April 27, 2013

Cardio Could Hold Key to Cancer Cure

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Virtual Press Office

26 April 2013

Amsterdam, The Netherlands, Friday 26 April 2013: Regular exercise has been proven to reduce the chance of developing liver cancer in a world-first mice study that carries hope for patients at risk from hepatocellular carcinoma (HCC).

The research announced at the International Liver Congress™ 2013 involved two groups of mice fed a control diet and a high fat diet then divided into separate exercise and sedentary groups.[1] The exercise groups ran on a motorised treadmill for 60 minutes per day, five days a week.

After 32 weeks of regular exercise, 71% of mice on the controlled diet developed tumours larger than 10mm versus 100% in the sedentary group. The mean number and volume of HCC tumours per liver was also reduced in the exercise group compared to the sedentary group.

EASL’s Educational Councillor Prof. Jean-Francois Dufour said the data showed the significant benefit of regular exercise on the development of HCC. Exercise decreased the level of non-alcoholic fatty liver disease in mice receiving a high-fat diet. He said: “We know that modern, unhealthy lifestyles predispose people to non-alcoholic fatty liver disease which may lead to liver cancer; however it’s been previously unknown whether regular exercise reduces the risk of developing HCC. This research is significant because it opens the door for further studies to prove that regular exercise can reduce the chance of people developing HCC.”

Prof. Jean-Francois Dufour added: “The results could eventually lead to some very tangible benefits for people staring down the barrel of liver cancer and I look forward to seeing human studies in this important area in the future. The prognosis for liver cancer patients is often bleak as only a proportion of patients are suitable for potentially curative treatments[ii] so any kind of positive news in this arena is warmly welcomed.”

HCC is a cancer originating in liver cells and is one of the most common types of tumour. Worldwide, HCC accounts for approximately 5.4% of all cancers[iii] and causes 695,000 deaths per year[iv], including 47,000 deaths in Europe per annum.[v] It is the fifth most common cause of cancer in men and the eighth most common cause in women.

Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2013.

- Ends -

Notes to Editors

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL’s main focus on education and research is delivered through numerous events and initiatives, including:

  • The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide
  • Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year
  • Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology
  • Journal of Hepatology published monthly
  • Participation in a number of policy initiatives at European level

About The International Liver CongressTM 2013

The International Liver Congress™ 2013, the 48th annual meeting of the European Association for the study of the Liver, is being held at the RAI Convention Centre in Amsterdam from April 24 – 28, 2013. The congress annually attracts in excess of 9000 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

For further information on the studies, or to request an interview, please do not hesitate to contact the EASL Press Office on:

Email: easlpressoffice@cohnwolfe.com

Dimple Natali +44 7900 138 904

Courtney Lock +44 7894 386 422

References

[1] A.C Piguet, EFFECT OF REGULAR TRAINING ON HEPATOCELLULAR CARCINOMA DEVELOPMENT IN HEPATOCYTE-SPECIFIC PTEN-DEFICIENT MICE. Abstract presented at the International Liver CongressTM 2013.

[ii] Hepatocellular Carcinoma. Wikipedia. Available at http://en.wikipedia.org/wiki/Hepatocellular_carcinoma. Accessed 04.04.12.

[iii] Kumar Vinay, Nelso Fausto and Abul Abbas. Robbins & Cotran Pathologic Basis of Disease, 7th ed. Saunders; 2004.

[iv] Cancer fact sheet. World Health Organisation. February 2006.

http://www.who.int/mediacentre/factsheets/fs297/en/ accessed 04.04.12

[v] EU Burden of Liver Disease: A review of available epidemiological data. European Association for the Study of the Liver Disease. 2013. http://www.easl.eu/assets/application/files/54ae845caec619f_file.pdf . Accessed 26.02.13.

Source

HIV Drug Combo Shows Promise in Hepatitis B

By Michael Smith, North American Correspondent, MedPage Today

Published: April 27, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

AMSTERDAM -- A drug combination widely used in HIV treatment can suppress hepatitis B (HBV) in patients whose immune systems tolerate the virus, a researcher said here.

After 4 years, 76% of patients taking tenofovir and emtricitabine had suppressed the virus, with no resistance and a good safety profile, according to Edward Gane, MD, of Auckland City Hospital in Auckland, New Zealand.

That was significantly more (P=0.016) than the 55% who suppressed the virus while taking tenofovir alone, Gane reported at the meeting of the European Association for the Study of the Liver (EASL).

But "disappointingly" few patients managed to restore their immune response to the virus and those who stopped the therapy after the trial saw their viral loads rebound to earlier levels, Gane said.

Patients in the so-called "immune-tolerant" stage of HBV have high viral loads and no significant immune response; current guidelines do not recommend treatment, although previous studies have shown that tenofovir can suppress the virus.

Gane said it's still not clear whether those guidelines should be altered despite his findings, and urged that long-term prospective studies be conducted to see if the suppression of viral load reduces complications such as cirrhosis and liver cancer.

The researchers enrolled 126 HBV patients with HBV viral loads of at least 1.7 x 107 IU per mL of blood and normal levels of alanine aminotransferase.

They were randomly assigned to daily tenofovir and a placebo or tenofovir and emtricitabine.

The primary endpoint was the proportion of patients who reached a viral load of less than 69 IU per mL, and secondary endpoints included loss of the HBV e antigen (HBeAg) and the development of antibodies to the antigen (HBeAg seroconversion).

A substantial number of people reached the primary endpoint -- 35 of 64 in the tenofovir arm and 47 of 62 in the combination arm -- and even among those with continuing viremia, there were no resistance mutations, Gane reported.

But only five participants had HBeAg loss and only three seroconverted. Also, no patients had a loss of the viral surface antigen (HBsAg) -- a sign of infection -- and none developed antibodies to the antigen.

About half of the patients stopped therapy after the study and all saw their viral loads rebound to pre-study levels within 24 weeks, Gane said.

The study is "very important," commented Fabien Zoulim, MD, PhD, of Hôtel Dieu Hospital in Lyons, France, who was not involved in the research. Zoulim moderated an EASL press conference.

"But it's a first step," he told MedPage Today. "We have shown we can suppress the virus. Next step: Can we prevent some disease outcomes?"

He noted that guidelines leave open the option of treating selected immune-tolerated patients such as those with a family history of cirrhosis or liver cancer. "Now we have more data, so we'll be more confident when we have this type of patients," he said.

The study was supported by Gilead. Gane reported financial links with Gilead, Janssen-Zilag, Novartis, AbbVie, Roche, and Vertex.

Zoulim reported financial links with BMS, Gilead, and Roche.

Primary source: European Association for the Study of the Liver
Source reference:
Chan HL, et al. "Tenofovir DF (TDF) compared to emtricitabine (FTC)/TDF in HBEAG-positive, chronic hepatitis B (CHB) virus-infected patients in the immune tolerant (IT) phase" EASL 2013; Abstract 101.

