September 21, 2012

Despite Setbacks, Optimism on Drugs for Hepatitis C

Science 21 September 2012:
Vol. 337 no. 6101 pp. 1450-1451
DOI: 10.1126/science.337.6101.1450

News Focus

Infectious Disease

Jon Cohen


Bristol-Myers Squibb recently pulled the plug on a drug against hepatitis C virus, one of the furthest along in clinical trials of a new class of agents against HCV, because of toxicity. Researchers are now trying to understand why the drug failed and the impact it might have on other drugs in the pipeline—some of which work through similar mechanisms. Most are cautiously optimistic, however, that other drugs in development will pan out and that the failure will not seriously dent hopes of curing the disease with a short, relatively safe course of treatment that would work worldwide.

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New health education website launched

Thursday, 20 September 2012 21:41 AJPress

A NEW health education website,, sponsored by Gilead Sciences, Inc., intended for audiences in the United States, is launching Friday, September 7. contains practical information about chronic hepatitis B (CHB), a potentially life-threatening liver disease that affects an estimated two million people in the United States and is the leading cause of liver cancer.

Chronic hepatitis B is caused by a virus and can slowly damage the liver, without causing obvious symptoms. Chronic hepatitis B can be diagnosed with a simple blood test, prevented with a vaccine, and managed with appropriate care – but alarmingly, most people living with the disease don’t know they are infected.

Without treatment, 1 in 4 people with CHB may die of disease-related complications. The impact of chronic hepatitis B in the United States is more severe among Asian American communities. features:

• Information on how to prevent CHB, testing for the disease, and management of CHB.

• An innovative animated video depicting a CHB patient’s journey from diagnosis to care (available in 14 languages with subtitles).

• Educational brochures in 14 languages, including Chinese, Korean, Vietnamese, and Tagalog among others. is an educational website created by Gilead Sciences, a maker of medicines for chronic hepatitis B. The website is part of Gilead’s ongoing effort to raise community awareness of chronic hepatitis B.


Idenix Pharma: Guilty By Association

By Nathan Sadeghi-Nejad 09/21/12 - 07:48 AM EDT

Stock quotes in this article: IDIX, BMY

NEW YORK (TheStreet) -- Thursday, Idenix Pharmaceuticals (IDIX) presented investors with a detailed update on IDX-184 and the earlier-stage IDX-19368, two hepatitis C drug candidates that were placed on clinical hold by the FDA last month.

Idenix' new investor slide deck, also filed as an SEC Form 8-K, offers lots of detail about the compounds' status and highlights management's admirably open-minded communication style. Unfortunately, I'm not convinced the company's woes will be easily fixed.

IDX-184 has had no safety issues to date. Nonetheless, structural similarities between Idenix's IDX-184 and Bristol-Myers Squibb's (BMY) BMS-094 were sufficient to warrant concern. Clinical development of the latter drug, which Bristol-Myers acquired in the $2.5 billion takeover of Inhibitex, has been discontinued because of severe cardiovascular toxicity.

The FDA's clinical hold -- effectively a "stop work" order triggered by unexpected safety issues -- suggests that regulators are also concerned about the safety of IDX-184. In order to get the clinical hold lifted and continue development, Idenix must now convince the FDA that IDX-184 doesn't put patients' lives at unnecessary risk. (At least one patient in the Bristol-Myers study died.)

Continue reading full article here …

Centre for Public Health report featured on BBC and ITV

21 September 2012

The outstanding research from LJMU’s Centre for Public Health has once again been recognised by the national media.

The report ‘Burden of Liver Disease and Inequalities in the North West of England’ published by the Centre and the Health Protection Agency North West in collaboration with the National Treatment Agency North West, North West Cancer Intelligence Service and NHS North West, presents data on liver disease and has received coverage on BBC and ITV, among others.

Liver disease currently accounts for 2% of all deaths in England, and its main causes are alcohol, hepatitis B and C, and fatty liver disease by age, gender, deprivation and geography.

