November 2, 2010

Diet and cognition in chronic liver disease

Curr Opin Gastroenterol. 2010 Oct 21. [Epub ahead of print]

Kachaamy T, Bajaj JS.

Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA.

Abstract

PURPOSE OF REVIEW: The spectrum of neurocognitive impairment in cirrhosis spans a continuum of minimal hepatic encephalopathy (MHE) to overt hepatic encephalopathy (OHE), the pathophysiology of which remains incompletely understood. The current available evidence, however, suggests that nutrition plays an important role in its development and points to the fact that malnutrition increases the morbidity and mortality of patients with cirrhosis. This review incorporates recent findings published in the last 2 years within the evolution of evidence regarding the role dietary manipulation can play in the comprehensive management of patients with cirrhosis and cognitive dysfunction.

RECENT FINDINGS: In patients with cirrhosis it is important to prevent starvation physiology which occurs after few hours of caloric deprivation as compared to 3 days in noncirrhotics. This can be accomplished by making sure that cirrhotic patients have daily breakfast and a late evening snack. In addition, probiotics and symbiotics are well tolerated and improve cognitive function in patients with MHE.

SUMMARY: The long-time held belief that protein restriction is needed to improve encephalopathy has no scientific basis but remains widely practiced. Branched-chain amino acids supplement may be helpful in patients who continue to suffer from OHE despite treatment of precipitating events and pharmacologic treatment with lactulose and rifaximin. Preventing starvation physiology and supplementing the diet with prebiotics and symbiotics are helpful in patients with MHE.

PMID: 20975555 [PubMed - as supplied by publisher]

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New alternatives to the treatment of acute liver failure

Transplant Proc. 2010 Oct;42(8):2959-61.

Pareja E, Cortes M, Bonora A, Fuset P, Orbis F, Lopez R, Mir J.

Unidad de Cirugía Hepatobiliopancreática y Trasplante Hepático, Hospital La Fe, Valencia, Spain. pareja_eug@gva.es

Abstract

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is defined as an acute deterioration of a chronic liver disease. The most effective treatment in these patients is orthotopic liver transplantation (OLT), which is highly limited by the donor shortage. The aim of this study was to increase the usefulness of hepatocyte transplantation (HT) as a bridge or alternative to OLT.

METHODS: During the last 2 years, we have performed HT in 3 patients with ACLF. The diagnosis was graft cirrhosis due to hepatitis C virus in 2 of them, who were already included on waiting lists for retransplantation, and the third, unknown alcoholic cirrhosis.

RESULTS: After the first HT infusion, we observed an improvement in the clinical condition in all patients, hyperammonemia, and a partial correction of the degree of encephalopathy; 1 patient was retransplanted 6 days after the first HT.

DISCUSSION: The main indications for HT are inborn errors of metabolism in children. Other indications especially in adults, are acute liver failure, ACLF in patients with end-stage-liver disease who are a waiting OLT, and acute liver failure after an hepatectomy. HT may be a new treatment to improve the clinical condition in patients awaiting OLT.

Copyright © 2010 Elsevier Inc. All rights reserved.

PMID: 20970581 [PubMed - in process]

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AASLD: Rapid Response for Once-Daily Protease Inhibitor

By Kristina Fiore , Staff Writer, MedPage Today
Published: November 02, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
 
BOSTON -- The vast majority of patients with hepatitis C virus infection respond rapidly to a novel, once-daily protease inhibitor that may also mitigate the effects of a mutation predicting worse response to standard combination therapy, researchers reported here.

In an interim analysis of a phase IIb, five-arm trial, genotype 1 hepatitis C patients taking various doses of TMC435 in addition to peginterferon and ribavirin had significantly greater responses at four weeks than those on combination therapy plus placebo (68% to 79% versus 5%), according to Michael Fried, MD, of the University of North Carolina Chapel Hill, and colleagues.

The drug also appeared to enhance response to treatment among those with the CT and TT variants of the IL28B genotype, which are associated with diminished response to interferon and ribavirin therapy.

Fried presented the findings during a late-breaking session at the American Association for the Study of Liver Diseases meeting here.

"All treatment groups had a rapid and steep decline [in hepatitis C virus RNA] during the first four weeks that was maintained through weeks 12 and 24," Fried said.

He added that researchers are "encouraged that regimens containing TMC435 will mitigate the effects of IL28 genotype."

The compound is given once a day -- an easier regimen than that of the two protease inhibitors closest to market, boceprevir and telaprevir, which are administered thrice daily.

To evaluate the drug's safety and efficacy, the researchers conducted the five-arm, phase-IIb PILLAR study in 386 treatment-naive patients with genotype 1 disease.

Patients were randomized to one of five groups:

• 75 mg or 150 mg of TMC435 daily along with peginterferon and ribavirin for 12 weeks, followed by peginterferon and ribavirin only for another 12 weeks;

• 75 mg or 150 mg of TMC435 daily along with peginterferon and ribavirin for 24 weeks; or

• Standard combination therapy plus placebo for 48 weeks.

They were allowed to stop treatment at week 24 if their HCV RNA levels were under 25 IU/mL at week four and then again at weeks 12, 16, and 20.

If they didn't meet that criteria, they were continued on standard combination therapy until week 48.

The endpoint was response at 72 weeks, and secondary endpoints included viral breakthrough, relapse, and tolerability.

Fried reported the results of an interim analysis at week 24.

All treatment arms had significant responses after four weeks compared with the placebo group (68% to 79% versus 5%), and continued to have "potent antiviral activity" over 12 and 24 weeks, Fried said.

At week 12, response rates fell between 91% and 97% for the four drug arms, compared with 58% for the placebo group.

Through 24 weeks of treatment, response levels somewhat converged but were still greater in the drug groups (94% to 97% versus 82%).

Between 79% and 86% of patients in the drug arms ended therapy at week 24 as per protocol-defined response criteria.

Viral breakthrough was comparable across all five arms, occurring in 2.5% to 7.8% of patients across the different treatment arms, compared with 3.9% for placebo.

The researchers also found that TMC435 increased response rates among those with IL28B variants known to diminish response to interferon and ribavirin therapy.

Those with genotype CT and TT appeared to have comparable responses to those with genotype CC if they were taking the drug, Fried said.

There were no differences in adverse events, including rash, anemia, or gastrointestinal events, and the most common effects were headache and fatigue, which were comparable across all groups.

Discontinuation rates were similar across all groups as well.

There were, however, "small and transient" elevations in bilirubin levels for patients in the 150-mg dose groups, which Fried said resolved after treatment ended.

"We see some increase in bilirubin, but it's completely reversible," he said, adding the effects are "clearly related to a transporter mechanism as opposed to hepatotoxicity."

