May 2, 2012

Lab Values Predict Acute-on-Chronic Liver Failure Mortality

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From Medscape Medical News

Daniel M. Keller, PhD

May 2, 2012 (Barcelona, Spain) — High international normalized ratio (INR), serum creatinine, and serum bilirubin levels independently predict mortality in patients with acute-on-chronic liver failure (ACLF).

Although the causes of underlying liver disease and acute liver insults differ in Asia and Western countries, the mortality rates are similar, Hitendra Garg, MD, DM, assistant professor at the Institute of Liver and Biliary Sciences and member of the Department of Gastroenterology at the G.B. Pant Hospital in New Delhi, India, reported here at the International Liver Congress 2012.

ACLF, a condition with high mortality, results from an acute hepatic insult in a patient with diagnosed or undiagnosed chronic liver disease. It manifests as jaundice and coagulopathy followed by ascites and/or encephalopathy. Little is known about the natural history of ACLF and the predictors of survival.

Dr. Garg explained that chronic liver disease in the West is mainly of alcoholic (65%) and viral (17%) origin; in the East, the main causes are hepatitis B virus (HBV) infection (37%) and alcohol (34%).

For this prospective study involving 8 Asian and South Asian countries, the investigators enrolled 340 patients from October 2009 to October 2011 with an acute hepatic insult, bilirubin of at least 5 mg/dL, and INR greater than 1.5, complicated within 4 weeks by ascites and/or encephalopathy in patients with chronic liver disease. Patients were excluded if they had hepatocellular carcinoma, portal vein thrombosis, cardiovascular comorbidities, or sepsis.

Mean patient age was 42 ± 13 years, and there were 3 times as many men as women. They were evaluated and given standard medical treatment.

As expected, the most common causes of chronic liver disease were alcohol and HBV. The most common causes of acute liver insult were alcoholic hepatitis, hepatitis E virus infection, and reactivation of chronic HBV. Dr. Garg said that most of the patients with HBV were given the antiviral drug tenofovir.

At 3-month follow-up, 53% (176 of 340) of the cohort had died. At 1 month, the mortality was 40%. For the 126 evaluated patients who died, the cause was multiorgan failure in 75%, progressive liver failure in 10%, and upper gastrointestinal bleeding in 6%.

In a multivariate analysis, 3 baseline parameters emerged as significant predictors of mortality within 3 months: hepatic encephalopathy (odds ratio [OR], 2.5; 95% confidence interval [CI], 0.28 to 0.73; P = .001), serum bilirubin greater than 21.7 mg/dL (OR, 1.8; 95% CI, 1.02 to 1.10; P = .006), and INR greater than 2.2 (OR, 1.6; 95% CI, 1.1 to 1.7; P = .001).

There was no difference in mortality between patients with HBV reactivation, those with alcoholic hepatitis, and those with other causes, Dr. Garg said.

Session moderator Rajendar Reddy, MD, professor of medicine, director of hepatology, and medical director of liver transplantation at the University of Pennsylvania in Philadelphia, told Medscape Medical News that the definitions of ACLF are different in the East and the West; there is a lot of alcoholic hepatitis, reactivation of HBV, and superinfection with hepatitis A or E in the East.

"In the United States...we see acute infections that cause liver failure in a patient who has stable underlying liver disease, so fundamentally, there's a difference in the definitions," he said. Although Dr. Reddy struggles with whether these findings are clinically useful in the West, he said that ACLF in both regions is associated with increased morbidity and mortality, and that all the patients go on to multiorgan failure.

Dr. Reddy thinks the predictors of mortality should be valid regardless of the causes of ACLF, "although there's one other major difference.... In areas where liver transplantation is available, we potentially could rescue quite a few of those patients, so the mortality rate may not be similar." Dr. Reddy explained.

He called ACLF "an ominous phenomenon," and said strategies are needed to prevent it, including ways to prevent infections.

Dr. Reddy has disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 69. Presented April 20, 2012.

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Canadian organ donors spike just a day after Facebook tool launch

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FILE - In this Sept. 22;2011 file photo;Facebook CEO Mark Zuckerberg smiles during the f/8 conference in San Francisco. Facebook will go public on May 18;2012;a published report says;in one of the most highly anticipated tech initial public offerings since Google went public in August 2004.

Photo Credit: Paul Sakuma;File , AP Photo

Victoria Revay, Global News : Wednesday, May 02, 2012 1:30 PM

TORONTO – The saying, “If you build it, they will come” has inspired many to action in achieving their goals. But when it comes to Facebook’s influence, just talking about a cause can incite people to action.

Since announcing the launch of a new organ donor tool on Tuesday, currently only available in the United States and the United Kingdom, Canadian organ donation has already seen a steep increase, according to a spokesperson at Toronto-based Trillium Gift of Life Network.

Trillium is Ontario’s organ and tissue donation agency. Leona Hollingsworth, media advisor for Trillium, confirmed to Globalnews.ca on Wednesday that even though the donor tool isn’t available to Canadian Facebook users yet, the organization already saw a sharp climb in donors due to the recent media coverage.

“We had 363 registrations yesterday, while our average would be about 50 a day.”

Facebook CEO Mark Zuckerberg said that the social media giant decided to start this initiative after realizing that users were interacting with the site to solve issues, such as finding missing people and items during emergency events, pointing to recent tornadoes that slammed the U.S. Midwest as an example. The late CEO of Apple, Steve Jobs, a friend of Zuckerberg was also an influence for the project, since he received a liver transplant.

In the U.S., media is reporting that in just one day, 10 states have seen a “significant spike” in organ donor registration as a result of the tool. By Tuesday evening, 100,000 users declared themselves organ donors on Facebook and amongst them, 10,000 had linked through Facebook to sign-up directly with their state organ donation registries.

Versha Prakash, vice president of operations at Trillium says the organization is “very excited that Facebook has chosen to highlight the importance of organ and tissue donation.” Prakash says their own initiative called the Gift of 8 Movement also harnesses the power of social media by allowing anyone to sign up for organ donation through www.BeADonor.ca. Once signed-up, donors can share this as an update through Facebook and Twitter.

Facebook says the organ donor tool will be available in Canada and the rest of the world in a few weeks to a few months, but couldn’t offer more specific details of the launch.

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Two Oral Drugs Clear HCV Without Interferon

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From Medscape Medical News

Daniel M. Keller, PhD

May 2, 2012 (Barcelona, Spain) — Twelve weeks of treatment with a combination of 2 direct-acting antiviral drugs plus ribavirin achieved a sustained virologic response rate of more than 80% in patients chronically infected with genotype 1 hepatitis C virus (HCV), Eric Lawitz, MD, from Alamo Medical Research in San Antonio, Texas, reported here at the International Liver Congress 2012.

In a pilot study of 11 treatment-naive noncirrhotic patients, 91% achieved a sustained virologic response at 12 weeks after the end of treatment (SVR12), and 82% had a sustained virologic response at 36 weeks (SVR36).

Currently, the only approved regimens for the treatment of patients with genotype 1 HCV contain interferon. For patients who cannot tolerate interferon, there are no other options.

The 2 direct-acting antiviral drugs are ABT-450, a potent inhibitor of the HCV NS3 protease, and ABT-072 (Abbott Labs), a nonnucleoside inhibitor of HCV NS5B RNA polymerase. Both drugs are dosed orally once daily. ABT-450 is boosted with ritonavir (ABT-450/r) to maintain high ABT-450 exposure and to allow once-daily dosing.

This trial is the first to evaluate the 2 drugs plus ribavirin in an interferon-free regimen for the treatment of HCV genotype 1.

The researchers enrolled only patients who were of the interleukin-28B CC genotype, which is the genotype most amenable to treatment with pegylated interferon and ribavirin, in case the trial regimen failed.

Patients were treated with ABT-450/r plus ABT-072 daily plus ribavirin for 12 weeks and then followed for 48 weeks after the end of treatment. To be eligible for the study, patients had to be 18 to 65 years of age; had to have HCV genotype 1 infection for at least 6 months, no evidence of cirrhosis or bridging fibrosis, and no coinfection with hepatitis B or HIV; and had to be eligible for treatment with pegylated interferon plus ribavirin.