The key findings from the report are that:

  • Numbers of men dying from liver disease each year in the North West are up 20% since 2005 (27 per 100,000 population in 2005 to 30.9 per 100,000 population in 2010), and deaths occur at a relatively young age (peak ages are 55 to 64 years). Numbers of deaths among women have remained fairly constant over time.
  • Deaths from liver disease are 42% higher in the North West compared to England (23.5 per 100,000 in North West, 16.6 per 100,000 in England, in 2010) and there are substantial variations within the region (42.7 per 100,000 population in Blackpool and 8.2 per 100,000 population in Eden in 2006 to 2010).
  • Hospital admissions for liver disease as the primary diagnosis increased 30% between 2005/6 and 2010/11 (from 6,413 to 8,334).
  • Alcohol-related liver disease1 accounts for 47% of liver disease deaths in men and 43% in women and affects more people living in deprived areas.
  • Hospital admissions due to fatty liver disease2 as a primary or secondary diagnosis have increased 182% (from 913 in 2005/6 to 2,578 in 2010/11).
  • Hepatocellular cancer3 accounts for 15% of male and 5% of female deaths from liver disease and chances of survival at five years for patients diagnosed with hepatocellular cancer are worse in the North West than in other areas of England (8.3% in the North West, 12.3% for England).
  • Laboratory reports of hepatitis C4 have increased 123% in the North West over the last decade (from 898 in 2000 to 2000 in 2010) and hospital admissions for hepatitis C as a primary or secondary diagnosis increased 65% since 2005 (from 2,929 in 2005 to 4,841 in 2010). 65% of injecting drug users tested positive for the hepatitis C virus in 2010.

Professor Martin Lombard, National Clinical Director for Liver Disease, commented: “Liver disease is emerging as one of the major health problems for our population. People can be at risk of developing liver disease from an early age and may not even know they have a liver problem until the disease is at an advanced stage. The main causes are alcohol, obesity and hepatitis viruses and there is a lot people can do to avoid liver disease or prevent its progression by looking after themselves, paying particular attention to their diet and reducing their habitual alcohol consumption. This report highlights the fact that in the North West liver disease has reached a very significant level, getting to the stage where most residents will know someone, or know someone who knows someone else, who has died of liver disease or has a health issue from liver disease. The report is a call to action to everyone interested in health and well being, to tackle this issue."

Professor Mark Bellis, Director of the Centre for Public Health, commented: “The increasing levels of obesity and alcohol consumption we have seen over recent decades have resulted in rising levels of liver disease across the North West, while much of Europe has seen levels fall. Liver disease is the tip of a growing iceberg of ill health resulting from poor diet and excessive drinking and a stark reminder that so far we have failed to tackle either.”

To see some of the coverage generated by the report, go to:


The odds are too high to ignore

PUBLISHED: 19 Sep 2012 00:06:21 | UPDATED: 20 Sep 2012 00:45:58PUBLISHED: 19 Sep 2012

If 100 people are infected with hepatitis C, about 25 will clear the virus spontaneously and completely within six months of infection. They will still have antibodies in their blood and if exposed again can become re-infected.

The other 75 will develop a chronic infection and be at risk of cirrhosis of the liver. About 20 will experience no noticeable illness but will still be infectious and can transmit the virus to others.

About 15 years later, 40 to 60 of those with chronic infection will experience symptoms and develop some liver damage.

By 20 years, up to 10 of those with liver damage will develop cirrhosis. Of them, up to half will have liver failure or develop liver cancer.

The length of time from initial infection is a major determinant of the risk of cirrhosis and cancer.

Other determinants include alcohol intake, being male, being overweight and the age of infection. Beyond 40, the disease progresses faster. Hepatitis B and HIV are also factors.


Race For Next Hepatitis C Drug Gets Tighter


A Bristol-Myers Squibb scientist conducts lab research. The company halted its phase-two study of a hepatitis C drug after a patient death.


Posted 09/18/2012 05:52 PM ET

The race for the next blockbuster hepatitis C drug is still at full speed, but the field is thinning out.

Last month, Bristol-Myers Squibb (BMY) officially pulled the plug on its candidate, BMS-986094, after it had to halt a phase-two study after the death of one of its subjects from heart failure. The Food and Drug Administration was so concerned about this development that it also put a hold on two similar drugs by Idenix (IDIX), punishing that biotech's already low-priced stock.

Bristol-Myers said it will take a $1.8 billion charge to end the study, which resulted not only in the one death but in the hospitalization of eight other people. "While the cause of these unexpected events, which involve heart and kidney toxicity, has not been definitively established, the company has determined that it is in the best interest of patients to halt development of BMS-986094," the company said.

Yet, the Centers for Disease Control at about the same time affirmed that the potential market for such a drug is huge. On Aug. 16, the CDC released new guidelines urging everyone born between 1945 and 1965 — baby boomers — should be tested for HCV, the hepatitis C virus. Previously it had only recommended testing for people who've injected illegal drugs or who received blood or organ donations before these things were properly screened. But the new report noted the "limited effectiveness" of this approach, and concluded that everyone from that generation notorious for its drug use and sexual activity is at sufficient risk for a test.

