orlistat. All but two involved prescription Xenical and occurred outside the United States.
Twenty-seven patients were hospitalized, and six cases resulted in liver failure, the FDA said.
"The FDA's analysis of these data is ongoing, and no definite association between liver injury and orlistat has been established at this time," the agency said.
People who are taking the drug should continue to use it as directed, the FDA said.
Officials at Roche and Glaxo could not immediately be reached for comment.
Mike Krensavage, principal of Krensavage Asset Management LLC, said news of the FDA probe could hurt sales of the diet pills.
"Any time the FDA raises an issue like this, demand is likely to suffer, at least temporarily," he said.
He noted that the drug only slightly reduces weight and has been associated with digestive problems. "If there's a minimal benefit to begin with, risks perhaps take more of a toll on sales," he said.
The FDA said 30 of the liver injury cases occurred outside the United States and involved 120 milligram doses of prescription Xenical. The two U.S. cases were associated with Glaxo's nonprescription version of the drug, which is sold under the name Alli, the FDA said. The nonprescription dose is half of the prescription dose.
Roche reported first-half 2009 sales for Xenical of 209 million Swiss francs ($197 million). Glaxo reported Alli sales of $125 million for the second quarter.
People who have used orlistat should consult a doctor if they have symptoms of liver injury such as weakness, fatigue, fever, jaundice or brown urine, the FDA said.
Glaxo shares fell nearly 1.5 percent to $39.44 on the New York Stock Exchange after the FDA disclosed the probe. Roche shares earlier fell 0.4 percent in Swiss trading.
The FDA notice was posted here
(Reporting by Lisa Richwine and Ransdell Pierson, Editing by Tim Dobbyn and Carol Bishopric)
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Salix Pharmaceuticals Announces FDA Acceptance for Filing and Priority Review Designation for Rifaximin NDA for the Maintenance of Remission of Hepatic Encephalopathy
www.salix.com
RALEIGH, N.C.--(BUSINESS WIRE)--Salix Pharmaceuticals, Ltd. (NASDAQ:SLXP) today announced the Food and Drug Administration (FDA) has accepted for filing and designated for Priority Review the Company’s New Drug Application (NDA) for rifaximin tablets 550 mg for the maintenance of remission of hepatic encephalopathy (HE). Additionally, the FDA has informed the Company of its plan to schedule an Advisory Committee meeting in late February 2010 to discuss the application.
A Priority Review classification is granted to drugs offering major advances in treatment, or providing a treatment where no adequate therapy exists. Based on this classification, the FDA has issued an action date of December 24, 2009 under the Prescription Drug User Fee Act (PDUFA). However, the convening of an Advisory Committee in late February 2010 signals the December 24, 2009 action date will be delayed.
“We are pleased with the FDA’s acceptance for filing of the rifaximin NDA and their decision to grant Priority Review for our application,” stated Bill Forbes, Pharm.D., Senior Vice President and Chief Development Officer, Salix Pharmaceuticals. “This review classification signals that the FDA considers that rifaximin has the potential to provide a significant advance in the treatment of hepatic encephalopathy. We are not surprised at the FDA’s decision to convene an Advisory Committee to gain an independent recommendation from outside experts regarding rifaximin due to the fact that, if approved, rifaximin will be the first new option approved for the management of HE in over 30 years. We believe the availability of rifaximin has the potential to change the treatment paradigm for HE. Today’s news marks a milestone for Salix, rifaximin and patients suffering from this serious condition.”
Currently Salix estimates the U.S. commercial opportunity represented by the HE market is approximately $600 million. Hepatic encephalopathy occurs frequently in patients with cirrhosis as a result of their end-stage liver disease. Typically the cirrhosis is caused by a number of factors, such as alcohol and/or drug abuse, chronic viral hepatitis and autoimmune disease. Cirrhosis is a leading cause of death in the United States. The number of cases of liver disease in the United States and around the world is rapidly increasing, with more than 7 million people in the United States being diagnosed with chronic liver disease. There are reported to be more than 100,000 patients in the United States with overt HE.
Rifaximin has been granted Orphan Drug designation by the FDA for use in hepatic encephalopathy. Salix believes this designation will provide seven years of marketing exclusivity in the United States if rifaximin gains approval from the FDA for HE.
About Hepatic Encephalopathy
Hepatic encephalopathy (HE) is a neurological disorder caused by chronic liver failure resulting in cognitive, psychiatric and motor impairments. The condition encompasses a wide spectrum of often reversible neuropsychiatric abnormalities caused by the inability of the liver to remove toxic products in the gut, most notably ammonia-producing bacteria. When toxins reach the central nervous system, this condition can result in symptoms ranging in severity from mild cerebral function deficits to coma and characterized by disruption in sleep patterns, changes in personality and intellectual capacity, high blood ammonia levels, altered neuromuscular activity and electroencephalogram (EEG) abnormalities.
About XIFAXAN® (rifaximin)
Rifaximin tablets 200 mg, which Salix markets in the United States under the trade name XIFAXAN® (rifaximin) tablets 200 mg, currently is approved for the treatment of patients, 12 years of age or older, with travelers' diarrhea caused by non–invasive strains of Escherichia coli. XIFAXAN (rifaximin) is a gut–selective antibiotic with negligible systemic absorption (<0.4%) and broad–spectrum activity in vitro against both gram–positive and gram–negative pathogens. Rifaximin has a similar tolerability profile to that of placebo and has activity against the most common TD pathogens. XIFAXAN should not be used in patients with diarrhea complicated by fever or blood in the stool or diarrhea due to pathogens other than Escherichia coli. XIFAXAN should be discontinued if diarrhea symptoms get worse or persist more than 24–48 hours and alternative antibiotic therapy should be considered. In clinical trials, XIFAXAN was generally well tolerated. The most common side effects (vs. placebo) were flatulence 11.3% (versus 19.7%), headache 9.7% (versus 9.2%), abdominal pain 7.2% (versus 10.1 %) and rectal tenesmus 7.2% (versus 8.8%).