He added that despite these effects, "in my opinion, the 150-mg dose is probably the way to go."

Douglas LaBrecque, MD, of the University of Iowa, who moderated the session at which the data were presented, told MedPage Today that the findings are hopeful, but are still in very preliminary stages.

"We just don't have enough data yet," he said.

Drugmaker Tibotec is currently planning phase III trials for the compound.

Fried reported relationships with Tibotec, Roche, Vertex, Merck/Schering, Pharmasset, Bristol-Myers Squibb, Anadys, Conatus, and Human Genome Sciences.

LaBrecque said he had no disclosures.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Fried MW, et al "Efficacy and safety of TMC435 in combination with peginterferon alpha-2a and ribavirin in treatment-naive genotype 1 HCV patients: 24-week interim results of the PILLAR study" AASLD 2010; Abstract LB-5.

Source

AIDSinfo Expands Live Help Chat Service for Clinical Trials Searches

SUMMARY: The U.S. government's AIDSinfo web site[http://www.aidsinfo.nih.gov/] is now offering expanded assistance to prospective clinical trial participants, helping them locate appropriate trials using a live chat service. The new service will focus on the federal ClinicalTrials.gov site, a database of trials for HIV/AIDS as well as other diseases.

Below is a recent announcement from AIDSinfo describing the expanded service.

AIDSinfo Announces Enhanced Live Help Capability

AIDSinfo recently expanded the Live Help chat service to allow AIDSinfo information specialists to actively engage Web site users and assist with clinical trial searches. When a user is navigating through the AIDSinfo clinical trials search page, a pop-up invitation will appear, alerting them that assistance is available for locating HIV/AIDS clinical trials. The user can choose to take advantage of this assistance or simply close the window and continue searching. The purpose of this feature is to provide immediate, interactive assistance to people searching for HIV/AIDS clinical trials.

Live Help is available Monday to Friday, from 12:00 p.m. to 4:00 p.m. Eastern Time (ET). Assistance is also available by calling 1-800-HIV-0440 (1-800-448-0440), Monday to Friday, from 12:00 p.m. to 5:00 p.m. ET, or by sending an e-mail to ContactUs@aidsinfo.nih.gov.

11/2/10

Source
AIDSinfo Announces Enhanced Live Help Capability. AIDSinfo At-a-Glance 45. October 29, 2010.

Source
November 2, 2010

Three-year survival rates after a diagnosis of hepatocellular carcinoma (liver cancer) are similar between people living with HIV and HIV-negative people, according to a study presented at the American Association for the Study of Liver Diseases being held October 29 to November 2 in Boston.

Liver disease and liver cancer have become some of the leading causes of illness and death in people with HIV in recent years—particularly among people coinfected with hepatitis C virus (HCV) or hepatitis B virus (HBV). What’s more, some studies have suggested that people with HIV are more likely to progress to liver cancer and have more aggressive disease than HIV-negative people. These studies, however, have often been quite small, and their study designs have differed.

To better understand survival following a liver cancer diagnosis in people with HIV, Anne Gervais, MD, from the Hopital Bichat in Paris, and her colleagues examined the medical records of 687 people diagnosed with liver cancer, 23 of whom were HIV positive.

Most all of the HIV-positive participants were coinfected with HCV or HBV, nearly all were taking HIV antiretroviral (ARV) therapy, and the majority had a CD4 count over 200 at the time of their cancer diagnosis. In most regards, the HIV-positive and HIV-negative study volunteers were similar, but the HIV-positive participants were much younger at the time of their cancer diagnoses—49 years old on average—than the HIV-negative participants, where the average age was 58.

Gervais’s team found that rigorous screening, the stage of the cancer and estimates of the cancer’s speed of progression (a process called preoperative surveillance) significantly affected survival rates among the HIV-positive participants. People who had good preoperative surveillance had much smaller tumors at the time of diagnoses and were far more likely to be alive three years after receiving treatment than those who had poor surveillance. The three-year survival rates were 63 percent in those with good surveillance compared with just 17 percent in those with poor surveillance.

One encouraging finding was that on average, people living with HIV had similar three-year survival rates as HIV-negative participants. Overall three-year survival was 42 percent among the HIV-negative volunteers and 39 percent among the HIV-positive volunteers.

“Screening of the HIV-positive population should be reinforced as the prognosis after curative treatment is at least equal to that of HIV-negative [patients],” concluded the authors.

Source

AASLD: Early Study Shows HCV Vaccine Works

By Michael Smith , North American Correspondent, MedPage Today
Published: November 02, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
 
BOSTON -- An experimental therapeutic vaccine against hepatitis C improved response rates by 12% compared with standard care in a small clinical trial, a researcher reported here.

The phase II trial included both treatment-naive patients and those who had not responded to previous care with the standard combination of ribavirin and pegylated interferon, according to Paul Pockros, MD, of the Scripps Clinic in La Jolla, Calif.

Results in both subgroups were similar to the overall outcome but did not reach statistical significance compared with standard care, Pockros told a late-breaker session at the annual meeting of the American Association for the Study of Liver Diseases.

But the findings, based on just 133 patients, are enough to justify continued development of the vaccine, Pockros said, including tests to see if it can be effective without the standard hepatitis C treatment regimen, which has difficult side effects.

The vaccine -- dubbed GI-5005 -- is a recombinant, inactivated yeast that expresses hepatitis antigens, Pockros said.

The immune response generated by the vaccine is similar to that seen among patients who are able to clear the virus without medication -- a modest response to the viral envelope proteins and a robust response to the nonstructural proteins NS3 and NS5.

Patients in the study were randomly assigned to get the vaccine or not. Those getting vaccine first had a 12-week run-in, during which they got five weekly doses of GI-5005, delivered subcutaneously then followed by two monthly doses.

They then got the vaccine on a monthly basis, along with the two standard hepatitis C drugs, ribavirin, and pegylated interferon.

The comparison group, including 65 of the 133 participants, got standard care only.

In both groups, treatment-naive patients were treated for 48 weeks, while previous nonresponders got 72 weeks of treatment. The primary endpoint was sustained virologic response, defined as undetectable virus six months after the end of treatment.

The researchers found:

• 58% of treatment-naive patients who got the vaccine had a sustained virologic response, compared with 48% of those getting standard treatment.

• 17% of previous nonresponders had a sustained virologic response if they got the vaccine compared with 5% of those on standard care.

• And overall, the vaccine yielded a 47% response rate, compared with 35% for standard care.

• The first two results did not reach statistical significance, but the last was significant at P=0.037.

Pockros said that no unexpected adverse effects surfaced during the trial; there was a 13% rate of discontinuation in each study arm due to side effects.