Baseline characteristics were similar in the the 2 groups (mean age, 56.4 years; mean weight, 79.6 kg). Mean HCV RNA level was 6.93 ± 0.22 log10 IU/mL, and all patients had HCV RNA levels above 800,000 IU/mL.

Rapid, Sustained Virologic Responses

All 11 patients achieved a rapid virologic response and an extended rapid virologic response. Sustained virologic responses at 12, 24, and 36 weeks occurred in 91%, 91%, and 82% of the cohort, respectively.

There were no virologic breakthroughs on therapy, but 2 patients relapsed after therapy ended — one at week 12 and the other at week 36.

All patients experienced adverse effects, but most were mild and included headache, nausea, fatigue, dry skin, and rash. One person had a fasting glucose level above 250 mg/dL, and 2 had indirect bilirubin elevations without concomitant transaminase elevations 1 week after treatment initiation, which resolved with continued dosing. The elevation was consistent with the known effect of ABT-450 on the OATP1B1 bilirubin transporter.

The were no study drug interruptions or discontinuations and no early trial discontinuations. There were also no deaths or serious adverse effects.

Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital in Athens, Greece, and member of the European Association for the Study of the Liver Governing Board Scientific Committee, told Medscape Medical News that in light of the small sample size, the 1 late relapse at 36 weeks may or may not be important.

"If these very late relapsers are just 1% or 2%, then it will be of no clinical relevance.... If it's really 1 of 11 (so close to 10%), these late relapsers will be very important," he said. "Because these are new regimens, we don't know how the responders will behave in the long term, so I think the SVR12 should be the gold standard for reporting the results of the trials. [In addition], all trials should still have at least 1 HCV RNA follow-up...1 year after these SVR12 determinations."

Dr. Lawitz reports financial relationships with Abbott, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Roche, sanofi-aventis, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, and ZymoGenetics. Dr. Papatheodoridis has disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 13. Presented April 19, 2012.

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Combination of 2 drugs reverses liver tumors

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May 2, 2012 in Medications

The combination of two inhibitors of protein mTOR stops the growth of primary liver cancer and destroys tumour cells, according to a study by researchers of the Group of Metabolism and Cancer at Bellvitge Biomedical Research Institute (IDIBELL). The study results are been published on the online edition of the journal Science Translational Medicine.

Primary liver cancer or hepatocellular carcinoma is the fifth most common cancer and, due to its aggressiveness, is the third most deadly. It affects half a million people worldwide. Two of every three cases are related to chronic alcoholism, the exposure of toxic agents or infection with hepatitis B or C. The remaining third is related to non-alcoholic steatohepatitis, a disease related to obesity.

Promising candidates

Currently, the antitumor sorafenib shows the better patient outcomes, but its effectiveness decreases over time. For this reason, it is necessary to find new therapies. Among the most promising candidates are the inhibitors of the mTOR signalling pathway, which is hyperactivated in half of those affected by hepatocellular carcinoma.

The study led by IDIBELL researchers compared the effects in mice of two inhibitors of mTOR. The first was a derivative of rapamycin, called everolimus (RAD001), which is already used as an immunosuppressant and to treat specific cancers. The second is a new generation drug that inhibits mTOR called BEZ235.

During the study, researchers found unexpectedly that the combination of the two drugs had a more potent effect than any of the two drugs separately. Coadministration of BEZ235 and RAD001 limits the development of tumour and causes the self-destruction of tumour cells.

Based on these results a clinical trial, funded by Novartis, has started in the United States to evaluate the efficacy of the combination of these two inhibitors of mTOR in humans. The study coordinator, Sara Kozma, noted that "because rapamycin and its derivatives are already approved for the treatment of other diseases, their combination to BEZ235, would be a rapid strategy to test the efficacy of this drug and fast track its approval for clinical use."

Metabolism and Cancer Group

Dr. Kozma has recently joined the IDIBELL, along with Dr. George Thomas, who also participated in the study. The researchers, coming from the University of Cincinnati, have launched a new group of Metabolism and Cancer in IDIBELL.

The study published in Science Translational Medicine has been conducted in the University of Cincinnati, in collaboration with the Center for Cancer Research National Cancer Institute U.S. medical school at the University of California, Los Angeles, Cincinnati Children 's Hospital Medical Center and research institutes of Novartis.

More information: Sci. Transl. Med. April 25 2012 DOI: 10.1126/scitranslmed.3003923

Provided by Bellvitge Biomedical Research Institute (news : web)

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Need for liver transplants at all-time high

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Illustration: P.K. Job.

May 1, 2012 By Vidyashree Dharmaraj

The waiting list for those wanting to undergo liver transplant seems to be endless with lack of awareness among living donors and absence of medical facilities.

The number of deaths related to liver disease has gone up by 25 per cent which is a record high, says Prof Dr Mohammed Rela, an authority on liver transplant.

He attributes this alarming increase to heavy drinking, obesity, besides Hepatitis B- and C-related liver diseases. Even as surgical care is lacking in India, Tamil Nadu has to its credit 150 transplants of which 120 are from live donors.

The need for live donors has gained significance because of the insufficient availability of cadavers for donation.

Stating that India is growing rapidly in terms of liver transplant with living donors, he said the West has been largely using organs from cadavers.

Elaborating, he said transplanting by means of a living donor originated in the East as it was not part of their tradition to donate the organs of the dead.

Tamil Nadu has to its credit 150 cadaver transplants performed in the last two years, which is way ahead of the national average.

But, unfortunately, the state requires at least 1,000 donors a year, he said, and added that Coimbatore district alone needs at least 250 liver donors annually.

Even as the living donor transplant technique is complex, India is now in a position to teach the West its expertise, said Dr K. Ravindranath, chairman and managing director of Global Hospital Group, Chennai.

On the male-female ratio pertaining to liver diseases, he said it is more common among men, and added that there were several children who could survive only by liver transplants.

However, only 3 per cent of those having liver problems will undergo liver transplant, he said.

Calling for a change in lifestyle, he said poor diet, including excess intake of fat, carbohydrates and lack of exercise added to excessive alcohol intake may end in chronic liver diseases.

With a view to facilitating liver transplants in Coimbatore, Global Health City, Chennai, and Kovai Medical Centre and Hospital have entered into a partnership to provide transplant facilities at affordable rates.

Dr K. Ravindranath, chairman and managing director, Global Hospital Group, said that Global Health in Chennai offers liver, pancreas transplantation for related diseases.

The aim of the facility in KMCH is to provide quality health care in Hepatobiliary and liver transplant facilities wherein specialists from Global Health City will visit KMCH on a weekly basis for one day OPD clinics, he said.

Dr Nalla G Palaniswami, chairman, Kovai Medical Centre and Hospital, said that the exchange of knowledge will be provided through scientific programmes and high end, complex surgeries will be referred to the Global Health City which has a comprehensive set up for organ transplant.

Organ donation related counseling will also be provided to patients or relatives, especially if a patient is declared brain dead.

The Chennai centre will also provide logistics to KMCH for timely organ retrieval. Further training will be provided to KMCH staff as per protocols accepted under the laws of the State, he added.

If the proposed air ambulance comes through, then treatment within the golden hour which is limited by the distance factor will be resolved.

With all the hospitals in Coimbatore showing concerted interest in air ambulance, the dream will come true, he said.

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PRESS RELEAE

May 1, 2012, 6:06 p.m. EDT

 

DISH-Network refuses to run advocacy ad in L.A. market targeting Hershey Company over its rejection of a 13-year-old boy for enrollment at the Milton Hershey School due to his HIV-positive status; TV network states it has contracts with the agency representing Hershey as well as other networks that Hershey advertises on and it would be a conflict of interest to run an anti--Hershey campaign

LOS ANGELES, May 01, 2012 (BUSINESS WIRE) -- --AIDS advocates will continue to press Hershey Company--which funds the school--to denounce the discrimination and facilitate the boy's enrollment at the school

AIDS Healthcare Foundation (AHF), today criticized the DISH Television Network over its refusal to broadcast a 30 second paid television advertisement in the Los Angeles market that was produced by AHF and targets the Hershey Company over a high profile case of AIDS discrimination at the prestigious, Hershey-funded Milton Hershey School. The television spot, which was to start running on stations on the DISH Network in the Los Angeles market May 1st, was rejected by DISH executives who stated they have contracts with the agency that represents Hershey as well as with other networks that Hershey advertises on and it would be a conflict of interest to run an anti--Hershey campaign.