Rifaximin (550 mg) is under investigation in the United States as a treatment for irritable bowel syndrome. Rifaximin has been used in Italy for 24 years and is approved in 33 countries. Salix acquired rights to market rifaximin in North America from Alfa Wassermann S.p.A. in Bologna, Italy. Alfa Wassermann markets rifaximin in Italy under the trade name Normix®.
About Salix Pharmaceuticals
Salix Pharmaceuticals, Ltd., headquartered in Raleigh, NC, develops and markets prescription pharmaceutical products for the treatment of gastrointestinal diseases. Salix’s strategy is to in-license late-stage or marketed proprietary therapeutic drugs, complete with any required development and regulatory submission of these products, and market them through the Company’s gastroenterology specialty sales and marketing team.
Salix also markets OSMOPREP® (sodium phosphate monobasic monohydrate, USP and sodium phosphate dibasic anhydrous, USP) Tablets, MOVIPREP® (PEG 3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution), VISICOL® (sodium phosphate monobasic monohydrate, USP, and sodium phosphate dibasic anhydrous, USP) Tablets, APRISO™ (mesalamine) extended-release capsules 0.375 g., PEPCID® (famotidine) for Oral Suspension, Oral Suspension DIURIL® (Chlorothiazide), AZASAN® Azathioprine Tablets, USP, 75/100 mg, ANUSOL-HC® 2.5% (Hydrocortisone Cream, USP), ANUSOL-HC® 25 mg Suppository (Hydrocortisone Acetate), PROCTOCORT® Cream (Hydrocortisone Cream, USP) 1% and PROCTOCORT® Suppository (Hydrocortisone Acetate Rectal Suppositories) 30 mg. METOZOLVTM ODT (metoclopramide), crofelemer, budesonide foam and rifaximin for additional indications are under development.
For full prescribing information on Salix products, please visit www.salix.com.
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Court to rule on whether hepatitis cases can proceed
http://www.lasvegassun.com
By Jeff German (contact)
Unless cooler heads prevail, this week’s hearing in U.S. Bankruptcy Court on whether the massive litigation over the valley’s 2008 hepatitis C outbreak can proceed is shaping up as a real donnybrook.
The litigation was put on hold last month after three endoscopy clinics owned by Dr. Dipak Desai, the man at the center of the hepatitis scare, filed for Chapter 7 bankruptcy protection.
Lawyers for Brian Shapiro, the bankruptcy trustee in charge of distributing assets in the case, and attorneys representing former patients suing the clinics for malpractice teed off on each other in bankruptcy court papers last week.
Shapiro’s attorneys contend the lawyers for the patients, in their “race to deplete” limited insurance money for potential malpractice judgments, are making it difficult for Shapiro to do his job.
They say he opposes allowing the District Court litigation to go forward because he’s looking out for the interests of all of the creditors, including the more than 4,000 former patients suing the clinics. More than 300 of those patients claim to have been infected with the hepatitis C virus.
The first malpractice trials are to get under way in October, and if those few plaintiffs prevail, they could gobble up all of the clinics’ $6 million in insurance money, leaving nothing for the majority of the plaintiffs whose trials are months down the line, Shapiro’s lawyers argue.
But plaintiffs’ attorney Will Kemp charges in his court papers that Shapiro doesn’t know what he’s talking about and is actually working against the interests of the former patients.
Kemp says there is no race to get to the insurance money. Plaintiffs’ lawyers have agreed to hold off attempting to collect any judgments so that an equitable compensation formula can be worked out for all plaintiffs.
Robert Cottle, a plaintiffs’ attorney who represents the majority of the 4,000-plus noninfected patients, says in an affidavit that he never gave Shapiro permission to make any arguments in Bankruptcy Court on behalf of his clients.
Cottle says his clients understand that, contrary to Shapiro’s belief, allowing the hepatitis litigation to move forward is in their best interests.
The early trials are viewed by plaintiffs’ lawyers as test cases to get verdicts that could end up leading to settlements in other cases and speed up the litigation.
Cottle plans to be in Bankruptcy Court for the big hearing Wednesday, as Kemp put it in his court papers, “to relieve the trustee of any temptation to make further arguments on behalf of Mr. Cottle’s clients.”
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August 25, 2009
Fat In the Liver -- Not the Belly -- Is a Better Marker for Disease Risk
www.medicalnewstoday.com
New findings from nutrition researchers at Washington University School of Medicine in St. Louis suggest that it's not whether body fat is stored in the belly that affects metabolic risk factors for diabetes, high blood triglycerides and cardiovascular disease, but whether it collects in the liver.
Having too much liver fat is known as nonalcoholic fatty liver disease. The researchers report online in the journal PNAS Early Edition that when fat collects in the liver, people experience serious metabolic problems such as insulin resistance, which affects the body's ability to metabolize sugar. They also have increases in production of fat particles in the liver that are secreted into the bloodstream and increase the level of triglycerides.
For years, scientists have noted that where individuals carried body fat influences their metabolic and cardiovascular risk. Increased fat inside the belly, known as visceral fat, is associated with an increased risk of diabetes and heart disease.
"Data from a large number of studies shows that visceral fat is associated with metabolic risk, which has led to the belief that visceral fat might even cause metabolic dysfunction," says senior investigator Samuel Klein, M.D. "However, visceral fat tracks closely with liver fat. We have found that excess fat in the liver, not visceral fat, is a key marker of metabolic dysfunction. Visceral fat might simply be an innocent bystander that is associated with liver fat."
