October 23, 2010

Year Ahead in HCV: Changes In Store


Ted Bosworth

New Orleans—Physicians who treat hepatitis C virus (HCV) infection should prepare themselves for major changes in 2011. One of the most anticipated may be the introduction of direct-acting HCV antiviral drugs, which a series of clinical trials have shown to be highly effective when combined with pegylated interferon (PegIFN) and ribavirin.

Additionally, new methods of patient stratification prior to treatment not only will yield better prognostic information, but also are likely to alter therapeutic approaches regarding the potential benefits and risks of HCV therapy.

“There has been a lot of talk about individualized care, but individualized care will actually become the dominant approach in treatment of HCV,” said Mark S. Sulkowski, MD, medical director of the Viral Hepatitis Center at Johns Hopkins University School of Medicine, in Baltimore.

At the 2010 Digestive Disease Week (DDW) meeting, Dr. Sulkowski summarized many recent developments that he predicts will affect patient management, providing a glimpse of how HCV treatment will change over the next year.

Based on clinical trial data to date, Dr. Sulkowski characterized direct HCV antiviral agents as the first major breakthrough in HCV treatment since the introduction of ribavirin. These direct antivirals may generate sustained virologic response (SVR) rates of approximately 85% among some genotype 1 subgroups, if used optimally.

However, optimal use may not just depend on combination therapy, but also on appropriate pre-treatment patient stratifications. Specifically, identifying the genotype 1 subtype, screening for inosine triphosphate pyrophosphatase (ITPA) deficiency and modifying therapy according to interleukin-28 (IL-28) polymorphisms have the potential to contribute to improved outcomes.

“I think we will be taking into account all three of these new factors and using them, along with the traditional factors, to try to individualize care,” said Dr. Sulkowski, whose list of traditional factors included conventional HCV genotypes and assessment of the stage of liver disease.

Two New Protease Inhibitors Available Soon

By 2011, the first direct HCV antivirals—boceprevir and telaprevir—are expected to be licensed by the FDA. Unlike available agents, these new direct-acting antivirals, which are protease inhibitors, target the HCV particle specifically. The major potential limitation of these agents is a high risk for drug resistance. However, the risk for resistance with either agent is substantially reduced when they are combined with PegIFN and ribavirin, resulting in more effective treatment.

Since Dr. Sulkowski’s lecture at the DDW meeting in May, two Phase III trials of boceprevir have been completed. Both trials evaluated boceprevir in combination with PegIFN and ribavirin. One, called SPRINT-2, was conducted in treatment-naïve patients. The other, RESPOND-2, enrolled patients who had not achieved SVR on PegIFN and ribavirin alone. In both trials, the addition of boceprevir substantially increased SVR rates compared with treatment that did not include boceprevir.

Similarly, three trials in the Phase III program with telaprevir have been completed since the DDW meeting. In HCV treatment–naïve patients, the ADVANCE and ILUMINATE studies have shown that telaprevir in combination with PegIFN and ribavirin led to substantially higher response rates than those observed with the standard treatment. In the REALIZE study, telaprevir was studied in treatment-experienced patients, and investigators found a similar increase in SVR when they added telaprevir to the combination of PegIFN and ribavirin.

Overall, these data show that adding direct-acting HCV antiviral agents to treatment protocols is effective.

Personalized Medicine Becoming a Reality

Dr. Sulkowski also predicts that treatment regimens will become increasingly individualized.

For starters, HCV genotype 1 will be divided into two subtypes—1a and 1b. These subtypes will demarcate different risks for genetic mutations and viral breakthrough. Although there are no hard guidelines on how to individualize treatment based on this differentiation, Dr. Sulkowski believes clinicians will need to be aware of the potential impact of viral subtypes when treating patients with HCV genotype 1 infection.

Additionally, ITPA deficiency has emerged as a clear risk factor for early onset of anemia in patients taking anti-HCV therapy. Although no test for ITPA is currently available, Dr. Sulkowski predicts that it will be soon, and that it may be useful for modifying HCV therapy, such as introducing erythropoietin to increase the likelihood that patients can remain on full doses of their regimen. And although the mechanism explaining why ITPA deficiency increases the risk for anemia in patients on HCV antivirals remains unknown, better methods of predicting this complication may be important because dose reductions or discontinuation of ribavirin has been a major obstacle to achieving SVR in otherwise responsive patients.

The IL-28 polymorphism adds to the complexity of treating HCV. One year ago, a study found that a host genetic polymorphism in a region near the gene for IL28B—a type 3 interferon found on chromosome 19—strongly affects a patient’s response to PegIFN and ribavirin. More recently, there has been considerable speculation as to how this genetic polymorphism will affect a patient’s response to therapy with boceprevir or telaprevir in combination with PegIFN and RBV. In one study, subjects with the favorable IL28B genotype were more than five times as likely to achieve SVR as those with the polymorphism. According to Dr. Sulkowski, there are some preliminary data suggesting that those who have the unfavorable polymorphism should be treated longer for HCV when a direct-acting antiviral is added.

Just the Beginning

Dr. Sulkowski noted that second-generation direct antivirals “are close behind” boceprevir and telaprevir, and that drugs in other classes, including polymerase inhibitors, are also on the horizon.

The new antivirals are attracting much attention in the evolving treatment of HCV infection, but Dr. Sulkowski indicated that better understanding of patient genetic and virus polymorphisms may help to improve treatment outcomes with these new medications.

“The pre-treatment classification of individuals with chronic HCV infection will be increasingly important I think as we move forward,” Dr. Sulkowski said.

Andrew J. Muir, MD, director of gastroenterology/hepatology research at the Duke Clinical Research Institute, at Duke University School of Medicine in Durham, N.C., emphasized the importance of these new developments in HCV.

“After almost a decade with no change in treatment, the addition of the protease inhibitors to our treatment regimen is a tremendous step forward for patients with hepatitis C,” Dr. Muir said. “With the current treatment, most American patients with genotype 1 infection had a 40% chance of cure. We are waiting on final results of the Phase III trials of the protease inhibitors, but it appears that the response rate will increase by approximately 30% with the addition of these medications.”

Like Dr. Sulkowski, Dr. Muir thinks this is just the beginning, noting that “we also have many other antiviral medications in development, and we are very hopeful that treatment will [become] more and more effective.”


HIV, alcohol topic for Brown study

01:00 AM EDT on Sunday, October 24, 2010

Brown University has won a $7.5-million, five-year federal grant to study how drinking alcohol affects people with HIV.

The money, from the National Institutes of Health, will establish the Brown Alcohol Research Center on HIV, which will conduct several studies on how alcohol affects both physical health and behavior.

Peter Monti, professor of alcohol and addiction studies and director of the new research center, said both alcohol and HIV weaken the brain and the liver. Alcohol use can also make a patient less likely to follow his or her medication regimen or to abstain from unsafe sex.

“We want healthier individuals living with HIV, especially now that they are living longer,” Monti said. “We’ll hopefully determine whether people have to stop drinking or reduce their drinking.”