"We are extremely disappointed that DISH Television censored a paid television advocacy ad in which AHF speaks out against the Hershey Company over HIV/AIDS discrimination at the Hershey School," said Michael Weinstein, President of AIDS Healthcare Foundation. "Technically, as a satellite broadcaster, DISH may have a bit more cover than a traditional broadcaster regarding infringing on our free speech rights under the first amendment; however, it is ironic that we specifically sought to place this spot through DISH on stations like MSNBC, which are filled with policy programs and serious talk shows whose bread and butter is lively debate and discussion about many controversial issues and topics. We think it is cowardly of DISH to block our message as they have."

In rejecting the spot, DISH officials also noted that they would have to apply a 'Controversial Issues' filter to the TV spot, a move which would block it from almost every network they air, based on the restriction documents DISH receives from the programmers. DISH officials also added that even on the networks that technically allow this type of content, they would risk receiving subscriber complaints.

Background on Hershey School AIDS Discrimination

The Milton Hershey School--a boarding school for low-income students funded by the Hershey Company--recently rejected the boy for admission citing his HIV-positive status as the reason, misguidedly calling him a "direct threat to the health and safety of others." AHF has also launched a website www.EndHIVStigma.org where the public can learn more about the case, learn the facts about HIV/AIDS and send e-letters to three Hershey Company board members who also sit on the board of the Milton Hershey School Trust, urging them to denounce the discrimination and facilitate the boy's admission into the school.

According to the Associated Press (claim:Hershey School Rejects HIV-Positive Pa. Boy)(claim:By Peter Jackson)(claim:12/1/11): "A private boarding school connected with the Hershey chocolate company says it was trying to protect other students when it denied admission to a Philadelphia-area teenager because he is HIV-positive. The AIDS Law Project of Pennsylvania filed a lawsuit on behalf of the unidentified boy in U.S. District Court in Philadelphia on Wednesday, claiming the Milton Hershey School for disadvantaged students violated the Americans with Disabilities Act. School officials acknowledged that the 13-year-old boy was denied admission because of his medical condition. They said they believed it was necessary to protect the health and safety of the 1,850 others enrolled in the residential institution, which serves children in pre-kindergarten to 12th grade and where students live in homes with 10 to 12 others."

Ryan White was an American teenager from Kokomo, Indiana who, in the mid-1980s, was expelled from middle school because he was HIV-positive. A lengthy legal battle with the school ensued and White became a galvanizing force in educating the country about HIV & AIDS at a time when misinformation about the disease was widespread. After his death in 1990, the U.S. Congress passed a major piece of legislation named in his honor, the Ryan White CARE Act, which provides funding for HIV/AIDS programs for low-income American.

AIDS Healthcare Foundation (AHF), the largest global AIDS organization, currently provides medical care and/or services to more than 166,000 individuals in 25 countries worldwide in the US, Africa, Latin America/Caribbean, the Asia/Pacific Region and Eastern Europe. www.aidshealth.org

SOURCE: AIDS Healthcare Foundation

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Prison puzzle: Treating hepatitis C

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Two new drugs, boceprevir and telaprevir, have come on the market that experts say are substantially more effective in treating hepatitis C in conjunction with traditional therapy, but they will apparently hike treatment costs to about $60 000 per inmate.

Photo credit: ©2012 Thinkstock

May 2, 2012

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Two new drugs, boceprevir and telaprevir, have come on the market that experts say are substantially more effective in treating hepatitis C in conjunction with traditional therapy, but they will apparently hike treatment costs to about $60 000 per inmate.

Call it a quandary of epidemic proportions. Imagine a population group in which 30% of its members have a specific disease. It can be treated, but at a relatively stiff price that strains a limited budget. Along comes a new treatment that’s much more effective but at threefold cost. Failure to effectively treat a patient will likely result in a long-term health condition that will constitute an even greater drain on resources. Complicating the task is that the political mandarins who ultimately fix the budget appear to be ideologically opposed to harm reduction programs that could reduce the incidence rate and treatment costs that appear to be rising exponentially.

That’s precisely the dilemma and the scenario playing out in Canada’s prisons as perplexed health providers scramble to treat an epidemic rate of hepatitis C infections.

According to figures obtained by CMAJ through a federal freedom of information request, Correctional Services of Canada’s (CSC) bill for hepatitis drug treatment has increased almost sevenfold since 2005 to $4.7-million in 2010, roughly 4% of the agency’s health budget for inmates.

A projected 30% of the 14 900 inmates now housed in federal prisons are infected with hepatitis C, which costs an estimated $15 000–$20 000 to treat using a combination therapy containing peginterferon Alfa-2b and ribavirin. But two new drugs, boceprevir and telaprevir, have come on the market that experts say are substantially more effective in treating hepatitis C in conjunction with traditional therapy, but will hike treatment costs to about $60 000 per patient.

Their use is now being evaluated by CSC officials and could easily triple the cost of treating hepatitis C within Canada’s archipelago of 57 federal correctional facilities, says Dr. John Farley, a Vancouver, British Columbia-based physician.

The public health consequences of not providing treatment to inmates infected with hepatitis C are enormous, says Farley, noting that prisons serve as a major reservoir for a disease that infects an estimated 242 000 Canadians. Untreated hepatitis invariably results in more infections within the general population, as well as a higher incidence rate of liver disease, which is even more costly to treat, he adds.

There’s no question CSC has substantially ramped up its provision of treatment for hepatitis C, says Dr. Peter Ford, a Manitoulin Island, Ontario-based physician who oversees HIV and hepatitis treatment in federal prisons. “Just five years ago in some regions hardly anyone was getting treatment at all. There has been a dramatic increase in awareness of the treatment programs and growing numbers of inmates now seek treatment.”

But demand continues to skyrocket and far outstrips treatment capacity.

In BC, “I now have almost 80 patients in treatment, with many more on my waiting list,” says Farley.

Compounding the problem is that the federal government seems to find harm reduction programs in prisons to be anathema, the physicians say. CSC’s “rejection of strategies such as needle exchange and safer tattooing programs in prisons is a well-known public health menace,” Ford notes. “But the vastly increasing cost of HIV treatment in prisons proves that CSC’s policies are financially irresponsible as well.”

Farley says treating patients who became re-infected while in prison has become a nation-wide phenomenon. “We are now seeing many people being treated for hepatitis C at significant public expense and then getting re-infected because of the government’s rejection of basic harm reduction measures. The financial cost of hepatitis C in the prisons is becoming horrific.”

Both physicians abhor the federal government’s dismantling of a pilot project aimed at promoting safer tattooing within six federal prisons in 2006. An estimated 45% of inmates receive unsterile tattoos (www.cmaj.ca/lookup/doi/10.1503/cmaj.1070017), while an estimated 25% of inmates use needles to inject illegal substances (QJM 2000; 93:113-19).

Some of the latter are first-time users, Farley says. “I usually ask my patients where they started injecting drugs and between 5-and-10% say it was while in prison.”

Harm reduction programs in federal prisons are now essentially limited to such “half-measures” as providing bleach to sterilize needles, Farley says. Yet, “bleach is known to be an ineffective way of preventing disease transmission.”

Failure to implement adequate harm reduction measures, lack of adequate access to care, and lack of consistency between federal institutions lay at heart of a failing grade that CSC received in 2011 from the Canadian Coalition of Organizations Responding to Hepatitis B and C (www.canadianhepatitiscoalition.ca/wp-content/uploads/2011/07/2011-Hepatitis-Strategy-Report-Card.pdf)

“We gave them an F because we have to believe that CSC is fully aware that people engage in risky behaviour in prison,” says coalition spokeswoman Deb Shmitz. “It’s a denial of the reality not to provide full harm reduction. Just as there is a duty to treat inmates with hepatitis, there is a similar duty to do harm reduction as well. And that includes distributing needles and collecting used needles.”