Klein, the Danforth Professor of Medicine and Nutritional Science, directs the Division of Geriatrics and Nutritional Science and the Center for Applied Research Studies, as well as Washington University's Center for Human Nutrition. He says most of our body fat, called subcutaneous fat, is located under our skin, but about 10 percent is present inside the belly, while much smaller amounts are found inside organs such as the liver and muscle.
This study compared obese people with elevated and normal amounts of liver fat. All subjects were matched by age, sex, body mass index, percent body fat and degree of obesity. Through careful evaluations of obese people with different amounts of visceral fat or liver fat, Klein's team determined that excess fat inside the liver identifies those individuals who are at risk for metabolic problems.
"We don't know exactly why some fats, particularly triglycerides, will accumulate inside the liver and muscle in some people but not in others," says first author Elisa Fabbrini, M.D., Ph.D., assistant professor of medicine. "But our data suggest that a protein called CD36, which controls the transport of fatty acids from the bloodstream into different tissues, is involved."
Fatty acids are the building blocks for making fats, known as triglycerides. Klein, Fabbrini and their colleagues found that CD36 levels were lower in fat tissue and higher in muscle tissue among people with elevated liver fat.
Fabbrini and Klein say changes in CD36 activity could be responsible for diverting circulating fatty acids away from fat tissue and into liver and muscle tissue, where they are converted to triglyceride. Increased tissue uptake of fatty acids could be responsible for metabolic dysfunction.
Klein says those who are obese but don't have high levels of fat in the liver should be encouraged to lose weight, but those with elevated liver fat are at particularly high risk for heart disease and diabetes. He says they need to be treated aggressively to help them lose weight because dropping pounds can make a big difference.
"Fatty liver disease is completely reversible," he says. "If you lose a small amount of weight, you can markedly reduce the fat content in your liver. In fact, even two days of calorie restriction can cause a large reduction in liver fat and improvement in liver insulin sensitivity."
Fabbrini E, Magkos F, Mohammed S, Pietka T, Abumrad NA, Patterson BW, Okunade A, Klein S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. PNAS Early Edition (2009), published online Aug. 24, 2009
Deivanayagam S, Mohammed BS, Vitola BE, Naguib GH, Keshen TH, Kirk EP, Klein S. Nonalcoholic fatty liver disease is associated with hepatic and skeletal muscle insulin resistance in overweight adolescents. American Journal of Clinical Nutrition, 88(2) pp. 257-262, Aug. 2008.
Korenblat K, Fabbrini E, Mohammed BS, Klein S. Liver, muscle and adipose tissue insulin resistance is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 134: 1369-1375, 2008.
Kirk E, Reeds DN, Finck BN, Mayurranjan MS, Klein S. Effects of acute and chronic calorie restriction on insulin action in obese men and women. Gastroenterology 136: 1552-1560, 2009.
This research was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Research Resources of the National Institutes of Health.
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Source: WashingtonUniversity in St. Louis
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August 26, 2009
Bradley Corp Releases Results of National Hand Washing Survey
By Racine News Team
Majority of Respondents Haven’t Changed Hand Washing Habits in Response to H1N1 Virus
Milwaukee,WI - Worries about the spread of the H1N1 virus haven’t changed the majority of Americans’ hand washing habits, according to a national survey conducted by Bradley Corporation of Menomonee Falls, a leading manufacturer of bathroom and locker room furnishings, including sinks, faucets, hand dryers, showers and lockers.
In Bradley’s first Healthy Hand Washing Survey, 54 percent of the 1,020 respondents said they “wash their hands no more or less frequently” in public restrooms as a result of the H1N1 virus.
“Influenza A viruses, of which swine flu is one, are fragile viruses that can be easily destroyed through proper hygiene, including use of soap and water and alcohol-based hand sanitizers,” says Dr. Judy Daly, spokesperson for the American Society for Microbiology, director of the clinical microbiology laboratories, primary children’s medical center, Salt Lake City. “Flu viruses most frequently enter the body when contaminated hands touch mucous membranes of the nose, eyes, and mouth. Frequent hand hygiene certainly makes this transfer less likely.”
“We found the response to the H1N1 question extremely surprising, especially since the medical community has said over and over that hand washing is the best defense against the spread of cold and flu viruses,” says Jon Dommisse, director of marketing and product development at Bradley Corporation.
Bradley’s Healthy Hand Washing Survey was conducted online July 28-31, 2009, and queried 1,020 American adults about their hand washing habits in public restrooms. Participants were from around the country, evenly divided among men and women, and ranged in age from 18 to 65 and older.
Self-reported Hand Washing Habits Contrast with Observational Research
Overall, 87 percent of respondents said they did wash their hands after using public lavatories, but other responses indicated that some may have exaggerated how often they actually did the job correctly. When asked if they had also used soap, the numbers declined only slightly, to 86 percent; yet 55 percent of the group admitted on occasion they’ve simply rinsed, without using soap.
In contrast to what people say they do, numerous observational studies question what Americans actually do. In 2007, researchers for the American Society of Microbiology found that only 77 percent actually wash their hands after using a public restroom. In 2003 and 2004, the Minnesota Department of Health, Division of Environmental Health observed hand washing practices at the Minnesota state fairgrounds. During the 2004 Minnesota State Fair, 75 percent of women and just 51 percent of men washed their hands with soap and water after using the public restroom.