In one study, researchers will examine over three years the changes in brain structure, metabolism and cognitive functioning of people with HIV who are heavy drinkers or light drinkers.

Another will reach out to heavy drinkers with HIV when they show up in emergency rooms, offering them facts and feedback about their drinking. “You ask them whether they’d be interested in changing and if the answer is yes, you give them some thumbnail sketches about how they might want to go about that,” Monti said.


Are Biopsies Safe for Patients with Advanced Liver Disease?

Posted on October 14, 2010 by Kristine Novak, PhD, Science Editor

Liver biopsies are relatively safe and well tolerated among patients with advanced chronic hepatitis C, based on data from the HALT-C trial.

Liver biopsy analysis provides information for diagnosis and planning of treatment strategies for patients with acute and chronic liver diseases, such as chronic hepatitis C infection. However, biopsies are invasive and come with complications such as bleeding, which occurs in 0.8%–1.7% of cases. This risk has been presumed to be higher in patients with advanced liver disease, but a detailed analysis has not been performed until now.

In the October issue of Clinical Gastroenterology and Hepatology, Leonard Seeff et al. analyzed case reports from 2740 liver biopsies of patients with hepatitis C-related bridging fibrosis or cirrhosis who were enrolled in the HALT-C trial at 10 different centers. The rate of serious adverse events in this cohort was 1.2%—no higher than that of other patients, but bleeding was the most common event, occurring in 0.6% of cases. Low levels of albumin, platelet counts of 60,000 mm3 or less, an international normalized ratio (INR) of 1.3 or greater, and esophageal varices all associated significantly with serious adverse events. Seeff et al. calculated that if liver biopsies had been avoided when platelet counts were 60,000 mm3 or less, the incidence of bleeding would have been reduced by 25%.

Bleeding risk should therefore be assessed before patients receive percutaneous liver biopsies. The authors also observed that patients with histologically proven cirrhosis were no more likely than those with bridging fibrosis to develop a serious adverse event or bleeding.

In an accompanying editorial, Stephen Caldwell and Patrick Northup suggest considering platelet counts, as well as conditions such as hyperfibrinolysis, before performing biopsies. They add that it will be important to identify better measures of the hemostatic system balance in patients with cirrhosis and investigate the roles of pro-coagulants in this important diagnostic procedure.

Computerized tomography showing site of bleeding (arrow) following liver biopsy.

Read the article online. This article has an accompanying podcast.

Seeff LB, Everson GT, Morgan TR et al. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol and Hepatol 2010;8:877–883.

Read the accompanying editorial:
Caldwell Sand Northup PG. Bleeding complication with liver biopsy: is it predictable? Clin Gastroenterol and Hepatol 2010;8:826–829.

Read the complementary Gastroenterology article:
West J and Card TR. Reduced mortality rates following elective percutaneous liver biopsies. Gastroenterology 2010;139:1230–1237.


Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study

J Epidemiol Community Health doi:10.1136/jech.2009.104125

Short report

Winnie Wing-man Leung 1, Suzanne C Ho 1,2, Henry L Y Chan 3, Vincent Wong 3, Winnie Yeo 4, Tony S K Mok 4

1 School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China

2 Department of Community and Family Medicine, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China

3 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China

4 Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China

Correspondence to

Ms Winnie W Leung, c/o Ms Joyce Leung, 2/F PEC Building, School of Public Health and Primary Care, Prince of Wales Hospital, Shatin, N.T., Hong Kong; winnieleung@cuhk.edu.hk

Accepted 2 June 2010
Published Online First 6 August 2010

Recent epidemiological studies have reported a dose-dependent protective effect of coffee on hepatocellular carcinoma (HCC) with risk reduction ranging from 30% to 80% in daily coffee drinkers compared with non-drinkers. This study examined whether coffee has a similar protective effect when consumed in moderate quantities in chronic hepatitis B virus (HBV) carriers, a group at high risk of developing liver cancer.

A case-control design was employed. 234 HBV chronic carriers (109 cases and 125 controls) were recruited from the Prince of Wales Hospital in Hong Kong from December 2007 to May 2008. Data collection included review of medical records and face-to-face interview. Univariate and multivariate logistic regressions adjusting for age, gender, cigarette smoking, alcohol use, tea consumption and physical activity were conducted with dose-response analysis.

Moderate coffee consumption significantly reduced the risk of HCC by almost half (OR 0.54, 95% CI 0.30 to 0.97) with a significant dose-response effect (χ2=5.41, df=1, p=0.02), reducing the risk for moderate drinkers by 59% (OR 0.41, 95% CI 0.19 to 0.89).

The findings provided evidence to support the protective effect of coffee consumption in moderate quantities in HBV chronic carriers.


Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy

Hepatology. 2010 Sep;52(3):864-74.

Harrison SA, Rossaro L, Hu KQ, Patel K, Tillmann H, Dhaliwal S, Torres DM, Koury K, Goteti VS, Noviello S, Brass CA, Albrecht JK, McHutchison JG, Sulkowski MS.

Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, San Antonio, TX 78234, USA. stephen.harrison@amedd.army.mil


Elevated low-density lipoprotein (LDL) levels and statin use have been associated with higher sustained virological response (SVR) rates in patients receiving chronic hepatitis C therapy. However, these relationships have not been well characterized in randomized controlled trials. Furthermore, little is known about the relationship between high-density lipoprotein (HDL) and virological response. To determine whether baseline LDL or HDL levels and statin use affect SVR rates, we retrospectively evaluated the IDEAL (Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial, in which 3070 treatment-naive, hepatitis C virus (HCV) genotype 1-infected patients were treated for up to 48 weeks in one of the following arms: (1) peginterferon (PEG-IFN) alfa-2b at 1.5 microg/kg/week with ribavirin (RBV) at 800 to 1400 mg/day, (2) PEG-IFN alfa-2b at 1.0 microg/kg/week with RBV at 800 to 1400 mg/day, or (3) PEG-IFN alfa-2a at 180 microg/week with RBV at 1000 to 1200 mg/day. Virological responses were assessed by pretreatment statin use and baseline elevated LDL levels (> or =130 mg/dL) or low HDL levels (<40 mg/dL for men and <50 mg/dL for women). In 1464 patients with baseline elevated LDL levels or low HDL levels, the SVR rate was significantly higher than that in patients with normal levels (44.9% versus 34.0%, P < 0.001). In 66 patients receiving a statin pretreatment, the SVR rate was higher than the rate of those not receiving it (53.0% versus 39.3%, P = 0.02). In a multivariate logistic regression analysis using the stepwise selection method with baseline characteristics, a high LDL level [odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.4-1.8, P < 0.001], a low HDL level (OR = 0.5, 95% CI = 0.3-0.8, P = 0.004), and statin use (OR = 2.0, 95% CI = 1.1-3.7, P = 0.02) were independently associated with SVR. CONCLUSION: Baseline elevated LDL levels or low HDL levels and preemptive statin usage were associated with higher SVR rates. Prospective studies may be considered to explore the biological impact of these factors on HCV RNA replication and treatment response.