Shmitz argues CSC should be held partially responsible for the rising rate of hepatitis C infection in non-inmate population groups as it’s fully aware inmates typically join the ranks of intravenous drug users and homeless when they are released into the general population. “The public needs to know that failure to prevent hepatitis transmission inflicts a severe long-term financial burden on public health systems.”

For its part, CSC argues that its approach is working. The hepatitis C prevalence rate “appears to leveling” at about 30%,” says Dr. Linda Panaro, public health medical advisor for CSC, ascribing that to the efficacy of treatment programs and harm reduction measures such as bleach provision. “The harm reductions materials we distribute are having an effect.”

Panaro adds that the sevenfold increase in hepatitis C treatment costs within prisons is the product of more rigorous cost accounting measures but acknowledges those costs may skyrocket if the new therapies are approved for use.

DOI:10.1503/cmaj.109-4191

— Paul Christopher Webster, Toronto, Ont.

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Chronic Fatigue Syndrome: Real, Weird, and Mysterious as Ever

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Marco Arment/flickr

May 2 2012, 11:34 AM ET

by Alice G. Walton

A new study find some biological differences in the brains of people suffering fro chronic fatigue syndrome, but little that can explain the problem.

Chronic Fatigue Syndrome (CFS) has remained a mystery for a long time, and in some ways it's only deepening. It was once believed that the syndrome was caused by a virus - but this theory was recently discredited, leaving researchers to search for a new explanation.

Some are now interested in understanding the brains of people with CFS, and hoping to find some answers there. A new study has reported that there are some fundamental differences between people with and without CFS. Whether the findings will truly uncover more answers is still unclear.

the team found that people with CFS had less change in blood flow between winning and losing. What's more, people with more severe CFS had even less change in blood flow.

The team had noticed that people who were treated with interferon for Hepatitis C often experienced extreme fatigue as a result. They also had less activity in an area of the brain called the basal ganglia, which is responsible for the perception of pleasure, and often referred to as the brain's "reward center." So they reasoned that similar brain changes might be going on in people with CFS, for whom fatigue is ever-present and pleasure is often elusive.

They had CFS patients and healthy people play a card game that involved a monetary reward for correct guesses. The participants' brains were scanned while they were playing the game, so the team could compare any differences in activation.

When healthy people are rewarded, blood flow to the basal ganglia usually increases markedly. But the team found that people with CFS had less change in blood flow between winning and losing. What's more, people with more severe CFS had even less change in blood flow.

"Many patients with chronic fatigue syndrome encounter a lot of skepticism about their illness," lead author Dr. Elizabeth Unger, chief of the chronic viral diseases branch of the U.S. Centers for Disease Control and Prevention, said in a news release. "They have difficulty getting their friends, colleagues, coworkers, and even some physicians to understand their illness. These results provide another clue into the biology of chronic fatigue syndrome."

The researchers aren't quite sure why the brain changes exist as they do, but it may have something to do with increased inflammation, which is being linked to a growing list of serious health problems. More research will need to look into the possibilities, but the study presents at least a new avenue to explore in this enigmatic syndrome.

The study was carried out by researchers at the CDC and was presented at the Experimental Biology annual meeting in San Diego, CA.

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Twelve Weeks of GS-7977 Eliminates HCV as Well as 24 Weeks

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From Medscape Medical News

Daniel M. Keller, PhD

May 2, 2012 (Barcelona, Spain) — Twelve weeks of GS-7977 (Gilead Sciences) plus pegylated interferon (pegIFN) and ribavirin was as effective as 24 weeks of treatment in eliminating hepatitis C virus (HCV) genotype 1.

In the phase 2 ATOMIC trial, the drug was found to be safe and well tolerated, according to Kris Kowdley, MD, director of the Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, and clinical professor of medicine at the University of Washington in Seattle, who reported the interim results here at the International Liver Congress 2012.

GS-7977 is a potent oral nucleotide analogue inhibitor of HCV NS5B RNA polymerase that has a high barrier to the development of viral resistance. In another trial (PROTON), 12 weeks of GS-7977 in combination with pegIFN/ribavirin followed by 12 weeks of pegIFN/ribavirin was associated with a sustained virologic response (SVR) rate of 91% at 12 (SVR12) and 24 weeks (SVR24) after the end of therapy in patients infected with HCV genotype 1. In light of those results, the aim of the ATOMIC trial was to see if only 12 weeks of therapy could achieve similar results.

In the ATOMIC trial, treatment-naive patients chronically infected with HCV genotype 1 were randomly assigned to 1 of 3 treatment groups: GS-7977 plus pegIFN/ribavirin for 12 weeks (n = 52), GS-7977 plus pegIFN/ribavirin for 24 weeks (n = 125), or GS-7977 plus pegIFN/ribavirin for 12 weeks followed by 12 weeks of GS-7977 alone (n = 75) or in combination with pegIFN/ribavirin (n = 75).

Participants were predominantly white, male, about 50 years of age, had HCV RNA levels of at least 50,000 IU/mL, and had adequate hematologic values. The treatment groups were generally well matched for baseline characteristics.

Drug Combination Yields Rapid and Sustained Virologic Response

In all treatment groups, there was rapid viral suppression over the first 2 weeks of therapy, regardless of interleukin-28B genotype. At the end of treatment, 98% to 99% of patients in each group had achieved HCV RNA levels below the limits of detection, and 92% to 94% achieved a sustained virologic response at 4 weeks (SVR4).

An SVR12 of 90% was achieved in all treatment groups. At the time of the presentation, SVR12 data were available for only some of the patients treated with GS-7977 plus pegIFN/ribavirin for 12 weeks, When only those patients were included, an SVR12 of 94% was achieved, "suggesting that this is a very effective and successful combination," Dr. Kowdley said.

"In fact, when we examined the reasons for failure to achieve an SVR, in most cases it was because of a lack of follow-up rather than because of virologic failure or relapse," he reported. Only 4 patients in the 3 groups experienced a relapse at the SVR4 time point. In the 4 patients who relapsed, no S282T resistance mutations have been detected in the viral NS5B RNA polymerase.

GS-7977 plus pegIFN/ribavirin was generally well tolerated. Less than 5% of patients discontinued the study because of adverse effects related to GS-7977. Most adverse effects were constitutional symptoms generally associated with pegIFN/ribavirin. Neutrophil and lymphocyte counts and hemoglobin and alanine aminotransferase levels quickly improved after pegIFN/ribavirin was discontinued.

Dr. Kowdley concluded that 12 weeks of GS-7977 in combination with pegIFN/ribavirin appears to be as effective as 24 weeks of the same therapy.

Session moderator Mark Thursz, MBBS, MD, professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, and secretary general of the European Association for the Study of the Liver, who was not involved in the ATOMIC trial, said during a news conference that SVR24, an absence of viremia for 6 months after the end of treatment, has been the standard definition of cure until recently. Now, "we've started to become used to SVR12 as an end point. I understand that the FDA [US Food and Drug Administration] is now interested in SVR12 if it can be subsequently established as meaning a cure," he said.

"Now the companies are coming to us with SVR4 data.... SVR4 certainly predicts the final outcome. It may not be quite the same as the cure rate, the SVR24 rate, but it's pretty close and gives us a very good indication," Dr. Thursz explained. The implication is that when abstracts are submitted to meetings, "SVR4 is something that we have to take seriously...whereas previously we would regard [the results] as merely interim data," he said.

He told Medscape Medical News that the program for the development of GS-7977 is "progressing very rapidly. I know that Gilead [the drug's manufacturer] is looking at what the best option is" to get the drug approved and available to patients as quickly as possible. He said that some reports suggest that Gilead could file for approval with the FDA in late 2013, with the potential for approval in 2014.

Dr. Kowdley reports being a consultant/advisor for Novartis, Vertex, Pharmasset, Merck, and Abbott; and receiving grants and research support from BMS, Intercept, Abbott, Pharmasset, Merck, Gilead, GSK, Mochida, Conatus, Boeringer Ingelheim, and Genentech. Dr. Thurzs has disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 1. Presented April 19, 2012.