The GI-5005 vaccine, he said, is a "novel approach to hepatitis C" that appears to be safe but needs more study.

A "benign" therapeutic vaccine might be advantageous, according to Douglas LaBrecque, MD, of the University of Iowa in Iowa City, Iowa, who was not part of the study but who moderated the session at which the data was presented.

That would be especially true, he told MedPage Today "if you could eliminate some of the other medications, either interferon or the small molecules, which have their own side effects."

But this study was so preliminary and had such small numbers, LaBrecque stressed, that "all you can say is that it wasn't a total failure."

The study was supported by GlobeImmune, of Louisville, Colo. Pockros reported financial links with Genentech, Vertex, Merck, Gilead, Abbott, Pfizer, Phenomix, Tibotec, Pharmasset, 3RT, Novartis, J&J, Achillon, Regulus, GlobeImmune, Debio, Zymogenetics, and Human Genome Sciences.

LaBrecque had no disclosures.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Pockros P, et al "GI-5005 Therapeutic vaccine plus peg-IFN/ribavirin improves sustained virologic response versus peg-IFN/ribavirin in prior non-responders with genotype 1 chronic HCV Infection" AASLD 2010; Abstract LB-6.

Source

AASLD: Anti-HCV Drug Boosts Response Rates

By Michael Smith , North American Correspondent, MedPage Today
Published: November 02, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
 
BOSTON -- Combining the direct anti-viral agent telaprevir with standard hepatitis C care can sharply improve response rates and shorten the treatment period, researchers reported.
 
The findings -- from two major phase III trials encompassing more than 1,500 patients -- suggest that treatment of hepatitis C, which affects about two million Americans, is about to undergo a dramatic change, observers here said.

With standard care -- 48 weeks of ribavirin and pegylated interferon -- about 45% of patients with the most refractory form of the disease can expect a "sustained virologic response," defined as undetectable virus six months after the end of treatment.

But with the addition of the protease inhibitor telaprevir, that number can rise as high as 75%, according to the trial results, presented at the annual meeting of the American Association for the Study of Liver Diseases.

Moreover, in many cases, so-called "response-guided therapy" can cut the treatment period to 24 weeks, sharply reducing the exposure to interferon, which causes difficult and sometimes intolerable side effects.

The high response rates are "incredible, when you think about the time when we only had a 5% response rate (with interferon alone)," commented Arun Sanyal, MD, of Virginia Commonwealth University Medical Center in Richmond, Va., who was not part of either study.

Sanyal, president of the AASLD, said other reports presented here suggest that a sustained virologic response is essentially a cure for the disease -- so that higher response rates make the battle against hepatitis C "winnable."

He told MedPage Today one of the barriers to that goal is diagnosis -- some 80% of people infected with hepatitis C are not aware of their condition.

The two clinical trials presented at the AASLD meeting had slightly different goals:

• The ILLUMINATE study compared two telaprevir-based regimens of 24 and 48 weeks duration, with the goal of showing the noninferiority of the shorter course. It was an open-label trial and all patients also got standard treatment with ribavirin and peginterferon.

• The ADVANCE study compared two telaprevir regimens -- of eight and 12 weeks -- with standard care alone; its goal was to show that either regimen would be as good as the other and could shorten the treatment period. The trial was randomized, double-blinded, and placebo-controlled during the telaprevir phases.

Telaprevir is a protease inhibitor aimed at the NS3-4A enzyme, which is needed for the hepatitis C virus to replicate. The drug is still not approved.

Illuminating Study Results

In the ILLUMINATE study, 540 patients new to treatment and infected with genotype 1 hepatitis C were treated with telaprevir, ribavirin, and peginterferon for 12 weeks, according to Kenneth Sherman, MD, PhD, of the University of Cincinnati College of Medicine, who presented the study at a late-breaker session.

Patients then had eight more weeks of ribavirin and peginterferon and, at week 20, those who had demonstrated undetectable virus at weeks four and 12 (a so-called "extended rapid virologic response") were re-randomized to get either four or 28 more weeks of the two drugs.

Patients who didn't have an extended rapid virologic response were also given an additional 28 weeks of standard therapy combining ribavirin and peginterferon, Sherman said.

Overall, 72% of the patients, on an intent-to-treat basis, had a sustained virologic response, Sherman reported.

But 65% of the patients also had an extended rapid virologic response and were randomized to a shorter or longer treatment course, he said. In that population, 92% of those treated for 24 weeks had a sustained virologic response, compared with 88% of those who had the longer course.

The difference was within a preset noninferiority margin, Sherman said.

The results were similar even after Sherman's team analyzed patient data according to the severity of disease or race and ethnicity, he said.

The most common adverse events were fatigue, pruritus, nausea, anemia, headache, and rash, and 17% of patients stopped all study drugs because of adverse events.

The ILLUMINATE study shows there's no clinical benefit in extending treatment with the three drugs -- as long as patients have an early and sustained virologic response, Sherman concluded.

The data "are certainly showing the best responses we've seen today for type 1 patients," said Douglas LaBrecque, MD, of the University of Iowa in Iowa City, Iowa, who was not part of the study but who moderated the session at which the data were presented.

"It's another step forward," he told MedPage Today, "but it's not 100%."

LaBrecque also commented that the regimen does not do away with the use of interferon. "It's triple therapy, without question, but it's still a significant step forward," he said.

Advancing Hep C Treatment

The ADVANCE study also enrolled treatment-naive, genotype 1 patients, but they were randomized to three arms:

• Arm One patients were treated with telaprevir, ribavirin and peginterferon for 12 weeks, followed by 12 weeks of ribavirin and peginterferon alone. Those with an extended rapid virologic response stopped therapy, while lack of such a response meant another 24 weeks of ribavirin and peginterferon.

• Arm Two patients had eight weeks of triple therapy, followed by four weeks of placebo, ribavirin, and peginterferon. Again, an extended rapid virologic response stopped therapy, while lack of such a response meant another 24 weeks of standard care.

• Arm Three was the control arm. Patients were given standard treatment for 48 weeks, with a placebo to maintain blinding for the first 12.

The primary endpoint of ADVANCE was a sustained virologic response six months after the last planned dose, according to Ira Jacobson, MD, of the Weill Cornell Medical Center in New York City.

Overall, Jacobson and colleagues reported sustained virologic response rates among the more than 1,000 patients enrolled in the trial were as follows:

• 44% among control patients

•69% among those in Arm Two, who got eight weeks of telaprevir

• And 75% among those in Arm One, who got 12 weeks of telaprevir

• Both results were significantly different from controls at P<0.0001

In both telaprevir arms, slightly more than half of the ADVANCE patients (58% and 57%) had an extended rapid virologic response and were eligible to stop therapy at 24 weeks, Jacobson said.