PMID: 20568303 [PubMed - indexed for MEDLINE]


Peginterferon plus ribavirin and sustained virological response in HCV-related cirrhosis: outcomes and factors predicting response

Am J Gastroenterol. 2010 Oct;105(10):2164-72; quiz 2173. Epub 2010 Aug 10.

Fernández-Rodríguez CM, Alonso S, Martinez SM, Forns X, Sanchez-Tapias JM, Rincón D, Rodriguez-Caravaca G, Bárcena R, Serra MA, Romero-Gómez M, Fernandez I, Garcia-Samaniego J, Fuente J, Solá R, Moreno-Otero R, Planas R; Group for the Assessment of Prevention of Cirrhosis Complications and Virological Response (APREVIR).

Hospital Universitario Fundación Alcorcón, Madrid, Spain. cfernandez@fhalcorcon.es

Comment in:
Am J Gastroenterol. 2010 Oct;105(10):2174-6.


OBJECTIVES: Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response.

METHODS: Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes.

RESULTS: Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1-81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353-7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752-5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418-6.927); baseline viral load <6 × 10(5) (OR=2.597; 95% CI: 1.583-4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26-3.39). No patient with a HCV-RNA decline <1 log(10) at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32-5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81-5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546-4). Improved outcome was more evident in responders with less advanced disease at baseline.

CONCLUSIONS: SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.


Potent New Hepatitis C Drug: First Clinical Trials Successfully Completed

3-D structure of INX-189 anti-hepatitis C drug.
(Credit: Image courtesy of Cardiff University)

ScienceDaily (Oct. 18, 2010) — The first clinical trials on a new investigational drug being developed to treat infections caused by Hepatitis C virus have been successfully completed.

Completion of the initial phase (phase 1a) of trials of INX-189, discovered and first prepared by researchers at Cardiff University's Welsh School of Pharmacy in 2008, means the chances of it becoming an approved medicine have significantly improved.

Approximately 170 million people worldwide are affected with Hepatitis C, which can lead to liver cancer, cirrhosis and death. It is the leading cause of liver transplantation in western countries. The current treatment involves two drugs -- ribavirin and interferon, which has to be given as an injection. Side effects are often severe and lead to patients failing to complete the treatment.

Professor Chris McGuigan of the Welsh School of Pharmacy, academic lead on the project, said: "This is still a very early stage of the trials process but none the less a significant development. Successfully completing phase 1a demonstrates that the drug is safe, with no drug-related side effects at all in a single dose of 100mg.

"The efficiency of drug release in this study has also confirmed that one single dose a day is most likely enough in treating the virus.

"We believe that INX-189 offers the possibility of more potency against Hepatitis, more rapid action in the liver, and fewer side effects than existing treatments."

In 2008, laboratory tests showed INX-189 killed 90 per cent of the virus at very low (nanomolar) concentration, making it the most potent compound of its kind developed to date.

US pharmaceutical company Inhibitex, which owns the licence to INX-189 and has been working with the Cardiff team, has announced it is looking forward to a second trial (phase 1b), which would evaluate the compound's effectiveness in Hepatitis C patients.

Cardiff University and Inhibitex filed a patent on INX-189 earlier this year. It has been cleared for human clinical trials by the Food and Drug Administration in the US.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.


American Association for the Study of Liver Diseases Continues and Expands Educational Partnership With Clinical Care Options

RESTON, Va., Oct. 18 /PRNewswire-USNewswire/ -- Clinical Care Options (CCO), a leader in the development of innovative online, print, and live medical education for healthcare professionals, announced the expansion of its partnership with the American Association for the Study of Liver Diseases (AASLD). For the third year, CCO will serve as the official provider of online Conference Coverage of The Liver Meeting® held in Boston, Massachusetts, October 29 - November 2, 2010.

"Based on the past success of our joint educational programs, we are pleased to continue our collaboration with CCO to create exceptional and innovative online CME activities for healthcare providers treating hepatitis and other liver diseases," said Arun J. Sanyal, MD, 60th President of the AASLD. "We consistently receive positive feedback from our members about CCO's Conference Coverage and educational programs on our practice guidelines, and we depend on CCO to create and disseminate, through these relevant educational initiatives, the important data from The Liver Meeting® and our guidelines for hepatologists and other providers caring for patients with liver disease worldwide."

CCO's official Conference Coverage will include Capsule Summaries of the most important studies presented at the meeting as well as exclusive CME-certified Expert Analyses of the new data by internationally renowned experts. In addition, downloadable audio highlights and a CCO original slideset will also be available.

"We are pleased to continue our partnership with the AASLD to develop and deliver CME-certified activities to our global membership," said Jeffrey Drezner, MD, PhD, CEO of Clinical Care Options. "Our continued collaboration will use our unique technology and editorial expertise in the development of highly engaging interactive educational programs to improve the care of patients with hepatitis and other liver diseases."

In addition to the upcoming Conference Coverage partnership, CCO is collaborating with the AASLD to develop a comprehensive Clinical Management Series on the management of patients with hepatitis B. Through a series of online Interactive Virtual Presentations and Interactive Case Challenges, as well as downloadable resources, this program will provide additional guidance on how to incorporate the AASLD's updated HBV Practice Guidelines into daily practice.

About the AASLD

The AASLD is the leading medical organization for advancing the science and practice of hepatology. Founded by physicians in 1950, AASLD's vision is to prevent and cure liver diseases. This year's Liver Meeting®, held in Boston, Massachusetts, October 29 - November 2, 2010, will bring together more than 7000 researchers from 55 countries. The Liver Meeting® is the premier meeting in the science and practice of hepatology, including the latest findings on new drugs, novel treatments, and the results from pilot and multicenter studies. The approximately 2069 abstracts to be presented at the meeting address all of the important issues in liver disease and wellness, including hepatitis, hepatocellular carcinoma, liver transplantation, and fatty liver disease. For complete information about The Liver Meeting® and additional meetings organized by the AASLD, visit its Web site at http://www.aasld.org/.

About Clinical Care Options

Clinical Care Options, a leader in the development of innovative interactive CME-certified education programs for healthcare professionals, creates and publishes original CME and information resources that translate the latest developments in science and medicine into treatment options. Using internationally renowned experts, Clinical Care Options develops exceptional editorial content for its proprietary state-of-the-art technology and distributes it online via its own specialty portals in hepatitis, HIV, and oncology/hematology. In addition to its industry-leading Web-based programs, Clinical Care Options disseminates the latest strategies in medical management through live meetings and print materials, including books and monographs. For more information about the company and its programs, visit its Web site at http://clinicaloptions.com/.