Source

Hepatitis C a latent legacy of baby boomers' youth

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"It hangs over your head," said Harold Owens, who gave up heroin in the 1980s and tries to maintain a positive attitude about living with hepatitis C. (Genaro Molina / Los Angeles Times / April 25, 2012)

The Centers for Disease Control and Prevention urges people born between 1945 and 1965 to be tested, noting that roughly 75% of people with the disease are baby boomers.

By Anna Gorman, Los Angeles Times

May 2, 2012

The number of baby boomers dying from a "silent epidemic" of hepatitis C infections is increasing so rapidly that federal officials are planning a new nationwide push for widespread testing.

Three in four of the estimated 3.2 million people who have chronic hepatitis C — and a similar proportion of those who die from the disease — are baby boomers. Deaths from the virus nearly doubled between 1999 and 2007 to more than 15,000, according to a recent Centers for Disease Control and Prevention study.

Hepatitis C is the leading infectious cause of cirrhosis and liver cancer and is the most common reason for liver transplants in the United States, according to the CDC. In 2007, deaths from the disease surpassed those linked to HIV, and the numbers of fatalities are expected to continue increasing, researchers reported.

"We have sort of a perfect storm of an age wave of people who are moving through time who are progressively becoming sicker from an infection that was acquired several decades ago," said John Ward, director of the Division of Viral Hepatitis at the CDC. "We think we are at a very critical juncture."

Many boomers unknowingly contracted the virus in younger years from using drugs or having blood transfusions before screening was improved during the AIDS crisis. Unaware of the risk and without symptoms, most have never been tested for hepatitis C and don't know they have it. The disease — primarily contracted through blood — often remains hidden for decades while it slowly destroys liver cells. There is no vaccine.

"Hepatitis C is really a stealth virus," said Elizabeth Bancroft, medical epidemiologist with the Los Angeles County Department of Public Health. "It can live in you for many, many, many years."

There are at least 530,000 people living with hepatitis C in California, including an estimated 134,000 in Los Angeles County, according to health officials.

Harold Owens, who lives in Los Angeles and works at the Recording Academy, is among those paying the consequences for decisions made in his youth. He developed a heroin habit as a young man but says he hasn't touched drugs in nearly a quarter-century. He was diagnosed with hepatitis C in 2001. Now 59, he suspects he may have contracted the disease from sharing infected needles.

"I understand the risks now," said Owens, who directs a foundation for musicians dealing with addiction. "I didn't then. Nobody did."

Owens underwent treatment that slowed the disease's progression but didn't expel it from his body. He still worries about what it could do to his liver. "It hangs over your head," he said.

Concerned about the disease among baby boomers, the CDC plans to issue a recommendation this year that everyone born between 1945 and 1965 be tested. Up until now, the federal agency only urged screening for those believed to be at risk. That strategy hasn't worked, in part because of the stigma — doctors don't ask about previous drug use and patients don't offer up the information.

"I certainly would not have come forward that I shot drugs," said Leslie Benson, 63, of Sacramento, who was diagnosed in 1992.

Benson, who co-founded an advocacy coalition, California Hepatitis Alliance, said she experimented with drugs for a short time in the late 1960s and received five pints of blood after getting into a car accident as a teenager — both of which put her at risk for contracting hepatitis C.

The CDC recommendation is coming in an era when safer, faster and more effective drug treatments are becoming available, and more are being tested. The new medications still have side effects but increase the odds of suppressing the virus and its complications, according to research.

Health officials say the new medications, although they aren't cheap, are far less costly than liver transplants and liver cancer treatment, which can climb into the hundreds of thousands of dollars.

The disease is "a significant and very costly problem" in California, said Gil Chavez, deputy director of the center for infectious diseases for the state public health department. In California, officials said hospitalization charges for liver disease, cancer and transplants totaled more than $2 billion in 2010.

The state adopted a plan in 2009 to improve education about the disease and to increase access to testing and care, but Chavez said much more needs to be done.

The expected federal recommendation for screening baby boomers will help providers and patients understand the dangers, he said.

"I don't think people have a notion that something they did 20 or 30 years ago may cause them to have an infection today," Chavez said.

Danny Jenkins, 59, a grant writer, learned he was infected several years ago and underwent a grueling regimen of powerful medications that cleared the virus. A past drug user, he said he was lucky to learn of his infection before he needed a new liver.

A co-chair of the Hepatitis C Task Force for Los Angeles County, he works to raise awareness about the virus and encourage people to get tested.

"Lack of knowledge is everywhere," he said. "I'm worried about people who don't know about it and haven't been tested and may be moving toward liver disease."

Source

What do high iron levels in blood mean

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Wednesday, May 02, 2012

Iron is a vital element to our health, and humans have developed elaborate ways of handling iron, mostly absorbing and storing it. In fact, there is no mechanism for eliminating iron from the body, and therefore it can accumulate to excessive levels in some conditions, including iron poisoning.

Too high an iron level or poisoning can produce rapid deterioration of the kidneys, liver, and heart function. Poisoning is usually seen in children who have accidentally eaten their mother’s iron pills. It is very important that iron pills, in fact all medicines, be kept safely out of the hands of children.

A slow accumulation of excessive iron in the body is much more commonly seen in adults, and it can have a number of causes. Hemochromatosis is perhaps the most common condition in which this is seen.

Hemochromatosis is either genetic, or acquired, meaning that it is a result of another condition such as anemia. The genetic form of hemochromatosis is quite common, with about 10 percent of people of European origin carrying one of the genes, and about 0.3 percent of this population carrying both of the genes for this disease, meaning that they received one gene from each parent. It takes many years for someone even carrying two genes for this disease to build up enough iron in the body to be harmful, and women are protected from this condition by their monthly loss of iron until they stop menstruating. Nonetheless, people carrying two genes for the disease will often have high iron levels in the blood even before they have developed any of the signs of hemochromatosis, and this may serve as a warning to start treating the iron buildup by withdrawing blood on a regular basis. Such people with early cases of hemochromatosis should certainly not take iron supplements.

Some anemias — the most common is probably thalessemia major — will lead to an excessive buildup of iron because the anemia itself causes the body to absorb iron from food more efficiently, and people with these anemias often must be given transfusions that add iron to the body. Since the body has no way to dispose of this added iron, it will start to build up and eventually lead to symptoms of hemochromatosis.

Chronic alcoholics with liver disease will often have elevated levels of iron in the blood, probably because of iron released from liver cells that are damaged by the alcohol. Of course, many alcoholics may also carry the genes for hemochromatosis, and in these cases the increased iron in the body can produce the liver, kidney, and heart complications of that disease. Iron buildup in alcoholics who do not carry hemochromatosis genes will usually not lead to organ damage. (Enough of that is already caused by the alcohol.)

When doctors do tests to evaluate the amount of iron a person has, they will often do a ferritin test as well as or instead of measuring the iron directly. Ferritin is a protein that stores iron in the liver and elsewhere, and some can be measured in the blood. It will be high in hemochromatosis, alcoholic liver disease, anemias such as thalessemia major, and in any type of acute liver inflammation or hepatitis. Ferritin will be low, as will the iron in the blood, in the most common kind of anemia, iron deficiency anemia.

With rare exceptions, people who do not carry hemochromatosis genes, and don’t have thalessemia or alcoholic liver disease cannot damage themselves by taking small or medicinal doses of iron even for many years. However, since most of us don’t know if we are carrying hemochromatosis genes, taking iron routinely is not advised unless one is known to have iron deficiency anemia.

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Written Comments to FDA Advisory Committee Cite Compelling Evidence for PrEP and Urgent Need for Every Available Tool to End AIDS

NEW YORK, May 1, 2012 /PRNewswire-USNewswire/ -- In public comments submitted this week, a group of 14 leading HIV/AIDS and health organizations stated their support for Food and Drug Administration (FDA) approval of emtricitabine/ tenofovir disoproxil fumarate (TDF/FTC or Truvada®) as pre-exposure prophylaxis (PrEP) to prevent HIV infection in adult men and women. Their comments, submitted in advance of a May 10 FDA Advisory Committee meeting, pointed to compelling evidence on the efficacy of TDF/FTC as PrEP and highlighted the unique potential of this intervention to help slow the HIV epidemic in the U.S.