Source

Novel screening tests for liver cancer

Public release date: 26-Apr-2013

Contact: Dimple Natali
easlpressoffice@cohnwolfe.com
44-790-013-8904
European Association for the Study of the Liver

Amsterdam, The Netherlands, Friday 26 April 2013: New data from two clinical trials presented today at the International Liver Congress™ 2013 demonstrate substantial improvements in the detection of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) using diagnostic urine tests.

HCC is common throughout the world and most often develops as a late complication of chronic viral hepatitis or cirrhosis of any cause. The overall survival rate of HCC is poor and so screening for HCC offers the best hope for early detection, eligibility for treatment, and improved survival. While effective therapies exist, the available screening tests to detect HCC – alpha-fetoprotein (AFP) and ultrasound – are reported to have low sensitivity and specificity (50–85% and 70–90%, respectively).

Preliminary data demonstrate the performance of urinary metabolites in helping to diagnose HCC. Urine samples were collected from four subject groups in West Africa on the case-control platform of PROLIFICA 'Prevention of Liver Fibrosis and Carcinoma in Africa' as follows: patients with HCC (n=65), cirrhosis (Cir, n=36), non-cirrhotic liver disease (DC, n=110) and healthy controls (NC, n=91). HCC patients were diagnosed using EASL guidelines.

Multivariate analyses of urinary nuclear magnetic resonance (NMR) spectra showed a distinct profile for urine of patients with HCC compared to Cir, DC and NC with sensitivity of 87%, 86% and 97% respectively. These results suggest that Urinary metabolite profile outperforms serum AFP which only differentiated HCC from these groups by 79% (Cir), 75% (DC) and 76% NC) respectively. The metabolites that were significantly increased (p< 0.001) in HCC patients compared to all groups of control were methionine, acetylcarnitine, carnitine, N-acetylglutamate, 2-oxoglutarate, indole-3-acetate, and creatine; whereas creatinine was significantly lower in HCC than controls.

EASL General Secretary, Prof. Mark Thursz commented: "These findings will be welcomed by physicians as they validate urinary metabolic profiling as a potential screening tool for HCC, with superior diagnostic accuracy to serum AFP and – if investigated further and put into practice – this non-invasive technique could simplify and improve clinical diagnosis and outcomes for patients."

Similarly, detection of CC remains a diagnostic challenge and physicians will be encouraged by results from a Phase II study showing that a combined bile and urine proteomic test increased diagnostic accuracy of CC in patients with biliary strictures (an abnormal narrowing of the common bile duct) of unknown origin.

Having recently established diagnostic peptide marker models in bile and urine to detect both local and systemic changes during CC progression, investigators combined both models with the aim of reaching a higher diagnostic accuracy.

The data demonstrated this model enables impressive CC-diagnosis with an accuracy of more than 90% that is most applicable for patients with biliary strictures of unknown origin referred to endoscopy.

Prof. Mark Thursz added: "These important findings substantially improve the diagnosis of CC and may lead to early therapy and improved prognosis. Overall both data sets demonstrate the increasing value of proteomic and metabonomic techniques and if confirmed by further investigation, clinicians may soon be using simple urine dip-stick tests to diagnose HCC and CC."

A logistic regression model composed of the bile and urine proteomic classification factors lead to an area under curve (AUC) of 0.96, and 92% sensitivity and 84% specificity at the best cut-off. Only three of the 36 CC patients were false negative and two of the 33 PSC patients were false positive classified. Inclusion of CA19-9 and bilirubin values to the logistic regression model was of minor benefit.

Cholangiocarcinoma or bile duct cancer is rare and almost always adenocarcinoma which starts in the lining of the bile duct. The cause of most cholangiocarcinomas is unknown but people with chronic inflammatory bowel conditions or congential abnormalities of the bile duct have a higher risk of developing the cancer.

Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2013.

###

Notes to Editors

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL's main focus on education and research is delivered through numerous events and initiatives, including:

  • The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide
  • Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year
  • Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology
  • Journal of Hepatology published monthly
  • Participation in a number of policy initiatives at European level

About The International Liver Congress™ 2013

The International Liver Congress™ 2013, the 48th annual meeting of the European Association for the study of the Liver, is being held at the RAI Convention Centre in Amsterdam from April 24 – 28, 2013. The congress annually attracts in excess of 9000 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

References:

1 De Masi S et al, Screening for hepatocellular carcinoma. Digestive and Liver Disease 2005;3(4): 219 300.

2 Ladep NG et al, URINARY METABOLIC PROFILE DISCRIMINATES HEPATOCELLULAR CARCINOMA BETTER THAN SERUM ALPHA FETOPROTEIN IN WEST AFRICANS. Presented at the International Liver Congress™ 2013

3 EASL Guidelines: Management of Hepatocellular Carcinoma. Available at http://www.easl.eu/_clinical-practice-guideline/issue-7-april-2012-management-of-hepatocellular-carcinoma [Accessed 11/4/13]

4 Metzger J, et al, A COMBINED BILE AND URINE PROTEOMIC TEST INCREASES DIAGNOSTIC ACCURACY OF CHOLANGIOCARCINOMA IN PATIENTS WITH BILIARY STRICTURES OF UNKNOWN ORIGIN. Presented at the International Liver Congress™ 2013

5 Macmillan Cancer Support. Bile duct cancer (cholangiocarcinoma). Available at http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Bileduct/Bileductcancer.aspx [Accessed 9/4/13]

Source

Interferon-free, triple-DAA regimen safe, effective for chronic HCV

April 26, 2013

Nearly all patients with chronic hepatitis C treated with an interferon-free drug regimen for 12 or 24 weeks experienced sustained virologic response in a study presented at the International Liver Congress in Amsterdam.

Researchers administered 100-200 mg HCV protease inhibitor ABT-450 (AbbVie) with 100 mg ritonavir (ABT-450/r) once daily to patients with chronic hepatitis C genotype 1, along with 25 mg NS5A inhibitor ABT-267 once daily and 400 mg non-nucleoside NS5B inhibitor ABT-333 twice a day, and weight-based ribavirin, for 12 or 24 weeks. The cohort included 79 12-week and 80 24-week recipients among treatment-naive patients, and 45 12-week and 43 24-week recipients among previous nonresponders. Patients were either treatment-naive or nonresponsive to prior pegylated interferon/ribavirin therapy.

Sustained virologic response (SVR) rates at 4 weeks among treatment-naive participants were 98.7% in the 12-week and 96.2% in the 24-week group. Among prior nonresponders, SVR4 rates were 93.3% in the 12-week and 97.7% in the 24-week groups.

Among treatment-naive patients, SVR12 was 99% in the 12-week and 93% in the 24-week group, while nonresponders experienced SVR12 in 93% of 12-week and 98% of 24-week cases. SVR24 was achieved by 96% of 12-week and 90% of 24-week treatment-naive participants and 93% of 12-week and 95% of 24-week nonresponders. Across the cohort, SVR was similar regardless of IL28B genotype, baseline HCV RNA levels, fibrosis stage and infection with HCV genotype 1a compared with 1b.