Soap and Water Best Preventative Medicine
The U.S. Centers for Disease Control and Prevention (CDC) is unequivocal about the benefits of hand washing, calling it critical in preventing infection and illness:
“Hand washing is a simple thing to do and it’s the best way to prevent infection and illness,” the agency says. And by “washing your hands,” the CDC notes that nothing beats good old soap and water. (See sidebar for CDC’s instructions on proper hand washing.)
Asked why they did not wash their hands before leaving a public restroom, respondents identified a number of reasons, such as the sinks weren’t working, the wash area appeared unclean, the sink area was crowded and they didn’t feel the need to wash. However, 28 percent of those who didn’t wash their hands said they used a hand sanitizer instead. The primary reason respondents cited for not using soap, rinsing only with water, was that the soap dispensers were empty.
Children’s Hand Washing Habits
The survey also asked parents about their children’s hand washing habits. The respondents indicated they believe their children wash their hands with soap and water 68 percent of the time after using the school restroom.
Hand washing among school-age children is especially important because it’s estimated that at least 22 million school days are lost every year due to the common cold, according to the CDC. Illness can spread from student to student throughout the school so it’s important that students wash their hands after using the bathroom, before eating and after coughing, sneezing or blowing their nose.
“Hand washing is a lifetime health practice that children should know about, understand the benefits of and take with them into adulthood,” says Dommisse.
Restroom Likes and Dislikes
When it came to the type of public restrooms they preferred, nearly half the survey respondents (45 percent) chose casual dining restaurants, followed by retail stores (15 percent) and airports (13 percent). Restrooms in movie theaters, fast-food restaurants and grocery stores scored below 10 percent, with parks, sports arenas and zoos all earning just 1 percent approval.
The least favorite public restroom type? Gas stations and convenience stores. The reasons some restroom categories ranked high or low were not surprising: Respondents preferred restrooms that were clean, well-maintained and uncrowded, and were turned off by those they found to be dirty, poorly maintained, not well stocked or unattended.
Parents helping their children were especially frustrated by empty or jammed towel dispensers, having no space to put belongings, water collecting on sink counters, and sinks and soap dispensers that were too high for children to reach.
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Is endotoxin receptor CD14 rs2569190/C-159T gene correlated with chronic hepatitis C?
http://www.eurekalert.org
It is still unknown why the natural history of chronic disease caused by hepatitis C virus (HCV), which currently infects 3% of the world's population, varies from mild in some patients to rapidly progressing in others. Age, sex, alcohol consumption and liver sensitivity to gut-derived bacterial endotoxins, were the early factors defined to enhance the risk of fibrosis progression. Host genetic variations, e.g., the CD14 single nucleotide polymorphism (SNP), rs2569190/C-159T, have been recently intensively investigated and suggested to be prognostic factors for cirrhosis in various liver diseases. Is this endotoxin receptor SNP correlated with liver disease features in chronic hepatitis C patients?
A research article to be published on August 21, 2009 in the World Journal of Gastroenterology addresses this question. The research team lead by Professor Sabine Mihm and her colleagues from the Department of Gastroenterology and Endocrinology, University Medical Center Göttingen, Germany, analyzed the distribution of various epidemiological, biochemical, and histological characteristics in 2 cohorts of Caucasian chronic hepatitis C patients with respect to their genotypes according to the CD14 rs2569190/C-159T SNP.
In one cohort, patients who carried 2 variant alleles (TT) were found to be younger than C allele carriers (CC or CT). Among the histological lesions studied, portal lymphoid aggregates were more frequently observed among TT than among C carriers. The presence of portal lymphoid aggregates was also closely correlated with another 2 lesions, moderate and severe hepatic inflammation and the presence of bile duct damage. However, the degree of fibrosis was not found to be related to the CD14 gene C-159T SNP.
The different situation between chronic liver diseases caused by HCV infection or by alcohol consumption in relation to TT status suggests that endotoxin sensitivity depends on both genetic and environmental factors (gene environment interaction). Our analysis suggests, for the first time, a relationship between the CD14 variation and the formation of portal lymphoid aggregates, which was attributed to the host's immunological participation in liver disease pathogenesis.
Reference:
Askar E, Ramadori G, Mihm S. Endotoxin receptor CD14 genevariants and histological features in chronic HCV infection. World J Gastroenterol 2009; 15(31): 3884-3890 http://www.wjgnet.com/1007-9327/15/3884.asp
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VA Negligence Suits Likely after Botched Colonoscopies
http://www.newsinferno.com
Botched medical procedures at veterans hospitals have left some with dangerous, deadly diseases, such as HIV, hepatitis B, and hepatitis C and others fearing for their health as they await test results.
The Department of Veterans Affairs (VA) was roundly criticized at a hearing before a House VA committee for not increasing safeguards and improving procedures at VA health facilities after shoddy colonoscopies and endoscopies were potentially linked to the spread of the pathogens. According to an Associated Press (AP) report last month, an attorney was planning on asking the U.S. Department of VA to pay disability benefits and damages for these mistakes.
Now, 55-year-old Army veteran, Juan Rivera, alleges that due to improper sterilization procedures at the VA hospital where he underwent a routine colonoscopy in 2008, he has been infected with HIV, reported the Washington Post. “The VA has issued me a death sentence,” Rivera said, according to his attorney, quoted the Washington Post.
We recently wrote that despite a nationwide scare, media attention, and suspected links to HIV, hepatitis B, and hepatitis C, less than half of all VA facilities were operating under appropriate procedures based on surprise investigations spurred by the scandal, which broke months earlier, citing a prior AP report.
HIV and hepatitis B and C are spread by contact with infected body fluids, especially blood. HIV—the human immunodeficiency virus—is the virus that causes AIDS (acquired immunodeficiency syndrome); AIDS is the final stage of HIV infection. Hepatitis B and C are liver diseases that can lead to cirrhosis or cancer of the liver. Vaccines exist only for hepatitis B. HIV/AIDS and hepatitis B and C can all be fatal.