With PrEP, HIV-negative individuals who are at risk for HIV take anti-HIV medications in order to reduce their chances of becoming infected if exposed to the virus. At the May 10 hearing, the FDA will consider data from clinical trials showing that TDF/FTC reduced the risk of sexual transmission of HIV in populations including men who have sex with men (MSM) and heterosexual women and men.

"The U.S. and international AIDS community overwhelmingly supports FDA's priority review of this potentially game-changing new tool to prevent HIV," said Mitchell Warren, executive director of AVAC. "The evidence is increasingly clear that daily PrEP can help reduce HIV risk in women and men who take it consistently as prescribed. While no single tool will be enough to stop the spread of HIV, PrEP could be a vital part of a comprehensive, global strategy to end the AIDS epidemic."

Despite some progress in reducing HIV incidence using other available methods, approximately 50,000 people become newly infected with HIV every year in the United States, and 2.6 million people were newly infected with HIV worldwide in 2010. Globally, half of all people infected with HIV are women and girls. In the United States, HIV infection continues to take a disproportionate toll on African Americans and Latinos; MSM, including transgender individuals; and the poor. Driving down HIV infection rates is a primary objective of the U.S. National HIV/AIDS Strategy, and is at the core of global efforts to end the AIDS epidemic.

"Today's HIV prevention tools, including condoms, remain as essential as ever, but it's clear that they aren't enough," said Deborah Cohan of the Bay Area Perinatal AIDS Center. "If approved, PrEP would help address important gaps, including the need for women to have more ways to protect themselves without having to rely on their male partners."

"Evaluation of new prevention tools is critical to reducing the devastating impact of HIV among Black Americans," said Douglas Brooks, MSW, Senior Vice President of the Justice Resource Institute. "No single approach will be right for everyone, but PrEP could offer a much needed option for some. The benefits could be especially great for Black gay or bisexual men, who account for nearly one-quarter of new HIV infections in our nation today."

Modeling studies have shown that widespread access to PrEP could reduce new HIV infections, and thus the scale of the global HIV epidemic, substantially around the world. The FDA's decision on TDF/FTC as PrEP could help pave the way for global health funders and developing countries to step up their planning for implementation.

Evidence for PrEP: What the Science Tells Us

At the May hearing, an FDA Advisory Committee will consider data from a wide range of safety and efficacy studies, including two pivotal clinical trials of TDF/FTC as PrEP:

  • The Partners PrEP trial, which found that daily TDF/FTC reduced HIV infections by 73 percent among heterosexual couples in Africa in which one partner was HIV infected and the other was not. Efficacy was 90 percent among those who adhered closely to their daily drug regimen.
  • An international study called iPrEx found that daily use of the drugs reduced HIV infections by 42 percent among MSM, and by more than 90 percent among participants who took their medication consistently enough for the drug to be detected in their blood.

These studies demonstrate that PrEP was safe, with minimal side effects and no significant risk of drug resistance. These and other trials also indicate that effectiveness of TDF/FTC as PrEP depends greatly on individuals' adherence to the PrEP regimen. In each trial, when adherence was low, there was low or no protection, pointing to the central importance of strategies to maximize adherence.

"If FDA approves PrEP, we'll still have a lot of work to do, just as with any other new drug. We'll have many questions to answer in order to use PrEP effectively to reduce HIV infections," said David Munar, President and CEO of the AIDS Foundation of Chicago. "The essential next step will be to launch additional demonstration projects in a wide range of populations and settings. These real-world projects will help us understand how to achieve higher levels of adherence, how to best combine PrEP with other approaches, and which specific populations can benefit the most. While a handful of these real-world studies are now being planned, we need to pick up the pace."

Summary of the Joint Comments to FDA

Based on the clinical trial results to date, the groups indicated their support for FDA approval of TDF/FTC among both men and women. They also highlighted evidence demonstrating the safety of TDF/FTC when used as PrEP, while urging the FDA to ensure appropriate labeling and post-marketing surveillance to ensure that any future safety concerns will be quickly identified and addressed. In addition, the groups also called for the full participation of communities most likely to benefit from PrEP in any future discussions about FDA-required educational/informational materials and programs to support safe use of TDF/FTC as PrEP.

The full text of the comments is available at www.avac.org/ht/a/GetDocumentAction/i/43821. The comments were signed by the following organizations:

  • AIDS Foundation of Chicago
  • AIDS United
  • AVAC: Global Advocacy for HIV Prevention
  • Bay Area Perinatal AIDS Center
  • Black AIDS Institute
  • The Fenway Institute
  • International Rectal Microbicide Advocates
  • Justice Resource Institute
  • National Black Gay Men's Advocacy Coalition (NBGMAC)
  • National Minority AIDS Council (NMAC)
  • Project Inform
  • San Francisco AIDS Foundation
  • SHERO Empowerment Network
  • SisterLove

SOURCE AVAC

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Public release date: 2-May-2012

Contact: Mary Jane Gore
mary.gore@duke.edu
919-660-1309
Duke University Medical Center

DURHAM, N.C. -- Obese people who consume increased amounts of fructose, a type of sugar that is found in particular in soft drinks and fruit juices, are at risk for nonalcoholic fatty liver disease (NFALD) and more its more severe forms, fatty inflammation and scarring.

Now researchers at Duke University Medical Center believe they better understand what mechanism may account for fructose-related liver injury.

Chronic fructose consumption in a diet puts people at risk for depleting their store of critically important molecules called ATP, which provide liver cells (and other body cells) energy for important cellular processes, including metabolism.

"The stores of liver ATP are decreased in obese and/or diabetic individuals who chronically consume increased amounts of fructose-containing beverages," said lead author Manal Abdelmalek, M.D., MPH, Associate Professor of Gastroenterology & Hepatology at Duke.

The study was published online at the Hepatology journal site on May 2.

Nonalcoholic fatty liver disease is currently the leading cause of chronic liver disease in the United States. This condition can lead to elevated liver enzymes, inflammation and rarely even advanced scarring (cirrhosis) in individuals who do not drink alcohol. In obesity and/or diabetes, the ability of the cells to optimally make ATP may already be impaired.

Unlike other simple sugars, fructose requires ATP for its metabolism. The inability to optimally generate cellular energy as well and the continued consumption of ATP from chronic fructose ingestion can result in the liver's depletion of energy. ATP depletion may increase risk for inflammation and scarring in the liver.

"The state of being insulin resistant impairs the ability of a vital enzyme, AMP kinase, to make new ATP molecules," Abdelmalek explained. "Increased fructose consumption, and excess utilization of ATP favors the increase in molecules that lead to increased fatty acid synthesis as well as increased uric acid."

The researchers also noted that more uric acid is produced in the body when excess fructose is consumed. Too much uric acid is associated with conditions that include gout, high blood pressure, cardiovascular disease, type 2 diabetes, metabolic syndrome and uric acid stones, a form of kidney stones.

The silver lining is that measuring the amount of uric acid in these individuals may help doctors predict the presence and monitor the severity of nonalcoholic fatty liver disease, Abdelmalek said.

Research Abdelmalek published in the Journal of Hepatology in 2008 showed that, within a small subset of patients, fructose-containing beverages were associated with NAFLD compared to patients with comparable weight, age, and gender. Her 2010 research, published in Hepatology, went further and linked fructose with the liver injury and scarring (fibrosis).

The current study evaluated adults enrolled in the NIH-sponsored Look Ahead Fatty Liver Disease Ancillary Study headed by senior author Jeanne M.Clark, M.D., MPH, at Johns Hopkins University. The researchers analyzed dietary questionnaires collected in patients who underwent a magnetic resonance imaging to measure liver fat as well as an intravenous fructose challenge to evaluate the liver's ATP stores and response to ATP depletion.

Patients enrolled in the Look Ahead study had been counseled on lower dietary sugar consumption for the management of diabetes. Despite the overall lower levels of fructose use in this study population, the researchers found evidence of liver ATP depletion in those who consumed more fructose.