SOURCE Clinical Care Options



Visceral adiposity index directly correlated to viral load in genotype 1 chronic hepatitis C

Public release date: 19-Oct-2010

Contact: Dawn Peters

Study finds adipose dysfunction also linked to steatosis and necroinflammation

Researchers at the University of Palermo in Italy provide the evidence that a higher visceral adiposity index score—a new index of adipose dysfunction—has a direct correlation with viral load and is independently associated with both steatosis and necroinflammatory activity in patients with genotype 1 chronic hepatitis C (G1 CHC). Details of this study are available in the November issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases (AASLD).

According to public health surveillance data gathered by the Centers for Disease Control and Prevention, nearly 75% of people with chronic hepatitis C virus infection in the U.S. have genotype 1, the hardest type to treat. Steatosis (fatty liver) and insulin resistance (IR), are frequent findings in patients with G1 CHC. Prior studies indicate that these metabolic features not only are independently associated with the severity of liver damage, but also are negative predictors of sustained virologic response (SVR) after standard antiviral therapy.

Visceral adipose tissue is believed to secrete a variety of substances that regulate metabolism, inflammation, and immunity, participating in the pathogenesis of cardiovascular disease, IR and diabetes. To determine whether visceral adiposity is directly associated with the metabolic factors that cause liver damage, a recent study introduced the visceral adiposity index (VAI) score, which uses both anthropometric (body mass index (BMI) and waist circumference) and metabolic (triglyceride and HDL) parameters to measure visceral fat mass, a key factor in metabolic alteration development, and the effect of visceral obesity on the histological features of liver disease. The VAI assesses fat distribution and function as well as cardiometabolic risk, and has been proposed as a surrogate marker of adipose tissue dysfunction.

In the current study, Salvatore Petta, M.D., and colleagues tested the VAI and its association with histological features and SVR in 236 patients with G1 CHC. Participants were evaluated by liver biopsy and anthropometric and metabolic measurements, including IR, the homeostasis model assessment (HOMA), and VAI by using waist circumference, BMI, triglycerides and HDL. All biopsies were scored for staging and grading, and graded for steatosis, which was considered moderate-severe if ≥30%. Patients were treated with the standard antiviral therapy of pegylated interferon plus ribavirin. The majority of study participants were in the overweight to obesity range, and nearly 25% were hypertensive. Diabetes was present in 11% of patients, and IR in 42.8%. Metabolic syndrome was diagnosed in 14.9% of patients. One patient in five had fibrosis ≥ 3 by Scheuer score, with a high prevalence of moderate/severe necroinflammation (grading 2-3). Half of the cases had histological evidence of steatosis, though of moderate/severe grade in only 40 cases (16.9%).

One hundred sixty-two patients completed the antiviral treatment program. SVR was achieved in 77 patients (47.5%). VAI score had a direct correlation with HCV viral load and was independently associated with higher HOMA score, higher HCV RNA levels, necroinflammatory activity, and steatosis, by multiple linear regression analysis. IR, higher VAI score, and fibrosis were linked to steatosis, suggesting adipose tissue may interfere with liver fatty accumulation not only by IR promotion, but also by exercising its well-known function as an endocrine organ able to modulate metabolic functions, including steatogenesis. Older age, high VAI score, and fibrosis were independently associated with moderate-severe necroinflammatory activity by logistic regression analysis.

"Our study found that moderate-severe necroinflammatory activity is independently associated not only with older age but also with VAI score," commented Dr. Petta. "To the best of our knowledge, we have provided the first evidence of an independent link between adipose dysfunction and liver inflammation in CHC." The authors indicate that the index may be able to reflect the ability of adipose tissue to generate proinflammatory mediators capable of participating in liver inflammatory response during HCV infection.

Dr. Petta concluded, "We suggest using VAI as an indicator of adipose-related liver damage, as predictor of liver disease progression, and as a new therapeutic outcome measure in the management of G1 CHC patients."


Article: "Visceral Adiposity Index is Associated with Histological Findings and with High Viral Load in Patients with Chronic Hepatitis C Due to Genotype 1." Salvatore Petta, Marco Amato, Daniela Cabibi, Calogero Cammà, Vito Di Marco, Carla Giordano, Aldo Galluzzo, Antonio Craxì. Hepatology; Published Online: JUL 29, 2010 (DOI: 10.1002/hep.23859); Print Issue Date: November 2010. http://onlinelibrary.wiley.com/doi/10.1002/hep.23859/abstract

This study is published in Hepatology. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.

Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350.

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, Inc., with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit http://www.wileyblackwell.com/ or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

Media Advisory

What: The 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)

Founded in 1950, AASLD is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease. AASLD has grown into an international society responsible for all aspects of hepatology, and the annual meeting attracts 8,500 physicians, surgeons, researchers, and allied health professionals from around the world.

The Liver Meeting® is the premier meeting in the science and practice of hepatology, including the latest findings on new drugs, novel treatments, and the results from pilot and multicenter studies.

When: October 30 – November 2, 2010

Where : Hynes Convention Center
900 Boylston Street
Boston, Massachusetts

Contact: Please contact Ann Haran at 703-299-9766 or aharan@aasld.org to obtain a press pass for this event.


Antiviral activity of narlaprevir combined with ritonavir and pegylated interferon in chronic hepatitis C patients

Hepatology. 2010 Aug 19. [Epub ahead of print]

de Bruijne J, Bergmann JF, Reesink HW, Weegink CJ, Molenkamp R, Schinkel J, Tong X, Li J, Treitel MA, Hughes EA, van Lier JJ, van Vliet AA, Janssen HL, de Knegt RJ.

Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.


Narlaprevir (SCH 900518) is a potent inhibitor of the hepatitis C virus (HCV) nonstructural protein 3 serine protease that is primarily metabolized by the cytochrome P450-3A4 system. In order to explore the use of ritonavir-based pharmacokinetic enhancement of an HCV protease inhibitor, this study investigated the safety, tolerability, pharmacokinetics, and antiviral activity of narlaprevir (with or without ritonavir) administered as monotherapy and as combination therapy with pegylated interferon-α-2b (PEG-IFN-α-2b) to HCV genotype 1-infected patients. This was a randomized, placebo-controlled, two-period, blinded study in 40 HCV genotype 1-infected patients (naïve and treatment-experienced). In period 1, narlaprevir was administered for 7 days as 800 mg three times daily without ritonavir or 400 mg twice daily with 200 mg ritonavir twice daily. In period 2, after a 4-week washout, the same dose and regimen of narlaprevir was administered in combination with PEG-IFN-α-2b for 14 days. Upon completion of period 2, all patients initiated PEG-IFN-α-2b and ribavirin treatment. A rapid and persistent decline in plasma HCV-RNA was observed in both treatment-experienced and treatment-naïve patients during period 1, with a mean viral load decline of at least 4 log(10) in all treatment groups. A high percentage of both treatment-experienced (50%) and treatment-naïve (≥60%) patients had undetectable HCV-RNA (<25 IU/mL) after period 2. Standard of care resulted in sustained virological response (SVR) rates of 38% and 81% in treatment-experienced and treatment-naïve patients, respectively. Narlaprevir (with or without ritonavir) alone or in combination with PEG-IFN-α-2b was safe and well tolerated. Conclusion: Narlaprevir administration resulted in a robust HCV-RNA decline and high SVR rates when followed by standard of care in both treatment-experienced and treatment-naïve HCV genotype 1-infected patients. (HEPATOLOGY 2010.