"With an HCV antibody prevalence of 3.25%, persons born during 1945—1965 account for approximately three-fourths of all chronic HCV infections among adults in the United States," the report said.

The CDC estimated that 2.7 million to 3.9 million Americans are living with HCV, though many don't realize it because the virus can germinate without causing symptoms for years. If left untreated, though, it can end up causing fatal liver damage.

Current treatment relies on pegylated interferon, which leaves much to be desired, so in the past year massive amounts of money have gone into creating better alternatives. Bristol's ill-fated drug came with its $2.5 billion buyout of Inhibitex in February, amid a rush by drugmakers to acquire hot HCV candidates. Not long before, Roche (RHHBY) shelled out $230 million for Anadys, and, in the most jaw-dropping development, Gilead Sciences (GILD) paid nearly $11 billion for Pharmasset.


Fructose Intake Linked to Liver Damage


By Michael Smith, North American Correspondent, MedPage Today

Published: September 20, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

In obese patients with diabetes, a high intake of fructose – a sugar widely used in soft drinks and other foods – is associated with impairment in cellular energy balance that may play a role in liver disease, researchers said.

A small pilot study also suggested that elevated uric acid levels in response to a fructose challenge might be a marker for energy depletion, according to Manal Abdelmalek, MD, of Duke University Medical Center, and colleagues.

The findings suggest that energy depletion in the liver might be a factor in the development and progression of nonalcoholic fatty liver disease (NAFLD), Abdelmalek and colleagues reported in the Sept. issue of Hepatology.

Increasing rates of NAFLD in the U.S. parallel those of type 2 diabetes and obesity, the researchers noted, while at the same time fructose consumption has more than doubled in the past 30 years.

The main player in that latter increase, Abdelmalek and colleagues wrote, is the use of high-fructose corn syrup -- a mixture of glucose and fructose -- to sweeten such foods as bread, cereal, and soft drinks.

"Given the concurrent rise in fructose consumption and metabolic diseases," Abdelmalek said in a statement, "we need to fully understand the impact of a high-fructose diet on liver function and liver disease."

Research has shown that in overweight or obese adults, fructose-sweetened beverages (but not their glucose-sweetened counterparts) increase lipogenesis, promote dyslipidemia, impair insulin sensitivity, and increase visceral fat.

There's also evidence linking fructose-sweetened beverages with the development of diabetes, so it's "plausible that habitual and/or excessive fructose consumption" might increase the risk of NAFLD and also exacerbate liver injury and promote fibrosis progression, the researchers wrote.

To investigate, they looked at the 244 participants in the Action for Health in Diabetes Fatty Liver Ancillary Study, where they have estimated dietary fructose consumption and measured both hepatic adenosine triphosphate (ATP) -- a compound involved in the energy transfer between cells -- and uric acid levels.

Abdelmalek and colleagues hypothesized that people with higher fructose intakes would have lower ATP, and that those with higher uric acid would be at higher risk for ATP depletion in the liver, following a fructose challenge.

To test those notions, they performed magnetic resonance spectroscopy and conducted a fructose challenge (with an intravenous bolus of the sugar) in a subset of 25 participants.

For the analysis, habitual fructose intake was classified as low or high -- below or above 15 g per day. The cutoff is about the same as Americans would have consumed -- mainly from fruits and vegetables -- before 1900, the researchers noted.

In addition, uric acid levels were deemed to be high if they were above 5.5 mg/dL of serum.

In the study subset, Abdelmalek and colleagues found that:

  • 64% had NAFLD, defined as more than 5% fat in the liver on magnetic resonance spectroscopy.
  • Average fructose consumption was 22.3 g per day in the high-intake group and 11.13 in the low-intake group, a significant difference (P<0.001).
  • Total energy intake averaged 1,716 calories a day in the high-fructose group and 1,497 in the low-fructose group (P=0.046).
  • Serum uric acid averaged 6.39 mg/dL in the high-uric acid group versus 4.35 in the low group (P<0.001).

The effect of the fructose challenge, they reported, was to lower hepatic ATP sharply before a rebound after 50 minutes.

Those with a habitually high fructose intake, they reported, began with lower hepatic ATP on average than those in the low-fructose group. They reached a lower nadir during the challenge, and their rebound was not as complete.

The pattern was similar for those with high uric acid levels, the researchers reported.