Commonly reported events included headache, fatigue, insomnia, diarrhea and nausea. Four patients withdrew from the study after experiencing serious adverse events.

“The consistency of high sustained viral response rates that we have seen in clinical trials across populations is encouraging, especially given the proportion of patients with these characteristics who have failed with interferon plus ribavirin treatment,” researcher KrisV. Kowdley, MD, director of research at the Digestive Disease Institute at Virginia Mason Medical Center in Seattle, said in a press release.

Phase 3 trials are under way for the 12-week regimen.

For more information:

Kowdley KV. #3: Safety and Efficacy of Interferon-Free Regimens of ABT-450/R, ABT-267, ABT333 ± Ribavirin in Patients With Chronic HCV GT1 Infection: Results From the Aviator Study. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam.

Source

Gilead-Bristol Hepatitis C Combo Cures 100% of Patients in Study

By Simeon Bennett

April 27, 2013

A combination of hepatitis C drugs from Gilead Sciences Inc. (GILD) and Bristol-Myers Squibb Co. (BMY) cured 100 percent of patients in a trial, showing the success of a cocktail that doctors say they want yet may never be approved.

In a study among 41 patients of Gilead’s sofosbuvir combined with Bristol’s daclatasvir, with or without the generic antiviral ribavirin, 40 had undetectable virus in their blood 12 weeks after finishing six months of treatment, according to results presented today at a meeting in Amsterdam. The other patient didn’t turn up to the last appointment and was later found to be virus-clear. Patients in both groups had failed prior treatment with either Vertex Pharmaceuticals Inc. (VRTX)’s Incivek or Merck & Co. (MRK)’s Victrelis.

The two companies have planned no further trials of the combo because Foster City, California-based Gilead is focusing on a cocktail that contains only its own drugs. The lack of a late-stage study, and the expense of the pills, will probably put the combination out of reach for doctors and patients, said Geoffrey Dusheiko, a professor of medicine at the Royal Free Hospital in London.

“It’s a conundrum for us,” Dusheiko said in an interview after the results were presented at the European Association For the Study of the Liver’s conference. “It looks a very promising regimen, it really does. But I’m really not sure it’ll see the light of day.”

‘Off-Label’ Option

Still, doctors may be tempted to prescribe the Gilead-Bristol combo “off-label” once both drugs are approved, said Mark Thursz, secretary-general of the European liver association.

“Lots of investigators around Europe and the U.S. are itching for the opportunity to put together what they believe to be the optimum combination for our patients,” Thursz said.“The only barrier to that is what is the combination cost going to be because I suspect there will be package deals to be had.”

The combination had previously demonstrated success in patients who hadn’t been treated before. Those who have failed Incivek or Victrelis are “perhaps the most difficult-to-treat population” and have no current options, said Mark Sulkowski, a doctor at Johns Hopkins University in Baltimore who presented the results.

Bristol-Myers, based in New York, was working on the combination with Pharmasset Inc., which developed sofosbuvir, when Gilead bought the company for $10.8 billion in 2011. Gilead subsequently focused on developing sofosbuvir in combination with its own drug, ledipasvir. That combination cured 100 percent of patients in a mid-stage patient study, and the company is testing it in two late-stage studies.

Genotypes

Still, while ledipasvir may be effective against patients with hepatitis C genotype 1, the most common form worldwide, it may not work for those with genotype 3, which accounts for about 25 percent of cases in Europe and 45 percent in the U.K., said Graham Cooke, a clinician at Imperial College London. Daclatasvir and sofosbuvir are both active in that group, he said.

“We probably have a better option for G3 that we could be using if the companies were cooperating,” Cooke said in an interview. “Daclatasvir and sofosbuvir looks much better but Gilead very clearly want to develop in-house.”

Prescribing the two drugs as an off-label combination may be too expensive because they’ll probably have high prices as individual therapies whereas Gilead’s cocktail may be cheaper, he said.

Off-label use may also be dangerous, said Jean-Michel Pawlotsky, a professor of medicine at the University of Paris-Est.

“We don’t have enough safety data,” Pawlotsky said in an interview. “If a doctor does that and there’s a major accident, the doctor is liable. It’s dangerous but I know that people will do it.”

Bristol-Myers agreed last week to study daclatasvir in combination with Merck’s MK-5172. This month it also agreed to test the drug together with Cambridge, Massachusetts-based Vertex’s VX-135.

To contact the reporter on this story: Simeon Bennett in Geneva at sbennett9@bloomberg.net

To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net

Source

Attention Baby Boomers: Get Screened for Hepatitis C

Released:4/26/2013 3:00 PM EDT
Source Newsroom: Association for Professionals in Infection Control and Epidemiology (APIC)

Newswise — If you were born during 1945-1965, talk to your doctor about getting tested for hepatitis C. Baby boomers are five times more likely than other adults to be infected. In fact, 75 percent of adults with hepatitis C were born during these years.

The word “hepatitis” means swelling of the liver. Hepatitis is most often caused by a virus. In the United States, the most common type of viral hepatitis is hepatitis C. Hepatitis C is primarily spread through contact with blood from an infected person. More than 15,000 Americans, most of them baby boomers, die each year from hepatitis C-related illness.

Deaths related to hepatitis C have been on the rise and are expected to increase. Hepatitis C is a leading cause of liver cancer and the leading reason for liver transplants. Other serious health problems related to hepatitis C include:

  • Liver damage
  • Cirrhosis
  • Liver failure

The reason that baby boomers have the highest rates of hepatitis C is not completely understood. Most boomers may have become infected in the 1970s and 1980s when rates of hepatitis C were the highest. Many baby boomers could have gotten infected from tainted blood and blood products before testing of the blood supply began in 1992. Others may have become infected from injecting drugs, even if only once in the past. Still, many baby boomers do not know how or when they were infected.

People with hepatitis C often have no symptoms and can live for decades without feeling sick. As baby boomers grow older, there is a greater chance that they will develop life-threatening liver disease from hepatitis C.

Risk factors for hepatitis infection include:

  • History of blood transfusions or other blood products (before July 1992)
  • Organ transplant before widespread testing for HIV and hepatitis (before July 1992)
  • Long-term dialysis treatment
  • Exposure to hepatitis C such as through a healthcare setting (healthcare needle sticks)
  • Infection with HIV, the AIDS virus
  • Children born to mothers who have hepatitis C
  • Any past use of injected illegal drugs
  • Having received a tattoo with needles that were not properly disinfected

The only way to know if you have hepatitis C is to get tested. Early detection can save lives. There is a simple blood test to determine if a person has ever been infected with the hepatitis C virus. It is estimated that one-time testing of everyone born during 1945 through 1965 will prevent more than 120,000 deaths.

Knowing your diagnosis early and getting treatment can help prevent liver damage, cirrhosis, and even liver cancer. There are no vaccines to prevent hepatitis C.