PMID: 20938912 [PubMed - as supplied by publisher]


Meta-analysis: re-treatment of genotype I hepatitis C nonresponders and relapsers after failing interferon and ribavirin combination therapy

Aliment Pharmacol Ther. 2010 Oct;32(8):969-83. doi: 10.1111/j.1365-2036.2010.04427.x. Epub 2010 Aug 15.

Singal AG, Waljee AK, Shiffman M, Bacon BR, Schoenfeld PS.

University of Michigan Medical Center, Ann Arbor, USA.


BACKGROUND: The efficacy of re-treating genotype I hepatitis C virus (HCV) patients who failed combination therapy with interferon/pegylated interferon (PEG-IFN) and ribavirin remains unclear.

AIMS: To quantify sustained virological response (SVR) rates with different re-treatment regimens through meta-analysis of randomized controlled trials (RCTs).

METHODS: Randomized controlled trials of genotype I HCV treatment failure patients that compared currently available re-treatment regimens were selected. Two investigators independently extracted data on patient population, methods and results. The pooled relative risk of SVR for treatment regimens was computed using a random effects model.

RESULTS: Eighteen RCTs were included. In nonresponders to standard interferon/ribavirin, re-treatment with high-dose PEG-IFN combination therapy improved SVR compared with standard PEG-IFN combination therapy (RR=1.49; 95% CI: 1.09-2.04), but SVR rates did not exceed 18% in most studies. In relapsers to standard interferon/ribavirin, re-treatment with high-dose PEG-IFN or prolonged CIFN improved SVR (RR=1.57; 95% CI: 1.16-2.14) and achieved SVR rates of 43-69%.

CONCLUSIONS: In genotype I HCV treatment failure patients who received combination therapy, re-treatment with high-dose PEG-IFN combination therapy is superior to re-treatment with standard combination therapy, although SVR rates are variable for nonresponders (≤18%) and relapsers (43-69%). Re-treatment may be appropriate for select patients, especially relapsers and individuals with bridging fibrosis or compensated cirrhosis.

© 2010 Blackwell Publishing Ltd.

PMID: 20937042 [PubMed - in process]


Hepatitis C virus: Up to the minute

Liver Transpl. 2010 Oct;16(S2):S26-S35.

Roche B, Samuel D.

Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, Villejuif, France.


Key Points1. Hepatitis C virus reinfection is almost universal in patients who are polymerase chain reaction-positive at the time of transplantation, and it significantly impairs patient and graft survival.2. The virus infects the graft a few hours after transplantation and leads within weeks to a viral load higher than the pretransplant levels; this is associated with an accelerated progression to cirrhosis, graft loss, and death.3. Multiple host, donor, and viral factors are associated with rapid fibrosis progression: high pretransplant and posttransplant viral loads, severe early histological recurrence, more potent immunosuppression and treatment of rejection episodes, cytomegalovirus or human immunodeficiency virus coinfections, and increasing donor age.4. Annual protocol biopsy, noninvasive fibrosis evaluation, or both are recommended to evaluate fibrosis progression and determine the time for antiviral therapy.5. Pretransplant antiviral therapy may reduce or eliminate the risk of recurrent infection. However, this approach is limited because of side effects and a risk of complications in decompensated patients.6. Preemptive therapy early after transplantation is less effective because of the high level of immunosuppression and is limited by low applicability and poor tolerance.7. The treatment of established graft lesions with a therapy combining pegylated interferon and ribavirin yielded promising results, and a sustained virological response was achieved in approximately 30% of the patients. Sustained virological responders experienced long-term beneficial effects with respect to fibrosis progression and graft and patient survival. Variables associated with a sustained virological response include the following: non-1 genotype, absence of previous antiviral therapy, early virological response, adherence to therapy, and low pretreatment viral load. However, antiviral therapy is limited by the frequent need for dose reductions or discontinuation and a low risk of acute or chronic rejection and autoimmune-like hepatitis.8. Patients infected with hepatitis C virus before and after transplantation are those who will benefit the most from new classes of direct antiviral agents. Liver Transpl 16:S26-S35, 2010. © 2010 AASLD.

PMID: 20928858 [PubMed - as supplied by publisher]


High ability to predict the treatment outcome of peginterferon and ribavirin combination therapy based on the reduction in HCV RNA levels at 4 weeks after starting therapy and amino acid substitutions in the hepatitis C virus in patients infected with HCV genotype 1b

J Gastroenterol. 2010 Oct 7. [Epub ahead of print]

Toyoda H, Kumada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Tada T, Arakawa T, Fujimori M, Niinomi T, Ando N, Yasuda S, Sakai K, Kimura J.

Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, Gifu, 503-8502, Japan, hmtoyoda@spice.ocn.ne.jp.


BACKGROUND: The ability to predict the outcome of peginterferon (PEG-IFN) and ribavirin combination therapy based on the reduction in hepatitis C virus (HCV) RNA levels at 4 weeks after starting the therapy and amino acid substitutions in HCV was to be confirmed.

METHODS: We measured the reduction in HCV RNA levels at 4 weeks after starting the combination therapy, as well as examining amino acid substitutions at residue 70 in the HCV core and within the interferon sensitivity-determining region (ISDR) of HCV non-structural protein 5A (NS5A), for 101 patients infected with HCV genotype 1b. The ability of these factors to predict a sustained virologic response (SVR) was analyzed.

RESULTS: When a 3 log(10) reduction in HCV RNA levels at 4 weeks after starting therapy was set as the cut-off value, an SVR was achieved in 37 of the 46 patients (80.4%) with a ≥3 log(10) decrease and in 4 of the 55 patients (7.3%) with a <3 log(10) decrease. All 4 patients who achieved an SVR despite a <3 log(10) reduction in HCV RNA levels at 4 weeks had an arginine at residue 70 in the HCV core and a non-wild-type sequence for the ISDR of HCV NS5A.

CONCLUSION: A ≥3 log(10) reduction in HCV RNA levels at 4 weeks after starting therapy indicates that a patient has a high likelihood of achieving an SVR as a final outcome. Additional information on the amino acid substitutions at residue 70 in the HCV core and within NS5A-ISDR will further increase the ability to predict a clinical response.

PMID: 20927636 [PubMed - as supplied by publisher]


IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C

Hepatology. 2010 Aug 20. [Epub ahead of print]

Urban TJ, Thompson AJ, Bradrick SS, Fellay J, Schuppan D, Cronin KD, Hong L, McKenzie A, Patel K, Shianna KV, McHutchison JG, Goldstein DB, Afdhal N.

Center for Human Genome Variation, Duke University Medical Center, Durham, NC.