Among those patients, he said, the sustained virologic response rates were 89% for the 12-week regimen and 83% for the eight-week course. In contrast, among those who took the full 48-week course, the rates were 54% and 50% respectively.

Among controls who had an extended rapid virologic response, 97% went on to have a sustained virologic response, Jacobson noted, but there were only 29 such patients. Among the 332 controls who did not have an early response, the sustained virologic response rate was 39%, he said.

As in the ILLUMINATE study, the researchers found high response rates among telaprevir patients regardless of severity of disease, race, or ethnicity, Jacobson said. The adverse event profile was also similar.

Telaprevir improved response rates compared with placebo, Jacobson concluded, but the 12-week regimen was slightly better. A majority of patients, he noted, were able to finish treatment in 24 weeks.

Both studies were co-sponsored by Vertex and Tibotec, which are developing telaprevir.

Sherman reported financial links with Anadys, Bristol-Myers Squibb, Merck, Roche, Schering-Plough, Valeant, and Vertex.

Jacobson reported financial links with Abbott, Roche, Genentech, Tibotec, Bristol-Myers Squibb, Novartis, Gilead, Progenics, Pfizer, GlobeImmune, Human Genome Sciences, Schering-Plough, March, Boehringer Ingelheim, Pharmasset, Zymogenetics, Vertex, and Anadys.

LaBrecque made no disclosures.

Sanyal reported financial links with Takeda, Salix, Ikaria, Exhalenz, Bayer Onyx, Norgine, Gore, Gilead, Intercept, Roche, and Astellas.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Sherman KE, et al "Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: Final results of phase 3 ILLUMINATE study" AASLD 2010; Abstract LB-2.

Additional source: American Association for the Study of Liver Diseases

Source reference:
Jacobson IM, et al "Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: Final results of phase 3 ADVANCE study" AASLD 2010; Abstract 211.

Source

Why Aren’t There AIDS-Style Cocktails for Hepatitis C?

Nov. 2 2010 - 2:02 pm
By ROBERT LANGRETH

In the heated race to develop new hepatitis C drugs that boost the cure rate, Wall Street thinks Vertex Pharmaceuticals has a slightly better drug than a rival entry from Merck, and thus will garner the large majority of sales.

Both companies were talking a good game as they presented new data at a conference of liver specialists wrapping up today(11/2). “The case for boceprevir is compelling,” Merck research head Peter Kim said in an brief phone interview with Forbes. “I am really excited about the profile we have. It is going to have a significant impact.” He touted his drug as “the only drug” whose trials have shown that shorter regimens are possible in patients who failed previous therapy. (Both drugs have been able to shorten the treatment regimen in some patients receiving initial treatment.)

“We think our data is the leading data,” counters Vertex chief medical officer Robert Kauffman. The Vertex drug’s cure rate of up to 75% “sets quite a high bar for the competition.” While Merck and Vertex are touting the ability of their drugs to cure difficult-to-treat “null responders” whose viral levels barely budged on existing therapy, Kauffman argued that Merck’s trial used potentially looser criteria that included patients who “would not fit the standard definition of null responder”.

But even with shorter regimens, both drugs will still have to be given with interferon alpha, the two-decade old antiviral drug made by Merck and Roche that causes nasty flu like side-effects, including fever and fatigue. It is a general antiviral agent that does not specifically target the hepatitis C virus at all.

This stands in contrast to AIDS where patients get cocktails of targeted pills that keep the HIV virus at bay for years. Company’s like Bristol-Myers and Gilead Sciences are trying hard, but no one has yet come up with a cocktail of antiviral pills that can kill off the hepatitis C virus without the need for interferon.

One reason is that the flat geometry of the hepatitis C protease protein made it is difficult target to hit with small-chemical drugs. Direct antiviral drugs for hep C are only now coming out after over a decade of work.

A bigger reason, says Vertex’s Kauffman, is that hepatitis c is a hugely efficient reproducer. It produces 1 trillion new viral particles a day–a far greater replication rate than HIV. Hepatitis C also makes many mistakes when it copies itself.

All this means that patients already have mutant viral particles inside their bodies that are likely to be resistant to direct antiviral drugs. Giving a cocktail of one or two antiviral drugs will smash down the viral levels in the short term, but ultimately will select for the resistant viruses in the long term. Interferon helps, despite the nasty side effects, because it works by a general antiviral mechanism that avoids these problems.

It is a numbers game. Until researchers can come out with a potent enough antiviral combo to account for the massive numbers of mutations that hepatitis c virus can produce, interferon will remain part of hepatitis C treatments.

Source

AASLD: Six Months of Novel Agent Works in Hep C

By Kristina Fiore , Staff Writer, MedPage Today
Published: November 02, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine
 
BOSTON -- A shorter, six-month course of the investigational protease inhibitor boceprevir added to standard combination treatment appears just as effective as almost a full year of therapy for patients with a challenging subtype of hepatitis C, researchers reported here.

Sustained virologic response (SVR) rates were similar with both regimens -- 67% for the short course, 68% for the full treatment -- and were both significantly greater than those seen with peginterferon and ribavirin alone (40%, P<0.0001), according to Fred Poordad, MD, of Cedars-Sinai Medical Center in Los Angeles, and colleagues.

They reported their findings during a late-breaking oral session at the American Association for the Study of Liver Diseases meeting here.

Patients with genotype 1 hepatitis C virus have had meager treatment response rates compared with genotype 2 and 3 patients -- especially if they're African American.

So to compare the safety and efficacy of the two strategies in this genotype, as well as outcomes for blacks with this subtype, the researchers enrolled 1,097 treatment-naive patients, 159 of whom were African American, in the SPRINT-2 trial.

Patients were randomized to one of three groups: 48 weeks of interferon and ribavirin along with placebo, 48 weeks of the standard combination plus boceprevir, or 24 weeks of triple therapy.

All three arms had a four-week lead-in phase with peginterferon and ribavirin alone. After that, the two drug groups received an additional 800 mg of boceprevir three times a day.

The primary endpoint was sustained virologic response 24 weeks after therapy.

The researchers found that both boceprevir groups had higher SVR rates at that point than the control group.

In an intention-to-treat analysis among white patients, 67% of those in the short-course group achieved sustained viral response, as did 68% of the long-treatment-course group, compared with just 40% of controls (P<0.0001).

Only 8% of those on full treatment and 9% of those on the short course relapsed, compared with 23% of those on placebo.

Among black patients, 53% of those on the full treatment and 42% of those on the short course had sustained virologic response, compared with 23% of those on placebo (P=0.004 and P=0.044, respectively).