Many people who have been diagnosed with hepatitis C can be successfully treated with medications called antivirals. Two new medicines are now available (telaprevir and boceprevir), that when added to the standard treatment can increase the effectiveness and shorten treatment time for many people. For many people, medical treatment can result in clearing hepatitis C from the bloodstream.

Talk to your doctor about getting tested—it could save your life!

Additional resources:
http://www.cdc.gov/knowmorehepatitis/HepC-FAQ.htm
http://www.cdc.gov/features/HepatitisCTesting/index.html
http://www.cdc.gov/hepatitis/RiskAssessment/ (Take a quiz to find out if you're at risk for hepatitis C)
http://www.cdc.gov/knowmorehepatitis/infographic/index.htm
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm

Source

Sofosbuvir-Based Therapy for HCV Infection: The Results Are In

Published in Journal Watch Gastroenterology April 23, 2013

The evidence shows superior efficacy and tolerability of sofosbuvir-based regimens versus those currently available, particularly in patients with HCV genotype 1.

On the heels of the phase II trial results (JW Gastroenterol Apr 12 2013), phase III trial results are now available on sofosbuvir-based regimens for the treatment of chronic hepatitis C virus (HCV) infection in treatment-naive patients. The primary endpoint of the two industry-funded, phase III trials was sustained virologic response at 12 weeks after end of treatment (SVR12).

In the single-group, open-label NEUTRINO trial, 327 patients with HCV genotypes 1 (89%), 4 (9%), 5 (<1%), and 6 (2%) received oral sofosbuvir (400 mg daily), peginterferon (180 µg weekly), and ribavirin (1000–1200 mg daily) for 12 weeks. Among the study group, 17% were black, 71% had IL28B genotype TT or TC, and 17% had cirrhosis. SVR12 was 89% for genotype 1 (92% for genotype 1a and 82% for genotype 1b), 96% for genotype 4, and 100% for genotype 5 or 6. SVR12 was significantly lower for patients with cirrhosis versus without cirrhosis (80% vs. 92%) and for patients with IL28B genotypes TT or TC versus genotype CC (87% vs. 98%). SVR12 did not vary by race or Hispanic ethnicity.

In the open-label FISSION trial, 499 patients with HCV genotypes 2 and 3 were randomized to oral sofosbuvir (400 mg daily) and ribavirin (1000–1200 mg daily) for 12 weeks or peginterferon (180 µg weekly) and ribavirin (800 mg daily) for 24 weeks. Cirrhosis was present in 20% of the sofosbuvir group and in 21% of the control group. In the sofosbuvir group, SVR12 was 97% for genotype 2 and 56% for genotype 3 in the sofosbuvir group compared with 78% for genotype 2 and 63% for genotype 3 in the control group. Noninferiority analysis demonstrated similar efficacy between the two groups. Efficacy among patients with cirrhosis was similar between the sofosbuvir and control groups (47% vs. 38%).

In both studies, resistance did not develop with sofosbuvir treatment. Treatment discontinuation was only 1% to 2% in patients receiving 12-week sofosbuvir regimens with or without interferon compared with 11% in patients receiving the 24-week peginterferon/ribavirin regimen.

Comment: These final results of phase III trials of sofosbuvir in treatment-naive patients with hepatitis C virus genotypes 1 to 6 demonstrate that patients with genotype 1 have excellent treatment response that is superior overall to published response rates for combination therapy and currently available triple therapies. For patients with genotypes 2 and 3, efficacy was similar between an interferon-free sofosbuvir regimen and a standard peginterferon/ribavirin regimen. Furthermore, sofosbuvir is achieving sustained response with a shorter duration of therapy, better tolerability, and no resistance development. The sofosbuvir regimen has recently been submitted to the FDA and, once approved, will usher in the next generation of treatment for HCV infection. A phase III trial of sofosbuvir in patients coinfected with HIV and HCV is ongoing.

Atif Zaman, MD, MPH

Citation(s):

Lawitz E et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013 Apr 23; [e-print ahead of print]. (http://dx.doi.org/10.1056/NEJMoa1214853)

Source

Also See: Data from Phase 3 Studies of Gilead’s Sofosbuvir for Hepatitis C To Be Presented at 48th Annual EASL Meeting; Findings Published Online Today in The New England Journal of Medicine

Hepatitis C: Closing in on its viral origins

26 April 2013 Last updated at 21:17 ET

_67268964_c0134623-hepatitis_c_virus,_artwork-spl

The virus behind Hepatitis C has been the target of virologists, epidemiologists and geneticists for years, in a bid to find out the animal host from which it likely came. But Prof Jonathan Ball, a virologist at the University of Nottingham, UK, says early indications that bats are the culprit may yet be proven wrong.

The omnipresent bat represents around one fifth of mammal species, yet remains strangely enigmatic.

Known to be the source of a range of human viral infections such as Sars and ebola, a recent study published in PNAS suggests that bats are a large natural reservoir to groups of viruses similar to the hepatitis C virus (HCV).

HCV is a life-threatening infection affecting more than 150 million people worldwide and its origin has eluded scientists for years.

To define if bats were a possible source for HCV-like viruses, Phenix-Lan Quan from Columbia University in New York and her colleagues analysed the blood from hundreds of bats living in South America, Africa and Asia.

To expose any infectious payload that the bats carried, the team used a method called high-throughput sequencing, which surveys all of the genetic material - nucleic acids - present in their blood.

In amongst the bat DNA, in approximately 5% of the animals tested, they discovered novel genetic sequences that were similar to nucleic acid present in viruses belonging to two groups - or genera - called pegiviruses and hepaciviruses. HCV is a member of the hepacivirus genus.

Continue reading the main story

“Start Quote

My prediction is that we will find a range of bat and/or rodent species to be infected with viruses that represent the immediate source of human infections in those parts of Africa and South Asia where HCV seems to have originated”

End Quote Prof Peter Simmonds University of Edinburgh

To determine the evolutionary history and relatedness of these viruses, they performed computer analyses to build what is called a phylogenetic tree.

Unlike a family tree, which is built using archive records of significant events like births, deaths and marriages, phylogenetic trees use the historic record written into the sequence of information stored in nucleic acids.

During replication, virus genetic material changes, or mutates, and these mutations accumulate over time allowing the virus to evolve.

Determining the number of genetic differences that exist between viruses gives an idea of how related they are - the fewer the changes, the more closely related - and phylogenetic trees represent this genetic relationship.

Viruses located on connecting branches are most related and the shorter the branches, the more related they are.

In the pegivirus and hepacivirus tree constructed by Dr Quan, the branches leading to clusters of bat virus sequences were numerous and long, indicating that bats have long been infected by a great variety of strains; more so than humans.

The branching pattern of the phylogenetic tree can also provide a clue to the origins of HCV.

If bats are the source of this virus, then the HCV sequences should nestle amongst the branches of the bat hepaciviruses - and at first sight they do.

But before we designate the much-maligned bat as public enemy number one, is there sufficient evidence to suggest that these vital pollinators and insect predators are the direct source of deadly HCV?

Equine enigma

Scientists have used phylogenetic trees to identify the source of many viral infections.