Genetic variation in the IL28B (interleukin 28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC) who were treated with peginterferon-α and ribavirin. We hypothesized that IL28B polymorphism is associated with intrahepatic expression of interferon-stimulated genes (ISGs), known to influence treatment outcome. IL28B genotyping (rs12979860) and whole-genome RNA expression were performed using liver biopsies from 61 North American patients with CHC. After correction for multiple testing (false discovery rate < 0.10), 164 transcripts were found to be differentially expressed by IL28B-type. The interferon signaling pathway was the most enriched canonical pathway differentially expressed by IL28B-type (P < 10(-5)), with most genes showing higher expression in livers of individuals carrying the poor-response IL28B-type. In 25 patients for which treatment response data were available, IL28B-type was associated with SVR (P = 0.0054). ISG expression was also associated with SVR; however, this was not independent of IL28B-type. Analysis of miR-122 expression in liver biopsies showed reduced miR-122 levels associated with poorer treatment outcome, independently of IL28B-type. No association was observed between IL28B-type and levels of liver IL28B or IL28A messenger RNA expression. IL28B protein sequence variants associated with rs12979860 were therefore investigated in vitro: no differences in ISG induction or inhibition of HCV replication were observed in Huh7.5 cells. Conclusion: The good response IL28B variant was strongly associated with lower level ISG expression. The results suggest that IL28B genotype may explain the relationship between hepatic ISG expression and HCV treatment outcome, and this is independent of miR-122 expression. IL28B-type was not associated with intrahepatic IL28B messenger RNA expression in vivo. Further investigation of the precise molecular mechanism(s) by which IL28B genetic variation influences HCV outcomes is warranted. (HEPATOLOGY 2010).

PMID: 20931559 [PubMed - as supplied by publisher]


Intercell and Romark Join Forces in Combining Therapies Against Hepatitis C

-- The companies are designing a treatment that combines Intercell's investigational Hepatitis C vaccine, IC41, with Romark's antiviral drug, nitazoxanide.

-- A combination Phase II trial is expected to start in H1/2011.

-- The trial will be sponsored by Romark. Intercell will provide the vaccine candidate IC41.

VIENNA, Oct. 21 /PRNewswire/ -- Intercell AG (VSE; "ICLL") and Romark Laboratories L.C. today announced plans to commence clinical trials of Intercell's investigational therapeutic Hepatitis C virus (HCV) vaccine, IC41, in combination with Romark's antiviral drug, nitazoxanide, during the first half of 2011.

Intercell's vaccine candidate has demonstrated a sustained reduction of viral load in chronic Hepatitis C (CHC) patients in a Phase II proof-of-concept trial. Nitazoxanide is an oral therapy that targets host cell factors involved in HCV replication and is not associated with viral mutations conferring resistance. Nitazoxanide has been shown to induce sustained virologic response as monotherapy in some patients chronically infected with HCV.

The planned European Phase II trial will include about 60 treatment-naïve patients chronically infected with HCV genotype-1 in three treatment arms: (1) IC41 plus nitazoxanide, (2) IC41 plus nitazoxanide and Pegasys® (peginterferon alfa-2a) and (3) Pegasys and Copegus® (ribavirin), the current standard of care, as an active control. The primary endpoint will be sustained virologic response (no detectable HCV RNA 24 weeks after end-of-treatment).

The companies involved in the combination study will retain commercial rights for their respective products.

"We are very pleased about this important next step in the development of our vaccine candidate against Hepatitis C. The distinctly different mode-of-action and the outstanding tolerability of both treatments create a joint approach in a field that will continue to have high unmet medical need over the next decades," stated Gerd Zettlmeissl, CEO of Intercell.

"We are excited about this novel therapeutic approach for chronic Hepatitis C," said Jean-Francois Rossignol, M.D., Ph.D., Chairman and Chief Science Officer of Romark. "There is an important need for novel therapies that offer improvements in safety and efficacy compared to current standard therapy. Our development program for nitazoxanide in combination with peginterferon addresses this need and promises to change paradigms for therapy of chronic Hepatitis C. The planned study of nitazoxanide in combination with Intercell's therapeutic vaccine further underscores our commitment to being a leader in the development of next-generation therapies."

Intercell's investigational therapeutic vaccine has been designed to restore an effective immune response against HCV, which ultimately is deemed necessary for sustained clearance of the virus. In a successful proof-of-concept trial involving around 50 treatment-naïve genotype-1 CHC patients, an optimized schedule of therapeutic vaccination achieved viral load reductions of more than 75% (0.6 log) in patients with high baseline RNA levels. Importantly, this reduction was sustained for at least six months following the end of treatment. As in previous trials with the vaccine from Intercell, vaccination was safe and well tolerated with minimal side effects.

Nitazoxanide, the first of a new class of broad-spectrum antiviral drugs called the thiazolides,(1,2,3) is an investigational new drug for CHC. It is a potent inhibitor of HCV in replicon studies,(2) and laboratory studies indicate that it does not induce viral mutations that confer drug resistance.(3,4) Nitazoxanide is synergistic with interferon and direct acting antivirals in replicon studies.(2,5) In a clinical trial of nitazoxanide monotherapy in patients with genotype 4 CHC, 17% (4 of 23) patients achieved sustained virologic response (undetectable serum HCV RNA 24 weeks after end of therapy), with all responders having low baseline serum HCV RNA levels (<400,000 IU/mL).(6) In other clinical trials, the addition of nitazoxanide to peginterferon or peginterferon plus ribavirin was associated with improvement in sustained virologic response rates without increasing the toxicities associated with peginterferon and ribavirin.(7,8) Romark is preparing to initiate Phase III clinical trials of nitazoxanide plus peginterferon for treatment of CHC.

About Hepatitis C

HCV is a major cause of chronic liver disease, including cirrhosis and liver cancer. According to the World Health Organization (WHO), approximately 170 million people worldwide are chronic HCV carriers (3% of the world's population), including about 10 million Europeans, 3.9 million Americans and 2 million Japanese. 35,000 new infections occur in the United States alone each year. The substantial unmet medical need is underscored by the fact that each year 8,000 to 10,000 deaths and 1,000 liver transplants in the United States are due to HCV.

Currently, there is no vaccine against HCV available, and the infection can only be treated with a combination of interferon and ribavirin – a long-term therapy with limited efficacy and substantial side effects. It also gives rise to high treatment costs for patients. In 2002, worldwide sales of HCV drugs totaled around EUR 2.8bn, and demand has since grown significantly. The market has been seen to expand to about EUR 3.5bn by 2006.

About Romark Laboratories

Romark Laboratories, L.C. (www.romark.com) is a privately owned biopharmaceutical company committed to the discovery and development of innovative new small molecules for treating infectious diseases and cancers.

The Company is developing a new class of broad-spectrum antiviral drugs called the thiazolides. The first thiazolide, nitazoxanide, is in late-stage clinical development as a treatment of chronic hepatitis C and influenza. Other new thiazolides are expected to enter clinical development in 2011.