With full treatment, 17% of blacks relapsed, along with 12% of those on the short course and 14% of those on placebo.

The trial had a "stopping rule" mandating that patients discontinue treatment if they don't respond in the first 24 weeks. Among white patients, 27% of those on standard combination therapy discontinued compared with 8% of those on short therapy and 9% of those on the full course.

For blacks, 46% of those on placebo discontinued treatment, compared with 17% of those on the short course and 15% of those on the full course of triple therapy.

Treatment appeared to be associated with two side effects compared with placebo -- anemia and a distorted sense of taste, or disgeusia.

Overall, patients on treatment had greater use of erythropoietin to treat anemia compared with controls (43% for short- and full-course, versus 24% of those on placebo).

More boceprevir patients also had to reduce their treatment dose due to anemia (20% and 21% versus 13%).

Other adverse events included nausea, headache, and fatigue, at similar rates across all three groups.

In a separate trial reported here -- the RESPOND-2 trial -- genotype 1 patients who'd failed prior therapy had better sustained virologic response rates with both the short- and long-course of boceprevir treatment compared with placebo (59% and 67% versus 21%, P<0.0001).

Anemia also appeared to be problematic for the treatment groups in the 403-patient study.

Douglas LaBrecque, MD, of the University of Iowa, who moderated the session at which the SPRINT data were presented, told MedPage Today that the findings are preliminary, but they're still "the best we've seen to date for type 1 patients," especially with regard to results for African-American patients and previous nonresponders.

"It's another step forward, but we're not there yet," he said, adding that triple therapy is still necessary and the standard interferon-ribavirin regimen won't be going away any time soon.

Triple therapy appears to keep resistance issues at bay -- a key area of concern for protease inhibitors, LaBrecque said.

"That's going to be the Achilles' heel of all small-molecule [therapy] trying to get away from [interferon and ribavirin]," he said. "If they start producing significant numbers of resistant virus, then you're developing a much more resistant virus and we don't want to see that."

Drugmaker Merck began submission of a new drug application for boceprevir on a rolling basis and expects to complete that process by the end of the year.

The study was supported by Merck.

Poordad reported relationships with Schering-Plough, Merck, Vertex, Genentech, Bristol-Myers Squibb, Gilead, Pfizer, Salix, Idenix, Valcant, Tibotec, and Abbott.

LaBrecque said he had no disclosures.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Poordad F, et al "Boceprevir combined with peginterferon alfa-2b/ribavirin for treatment-naive patients with hepatitis C virus genotype 1: SPRINT-2 final results" AASLD 2010; Abstract LB-4.

Source
Michael Carter
Published: 02 November 2010

Spanish investigators have developed a non-invasive diagnostic tool that can accurately predict which HIV-positive patients who are co-infected with hepatitis C virus will successfully respond to treatment for hepatitis C. Their findings are reported in the November 15th edition of Clinical Infectious Diseases.

Called Prometheus, the diagnostic tool can be downloaded for free here.

Four variables were included in the investigators’ model. Two of these – hepatitis C genotype and viral load – are well-known predictors of treatment outcome. The researchers also included two novel diagnostic markers: liver stiffness and genetic variations near the IL28B gene.

All these markers can be monitored without the need for an invasive liver biopsy, which the investigators believe makes their model especially attractive for use in routine care.

It is estimated that approximately 20% of HIV-positive individuals are co-infected with hepatitis C. In the era of modern HIV treatment, liver disease caused by hepatitis C is a leading cause of illness and death in co-infected patients.

Treatment for hepatitis C is available. Involving pegylated interferon and ribavirin, its aim is an undetectable hepatitis C viral load six months after the completion of therapy. This is often called a sustained virological response, and only a third of co-infected patients achieve this outcome.

Poorer outcomes are seen in patients infected with hepatitis C genotypes 1 and 4 (as opposed to 2 and 3), and in individuals with a higher hepatitis C viral load at the start of therapy.

Recently, genetics have also been identified as predicting treatment response. Improved outcomes were seen in patients with a variation in the polymorphism rs12979860 close to the IL28B gene. Patients with the CC genotype were twice as likely as individuals with the CT or TT genotype to have a successful treatment response.

Assessment of liver stiffness using FibroScan has also been shown to be an accurate way of monitoring liver damage in patients with hepatitis C. This method of monitoring involves placing a small device against the patient’s skin and therefore, unlike liver biopsy, does not require surgery.

Therefore, the investigators developed a predictive model including these four variables.

Their main study population included a cohort of 159 co-infected patients who received hepatitis C therapy at the Hospital Carlos III, Madrid, between November 2004 and December 2008. To validate their results, the diagnostic tool was also tested on 86 co-infected patients who received treatment at two other clinics.

The two cohorts were generally well matched. However, individuals in the validation population had a higher baseline hepatitis C viral load (p < 0.001) and lower liver stiffness scores (p = 0.03). Overall, approximately 55% of patients in both cohorts had a sustained virological response.

However, the investigators stress that they excluded “nonadherent patients and patients who discontinued therapy because of side-effects and only evaluated the subjects who had completed the course of therapy.” Moreover, 99% of patients were male and the average body mass index (BMI) was well within the normal range (23 kg/m2).

In both groups of patients, hepatitis C genotype, liver stiffness, the CT or TT polymorphism and hepatitis C viral load were predictive of treatment outcome.

The strongest predictor of outcome was CT or TT polymorphism versus CC (odds ratio [OR] = 0.170; 95% CI, 0.065-0.442; p < 0.001).

This was followed by baseline hepatitis C viral load and 3 (OR, 0.186; 95% CI, 0.091-0.381; p < 0.001), genotype 1 and 4 versus 2 and 3 (OR, 0.212; 95% CI, 0.078-0.577; p = 0.002), and increased liver stiffness (OR, 0.920; 95% CI, 0.865-0.977; p = 0.007).

Using these data, the investigators developed their tool to predict treatment response.

They used the control cohorts to test the accuracy of their model at three cutoff points. These assessed different degrees of sensitivity and specificity.

Using the lowest point (highest sensitivity and lowest negative predictive value`), a lack of treatment response was correctly predicted in 89% of patients.

A similar accuracy – 90% - was seen when the investigators used the highest cutoff (highest specificity and positive predictive value).
An intermediate cutoff (highest sensitivity and specificity) accurately predicted a successful treatment response in 83% of patients and a lack of response in 79%.

Therefore, the assessed the accuracy of their model as between “excellent” and “good”.

The investigators believe that their tool “may be of great value for making adequate therapeutic decisions for HIV-HCV-coinfected patients.”

For example, use of current hepatitis C therapy could be encouraged for patients with the greatest chance of responding to treatment.