A 2005 paper in Science showed that Sars passed from bats to civet cats then on to humans, and a 2010 Royal Society journal article reported that HIV arose following transmission from African primates.

The evidence supporting these particular animal-human transmissions - or zoonoses - is strong.

For example, in trees of virus sequences derived from extensive sampling of wild primate and monkey species, HIV is embedded firmly on the branch of the tree containing chimpanzee viruses. Genetically, HIV is most closely related to its chimpanzee counterparts and they are the most likely source.

In the hepacivirus tree, research in Emerging Infections Diseases has shown that HCV is more related to viruses found in horses and dogs than it is to those present in bats, but the branch leading to HCV is very long - it contains lots of genetic change and therefore long evolutionary timeframe.

A virus could have made the jump into humans millennia ago, but this unlikely.

The key to it all is in the virus sampling.

_67268956_c0138080-beccari_s_freetail_bat-spl

Initial studies suggested that the bat was responsible, but other suspects have now entered the line-up

Just as an identity parade is only useful if the guilty party is present, phylogenetic analysis can only identify the cause of a virus outbreak if the most probable source is included.

Although Dr Quan's analysis includes far more viral sequences than has been possible before, the hepacivirus and pegivirus line-up still contained very few suspects.

"Our findings shed new light on the deep evolutionary history of those viruses that ultimately resulted in HCV," Dr Quan explained.

"We show that all known hepaciviruses and pegiviruses - including primates, horses and dogs - fall within the phylogenetic diversity of the bat-derived viruses, suggesting a longer evolutionary history of these viruses in bats than in primates, horses or dogs."

Whilst Dr Quan believes that bats harbour the greatest array of these important viruses, she stops short of arguing that her data prove that bats are the source of HCV.

"With our current data, we cannot conclude whether or not bats are the 'ultimate' reservoir of hepaciviruses and pegiviruses, nor whether HCV came from bats," she said. "To be truly able to answer this question, you would need to study a far larger sample of potential reservoir hosts."

Of mice and men

And to prove this point, a related study published in the journal mBio by a team led by Prof Amit Kapoor, also from Columbia University in New York, reported that numerous species of rodents also harbour hepacivirus and pegiviruses.

Just like the bat viruses, these too exhibited a large degree of genetic variability, hinting at an enduring history of infection.

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Future studies could see rodents emerge as the confirmed source of the virus

None of the rodent sequences was more related to HCV than the horse hepaciviruses, but one of the co-authors of this study, Prof Peter Simmonds from the University of Edinburgh, thinks that the large degree of variability observed in these rodent viruses might prove significant.

"It seems as though different bat and rodent species carry a remarkably diverse range of HCV-like viruses," he said.

"None of these are very close genetically to HCV, but with such limited sampling, it certainly remains possible that other variants exist in other species that match HCV more closely."

Although leaving open the possibility that other animals might be the source of HCV, he added: "My prediction is that we will find a range of bat and/or rodent species to be infected with viruses that represent the immediate source of human infections in those parts of Africa and South Asia where HCV seems to have originated. It's difficult to know what those species are, when and how such species jumps occurred."

So, despite recent growth spurts, the hepacivirus and pegivirus phylogeny is still more of a sapling than a fully grown tree.

Extensive virus sampling from global mammalian species will add further branches and bring us closer to understanding the origin of HCV.

Bats and rodents have been around for more than 50 million years, so it's no surprise they've picked up one or two viruses in their travels.

Some of these, driven by habitat encroachment and human activity, have undeniably passed into humans.

But whether HCV arose from bats or rodents remains to be seen.

Source

Obesity Plus Drinking Worst Combo for Liver

By Michael Smith, North American Correspondent, MedPage Today

Published: April 26, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM – Obesity and heavy drinking are each known risk factors for liver disease, but together they appear to be even worse, researchers said here.

Analysis of a large population-based cohort of women in England showed that the risk of liver cirrhosis and decompensation was markedly increased if participants were either obese or heavy drinkers, according to researchers led by William Rosenberg, MBBS, DPhil, of the University College London.

But the combination of the two was "super-additive," Rosenberg told MedPage Today during the meeting of the European Association for the Study of the Liver, more than doubling the risk seen with either of the other risk factors (P<0.001).

"At first glance, (the study finding) doesn't seem very surprising," he said.

But the analysis of 108,000 women ages 50 to 75 taking part in a cancer screening trial is the largest to look at the incidence of advanced liver disease in the context of overweight and alcohol use.

And it did find one surprise, Rosenberg said: that being overweight and being obese have different effects when combined with alcohol use.

In women who were overweight and drank, the two risks simply added up, but in those who were obese – usually defined as a body mass index (BMI) of 30 or higher – the risks were synergistic.

"If you're obese, the damage you can do to yourself (by drinking heavily) is much greater than if you're just overweight," Rosenberg said.

Among the 108,000 women in the analysis, there were 616 events of advanced liver disease over a median follow-up of 9.4 years, the researchers found.

Women with a low body mass index who also had low alcohol intake were at the lowest risk, with a cumulative hazard of less than 0.001. Those who had a high BMI but drank lightly had a similar but slightly higher hazard, they found.

Slimmer women who drank heavily had about double the hazard of those who were low in both categories, but heavy drinkers with a high BMI had a cumulative hazard of greater than 0.004.

"The public health message is enormously important," Rosenberg said. "People are not aware that they are putting themselves at this risk."

The study should be viewed in the context of common heavy drinking in Europe and a 10-fold increase in death from cirrhosis among middle-age women in England from 1970 to 2000, commented Daniele Prati, MD, of the Ospedale Alessandro Manzoni in Lecco, Italy, who was not involved in the study but who moderated a press conference at which some details were discussed.

Prati told MedPage Today that the findings are not surprising, but it's important to see that they've been established in a large population.

Now, it's up to governments to "sensitize the population about risk," he said.

The UKCTOCS study has support from the MRC, Cancer Research UK and National Health Service. Trembling and Rosenberg did not report any additional support or make any disclosures.

Prati reported financial links with Roche, BMS, Novartis, and AbbVie.

Primary source: European Association for the Study of the Liver
Source reference:
Trembling PM, et al "Influence of BMI and alcohol on liver-related morbidity and mortality in a cohort of 108,000 women from the general population from UKCTOCS" EASL 2013; Abstract 115.

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Liver Imaging Tests Vie to Replace Biopsy

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By John Gever, Deputy Managing Editor, MedPage Today

Published: April 26, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM -- Although biopsy remains the gold standard for diagnosing liver fibrosis, imaging tests increasingly appear to be a viable way to garner equivalent information with less patient discomfort and risk, researchers said here.

In presentations at the meeting of the European Association for the Study of the Liver, scientists from across Europe reported on the strengths and weaknesses of various imaging modalities as tools for routine clinical practice.