"High fructose consumption and elevated levels of uric acid are associated with more severe depletion of liver ATP," Abdelmalek said, adding that the findings suggest that increased dietary fructose intake impairs energy balance in the liver.

The researchers cautioned that the study was small, was not powered to determine significance, was cross-sectional without a control group, and had no randomized intervention.

Further research is needed, they added, to understand the role of uric acid and fructose in the development and progression of NAFLD.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Disorders and the Johns Hopkins University School of Medicine General Clinical Research Center. The journal said Abdelmalek did not make any disclosures.

Primary source: Hepatology
Source reference:
Abdelmalek MK, et al "Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes" Hepatology 2012; 56: 952-960.


Docs Don't Trust Pharma-Funded Studies

By Nancy Walsh, Staff Writer, MedPage Today

Published: September 20, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Physicians tended to be skeptical of clinical trials funded by the pharmaceutical industry, even if they considered the study design to be methodologically rigorous, an analysis based on hypothetical studies found.

In a survey of board-certified internists, participants expressed more willingness to prescribe a drug evaluated in a highly rigorous hypothetical study (OR 3.07, 95% CI 2.18 to 4.32, P<0.001) than if the trial design was considered to have low methodologic rigor, according to Aaron S. Kesselheim, MD, JD, of Harvard Medical School in Boston, and colleagues.

Yet they were less likely to view a trial as having a rigorous design if industry funding was disclosed -- regardless of the methodologic quality of the study -- than if no funding source was provided (OR 0.63, 95% CI 0.46 to 0.87, P=0.006), the researchers reported in the Sept. 20 New England Journal of Medicine.

Prominent medical journals have made major efforts in recent years to provide conflict of interest information for published studies, but considerable skepticism remains on the part of clinicians regarding potential bias.

To explore the effects of funding disclosures on physicians' perceptions of study credibility, the researchers asked 263 physicians to examine a series of abstracts describing drug trials for three hypothetical newly approved drugs, and to rate their impressions of the studies and their willingness to accept the results.

For each of the three drugs, the researchers constructed an abstract that reflected a highly rigorous trial -- being randomized, double-blinded, having a large sample size and long follow-up, and providing safety data -- as well as abstracts that would be considered as reflecting medium- or low-level rigor.

All the abstracts reported that the results were statistically significant.

Each abstract then was amended to report no funding, industry funding, or support by the National Institutes of Health (NIH).

The median age of survey participants was 48, and more than two-thirds were men.

Participants reported having read a median of four journal abstracts within the previous month that related to prescription drugs.

When presented with simulated studies having low, medium, or high degrees of rigorous design, clinicians were likely to correctly identify high-quality trials (OR 3.95, 95% CI 2.81 to 5.55, P<0.001).

They also reported being more confident in the results of studies they considered highly rigorous (OR 2.73, 95% CI 1.95 to 3.82, P<0.001), and that they would be more willing to prescribe drugs evaluated in these trials.

But they reported having less confidence overall in studies sponsored by industry (OR 0.71, 95% CI 0.51 to 0.98, P=0.04), and being less likely to prescribe drugs from those studies (OR 0.68, 95% CI 0.49 to 0.94, P=0.02).

Participants also said they were less willing to consider industry-sponsored studies as being "important" than those sponsored by NIH (OR 0.59, 95% CI 0.42 to 0.82, P=0.002).

Physicians' unwillingness to prescribe drugs studied in industry-sponsored trials was greater regardless of whether the study design was high versus medium in rigor (P=0.87) or medium versus low rigor (P=0.83).

Conversely, they were more likely to prescribe a drug evaluated in a trial sponsored by NIH regardless of whether the study design was high versus medium rigor (P=0.81) or medium versus low rigor (P=0.56).

And regardless of sponsorship disclosure or the degree of methodologic rigor, physicians who felt strongly that drug company funding had an influence on trial results were less likely to prescribe a drug than were physicians who disagreed that funding played a role in study outcomes (OR 0.58, 95% CI 0.37 to 0.91, P=0.02).

The findings that the surveyed physicians held negative views of industry-sponsored clinical trials had "important implications," according to the researchers.

"Despite the occasional scientific and ethical lapses in trials funded by pharmaceutical companies, it is also true that the pharmaceutical industry has supported many major drug trials that have been of particular clinical importance," they observed.

The researchers commented that they found it "reassuring" that participants in their survey clearly were interested in the methodologic quality of the hypothetical studies.

However, they noted that if clinicians are overly skeptical about all industry-sponsored studies, major advances in drug treatment could be undervalued.