Those with a low chance of sustained virological response could be counselled to “wait for new direct-acting antiviral agents against HCV”.

Although the investigators are encouraged by the accuracy of their model, they nevertheless caution, “as with any diagnostic tool used in clinical practice, misclassification may occur, and understanding the limits of estimated outcomes with predictive indexes is important before its widespread use.”

Reference
Medrano J et al. Modeling the probability of sustained virological response to therapy with pegylated interferon plus ribavirin in patients coinfected with hepatitis C virus and HIV. Clin Infect Dis, 51: 1209-16, 2010 (click here for the study’s free abstract).

Source

AASLD: Two New HCV Drugs Need Old Hands' Help

By Michael Smith , North American Correspondent, MedPage Today
Published: November 02, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.
 
BOSTON -- Two direct anti-viral agents showed robust activity against hepatitis C in treatment-naïve patients with the most refractory form of the virus, a researcher said here.
 
But the two drugs needed the standard medications -- ribavirin and pegylated interferon -- to get high response rates, according to Stefan Zeuzem, MD, of J.W. Goethe University Hospital in Frankfurt, Germany.

The findings come from a phase II randomized trial that tested the two drugs over a four-week period, followed by 44 weeks of ribavirin and interferon, Zeuzem told a late-breaker session at the annual meeting here of the American Association for the Study of Liver Diseases.

The hope has been that the direct-acting agents -- which target viral replication -- might allow physicians to avoid the use of interferon, which modulates the immune system and has unpleasant and often intolerable side effects.

But the research presented here doesn't support that hope, according to Douglas LaBrecque, MD, of the University of Iowa in Iowa City, Iowa, who was not part of the study but who moderated the session at which the data was presented.

The combination "didn't show a major promise of eliminating the standard two drugs," he told MedPage Today. "It's not the holy grail."

The two drugs are GS-9256, a protease inhibitor, and GS-9190, a polymerase inhibitor. Both showed significant reductions in hepatitis RNA in phase I studies, Zeuzem said.

To extend the findings, Zeuzem and colleagues enrolled 46 patients with genotype 1 -- the most difficult to treat -- and randomized them to get the two drugs alone, with ribavirin, or with ribavirin and peginterferon for four weeks.

All patients then got ribavirin and peginterferon for 44 weeks, followed by six months of follow-up. Zeuzem presented efficacy and safety data for the first four weeks, where a "rapid virologic response" was defined as 25 or fewer international units of hepatitis C RNA per milliliter of serum.

At 28 days, the researchers found:

• One of 15 patients getting the two drugs alone had a rapid virologic response.

• Five of 13 patients getting both drugs, with the addition of ribavirin, had a rapid virologic response.

• All 14 patients getting the two drugs, as well as ribavirin and peginterferon, had a rapid virologic response.

Zeuzem said the two direct-acting agents led to a rapid drop in hepatitis C RNA levels, but most patients rebounded within two weeks. But when ribavirin was added, the same rapid drop was observed and only a handful rebounded, while the addition of the fourth drug meant all patients responded, after a similar quick decline.

A key difference, he said, was that in the four-drug arm patients had such low levels of virus that it was impossible to perform the sequencing needed to identify resistance mutation against the two agents. In the three-drug arm, the same was true in 11 of 13 patients and the other two patients each had at least one resistance mutation.

On the other hand, 11 patients in the two-drug arm had two or more resistance mutations, two had a single mutation, and only two had virus levels so low that resistance sequencing was not possible.

Adverse effects were low in the two- and three-drug arms, but the addition of peginterferon introduced the gamut of side effects associated with the drug, Zeuzem said. Only one patient stopped therapy because of adverse events, he said.

There were two serious adverse events but only one -- a vasovagal collapse attributed to gastroenteritis -- was thought to be possibly linked to the study drug, in this case the four-drug regimen, he said.

Overall, the data are promising but need "much longer follow-up," LaBrecque told MedPage Today.

"It's too early to make too many conclusions," he told, especially when the main focus of the report was four-week data.

The study was supported by Gilead. Zeuzem reported financial links with Gilead, Intermune, Roche, Merck, Vertex, Human Genome Sciences, Abbott, BMS, Tibotec, Bayer, and Anadys.

Labrecque had no disclosures.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Zeuzem S, et al. "Dual, triple, and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PegIFN/RBV for up to 28 days in treatment naïve, genotype 1 HCV subjects" AASLD 2010; Abstract LB-1.

Source

AASLD: New HCV Drug Speeds Viral Clearance

By Michael Smith , North American Correspondent, MedPage Today
Published: November 02, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.
 
BOSTON -- Adding the investigational polymerase inhibitor ANA958 to standard care speeded up the clearance of hepatitis C, compared with standard care alone, a researcher reported here.
 
An ongoing double-blind, placebo-controlled phase II trial among more than 100 patients, found that after12 weeks of therapy with one of two doses of ANA958, 73% and 75% of patients had undetectable levels of hep C virus, depending on dose, according to Eric Lawitz, MD, of Alamo Medical Research in San Antonio, Tex.

In contrast, 63% of those getting only standard care with pegylated interferon alpha-2a and ribavirin had undetectable hep C levels, Lawitz said at the annual meeting of the American Association for the Study of Liver Diseases.

The difference at that point was not statistically significant -- but earlier in treatment significantly more of the ANA958 patients had reached undetectable levels of the virus, Lawitz added.

Specifically, at four weeks, between 42% and 56% had undetectable hepatitis C levels, depending on the dose of ANA958, while at eight weeks, the proportions were 69% and 72%, he explained.

For standard care, the proportions were 13% and 38% and all the differences were significant, Lawitz said.

ANA958 is intended to block viral replication by interfering with the hepatitis C genotype-1 polymerase NS5A. The current study was a follow-up to a phase I trial that showed a "rapid and sustained reduction" in viral RNA levels over three days, Lawitz said.

To examine the efficacy and safety of the compound, he and colleagues enrolled 105 treatment-naïve patients with genotype-1 virus and randomly assigned them to either 200 or 400 mg of ANA958 twice a day, or to placebo. Those getting active drug also had a loading dose of 800 mg on the first day of therapy.

All of the trial patients also got standard treatment with pegylated interferon alpha-2a and ribavirin.

Patients with undetectable hep C virus at weeks four and 12 weeks, Lawitz explained, were re-randomized to continue standard care for another 12 or 32 weeks.

There was little difference between the two arms in terms of the speed at which the drug cleared the virus, Lawitz said, but viral clearance was always faster than the standard care alone.

The main difference between the two arms was in the adverse events.

In general, adverse events were what would be expected with the standard therapy, but there was an elevated rate of rash among patients getting the 400-milligram dose of ANA958.