Romark markets Alinia® (nitazoxanide) tablets, 500 mg and Alinia® (nitazoxanide) for Oral Suspension, 100 mg/5 mL in the United States.

This communication expressly or implicitly contains certain forward-looking statements concerning Intercell AG and its business. Such statements involve certain known and unknown risks, uncertainties and other factors which could cause the actual results, financial condition, performance or achievements of Intercell AG to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Intercell AG is providing this communication as of this date and does not undertake to update any forward-looking statements contained herein as a result of new information, future events or otherwise.

(1) Rossignol JF. Thiazolides: A new class of antiviral drugs. Expert Opin Drug Metab Toxicol. 2009;5:667-674.

(2) Korba BE, Montero AB, Farrar K, et al. Nitazoxanide, tizoxanide, and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication. Antivir Res. 2008;77:56-63.

(3) Korba BE, Elazar M, Lui P, et al. Studies of the potential for hepatitis C virus resistance to nitazoxanide or tizoxanide. Antimicrob Agents Chemother. 2008;52:4069-4071.

(4) Yon C, Viswanathan P, Rossignol JF, Korba BE. Resistance to nitazoxanide is associated with alterations in the host and not the virus in HCV replicon-containing cultures. Submitted for publication.

(5) Korba BE, Elazar M, Liu P, et al. Potential role for nitazoxanide in combination with STAT-C agents for the inhibition of HCV replication without the development of resistance. Hepatology. 2008;48(suppl):356A.

(6) Rossignol JF, Kabil SM, El-Gohary Y, Elfert A, Keeffe EB. Clinical trial: randomized, double-blind, placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4. Aliment Pharmacol Ther. 2008;28:574-580.

(7) Rossignol JF, Elfert A, El-Gohary Y, et al. Improved virologic response in patients with chronic hepatitis C genotype 4 treated with nitazoxanide plus peginterferon alfa-2a with or without ribavirin. Gastroenterology. 2009;136:856-862.

(8) Rossignol JF, Elfert A, Keeffe EB. Treatment of chronic hepatitis C using a 4-week lead-in with nitazoxanide before peginterferon plus nitazoxanide. J Clin Gastroenterol. 2010;44:504-509.

SOURCE Intercell AG



Direct-acting Drugs Danoprevir plus RG7128 Suppress HCV without Interferon

SUMMARY: Results from the INFORM-1 trial, which evaluated 2 experimental agents that target different steps of the hepatitis C virus (HCV) lifecycle, showed that a combination of direct-acting drugs can suppress viral replication without interferon or ribavirin. As described in the October 14, 2010 advance online edition of The Lancet, the HCV protease inhibitor danoprevir (RG7227 or ITMN-191) plus the polymerase inhibitor RG7128 reduced HCV RNA by about 5 logs in both treatment-naive and previously treated patients, and caused no serious side effects in this 14-day study.

By Liz Highleyman

Standard therapy for chronic hepatitis C, consisting of pegylated interferon (Pegasys or PegIntron) plus ribavirin for 48 weeks, cures only about half of people with hard-to-treat HCV genotype 1. In addition, this regimen can cause difficult side effects that lead many patients to stop treatment prematurely.

Direct-acting agents, including HCV protease and polymerase inhibitors, target the virus directly -- rather than stimulating the immune system like interferon -- and therefore may be better tolerated. Most of these oral agents have so far been studied one at a time in combination with pegylated interferon and/or ribavirin, allowing for a shorter course of treatment. But ideally, people with HCV and their providers are hoping for a regimen that does not require interferon at all.

INFORM-1 is the first clinical trial to evaluate a combination of directing-acting agents without interferon. Edward Gane from Auckland Clinical Studies in New Zealand evaluated the safety, tolerability, and antiviral activity of an all-oral regimen consisting of the HCV NS3/4A protease inhibitor danoprevir plus the cytosine nucleoside polymerase inhibitor RG7128, both being developed by Roche.

A total of 88 genotype 1 chronic hepatitis C patients from 6 centers in New Zealand and Australia were randomly assigned to 7 treatment cohorts, receiving various combinations of danoprevir (100 or 200 mg every 8 hours, or 600 mg or 900 mg twice-daily), RG7128 (500 or 1000 mg twice-daily), and placebo for up to 13 days. Overall, 74 people were assigned to study drugs and 14 to placebo.

Treatment-naive patents received escalating doses, while prior non-responders to standard-of-care therapy were enrolled in higher-dose danoprevir cohorts. (A previous study showed that danoprevir works better when boosted with a low dose of ritonavir [Norvir], but that was not used in this trial.)

After the 14-day randomized study period, all participants started standard therapy with pegylated interferon plus ribavirin.

The primary outcome was changes in HCV RNA viral load from baseline to day 14 in patients who received 13 days of combination therapy. All participants who completed treatment were included in the analysis.

  • Median decreases in HCV RNA from baseline to day 14 ranged from 3.7 to 5.2 log IU/mL in the cohorts that received danoprevir/RG7128 combination treatment for 13 days.
  • Among treatment-naive participants who received the highest doses of both drugs (900 mg danoprevir twice-daily plus 1000 mg RG7128), the median decrease in HCV RNA at day 14 was 5.1 log IU/mL.
  • Among prior null responders receiving the same doses of both drugs, the median decrease was similar, at 4.9 log IU/mL.
  • Among placebo recipients, HCV RNA decreased by only a median 0.1 log IU/mL.
  • Viral load decreases were similar in patients with HCV genotypes 1a and 1b (4.8 and 5.1 log IU/mL, respectively).
  • In the highest dose cohorts, 5 of 8 treatment-naive patients and 2 of 8 prior null responders achieved undetectable HCV RNA (< 15 IU/mL).
  • The danoprevir plus RG7128 combination was generally well-tolerated.
  • No participants discontinued treatment or reduced drug doses due to safety concerns.
  • No treatment-related serious or severe adverse events and no grade 3 or 4 changes in laboratory parameters were observed.
  • No evidence of treatment-emergent resistance to either danoprevir or RG7128 was identified during the study. 
Based on these findings, the researchers stated, "This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV."

"Even though INFORM-1 is a short-term phase 1 study, the findings show that an interferon-free regimen can suppress viral replication," they elaborated in their discussion. "However, we did not show that interferon-free regimens can eradicate HCV (i.e., produce a sustained virological response)."

They noted that INFORM-1 combined drugs that were still in Phase 1 development, in contrast with the traditional development pathway in which studies of combination therapy are delayed until each drug is in late stages of development or has been approved.

"The combination of RG7128 and danoprevir should be further developed and might be a viable interferon-free, all-oral regimen for patients with chronic HCV infection," the authors concluded. "Promising results have been published for use of direct-acting antivirals as monotherapy. However, treatment of patients with an all-oral, interferon-free dual direct-acting antiviral drug combination, as assessed in our study, marks a major shift in the future management of HCV infection and the biggest development in treatment of the disease for the past two decades."