The shoddy endoscopies and colonoscopies were conducted as far back as five years ago and put VA patients at risk because they were treated with improperly sterilized equipment, thus exposing them to the bodily fluids of other patients, noted the AP previously. The VA acknowledged in the thousands of warning letters it sent to former patients that the invasive procedures potentially exposed them to other patients’ bodily fluids. Also, the VA admitted in late March that water tubes and reservoirs it used in colonoscopies and endoscopies were rinsed—not disinfected—between procedures, which could expose subsequent patients to contamination.
As of earlier this month, eight patients have tested positive for HIV, 12 for hepatitis B, and 37 to hepatitis C, said the Washington Post, citing the VA.
According to the Washington Post, this is just the beginning of an expected “rush” of lawsuits against the VA. One attorney told the Washington Post he plans on filing claims for about one dozen veterans who tested positive for hepatitis B or C and another 50-to-60 for veterans and their families in which emotional distress is cited.
The VA has admitted to the mistakes, which, it said, were caused by human error, reported the AP earlier, but says it is unable to prove if the infections are directly linked to VA procedures. The VA said the errors were isolated to three of its hospitals: Murfreesboro, Tennessee; Miami, Florida; and Augusta, Georgia, according to the AP. But, the AP recently reported that other VA patients were not warned about similar mistakes with the same equipment at more than 12 other VA centers.
“Facilities have not complied with management directives to ensure compliance with reprocessing of endoscopes, resulting in a risk of infectious disease to veterans,” according to the nationwide review, quoted the Washington Post. “The failure of medical facilities to comply on such a large scale with repeated alerts and directives suggests fundamental defects in organizational structure.”
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In HIV-HCV Coinfection, HCV Clearance Reduces Overall Mortality
www.medscape.com
By Scott Baltic
NEW YORK (Reuters Health) Aug 25 - In HIV-infected patients who also have chronic hepatitis C virus (HCV) infection, a sustained virological response to interferon and ribavirin reduces liver-related complications and overall mortality, according to findings by Spanish researchers.
Chronic HCV infection is "one of the most clinically relevant comorbid conditions in the HIV-infected population," and this study is the largest to date to assess the natural history of hepatitis C after interferon-ribavirin therapy in these patients, according to Dr. Juan Berenguer of the Hospital Gregorio Maranon, Madrid, and colleagues at 11 centers.
Sustained virological response was defined in this study as undetectable HCV RNA 24 weeks after the end of treatment.
In email correspondence with Reuters Health, Dr. Berenguer highlighted two findings in particular. First, the benefits of interferon-ribavirin therapy were seen in the relatively short average follow-up period of 20.8 months.
"Second," he said, "these benefits were independent of the presence of advanced fibrosis," whereas in patients with HCV alone, a sustained virological response reduces the risk of clinical events only in patients with advanced fibrosis or cirrhosis.
The researchers studied 711 patients with HIV and HCV who began therapy with interferon and ribavirin between January 2000 and December 2005. Their median age was 41 years, 72% were male, and the median time since HCV infection was 18 years. During the study period, 84% of the patients received highly active antiretroviral therapy.
The investigators report their findings in the August issue of Hepatology.
Overall, 218 patients (31%) achieved a sustained virological response. Independent predictors of sustained virological response were HCV genotype 2 or 3 (odds ratio 3.81), HCV RNA level below 500,000 IU/mL (OR 1.71), and nadir CD4-positive cell count (OR 1.01).
At a median follow-up of 18.7 months, responders had significantly lower rates than the group without a sustained virological response for liver-related deaths (0.5% versus 3.7%), deaths from any cause (0.9% versus 6.9%), and liver decompensation (0.5% versus 9.1%).
The authors point out that there was no reduction in the incidence of hepatocellular carcinoma, highlighting the need for continued surveillance, particularly in patients with advanced fibrosis and cirrhosis.
In addition, they warn that because their study was not prospective, its results could be biased.
Hepatology 2009;50:407-413.
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China donor drive aims to end prisoner organ trade
www.reuters.com
BEIJING (Reuters) - China launched its first national organ donation system in a bid to crack down on organ trafficking and create a source for transplants other than executed prisoners, who currently make up the majority of donors.
Executed criminals account for 65 percent of organ donors, the China Daily said on Wednesday, in an unusual admission of the prevalence of the practice.
"(Executed prisoners) are definitely not a proper source for organ transplants," Vice Health Minister Huang Jiefu told the paper.
Nearly 1.5 million people in China need organ transplants, but every year only 10,000 people can get one, according to the Health Ministry's website www.moh.gov.cn.
The shortage means that desperate patients bid up the price, and contributes to corruption and unfairness in organ allocation.
China's 2007 organ transplant law bans organ trafficking. But illegal transplants from living donors, and tales of foreigners traveling to China for the transplants, are frequently reported by media and the Ministry of Health.
"Transplants should not be a privilege for the rich," said Huang.
Chinese law only allows organs to be donated by living people in the case of blood relatives and spouses.
But organ middlemen who specialize in faking documents have helped bring living transplants to 40 percent of donations, from 15 percent in 2006, Chen Zhonghua, organ transplant specialist at Tongji Hospital in Shanghai, told the China Daily.
The new donation system, piloting in 10 provinces and cities, will encourage post-death donations and start a fund to provide financial aid to the needy and to donors' families.
"The system is in the public interest and will benefit patients regardless of social status and wealth in terms of fairness in organ allocation and better procurement," Huang said.