Among placebo patients, Lawitz said, 34% reported rash and all were grade one, compared with 43% among those getting 200 mg of ANA958, where all but one of the rashes were grade one.

On the other hand, he said, 62% of the patients getting 400 mg reported rash, including 17 with grade one, one with grade two, and three patients with grade three rash.

The findings "looked nice" but are still preliminary, according to Petra Munda, MD, of the University of Vienna, who was not part of the study.

"I'm always skeptical of week 12 data," she told MedPage Today, although she noted that of the 11 patients who have completed ANA958 therapy at 24 weeks, eight had undetectable hepatitis C virus, a level sustained through the following 12 weeks.

On the other hand, in the high-dose group, some 62% had rash and "that's a lot," Munda commented.

Rash is a common side effect of the drug class, she noted, and doctors are beginning to be more comfortable with it. "In the beginning we were all too much afraid of the rash," Munda said. "It's manageable, but it's not nice for the patients."

The study was sponsored by Anadys Pharmaceuticals of San Diego. Lawitz reported financial links with Abbott, Anadys, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Humman Genome Sciences, Idenix, Idera, Intarcia, Medarex, Medtronic, Merck & Co., Novartis, Pharmasset, Roche, Schering-Plough, Valeant, Vertex, ViroChem Pharma, and ZymoGenetics.

Munda said she had no disclosures.

Primary source: American Association for the Study of Liver Diseases

Source reference:
Lawitz E, et al. "Safety and antiviral activity of ANA598 in combination with pegylated interferon 2A plus ribavirin in treatment-naïve fenotype-1 chronic HCV patients" AASLD 2010; Abstract 31.

Source

AASLD: Vitamin E Resolves NASH in Children


By Kristina Fiore , Staff Writer, MedPage Today
Published: November 02, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

BOSTON -- Vitamin E may help resolve nonalcoholic steatohepatitis (NASH) in children -- although it won't lower alanine aminotransferase (ALT) levels, researchers reported here.

Although the 96-week randomized trial involving nearly 200 children missed its primary endpoint of lowering ALT, only vitamin E -- compared with metformin and placebo -- had significant effects on several histologic parameters, according to Joel Lavine, MD, of Columbia University, and colleagues.

"Vitamin E use should be supported for children with NASH," Lavine said during an oral presentation at the annual meeting of the American Association for the Study of Liver Diseases.

Similar findings were reported for adults last April, in which the PIVENS trial, published in the New England Journal of Medicine, found vitamin E significantly improved a composite of four histological features of NASH compared with placebo.

In that trial, pioglitazone (Actos) also improved these histologic features, but not significantly compared with placebo.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in American children, yet no pharmacologic therapy has yet been established.

So the researchers conducted a randomized, placebo-controlled trial among 173 children (ages 8 to 17) from eight centers in the NASH Clinical Research Network to see whether vitamin E or metformin would mitigate fatty liver disease.

The kids were randomized to 500 mg of metformin twice a day, 400 IU of vitamin E twice a day, or placebo. The mean age was 13, boys made up the majority of the population (80%); they were largely Hispanic and most were obese with a body mass index (BMI) in the 33 to 34 range, Lavine said.

They had biopsy-confirmed NAFLD, as well as an ALT over 60 at baseline. Those with diabetes, cirrhosis, or significant alcohol use were excluded.

All of the children in the trial were also given standard care, including advice on lifestyle modification.

Children had regular clinic visits during the 96-week trial, and were followed for an additional 24 weeks to assess treatment durability.

The primary endpoint was reduction in ALT, while the secondary endpoints looked at histological changes.

The researchers found that ALT decreased in all three groups -- most likely because they were all receiving the standard of care, which is education on diet and exercise, Lavine said.

There was a more rapid decline in those levels for children on vitamin E, but the data converged by the end of the trial (25.9% achieved a reduction with vitamin E, 15.8% with metformin, and 17.2% with placebo).

The results did not change after controlling for factors such as age, gender, and ethnicity, Lavine said.

Yet when the researchers looked at histological factors, they found that both vitamin E and metformin improved hepatocellular ballooning compared with placebo (44% and 44% versus 21%, P=0.006).

But only vitamin E significantly improved NAFLD scores compared with placebo (P=0.02).

In the subset of children with NASH at baseline, vitamin E significantly increased resolution of NASH on the 96 week liver biopsy compared with placebo (58% vs 28% P=0.006).

However, neither vitamin E nor metformin improved liver fibrosis, lobular formation, or portal inflammation scores.

There were equal changes in body weight across groups, with the children gaining a mean 13 kg (28.6 lbs) over the 96 weeks of the study -- despite the exercise and diet advice provided.

Lavine and colleagues concluded that while neither vitamin E nor metformin was superior to placebo for sustained ALT reduction, vitamin E improved several histologic markers for children with NASH.

He added that further work needs to be done with regard to the effects of the exercise and dietary intervention used in the trial.

Lavine concluded that the results "reinforce the PIVENS findings that vitamin E improved NASH in adults."

Arun Sanyal, MD, of Virginia Commonwealth University Medical Center in Richmond and president of the AASLD, said that fatty liver disease "is a very scary disease in children," since it is also an emerging risk factor for diabetes and coronary artery disease.

Sanyal, who was also an investigator in the adult PIVENS trial, said the improvement in steatohepatitis seen with vitamin E "is a small step forward in a very important area."

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, as well as the National Institute of Child Health & Human Development.

Vitamin E was provided by Pharmavite.

The researchers reported no conflicts of interest.

Primary source: American Association for the Study of Liver Disease

Source reference:
Lavine JE, et al "Vitamin E, metformin, or placebo treatment of nonalcoholic fatty liver disease in children" AASLD 2010; Abstract 110.

Source
November 02, 2010 09:00 AM Eastern Daylight Time

Covalent Inhibition Achieves Superior Potency Against Drug-Resistant HCV Mutants

BOSTON & WALTHAM, Mass.--(BUSINESS WIRE)--Avila Therapeutics™, Inc., a biotechnology company developing novel targeted covalent drugs, presented results today of preclinical studies that demonstrate its orally-available targeted covalent drug candidate, AVL-192, achieves superior potency against drug-resistant mutations of the Hepatitis C Virus (HCV). These new data were presented today at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) international meeting in Boston, Massachusetts.

HCV protease (also known as NS3) is a promising target of intervention for the treatment of hepatitis C infection. However, medicines currently in late stages of clinical development are vulnerable to drug-resistant mutations. AVL-192 is a novel, orally available compound that can rapidly and completely silence the HCV protease through highly selective, irreversible covalent bonding to the target protein. Preclinical data have demonstrated that AVL-192 achieves very high potency and selectivity for NS3 and also potently and effectively inhibits the drug-resistant mutations observed clinically.