Investigator affiliations: Auckland Clinical Studies, Auckland, New Zealand; The Alfred Hospital, Melbourne, Victoria, Australia; Christchurch Clinical Studies, Christchurch, New Zealand; Austin Hospital, Heidelberg, Victoria, Australia; Royal Adelaide Hospital, Adelaide, South Austraila, Australia; Roche Palo Alto, Palo Alto, CA; Pharmasset, Princeton, NJ; Intermune, Brisbane, CA.



EJ Gane, SK Roberts, CA Stedman, and others (INFORM-1 study team). Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet (Abstract). October 14, 2010 (Epub ahead of print).


Hepatic microRNA expression is associated with the response to interferon treatment of chronic hepatitis C

Published on: 2010-10-22

HCV infection frequently induces chronic liver diseases. The current standard treatment for chronic hepatitis (CH) C combines pegylated interferon (IFN) and ribavirin, and is less than ideal due to undesirable effects.

MicroRNAs (miRNAs) are endogenous small non-coding RNAs that control gene expression by degrading or suppressing the translation of target mRNAs. In this study we administered the standard combination treatment to CHC patients.

We then examined their miRNA expression profiles in order to identify the miRNAs that were associated with each patient's drug response.

Methods: 99 CHC patients with no anti-viral therapy history were enrolled. The expression level of 470 mature miRNAs found their biopsy specimen, obtained prior to the combination therapy, were quantified using microarray analysis.

The miRNA expression pattern was classified based on the final virological response to the combination therapy. Monte Carlo Cross Validation (MCCV) was used to validate the outcome of the prediction based on the miRNA expression profile.

Results: We found that the expression level of 9 miRNAs were significantly different in the sustained virological response (SVR) and non-responder (NR) groups.

MCCV revealed an accuracy, sensitivity, and specificity of 70.5%, 76.5% and 63.3% in SVR and non-SVR and 70.0%, 67.5%, and 73.7% in relapse (R) and NR, respectively.

Conclusions: The hepatic miRNA expression pattern that exists in CHC patients before combination therapy is associated with their therapeutic outcome. This information can be utilized as a novel biomarker to predict drug response and can also be applied to developing novel anti-viral therapy for CHC patients.

Author: Yoshiki MurakamiMasami TanakaHidenori ToyodaKatsuyuki HayashiMasahiko KurodaAtsushi TajimaKunitada Shimotohno

Credits/Source: BMC Medical Genomics 2010, 3:48


Hepatitis C Virus Can Damage Brain Cells

October 22, 2010

Hepatitis C virus (HCV) can damage not only the liver but also the brain, according to a new Canadian study.

"It has been a question for a long time," said study co-author Pornpun Vivithanaporn, a post-doctoral fellow in the University of Alberta's Faculty of Medicine and Dentistry. "It proves the virus has implications on neurological disease."

The study showed HCV "gets in [the brain], it infects, and it replicates," said lead author Dr. Christopher Power, a neurologist at the university. A buildup of HCV proteins in healthy brain cells eventually damages and kills the cells, as if the cells were drowning in their own refuse, he said.

"HCV core protein exposure caused neuronal injury through suppression of neuronal autophagy in addition to neuroimmune activation," the study concluded. "The additive neurotoxic effects of HCV- and HIV-encoded proteins highlight extrahepatic mechanisms by which HCV infection worsens the disease course of HIV infection."

Researchers already knew that severe liver damage can affect the patient's brain. The new findings support other studies showing that even when serious liver damage has not occurred, HCV patients might develop memory loss, trouble concentrating, apathy, and depression.

"It tells us we need to be vigilant for neurological problems for people who have hepatitis C," Power said. An HCV patient's treatment team might need to include a neurologist and a psychologist, as well as the liver specialist, he said.

The study, "Hepatitis C Virus Core Protein Induces Neuroimmune Activation and Potentiates Human Immunodeficiency Virus-1 Neurotoxicity," was published in Public Library of Science ONE (doi: 10.1371/journal.pone.0012856).


ACG: Obesity Linked to Noncirrhotic Liver Cancer

By Kristina Fiore, Staff Writer, MedPage Today Published: October 22, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

SAN ANTONIO -- Even in the absence of cirrhosis and fatty liver, obese patients may still be at increased risk for liver cancer, researchers said here.

Patients with noncirrhotic hepatocellular carcinoma had a higher body mass index (BMI) as well as a higher prevalence of diabetes than those in the general population, Benjamin Mitlyng, MD, of the University of Minnesota in Minneapolis, and colleagues reported at the American College of Gastroenterology meeting.

"This supports previous data that there may be an association with noncirrhotic hepatocellular carcinoma and an elevated BMI as well as diabetes, independent of steatosis," they wrote.

While still rare, it has been estimated that up to 10% of liver cancers occur in patients who don't have cirrhosis.

Insulin resistance and obesity have both been suggested as risk factors for noncirrhotic hepatocellular carcinoma.

To assess those relationships, the researchers looked at data from a cohort of 12 patients with noncirrhotic hepatocellular carcinoma who had a partial hepatectomy between January 2008 and September 2009 at a single center.

Their average age was 60, with an average BMI of 27.6.

A third of the patients had diabetes -- a much higher prevalence than that of the general population, the researchers said (33% versus 6%).

A higher proportion was overweight or obese compared with the general population as well (67% versus 60%).

All patients had preoperative testing for underlying liver disease that was negative in all but two patients, both of whom had hemochromatosis.

Only two patients had mild steatosis, the researchers said.

Vascular invasion was observed in five of the 12 lesions with six well-differentiated and six moderately-differentiated carcinomas. None were fibrolamellar.

The researchers said there were no recurrences during an average follow-up of 17.5 months.

They concluded that patients with noncirrhotic liver cancer had a high prevalence of diabetes and elevated BMI, despite a lack of steatosis.

David Johnson, MD, of Eastern Virginia Medical School in Norfolk, Va., who wasn't involved in the study, said the findings highlight the fact that some mechanism related to obesity or overweight is at work, perhaps one involved in the inflammatory response, which is elevated in this group.

"They don't have to have end-stage liver disease, but fat in the liver may be handled in the wrong way, so that it metabolically changes the liver dynamic to create an incremental cancer risk before patients get to that stage of cirrhosis," he said.

Johnson added that fatty tissue is metabolically active -- "that inflammation may generate a substance that creates havoc with every body system, particularly in the pathways that can result in precancerous growth."

Walter Coyle, MD, of Scripps Clinic in La Jolla, Calif., who was not involved in the study either, added that it would also be interesting to examine the role of gut microbiota in the development of liver cancer in this population.

The researchers reported no conflicts of interest.

Primary source: American College of Gastroenterology

Source reference:
Mitlyng B, et al "Hepatocellular carcinoma in the non-cirrhotic liver is associated with a high body mass index independent of steatosis" ACG 2010; Abstract 290.