(Reporting by Liu Zhen, Sally Huang and Lucy Hornby; Editing by Alex Richardson)
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August 27, 2009
Lower Tacrolimus Dose Is Suitable For Living Donor Liver Transplantation With Small-For-Size Graft
www.medicalnewstoday.com
Several studies have shown that living donor liver transplant (LDLT) recipients required smaller doses of tacrolimus compared with deceased donor liver transplant (DDLT) patients, which indicated that liver regeneration could affect the metabolism of tacrolimus in LDLT. In recent years, living donor liver transplantation in adult patients with SFS liver grafts has become increasingly accepted. However，there are few studies in the existing literature on tacrolimus dosage requirements in LDLT with SFS grafts which require adequate liver regeneration.
A research article published in the World Journal of Gastroenterology addresses this problem. The research team led by Professor Li from the Center of Liver Transplantation of Sichuan University collected the medical data from the Center of Liver Transplantation in West China Hospital of Sichuan University, which is one of the biggest centers for liver transplantation in China, to study tacrolimus dosage requirements and blood levels in LDLT recipients with SFS grafts. Previous studies have indicated a high variability of the optimal tacrolimus dose in LDLT. The current article further investigates the tacrolimus dosing requirements in SFS graft by comparing tacrolimus dosage requirements in patients who received a graft with adequate hepatic mass (Group N) and in patients who received a SFS graft (Group S) in LDLT.
The result of their study revealed that there was no difference in demographic characteristics, acute rejection rates, liver and renal function test results, or the number of potentially interacting medications administered between the groups. Moreover, Professor Li and colleagues recommended that relatively low tacrolimus doses should be administered to patients who receive living donor liver transplantation with SFS liver grafts.
The tacrolimus dosage requirements and blood levels in LDLT with SFS grafts were reported by Professor Li and colleagues in China, which have been previously neglected. These results demonstrate that low doses of tacrolimus may be required in SFS grafts in living donor liver transplantation, which will be a good guideline to follow for rational administration of tacrolimus in future LDLT recipients with SFS grafts.
Reference:
Liu F, Li Y, Lan X, Wei YG, Li B, Yan LN, Wen TF, Zhao JC,Xu MQ, Wang WT, Yang JY. Tacrolimus dosage requirements in living donor liver transplant recipients with small-for-size grafts. World J Gastroenterol 2009; 15(31): 3931-3936 http://www.wjgnet.com/1007-9327/15/3931.asp
Source: Lin Tian, World Journal of Gastroenterology
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A Potential Therapeutic Agent For Hepatic Fibrosis
www.medicalnewstoday.com
Accumulating evidence suggests that connective tissue growth factor (CCN2) plays a central role in fibrotic conditions in many organ systems. Fibrosis is a scarring condition that is characterized by excessive collagen production that impedes normal cell function and can cause organ dysfunction and failure. A hallmark of fibrosing injury in the liver is the activation of hepatic stellate cells (HSCs) which become highly proliferative, synthesize increased levels of transforming growth factor (TGF)-β and CCN2, and produce excessive amounts of collagen. Previous studies have not investigated the effect of CCN2 antagonism in HSCs of human origin.
A research team led by Dr. David Brigstock addresses this problem. Their work was published in World Journal of Gastroenterology.
By designing a novel antisense inhibitor that blocked CCN2 mRNA transcription and protein production, the investigators showed that in activated human HSCs, basal or TGF-β1-induced transcription and production of collagen I could be reduced, and the ability of the cells to actively divide was curtailed. The innovative features of this study involve the use of human HSCs and the delivery of the antisense molecule in the form of a hammerhead ribozyme, which has a more efficient blocking action than some other conventional antisense methods. The data show that the anti-fibrotic properties of CCN2 hammerhead ribozyme are to the result of a reduction of collagen production and cell proliferation.
The results suggest that CCN2 hammerhead ribozyme has utility as a therapeutic agent for treating hepatic fibrosis in vitro. This is important as therapy for liver fibrosis is currently lacking despite the fact that millions of individuals around the world suffer from liver fibrosis caused by hepatitis, alcohol consumption, and other types of chronic liver injury.
Reference:
Gao R, Brigstock D. Connective tissue growth factor hammerhead ribozyme attenuates human hepatic stellate cell function. World J Gastroenterol 2009; 15(30): 3807-3813 http://www.wjgnet.com/1007-9327/15/3807.asp
Source: Lai-Fu Li, World Journal of Gastroenterology
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The Flomax incident
http://www.newsreview.com
By Anthony Pignataro
A local CVS pharmacy gave the wrong medication to a patient who later died. His family sued to make sure it would never happen again.
Three pills. Arnold Bravo’s family says before he took them he was relatively stable and active—his stage IV liver disease was in check, and he was well on his way to getting a new liver. But after he took the pills, he was weak, severely debilitated, and in and out of the hospital. He died just three months later at the age of 53, leaving behind two sons and three grandchildren.
The pills Bravo took were Flomax, generally prescribed to treat enlarged prostates, not liver disease. In fact, the official Flomax prescribing information—published by Boehringer Ingelheim, the drug’s manufacturer—says patients should inform their doctors of “any kidney or liver problems” before taking the drug.
The truth is, Bravo shouldn’t have taken any Flomax, because it wasn’t actually prescribed to him. Rather, the name on the label said “Arnold Bryer.” Neither Bravo nor his family noticed the name mix-up until after he’d begun taking the medication.
Just as this article readied for print, a lawsuit detailing events leading up to Bravo’s death was settled out of court with a confidentiality clause. But the family’s claim against Longs Drugs (today CVS Pharmacy) remains of interest as a cautionary tale, if nothing else.
“There are certain professions—pharmacist is one of them—where there is zero margin for error,” said the Bravo family’s Sacramento attorney Piotr Reysner before the lawsuit was settled.