"The fact we found a difference in liver ATP stores at lower levels of dietary fructose intake does suggest that higher fructose consumption (as would occur with the consumption of processed food and sweetened beverages) could deplete the liver of energy and thus risk causing worse metabolic problems and potentially even liver injury," Abdelmalek said. In the past 30 years, Abdelmalek and authors wrote, fructose consumption has more than doubled.

###

Other authors include Dr. Anna Mae Diehl, chief of the Duke Division of Gastroenterology and Hepatology in the Department of Medicine; Mariana Lazo, Alana Horska, Susanne Bonekamp and Jeanne M. Clark, Departments of Epidemiology, Russel H. Morgan Department of Radiology and Radiological Science and Medicine, at Johns Hopkins University, Baltimore; Division of Metabolism, Edward W. Lipkin, Endocrinology & Nutrition, University of Washington, Seattle; Ashok Balasubramanyam, Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, Houston; John P. Bantle, Division of Endocrinology & Diabetes. University of Minnesota, Minneapolis; and Richard J. Johnson, Division of Nephrology, University of Colorado, Denver.

The study was supported by NIH/NIDDK grants and the Johns Hopkins University School of Medicine General Clinical Research Center, plus a NIH/NIDDK Career Development Award.

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New Antivirals Show Poor Safety in HCV With Cirrhosis

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From Medscape Medical News

Daniel M. Keller, PhD

May 2, 2012 (Barcelona, Spain) — Two relatively new direct-acting antiviral drugs have poor safety profiles in patients with hepatitis C virus (HCV) and cirrhosis, including a high rate of serious adverse events leading to study discontinuation. However, the efficacy of the drugs is good, as evidenced by high rates of on-treatment virologic responses, Christophe Hézode, MD, from Hôpital Henri Mondor in Créteil, France, reported here at the International Liver Congress 2012.

In phase 3 trials of the 2 drugs — telaprevir and boceprevir — rash, pruritus, and anemia were reported with telaprevir, and anemia and dysgeusia were reported with boceprevir. However, those trials included a relatively small number of patients with cirrhosis. A French compassionate-use program allowed the early use of these 2 protease inhibitors before they were approved for patients with cirrhosis, who were entered into a national multicenter registry to prospectively collect clinical data and biological specimens.

An interim analysis evaluated the safety and efficacy of the drugs in these patients who received at least 16 weeks of antiviral treatment (n = 455). The patients had compensated cirrhosis and had relapsed after previous treatment or were partial responders (defined as having had a decrease in HCV RNA of at least 2 log10 IU/mL at week 12 of therapy).

Telaprevir patients (n = 296) received 12 weeks of telaprevir with pegylated interferon (pegIFN) plus ribavirin and then continued only the pegIFN/ribavirin out to week 48. Boceprevir patients (n = 159) received pgIFN/ribavirin for 48 weeks, during which they also received boceprevir for weeks 4 to 48. Both groups were followed for virologic response after week 48.

The telaprevir and boceprevir groups were similar at baseline; mean age was 57 years, HCV RNA level was 6.5 log10 IU/mL, mean hemoglobin was 14.4 to 14.8 g/dL, mean neutrophil count was 3.2 to 3.3 × 109/mm3, and mean platelet count was 150,000/mm3.

High Serious Adverse Event Rate

"The rate of serious adverse events was high, around 50%, with early discontinuation due to severe adverse events observed in 14% of the patients," Dr. Hézode said.

"The second message is that 6 patients died — 2% of the cohort. The main reasons for these deaths were sepsis and hepatic decompensation" that was probably related to interferon, not telaprevir.

A third safety signal was the "difficult management of anemia," requiring the use of recombinant erythropoietin or transfusions, he explained.

Dr. Hézode said that in the boceprevir group, "the serious adverse event rate was high, around 40%, and early discontinuation due to serious adverse events was observed in 7% of patients." Two patients died from sepsis. Hepatic decompensation occurred in 4.4% of patients. Significant anemia occurred in one third of patients, two thirds required recombinant erythropoietin, and 10.7% received transfusions.

Dr. Hézode presented efficacy data on boceprevir, which was fairly good; 37% achieved undetectable HCV RNA levels at week 8 in an intention-to-treat analysis, rising to 58% at week 12 and 61% at week 16.

He concluded that the safety profile of these 2 direct-acting antiviral drugs in compensated cirrhotic patients is poor, but virologic responses are good. The high rate of serious adverse events (38.4% to 48.6%) was much higher than in phase 3 trials (9% to 14%).

Dr. Hézode recommended that patients with cirrhosis be treated cautiously with telaprevir or boceprevir and that they be monitored carefully, especially in light of the high incidence of anemia and its poor response to erythropoietin administration.

Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital in Athens, Greece, and member of the European Association for the Study of the Liver Governing Board Scientific Committee, told Medscape Medical News that "we were surprised by that high rate of so many serious adverse events, and even deaths, but I believe...they had included many patients with, in fact, contraindications to treatment."

He cited, for example, a low platelet count as a contraindication to interferon. "They went beyond the official indications, beyond the inclusion and exclusion criteria that were present in the phase 3 trials. I believe this is why they had such high rates of serious adverse events," Dr. Papatheodoridis said.

He noted that the number of platelets or neutrophils is a laboratory marker that reflects the severity of liver disease. "These were patients with very advanced liver disease who...should not have been treated with interferons," he said. "If you add the [protease inhibitor], which has more side effects, of course the safety profile will be worse."

Dr. Papatheodoridis said the investigators should do "the easy subanalysis" of patients with and without contraindications or who met or failed to meet prespecified criteria for entry into the trial, which Dr. Hézode said he plans to do.

Although there were no deaths in the telaprevir or boceprevir phase 3 trials, it is now obvious that it is very dangerous to use these drugs in such advanced patients.

"The usual indications are the indications for interferon — the inclusion criteria," Dr. Papatheodoridis said.

"For the new drugs, the only new contraindication might be other drugs that the patients take for other diseases because they might have drug–drug interactions."

Dr. Hézode and Dr. Papatheodoridis have disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 8. Presented April 19, 2012.

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PRESS RELEASE

May 2, 2012, 8:19 a.m. EDT

BOSTON, May 02, 2012 (BUSINESS WIRE) -- The New England Journal of Medicine (NEJM) announces the release of a documentary film, now available on the NEJM 200th Anniversary website, in celebration of 200 years of continuous publication. Getting Better is a three-part, 45-minute documentary that explores the evolution of knowledge in medicine and some of the remarkable advances reported in NEJM, including the use of anesthesia in surgery, successful cancer therapies, and treatments for HIV/AIDS.

"We've made so many advances in the field of medicine over the last 200 years, and people's lives have greatly improved as a result," says Dr. Jeffrey Drazen, editor-in-chief of the New England Journal of Medicine. "As a journal, the New England Journal of Medicine has played a role as an observer and an informer, and this film is a reflection of what we've seen. As patients, we have all benefited."

NEJM was founded in 1812 when surgery was unsanitary and performed without anesthesia, cancer went undiagnosed, and there was no understanding of infectious disease.

The first part of the film, "From Rough to Refined: The Rise of Surgery," takes the viewer from the first public demonstration of ether anesthesia in 1846 to a modern-day operating room, where Dr. Atul Gawande performs a thyroidectomy. A segment on leukemia, "Targeting Cancer: The Story of Leukemia," covers Dr. Sidney Farber's first successes in the treatment of early childhood leukemia in 1948 through the development of the first targeted therapy in 2001, the beginning of personalized medicine. In "The Plague of our Time: HIV/AIDS Epidemic," Drs. Tony Fauci and Paul Farmer recall the first cases of HIV/AIDS, how doctors came to understand and treat the disease, and how the epidemic has been part of a revolution in access to care and knowledge.

Each segment of the film traces the connection between research discoveries and current practice, telling the story through the voices of prominent experts, practicing clinicians, patients, and advocates. The documentary illustrates the importance of medical research in shaping clinical practice and patient care; and, how technological advances have changed the speed and trajectory of information sharing, transforming knowledge into action.