"Pharmaceutical companies seeking to enhance the appropriate use of important new products or to expand the appropriate uses of existing products must address the attitudes that our survey revealed, so that the credibility of the results of industry-supported trials is more likely to be based on methodologic rigor than on funding sources," Kesselheim and colleagues stated.

Among the strategies his group recommended were avoidance of "selective reporting" of trial results, ensuring the transparency of data, and allowing independent oversight of study endpoints.

In addition, because the physicians surveyed in this analysis rated NIH sponsorship highly, joint funding with industry might encourage trust in results.

"The methodologic rigor of a trial, not its funding disclosure, should be a primary determinant of its credibility," the researchers argued.

The study was supported by the Edmond J. Safra Center for Ethics at Harvard; the Agency for Healthcare Research and Quality; the Robert Wood Johnson Foundation; the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School; and the National Cancer Institute.

One author reported receiving grants from AstraZeneca and Novartis for data monitoring and trial analysis, and two others reported consulting for Merck and Genzyme/Sanofi.

Primary source: New England Journal of Medicine
Source reference:
Kesselheim A, et al "A randomized study of how physicians interpret research funding disclosures" N Engl J Med 2012; 367: 1119-1127.


Stamp-Sized Device Could Cut Liver Test Costs


By Michael Smith, North American Correspondent, MedPage Today

Published: September 20, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

A paper-based device about the size of a postage stamp could improve testing for drug-induced liver toxicity in the developing world, researchers reported.

In a series of experiments, the device agreed more than 90% of the time with the gold-standard tests for liver enzymes, according to Nira Pollock, MD, PhD, of Beth Israel Deaconess Medical Center in Boston, and colleagues.

At a projected cost of less than 10 cents a test, the device could make it significantly easier to monitor patients being treated for such diseases as TB and HIV in the developing world, where standard testing is difficult to obtain and costly, Pollock and colleagues reported in the Sept. 19 issue of Science Translational Medicine.

"Our device is designed to use a droplet of blood from a finger prick to deliver results in 15 minutes," Pollock said in a statement. "It could have significant implications around the world, particularly in developing nations where blood tests can be prohibitively expensive and the results can sometimes take weeks to return."

The device uses layers of patterned paper and a plasma separation membrane. Blood applied to the plasma separation membrane wicks into the layers of paper and travels through microfluidic channels to separate zones for testing aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

The read-out is a series of dots that change color to report levels of the enzymes in three "bins" – less than 3 times the upper limit of normal (ULN), 3 to 5 times ULN, and more than 5 times ULN – that correspond to cut-offs used for clinical management of patients with TB and HIV, Pollock and colleagues reported.

The device was developed in collaboration with Diagnostics For All, a Cambridge, Mass., nonprofit organization.

The researchers tested the device on paired whole-blood and serum specimens, drawn simultaneously from 223 patients within the previous 5 hours for routine clinical testing and for which results of standard automated transaminase testing were available.

They applied 30 microliters of blood or serum to the devices and – after 15 minutes – three readers blinded to the gold-standard outcomes analyzed the results.

ALT results were more accurate for the serum samples than for whole blood, the researchers noted, possibly because of the age of the specimens at the time of analysis. Previous experiments had shown that values drifted higher as the whole blood aged.

But overall, Pollock and colleagues reported, the paper device got it right at least 90% of the time and was especially accurate in placing specimens in the lowest bins – those that would usually mean no action was needed.

For example, the paper device correctly placed 88 of 89 serum samples tested for ALT in the less than 3 times ULN bin and 85 of 88 tested for AST – accuracies of 99% and 97%, respectively.

No specimens that the standard test placed above 5 times ULN were misread by the paper device to be below 3 times ULN, Pollock and colleagues reported – an important finding given that guidelines for TB treatment suggest that patients with levels more than 5 times ULN stop their medications even in the absence of symptoms.

Pollock and colleagues cautioned that the device has still to be tested in the field with TB and HIV patients. A planned field trial in Ho Chi Minh City, Vietnam, will evaluate the performance of the test in 600 HIV patients from that city's Hospital of Tropical Diseases.

The study had support from the Department of Defense/Center for Integration of Medicine and Innovative Technology, the National Institutes of Health, and the Bill & Melinda Gates Foundation. A patent application has been filed based on the results; four authors are listed as inventors.

Primary source: Science Translational Medicine
Source reference:
Pollock NR, et al "A paper-based multiplexed transaminase test for low-cost, point-of-care liver function testing" Sci Transl Med 2012; DOI: 10.1126/scitranslmed.3003981.