There was no clear winner among transient elastography, magnetic resonance elastography (MRE), real-time shear wave elastography (RTSWE), and acoustic radiation force impulse (ARFI) imaging, but all appeared to be nearly as accurate as liver biopsy in quantitative assessment of fibrosis and for predicting outcomes such as death and cirrhotic decompensation.

The role of liver imaging for these purposes in the U.S. has recently come to the fore with the FDA's clearance last week of the Fibroscan transient elastography device. Fibroscan is the established leader in noninvasive fibrosis imaging and, according to its French manufacturer, Echosens, the U.S. is the last major market to approve its device.

All these forms of elastography work by setting up shear waves in the liver. Patterns of propagation of these waves correspond to the degree of liver stiffness, which in turn correlates with the level of fibrosis. All but MRE use ultrasound to generate the waves.

Studies presented here evaluated one or more of these technologies against another, with or without liver biopsy as a reference standard, and in a variety of patient populations.

Transient Elastography Versus Biopsy

Perhaps the most direct assessment was reported by Juan Macias, MD, of Hospital Universitario de Valme in Seville, Spain. He reported a retrospective analysis of 297 patients coinfected with HIV and hepatitis C virus (HCV) who had been tested with liver biopsy as well as transient elastography, with these tests performed within a year of each other. The study period covered 2005 to 2011.

Findings indicated that fibrosis stage as established from biopsies and liver stiffness measurements from transient elastography were equally accurate in predicting overall mortality and decompensation of cirrhosis.

Kaplan-Meier curves for patients with stage F4 fibrosis (overt cirrhosis) and for those with elastography measurements in the highest quintile (21 kPa and above) were nearly identical through up to 6 years of follow-up, for both all-cause death and for decompensation of cirrhosis, Macias reported.

Point estimates of the increased risk for these outcomes were somewhat higher in models based on biopsy findings than in the elastography-based analyses, but the error bars in the latter were markedly smaller.

For example, the risk of decompensation doubled with each increase in fibrosis stage (hazard ratio 2.00, 95% CI 1.32 to 3.00), whereas each 5-kPa increase in liver stiffness corresponded to a hazard ratio of 1.42 (95% CI 1.31 to 1.55).

"The noninvasive nature of [transient elastography] should favor its use instead of liver biopsy when the only issue is predicting the clinical outcome of liver disease in HIV-HCV coinfection," Macias told attendees.

ARFI Versus Transient Elastography

Acoustic radiation force impulse imaging is another up-and-coming imaging method for liver disease. Like transient elastography, it uses ultrasound to generate mechanical waves within the liver, but the nature of the waves and the interpretation of the resultant patterns differs.

Derek Bardou of CHU Angers in Angers, France, noted that the two technologies have been compared head-to-head in previous studies, with pooled data suggesting that ARFI is less accurate.

But transient elastography has a significant drawback -- it doesn't work on obese patients. Bardou pointed out that the previous analyses were all conducted on a per-protocol basis, such that patients for whom the transient elastography attempt failed to yield usable results were excluded.

He argued that a more stringent "intent-to-diagnose" analysis would be a better reflection of the utility of the two methods in routine practice.

From 2009 to early 2013, he and his colleagues used both methods on a total of 267 patients with chronic, noncancerous liver disease (patients with cirrhotic complications or sepsis were excluded) who also underwent liver biopsies. Areas under the receiver-operating characteristic (AUROC) curves for classifying patients' liver disease stage were calculated for both test types, with biopsy results serving as the reference standard.

The researchers found that, on a per-protocol basis, AUROC values with ARFI were indeed lower -- indicating poorer accuracy -- than those seen with transient elastography. In this analysis, Bardou and colleagues excluded 6.7% of patients in whom transient elastography could not be performed. ARFI failed in fewer than 1%.

But in the intent-to-diagnosis analysis involving all 267 patients, there was no significant difference in AUROC values for the two methods.

Bardou added that whole-liver results with ARFI were more accurate than findings only in the right lobe, the "classical" way to perform ARFI, he explained.

RTSWE Versus Transient Elastography Versus Biopsy

Another study reported here sought to validate real-time shear wave elastography as an alternative -- not necessarily superior -- to liver biopsy.

Giovanna Ferraioli, MD, of Italy's University of Pavia, presented findings from 88 patients with chronic liver disease of varied origin and 33 healthy controls.

Patients underwent both RTSWE (using the ElastPQ system) and transient elastography as well as biopsy. The controls had only the noninvasive testing.

RTSWE, in this study, involved a fixed "sample box" located a maximum of 70 mm below the Glisson's capsule within the liver. Patients held their breath for 2 to 4 seconds and 10 images were collected, with the median stiffness value in kPa used as the final result. As the name suggests, and unlike transient elastography, RTSWE delivers readings almost immediately. In some studies, it has appeared to be more accurate as well.

Both imaging methods showed stiffness values that progressed upward with the degree of fibrosis ascertained with the biopsies. RTSWE yielded somewhat more detail, in that the median values for each patient group stratified according to fibrosis stage (F0/1 to F4) tracked steadily higher. Transient elastography results for patients with F2 fibrosis, on the other hand, were nearly identical to those with F0/1 disease (5.45 versus 5.5 kPa).

Ferraioli and colleagues found that, as expected, RTSWE values in the healthy controls were lower than in patients with liver disease (median 3.3 kPa, interquartile range 3.7 to 4.0).

Transient elastography readings tended to be higher (median 3.8 kPa, interquartile range 4.5 to 5.0) and overlapped in the controls with those from patients with liver disease (median in F2 patients 5.45, interquartile range 4.3 to 8.0).

RTSWE "compares favorably" with transient elastography, Ferraioli concluded.

MR Elastography Versus Biopsy

Use of MRI equipment to analyze liver stiffness is an even newer approach. It, too, can be used to generate vibrations that propagate through the liver. Rocio Gallego-Duran, also of the Hospital Universio de Valme, reported on a validation study in which artificial neural networks were used to generate elastography values from MRI scans.

Her study involved 63 patients with biopsy-confirmed non-alcoholic fatty liver disease, including 32 with non-alcoholic steatohepatitis (NASH) and 25 with significant fibrosis.

The first 22 of these patients were used as a "training cohort" for fine-tuning the software settings to match biopsy results as closely as possible. The resulting model was then tested in the remaining 41 patients, serving as a validation cohort.

For diagnosing NASH, the model showed sensitivity of 77% and specificity of 90%, Gallego-Duran reported. Positive and negative predictive values were 89% and 79%, respectively.

The model was not quite as good at diagnosing fibrosis. With the best-performing cutoff values, sensitivity was 87% but specificity was only 63%. As a result, the positive predictive value was just 59%, although the negative predictive value was a respectable 89%.

Gallego-Duran told attendees that the MRI-based technique holds some potential advantages over the ultrasound-based methods. Because it produces high-resolution images of the entire liver, it may provide a fuller picture of liver disease and can also reveal other types of liver injury. Patients' body fat also is not an issue for image quality, as it is for transient elastography, she said.

None of the studies had commercial funding.

All of the presenters declared that they had no relevant financial interests.