A Nancy Porter Production, the film was written and directed by Nancy Porter, an Emmy award-winning filmmaker who has made numerous documentaries for PBS including several for NOVA and American Experience, and produced by Kathryn Dietz, who has produced films for Frontline and American Experience.

About The New England Journal of Medicine

The New England Journal of Medicine (NEJM.org) is the world's leading medical journal and website. In 2012, NEJM celebrates 200 years of advancing medical science, practice and patient care. Each week, NEJM publishes peer-reviewed research and clinical content for physicians, educators and the global medical community. The New England Journal of Medicine is owned and published by the Massachusetts Medical Society.

Photos/Multimedia Gallery Available: http://www.businesswire.com/cgi-bin/mmg.cgi?eid=50261616&lang=en 

SOURCE: New England Journal of Medicine

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Stem cells vs. HIV

Provided by ScienceBlog.com

Posted May 2, 2012

UC Davis Health System researchers are a step closer to launching human clinical trials involving the use of an innovative stem cell therapy to fight the virus that causes AIDS.

In a paper published in the May issue of the Journal of Virology, the UC Davis HIV team demonstrated both the safety and efficacy of transplanting anti-HIV stem cells into mice that represent models of infected patients. The technique, which involves replacing the immune system with stem cells engineered with a triple combination of HIV-resistant genes, proved capable of replicating a normally functioning human immune system by protecting and expanding HIV-resistant immune cells. The cells thrived and self-renewed even when challenged with an HIV viral load.

“We envision this as a potential functional cure for patients infected with HIV, giving them the ability to maintain a normal immune system through genetic resistance,” said lead author Joseph Anderson, an assistant adjunct professor of internal medicine and a stem cell researcher at the UC Davis Institute for Regenerative Cures. “Ideally, it would be a one-time treatment through which stem cells express HIV-resistant genes, which in turn generate an entire HIV-resistant immune system.”

To establish immunity in mice whose immune systems paralleled those of patients with HIV, Anderson and his team genetically modified human blood stem cells, which are responsible for producing the various types of immune cells in the body.

Building on work that members of the team have pursued over the last decade, they developed several anti-HIV genes that were inserted into blood stem cells using standard gene-therapy techniques and viral vectors (viruses that efficiently insert the genes they carry into host cells). The resulting combination vector contained:

  • a human/rhesus macaque TRIM5 isoform, which disrupts HIV from uncoating in the cytoplasm
  • a CCR5 short hairpin RNA (shRNA), which prevents certain strains of HIV from attaching to target cells
  • a TAR decoy, which stops HIV genes from being expressed inside of the cell by soaking up a critical protein needed for HIV gene expression

These engineered blood stem cells, which could be differentiated into normal and functional human immune cells, were introduced into the mice. The goal was to validate whether this experimental treatment would result in an immune system that remained functional, even in the face of an HIV infection, and would halt or slow the progression toward AIDS.

The results were successful on all counts.

“After we challenged transplanted mice with live HIV, we demonstrated that the cells with HIV-resistant genes were protected from infection and survived in the face of a viral challenge, maintaining normal human CD4 levels,” said Anderson.
CD4+ T-cells are a type of specialized immune cell that HIV attacks and uses to make more copies of HIV.

“We actually saw an expansion of resistant cells after the viral challenge, because other cells which were not resistant were being killed off, and only the resistant cells remained, which took over the immune system and maintained normal CD4 levels,” added Anderson.

The data provided from the study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validated its potential application in future human clinical trials. The team has submitted a grant application for human clinical trials and is currently seeking regulatory approval, which is necessary to move on to clinical trials.

“This research represents an important step in our fight against HIV/AIDS,” said Richard Pollard, chief of infectious diseases at UC Davis and one of the study’s co-authors. “Clinical trials could give us the critical information we need to determine whether our approach truly represents a functional cure for a terrible disease that has affected millions and millions of people.”

The study was supported by UC Davis Health System start-up funds from the Dean’s office for the Stem Cell Program and by the James B. Pendleton Charitable Trust. This work was also supported in part by the Gin and Imy Mar stem cell research fund.

Other authors were Rachel X. Chen, Jon E. Walker, Jeannine McGee, Catherine Nacey, Richard B. Pollard, Mehrdad Abedi, Gerhard Bauer, and Jan A. Nolta, all affiliated with the UC Davis Institute of Regenerative Cures.

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Book “Einstein’s Table” Tells Story of Hepatitis B

Release Date: 2012-05-01

“Einstein’s Table: The Search to Find a Cure for Chronic Hepatitis B,” by Kimberly Jungkind, Raises Awareness and Chronicles Hepatitis B Foundation’s Inspirational Story

FOR IMMEDIATE RELEASE / PRURGENT

DOYLESTOWN, PA (May 2012) – The inspirational story of the Hepatitis B Foundation of Doylestown, Pa., has been chronicled in a new book, “Einstein’s Table: The Search to Find a Cure for Chronic Hepatitis B,” authored by Kimberly Jungkind, a Foundation board member. The book’s release comes during May which is National Hepatitis Awareness Month. There will be a book signing offered during the Foundation’s “B Informed” Parent Conference, a free event for parents of children with hepatitis B, to be held on May 19, 2012 at Holiday Inn Express Midtown in Philadelphia.

The only national nonprofit organization dedicated solely to finding a cure for hepatitis B and improving the quality of life for those affected worldwide, the Hepatitis B Foundation began its journey more than 20 years ago. Founders Paul and Janine Witte and Dr. Timothy and Joan Block were moved by the plight of a young family affected by hepatitis B. Dismayed that the affected family had nowhere to turn for support, the Wittes and Blocks gathered at Albert Einstein’s guest cottage in Bucks County, Pa., for a brainstorming session, and the Hepatitis B Foundation was born.

“If the strength and commitment of a community can make a difference in one person’s life in Pennsylvania, imagine what it can do for people across the nation and around the world,” said Jungkind. “I, too, share the dream of the Hepatitis B Foundation’s founders that this disease will be cured and eliminated in our lifetime.”

Jungkind is a nurse clinician and healthcare marketer with nearly 20 years of experience in the healthcare industry. She has lectured nationally on chronic diseases and disease management, and authored more than 15 articles and texts addressing disease management, clinical topics and information technology. Jungkind is the recipient of the Aster Award for Medical Marketing, two Healthcare Advertising Awards, a Dorland Health People Award, a Web Marketing Association Award, Merck’s Most Amazing Woman award and Wyeth’s President’s Golden Circle Award. “Einstein’s Table: The Search to Find a Cure for Chronic Hepatitis B” is available in soft and hard back editions through Amazon.com, with all proceeds benefitting the Hepatitis B Foundation. To learn more, go to http://hepb.org/einsteins_table.htm .

“We are grateful to Kim for telling the story of the Hepatitis B Foundation and raising awareness of this deadly disease,” said Foundation Executive Director and Co-founder Joan Block. “We are also indebted to her for the 15 years of dedicated service to our Board of Directors. Kim has been a valuable resource to our organization and we look forward to continuing our work together.”

Hepatitis B is the most common serious liver infection and the major cause of liver cancer worldwide. Nearly 2 billion people have been infected with the hepatitis B virus (1 out of 3) and 400 million are chronically infected. Each year, 1 million people die prematurely from hepatitis B-related liver disease and liver cancer. In the U.S., an estimated 2 million Americans are chronically infected with hepatitis B – that is 1 in 20. The good news is that hepatitis B is preventable and treatable. However, for the 400 million people living with chronic hepatitis B infections, there is still no complete cure.

About the Hepatitis B Foundation: The Hepatitis B Foundation is the only national nonprofit organization solely dedicated to finding a cure for hepatitis B and improving the quality of life for those affected worldwide through research, education and patient advocacy. To learn more, go to www.hepb.org, read our blog at http://wp.hepb.org, follow us on Twitter @HepBFoundation, find us on Facebook at www.facebook.com/hepbfoundation  or call (215) 489-4900.

Contact Info
Furia Rubel Communications
2 Hidden Lane
Doylestown, PA 18901
Phone: 215-340-0480
Website: http://www.hepb.org

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