Avila’s covalent approach to silencing the NS3 protein has resulted in a product candidate with a potential best-in-class profile due to the ability to retain potency against clinically-arising resistance mutations, and potential breadth of activity across HCV genotypes with anticipated once-per-day dosing.

In a poster presentation at the meeting, entitled, “Second Generation of Covalent Irreversible Inhibitors Have Superior Potency Across Genotypes and Drug Resistant Mutants,” data were presented from preclinical studies that evaluated the efficacy of AVL-192 in biochemical and cell culture studies. Highlights of the data demonstrate:

• AVL-192 has a time-dependent mode of action that delivers potent and rapid inhibition of WT NS3/4A and retains high potency against drug-resistant mutant NS3/4A proteases;

• AVL-192 is able to inhibit the protease long after the compound is removed, offering the benefit of less frequent dosing;

• AVL-192 as monotherapy can be curative in the replicon clearance assay;

• AVL-192 is highly selective and spares host proteases; and

• AVL-192 has high plasma exposure following oral administration in rats and dogs.

“These new data reinforce our belief that our targeted covalent drug candidate AVL-192 has the potential to be a best-in-class, pan-genotype HCV therapeutic due to its unique mechanism of action,” said Juswinder Singh, Ph.D., Avila’s Founder and Chief Scientific Officer.

About Avila Therapeutics™, Inc.

Avila focuses on design and development of targeted covalent drugs to achieve best-in-class outcomes that cannot be achieved through traditional chemistries. This approach is called “protein silencing”. The company’s product pipeline has been built using its proprietary Avilomics™ platform and is currently focused on viral infection, cancer and autoimmune disease. Avila is funded by leading venture capital firms: Abingworth, Advent Venture Partners, Atlas Venture, Novartis Option Fund, and Polaris Venture Partners. For additional information, please visit http://www.avilatx.com/.

Contacts
For Avila Therapeutics, Inc.
Adriana Jenkins, 617-744-1713
adriana@theyatesnetwork.com

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Mortality Rates from Liver Diseases Underestimated, Researchers Say

ScienceDaily (Nov. 1, 2010) — Statistics from the Centers for Disease Control and Prevention (CDC) rank mortality related to chronic liver disease and cirrhosis as the 12th most common cause of death in adults in the U.S. Using a modified definition that includes diseases such as viral hepatitis, liver cancer and obesity-related fatty liver disease (liver diseases), Mayo Clinic-led researchers have found that liver-related mortality is as high as fourth for some age groups, and eighth overall.

The findings are being presented November 1at the American Association for the Study of Liver Diseases 61st Annual Liver Meeting in Boston.

"The methodology that the CDC uses to define liver-related mortality is somewhat limited," says W. Ray Kim, M.D., a gastroenterologist with Mayo Clinic. "They only look at a certain diagnostic code, and deaths due to other facets of liver disease are not included.

"There are a large number of people with hepatitis C in the U.S. They are getting older and experiencing complications. Also, associated with the 'obesity epidemic,' a large number of individuals have fatty liver disease. Some go on to develop end-stage liver disease, cirrhosis, or liver cancer. In order to discover the true impact of liver disease on the population, we analyzed mortality data using these more comprehensive criteria."

The research team examined data from the CDC's national death registry for deaths among adults during 1979-2006 and compared their results to statistics from the Rochester Epidemiology Project, a long-term, collaborative medical records project among health care providers in Olmsted County, Minn.

"We had a good correlation between the national statistics and the Olmsted County mortality data," says Dr. Kim. "Of course, the most common cause of death for adults is cardiovascular disease and cancer. However, we found that liver disease is not far behind in terms of being No. 4 for people between the ages of 45 and 64 years."

Dr. Kim says that obese people and those with hepatitis C need to be watched especially closely for liver disease as part of their overall medical management program. "Liver disease is an important cause of morbidity and mortality in the U.S. -- more than we have recognized in the past -- and as physicians, we need to be aware of that," he says.

Co-authors of the study include Sumeet Asrani, M.D.; Patrick Kamath, M.D.; Rachel Pedersen; Jennifer St. Sauver, Ph.D.; and Terry Therneau, Ph.D., all of Mayo Clinic; and Barbara Yawn, M.D., of Olmsted Medical Center in Rochester.

Source
Nov. 2, 2010, 7:00 a.m. EDT

ATLANTA, Nov 02, 2010 (BUSINESS WIRE) -- Inhibitex, Inc. /quotes/comstock/15*!inhx/quotes/nls/inhx (INHX 1.87, -0.12, -6.03%) announced today that three posters describing preclinical data on INX-189, the Company's nucleotide polymerase inhibitor in clinical development for the treatment of chronic hepatitis C (HCV) infections, will be presented by various scientists from the Company at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, MA. The full abstracts can be viewed at the AASLD website at http://www.aasld.org/.

The three posters will be presented during the HCV Therapy: Preclinical and Early Clinical Development Poster Session, today, November 2, 2010, from 7:00 am - 12:00 pm. The posters are as follows:

#1888; Kolykhalov et al., "Characterization of in vitro selected Hepatitis C Virus Replicon Mutants Resistant to the Phosphoramidate Analog of 2'-C-Methylguanosine, INX-189"

#1874; Hall et al., "Metabolite Characterization of INX-189, a Potent HCV Inhibitor, in Fresh Human Primary Hepatocytes and Human Liver and Kidney Cell Lines"

#1889; Vernachio, et al. "In Vitro and In Vivo Metabolism of INX-189, a Potent HCV Inhibitor, in Rat and Cynomolgus Monkey Hepatocytes"

About Inhibitex

Inhibitex, Inc., a biopharmaceutical company focused on developing products to prevent and treat serious infectious diseases. The Company's pipeline includes FV-100, which is in Phase II clinical development for the treatment of shingles, and INX-189, a nucleotide polymerase inhibitor in development for the treatment of chronic hepatitis C infections. The Company also has additional HCV nucleotide polymerase inhibitors in preclinical development and has licensed the use of its proprietary MSCRAMM(R) protein platform to Pfizer for the development of staphylococcal vaccines. For additional information about the Company, please visit http://www.inhibitex.com/.

Inhibitex(R) and MSCRAMM(R) are registered trademarks of Inhibitex, Inc.

SOURCE: Inhibitex, Inc.

Inhibitex, Inc.
Russell H. Plumb, 678-746-1136
Chief Executive Officer
rplumb@inhibitex.com
or
The Trout Group
Lee M. Stern, CFA, 646-378-2922
lstern@troutgroup.com

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