Primary source: European Association for the Study of the Liver
Source reference:
Macias J, et al "Performance of liver stiffness compared with liver biopsy to predict survival and decompensations of cirrhosis among HIV/HCV-coinfected patients" EASL 2013; Abstract 20.

Additional source: European Association for the Study of the Liver
Source reference:
Bardou D, et al "First intention-to-diagnose comparison of ARFI and Fibroscan in chronic liver diseases" EASL 2013; Abstract 15.

Additional source: European Association for the Study of the Liver
Source reference:
Ferraioli G, et al "Performance of ELASTPQ® shear wave elastography technique for assessing fibrosis in chronic viral hepatitis" EASL 2013; Abstract 16.

Source

Anemia Top Side Effect of HCV Antivirals

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 26, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM -- Two years after direct-acting antiviral drugs for hepatitis C virus (HCV) infection hit the U.S. market, anemia has been far and away their most significant adverse effect, researchers said here.

Outcomes in more than 1,400 U.S. patients taking a HCV protease inhibitor in routine practice for chronic infection indicated that more than half had experienced anemia, whether they received boceprevir (Victrelis) or telaprevir (Incivek), according to Michael W. Fried, MD, of the University of North Carolina in Chapel Hill.

Triple therapy with one of these drugs plus ribavirin and pegylated interferon is now the standard of care for HCV genotype 1.

Although severe skin rashes have been telaprevir's most talked-about side effect, prompting the FDA to add a boxed warning to the drug's label, severe anemia was much more common. Of the 1,082 patients in the study taking telaprevir, 27 showed severe anemia, compared with five patients developing severe rash, Fried and colleagues found.

Among 344 patients on boceprevir, six developed severe anemia.

These data were collected by a consortium of 44 academic centers and 59 community-based clinics in the U.S., which have sought to enroll all patients receiving these drugs. The only exclusion criteria were consent refusal or participation in another study of HCV therapies.

Beyond that, clinicians were free to prescribe dosing regimens and manage adverse effects according to their own judgment.

Anemia in most patients was treated mainly by reducing ribavirin dosages, for patients with cirrhosis as well as those without (65% and 54%, respectively).

Clinicians resorted to erythropoietin-type drugs in 13% of cirrhotic patients and 19% of those with no cirrhosis. Transfusions were given to 17% and 8% of cirrhotic and noncirrhotic patients, respectively.

Baseline cirrhosis was a significant risk factor for severe anemia and premature discontinuation of treatment. Fried and colleagues found odds ratios of 1.5 to 2.2 (all P<0.05) for risk of these outcomes as well as for any serious adverse event and for early discontinuation attributed to adverse effects.

Some 11% of the 550 patients with cirrhosis developed decompensation on treatment, compared with 1% of noncirrhotic patients.

Fried and colleagues also found virologic response rates in their patients to be similar to, if not better than, those seen during the drugs' clinical trials.

Patients taking telaprevir had HCV viral loads below the limits of detection or quantitation at rates of 91% to 96% at treatment week 12, depending on prior treatment history.

Corresponding data for boceprevir patients ranged from 63% to 87%.

About one-quarter of patients in the study stopped all therapy prematurely. Lack of efficacy and adverse events accounted for 35% and 40% of discontinuations, respectively.

At a press briefing, Laurent Castera, MD, of Centre Hospitalier Universitaire de Bordeaux in France, who was not involved with the study, said it was noteworthy in representing a real-world patient population, as opposed to the carefully selected samples enrolled in clinical trials.

Despite the broader mix of patients seen in the post-marketing study, Castera said the efficacy results were "comparable" to those seen in the two drugs' registration trials. Rates of anemia and other adverse events also tracked closely with previous trial results, in which some degree of anemia occurred with both drugs in half of patients.

The study was funded by Vertex, Merck, Kadmon, and Genentech.

Fried reported relationships with Genentech, Merck, Vertex, Gilead, Bristol-Myers Squibb, and Abbott.

Castera reported relationships with Bristol-Myers Squibb, Merck, Gilead, and Echosens.

Primary source: European Association for the Study of the Liver
Source reference:
Fried M, et al "HCV-TARGET: a longitudinal, observational study of North American patients with chronic hepatitis C (HCV) treated with boceprevir or telaprevir" EASL 2013; Abstract 818.

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PR-Logo-Newswire

PRESS RELEASE

April 26, 2013, 4:39 p.m. EDT

Gilead Sciences Leads the Way in Delivering the First All Oral Treatment for HCV

NEW YORK, April 26, 2013 /PRNewswire via COMTEX/ -- Citeline�, an Informa business unit, and the world's leading research authority on pharmaceutical clinical trials has just published an exclusive whitepaper examining the current progress towards a remarkable improvement in the medical treatment for HCV.

With news of the impending breakthrough in HCV treatment, Citeline reviews the current landscape of clinical trials and drugs in this competitive space as well as the recent history of HCV-related financial deals. In addition the whitepaper takes a look at the timing of current Phase III trials evaluating all oral regimens to determine how long Gilead may be the sole player in this space.

Based on information in Citeline's clinical trial intelligence tool, Trialtrove�, 83% of the 200 planned and ongoing Phase I-III clinical trials for pipeline HCV drugs (excluding vaccines) are being conducted by 10 companies; these 10 companies, including Bristol-Myers Squibb, Gilead, Merck and AbbVie, among others, are the focus of this report. Gilead leads in the number of Phase II trials and is conducting over twice as many as the next most active Phase II sponsor, Bristol-Myers Squibb.

According to Doro Shin, MPH, Citeline's Senior Analyst, Infectious & Genitourinary Diseases, "Gilead's lead in direct acting antiviral (DAA) agents for the treatment of HCV could lead to a shorter, oral, and interferon free treatment of the disease, with a dramatic reduction in unwanted side effects. This is truly a new era in HCV treatment. "

Moreover, in reviewing deals over the last five years we discovered between March 2008 and March 2013, there were a total of 18 HCV specific industry partnerships. In both years partnerships comprised of research and discovery and commercialization agreements occurred most frequently; however, three partnerships in 2012 also included licensing agreements. The complete report provides details of these partnership and M&A details including deal values.

"DAAs are clearly dominating in the HCV treatment field as evidenced by the clinical trial landscape and recent financial dealings," remarks Ms. Shin. "With these DAAs, the race is on toward the first interferon free HCV treatment regimen, but the contenders have entered themselves into different events to ensure that they get the gold."

To read this exclusive whitepaper - The race toward an interferon free world: The current field of HCV treatment research, including recent financial deals go to www.citeline.com/resource-center/whitepapers

About Citeline Citeline, Inc., an Informa company. Citeline is the world's most comprehensive source of real-time R&D and commercial intelligence featuring an unmatched data collection of global clinical trials, clinical trial investigator profiles, drug development pipelines and commercial intelligence.