The family’s complaint against CVS, filed June 10 of this year, made for particularly brutal reading. “As a direct, legal and proximate result of defendants’ negligence and reckless disregard, defendants caused and/or contributed to the death of decedent,” stated the complaint.
Rick Rodgers, the Sacramento attorney representing CVS, did not respond to two calls for comment that were made prior to the settlement. But in his July 10 response to the Bravo complaint, he wrote that the “mistaken delivery of Arnold Bryer’s prescription to Mr. Arnold Bravo … cannot by any stretch of the imagination be viewed as extreme, outrageous or egregious. If the allegation is true, it would be a regrettable error—nothing more.”
Reysner scoffed when asked about that defense at the time. “It’s a wonderful admission of liability, but someone died,” he said.
Arnold Bravo’s troubles began about 15 years before his death on August 10 of last year. That’s when he contracted hepatitis C. He didn’t seem to be too bad off until late 2007, when his liver began to fail.
In April 2008, doctors at UC Davis Medical Center told him he had stage IV liver disease. They put him on a list for a donor liver and began prescribing him a cocktail of medication—at least half a dozen of them, according to papers Reysner filed with the court. These included the antibiotic Cipro, the diuretic Lasix, a beta blocker called Propranolol, the proton-pump inhibitor Protonix and a stool softener called Enulose. Bravo was taking so many drugs that he was visiting the Natomas Longs Drugs pharmacy department three times a week, where he quickly got on a first-name basis with the pharmacy staff.
And things were apparently going well, according to Micaela Van Dine, Bravo’s stepdaughter (she’s also married to Reysner and is currently acting as the legal guardian ad litem for Bravo’s three grandchildren in the suit). Then around Mother’s Day in 2008, Bravo told Van Dine he had a new drug to take, which he didn’t name.
“This was totally common,” Van Dine said. “He would get new medications every week.”
Van Dine said Bravo took the recommended two-pill-per-day dose that Friday, and again on Saturday. But that night, Bravo called Van Dine and said the new drug, Flomax, was actually prescribed for someone else—Arnold Bryer.
Thinking that the error might just have been a misspelling of Bravo’s name, Van Dine visited Bravo Sunday morning and called UC Davis Medical Center to ask what had happened. While waiting for a response, Bravo collapsed.
Though Bravo regained consciousness when the fire department arrived, he spent the next three days in the hospital. The Bravo family lawsuit alleged the Flomax caused Bravo to go into “liver shock.” His condition was now so far gone he was off the donor liver list, and it would take considerable time before his body could recover to the point where a liver transplant was possible. Van Dine said family members also immediately transferred all Bravo’s prescription needs to another pharmacy.
What’s more, Van Dine said Bravo was only home for a week before his kidneys failed, forcing him to return to the medical center. But then his condition improved, and in mid-June, Bravo received a liver transplant. He was pretty shaky, Van Dine said, adding that Bravo would have died without the transplant.
According to Van Dine, Bravo did well for about three weeks, then complications set in from the immunosuppressants doctors had prescribed. Designed to counteract organ rejection, the drugs also left Bravo vulnerable to infection. Once again, Bravo returned to the hospital.
On August 10, he died.
“Prior to the ‘Flomax incident,’ Arnold was fairly stable, active,” Van Dine said. “He could drive. There was no urgency for a transplant. But after the incident, there was urgency. Flomax thins the blood. It says if you have liver disease, don’t take this drug.”
By the time of Bravo’s death, attempts to recover at least some money from CVS had already begun (Van Dine estimated that the Bravo family’s post-Flomax incident hospital bills totaled $66,000). On May 29, just a few weeks after Bravo first collapsed, Reysner wrote a letter to Longs Drugs’ legal counsel, explaining what had happened and asking for $500,000.
“Certainly a lawsuit of this type would not be something Longs would like to be involved with, especially given the negative publicity Longs would be forced to endure,” Reysner wrote. According to Reysner, CVS (which bought out Longs) countered with an offer of just $50,000.
In early 2009, in response to Van Dine’s request for Bravo’s medical records, CVS’ pharmacy liability claims office sent what they considered the most “relevant” of their files. But Van Dine noticed a curious omission—there was a six-week gap in the records, from the time when Bravo first left the hospital after the Flomax incident until about a month before his death. CVS eventually provided those records as well, Van Dine said, though the company insisted they weren’t relevant.
On March 16 of this year, Reysner wrote another letter to CVS, this time dropping the settlement figure to $300,000. “Please accept this letter as our final demand for settlement of this claim,” he wrote. “We still contend that negligence related to medications issued to Mr. Bravo could have lead to his death. If this final demand is not accepted, we are prepared to take this case to court.”
Reysner said CVS ignored him, so on May 25, 2009, he wrote yet another letter, this time to each member of the CVS board of directors. Now his settlement figure had risen to $400,000. And Reysner’s patience had worn thin.
“I want you to think carefully on this matter,” Reysner wrote. “I have a big mouth and I love attention. … I give you until June 12, 2009, for one person with authority to settle this case to call me. After that, this letter, prior letters, the complaint, and anything else I can think of will be sent to every news agency I can find an address for.”
There was no reply, so Reysner filed suit.
Then, about two months later, Reysner got his way. At SN&R press time, the case was settled for an unknown dollar amount. And the charge against CVS for negligence and reckless disregard in the case of Arnold Bravo went into the silent vault of settled lawsuits.