Contact for Further InformationSean McIntoshDirector of MarketingCiteline Inc.52 Vanderbilt Ave7th FloorNew York, NY 10017212-520-2741sean.mcintosh@citeline.com www.citeline.com

SOURCE Citeline

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Stiff Spleen Predicts Decompensation in Cirrhotic Patients

Medscape Medical News > Conference News

Daniel M. Keller, PhD

Apr 26, 2013

Amsterdam, the Netherlands — In a multivariate analysis of compensated cirrhotic patients infected with hepatitis C virus, spleen stiffness and model for end-stage liver disease (MELD) score emerged as independent predictors of decompensation, leading investigators to develop a predictive model.

"In compensated hepatitis C–related cirrhotic patients, the proposed model…could replace hepatic venous pressure gradient for predicting portal-hypertension-related clinical decompensation," senior author Davide Festi, MD, from the University of Bologna in Italy, told delegates here at the International Liver Congress 2013.

Dr. Festi explained that the prognosis of compensated cirrhotic patients is strongly associated with the development of portal hypertension, and the gold standard for evaluating portal hypertension is the hepatic venous pressure gradient. However, it is an invasive technique that should be performed only by highly experienced operators. Potential complications include bleeding and supraventricular arrhythmias.

Noninvasive tests to predict portal hypertension include serum markers, ultrasonography, elastosonography, magnetic resonance elastography, and transient elastography (FibroScan). Elastography measurements correlate well with hepatic venous pressure gradient.

For their study, Dr. Festi and colleagues examined 85 patients with compensated hepatitis C–related cirrhosis and a normal body mass index. Median age was 59 years, just over half of patients had esophageal varices, and 66% were men.

After study participants were screened with transient elastography for liver and spleen stiffness, esophagogastroduodenoscopy, biochemical tests, abdominal ultrasonography, and hepatic venous pressure gradient, the investigators conducted clinical, biochemical, and ultrasound assessments every 6 months. If patients had a low risk for varices at baseline, they underwent esophagogastroduodenoscopy every 12 months. At follow-up, ascites, variceal bleeding, or hepatic encephalopathy were considered evidence of clinical decompensation.

At baseline, median aspartate aminotransferase and alanine aminotransferase values were each 56 U/L, platelet count was 109.5 × 103/L, median MELD score was 9, liver stiffness was 23 kPa, spleen stiffness was 56 kPa, and hepatic venous pressure gradient was 13 mm Hg. Median follow-up was 730 days. Five patients were lost to follow-up at 2 years, leaving 80 evaluable patients.

At 2 years, 26 of the 80 patients (32%) experienced clinical decompensation, and 11 (14%) experienced other events without decompensation (development of hepatocellular carcinoma, enlargement of varices, or spleen enlargement).

Model Predicts Chance of Decompensation at 2 Years

On multivariate analysis, independent predictors of clinical decompensation were spleen stiffness (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.04 - 1.13; P < .001) and MELD score (HR, 1.43; 95% CI, 1.07 - 1.91; P = .016). The investigators incorporated these 2 elements into an equation that predicted clinical decompensation at 2 years.

With an upper predicted-risk cutoff of 0.78, the model had a positive predictive value of 88% that a clinical decompensation event would occur within 2 years; with a lower cutoff of 0.2, the model had a negative predictive value of 97% that no event would occur within 2 years.

The investigators developed a decision algorithm for predicting decompensation. If spleen stiffness is less than 53.4 kPa, the patient has a 97% chance that no decompensation-defining event will occur within 2 years. If spleen stiffness is above 53.4 kPa, the equation they developed predicts decompensation with 88% accuracy.

After Dr. Festi's presentation, 2 audience members debated whether spleen stiffness results from congestion or fibrosis. In the end, there was no definitive resolution of the issue. However, regardless of the cause, the model stands.

The association between splenomegaly and portal hypertension has been known for years. "What is new is the idea of measuring spleen stiffness. So far what we have been measuring is spleen enlargement, which, along with platelet count, is usually a good sign of portal hypertension," session chair Laurent Castera, MD, from Hôpital Beaujon and the University of Paris in Clichy, France, told Medscape Medical News.

He explained that liver stiffness not only helps in the staging of liver fibrosis and the diagnosis of cirrhosis; it also helps determine prognosis. Recent studies have suggested that spleen stiffness correlates well with portal hypertension, "maybe even better than liver stiffness alone," he said. This model and algorithm "could be clinically useful because, although hepatic venous pressure gradient is a reference method for portal hypertension, it's only available in very few centers. For instance, in France, there are fewer than 5 centers.... So there's really a role for noninvasive methods to better diagnose and stage portal hypertension," Dr. Castera noted.

However, he advises caution when trying to draw conclusions from the study because of the limited number of patients involved and the short follow-up. Furthermore, from a technical standpoint, measuring spleen stiffness has its limitations "because, when using transient elastography, you cannot choose the region of interest. It's blind," he explained. "Also, it was not initially designed to measure spleen stiffness, but liver stiffness."

In addition, a limitation to measuring liver or spleen stiffness is obesity, which affects "around 20% of patients, at least in Europe, and possibly more in the United States," he said.

Dr. Castera cautions that at this point, the concept of using spleen stiffness is based on a single study. To establish relevant cutoffs and to validate the concept will require larger groups of patients and several independent studies.

With the increasing prevalence of compensated cirrhosis, especially from hepatitis C virus infection, but without signs of portal hypertension, such as varices, "what you want is an exam that is able to rule out very confidently the presence of varices," he noted. "The use of noninvasive methods may be useful because you would spare an invasive endoscopy exam."

Dr. Festi and Dr. Castera have disclosed no relevant financial relationships.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 22. Presented April 25, 2013.

Source

April 26, 2013

Gilead Sciences, Inc. (GILD) is set to take more market share of the hepatitis C space as the company develops HCV drugs with a duration of just under a year, and the potential to go even lower, providing a significant opportunity for GILD that could bring high rewards to investors, says David Ferreiro, Executive Director and Senior Analyst at Oppenheimer & Co. Inc.

“The company that I have the most conviction in within the biotech space is still Gilead (GILD), and they have a lot going on in their pipeline. The investor interests over the past year or more around the hepatitis C space, or HCV space, has been tremendous. And certainly Gilead has been leading that charge since they acquired Pharmasset early last year,” Ferreiro said.

FOR MORE INFORMATION ABOUT THIS INTERVIEW CLICK HERE.

There is considerable market opportunity in HCV due to a significant unmet medical need, large reservoir of patients and a lack of care standards, Ferreiro says. GILD is set to take more market share as it addresses the need to bring forth drugs that are more tolerable, have a shorter duration and are more efficacious, Ferreiro adds.

Gilead has few drugs in development that seem to work in a range of genotypes…the duration has moved down from just under a year, which is at the current standard of care to 12 to 24 weeks right now with the potential to go lower, so I’d say that’s probably the biggest opportunity out there for Gilead. We already understand this to be a huge opportunity, but there are ways that it can be bigger. For example, we are all still relatively conservative about how well new therapies can penetrate that market. I think that’s the unknown, and could bring much higher reward to the investor,” Ferreiro said.

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