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August 28, 2009
Study of Racial Disparity in Patients Undergoing Liver Transplantation for Hepatitis B
www.medicalnewstoday.com
According to the Centers for Disease Control and Prevention (CDC) 1.5 to 2 million Americans are infected with the hepatitis B virus (HBV). Prior studies have shown there to be significant racial differences in access to and outcomes of liver transplantation. Recently, doctors from across the U.S. conducted a multicenter retrospective-prospective study of the waitlist status and outcomes of liver transplant patients with HBV infection. This study led by Natalie Bzowej from California Pacific Medical Center and Anna Lok from the University of Michigan and funded by a grant from the National Institutes of Health (NIH), found there to be similar waitlist and post-transplant outcomes among Asian Americans, African Americans, and Caucasians with HBV. These research findings appear in the September issue of Liver Transplantation, a journal of the American Association for the Study of Liver Diseases, published by Wiley-Blackwell.
The NIH HBV liver transplant study had a total of 274 patients (116 Caucasians, 135 Asians and 23 African Americans) enrolled in 15 centers across the U.S. Participants were placed on the United Network of Organ Sharing (UNOS) liver transplantation recipient waitlist between 1996-2005. The probability of transplantation 1, 3 and 5 years after listing was 53%, 75%, and 88% for African Americans; 48%, 58% and 66% for Asian Americans; and 48%, 57% and 63% for Caucasians. "As expected, the interval between listing and transplantation was shortest for patients with acute liver failure, followed by those with hepatocelluler carcinoma (HCC), and those with endstage cirrhosis. Our research showed transplant indication and Model for End-stage Liver Disease (MELD) score for endstage cirrhosis patients were the only predictors of transplantation, but race was not," said researchers.
Of the total number of study participants, 170 received transplantations between 2001and 2007. The probability of post-transplant survival at 5 years was 94% for African Americans, 85% for Asian Americans, and 89% for Caucasians. "Analysis indicated that HCC recurrence was the only predictor of post-transplant mortality while race, indication for transplant, and HBV recurrence were not," the authors explained.
According to the research, Caucasians had a higher rate of HBV recurrence with the 4-year recurrence rate at 19% compared to 7% and 6% for Asian Americans and African Americans, respectively. "We found that hepatitis B e antigen (HBeAg) status at listing was the only factor significantly associated with HBV recurrence post-transplant, while race showed a trend," said Dr. Bzowej. "Our findings of a higher rate of HBV recurrence among Caucasians needs to be validated in other studies," she added.
Charles D. Howell, MD, Professor of Medicine, The University of Maryland School of Medicine, commented on the NIH HBV liver transplant study in his editorial also published in the September issue of Liver Transplantation. Dr. Howell cited earlier studies where outcomes across the races were varied. "The study of the Organ Procurement and Transplantation Network (OPTN) data from 1994-1998 (Reid et al) found that African Americans 18-70 were under-represented on the UNOS liver recipient waiting list. A 2008 study showed African American patients transplanted between 2002 and 2006 experienced lower survival rates than Caucasians," he noted.
Results from NIH HBV liver transplant study indicate similar waitlist and post-transplant outcomes across the three racial groups studied. "More study is necessary to determine whether the disparity between African Americans, Asians, and Caucasians in outcomes of liver transplantation for HBV persists in the most recent era," concluded Dr. Howell.
Article:
"Liver Transplantation Outcomes among Caucasians, Asian Americans and African Americans with Hepatitis B," Natalie Bzowej, Steven-Huy Han, Bulent Degertekin, Emmet Keeffe, Sukru Emre, Robert Brown, Rajender Reddy, Anna Lok, Liver Transplantation, September 2009.
Editorial:
"Racial Disparities in Liver Transplantation for Hepatitis B: To Be or Not to Be," Charles D. Howell, MD, Liver Transplantation, September 2009.
Source: Dawn Peters, Wiley-Blackwell
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Shortage of Donor Livers - An Every Day Dilemma for UK Doctors
www.medicalnewstoday.com
In the UK there is a shortage of donor livers for transplant. There are currently 380 patients waiting for a liver transplant, of whom 38 are aged 25 years or less. In July 2009 alone, 12 patients who were listed for liver transplant died before a liver could be found for them or because they became too ill to undergo the operation. Deciding who should get the precious donated liver is a dilemma that UK doctors face every day.
Liver allocation guidelines have been drawn up by the NHS Blood and Transplant Liver Advisory Group, after discussion with health care professionals and the public, to ensure there is transparency and fairness in organ allocation and to assist clinicians to decide whom amongst their patients will receive a life-saving liver transplant.
Dr Mark Hudson, Consultant Hepatologist of the Freeman Hospital in Newcastle, and a member of the NHS Blood and Transplant Liver Advisory Group said, "The decision whether to offer a transplant to patients with severe alcoholic liver disease is complex, involving many clinical advisors including transplant surgeons and physicians, psychiatrists and alcohol support counsellors. They take into account the risk to the patient of dying without a liver transplant, as well as the expected outcome and survival from a transplant.
"If the team believe that there is a high chance that a patient might return to alcohol consumption or any other behaviour which would harm the transplanted liver then that possibility must be considered as to whether a transplant is appropriate. There is no absolute rule that a patient must have been abstinent for 6 months prior to being accepted onto a transplant list. The guidelines are published on the NHSBT website at http://www.organdonation.nhs.uk."
Professor James Neuberger, Associate Medical Director of NHS Blood and Transplant, said, "The UK has one of the lowest organ donor rates in Europe. Decisions about whom should receive a life saving liver and other organ is a daily dilemma faced by transplant surgeons across the country. The solution to this problem lies in increasing the number of organ donors. I strongly urge everyone to join the NHS Organ Donor Register. Call the Donor Line on 0300 123 23 23, go to http://www.organdonation.nhs.uk or text SAVE to 84118 and let your family know of your wishes."
Source: NHS Blood and Transplant
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