November 6, 2010

Reported by Jules Levin
AASLD Nov 1 2010

P.Charatcharoenwitthaya; R.Sermsathanasawadi; S.Chainuvati; N.Pausawasdi; S.Nimanong; V.Prachayakul; S.Pongprasobchai; S.Leelakusolvong; S.Manatsathit; U.Kachintorn; T.Tanwandee Medicine, Gastroenterology Division, Siriraj Hospital, Bangkoknoi, Bangkok, Thailand

Background & Aims: The clinical utility of antiviral therapy in elderly patients with HCV-related cirrhosis has not been elucidated. The aims of this retrospective study were 1) to evaluate whether antiviral therapy had similar benefits between patients with HCV-related cirrhosis aged 60 years and those aged < 60 years and 2) to clarify the long-term effect of antiviral therapy on life expectancy and risk of hepatocellular carcinoma (HCC) and liver failure defined as new onset of ascites, variceal bleeding, jaundice, or hepatic encephalopathy.
Methods: This study analyzed data on 194 consecutive patients with compensated HCV-related cirrhosis who received more than 1 year periodic medical screening from 1997 through 2009.

Results: A total of 159 cirrhotic patients (85 female and 74 male; mean age, 53.7+/-8.1 years) were treated with a combination of conventional interferon or peginterferon and ribavirin; 36 of them (23%) were 60 years of age or older. The cohorts aged >/= 60 years had a median model of end-stage liver disease (MELD) score of 7 (range: 6-19); a median pretreatment viral load of 5.9 log10IU/L; and 61% were infected with HCV genotype 3. Clinical, hematologic, biochemical, and virological features were not different between patients aged >60 years and those aged < 60 years. Although the proportion of dose modification of antiviral agents was similar in both groups, sustained virological response (SVR) rates among patients aged >/=60 years were lower than those aged < 60 years (47% vs. 80%; p<.0001). Multivariate analysis showed that older age (p=.0002) and higher MELD score (p=.02) were associated with lower SVR while gender, HCV genotype and baseline viral load did not affect SVR. During a median follow-up of 56.5 months (range: 17-139), none of 17 elderly responders developed liver failure or died whereas 4 of 19 elderly nonresponders had liver failure and one of them died of cirrhotic complication. The annual incidence of HCC was 4.7% in elderly responders and 7.6% in elderly nonresponders. Comparison with patients aged 60 years who have never received antiviral therapy (n=35), SVR was found to be associated with a significant reduction in the risk of liver-related death (p=.04) and liver failure (p=.0008) but was not associated with a reduction in the risk of HCC development (p=.1) among elderly cirrhotic patients.

Conclusion: Although the efficacy of antiviral therapy among elderly patients with compensated HCV-related cirrhosis was inferior to that of young patients, achieving SVR in this population was associated with improved clinical outcomes, particularly prevention of decompensation of cirrhosis.

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Reported by Jules Levin
AASLD Nov 2 2010 Boston

N.D.Freedman1; T.M.Curto2; K.Lindsay3; E.C.Wright4; R.Sinha1; J.E.Everhart5 1. Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD; 2. New England Research Institutes, Watertown, MA; 3. Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA; 4. Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; 5. Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD

Introduction: Higher coffee consumption has been associated with slower progression of pre-existing liver disease and lower risk of hepatocellular carcinoma. The relationship between coffee consumption and response to anti-viral treatment in CHC has not been evaluated.

Methods: Eight hundred eighty five patients with CHC, Ishak stage 3-6, and failure to respond to previous standard interferon therapy completed a food frequency questionnaire assessing typical coffee intake prior to retreatment with peginterferon alfa-2a (180 ug/wk) and ribavirin (1000-1200 mg/day) in the lead-in phase of HALT-C. Outcomes included a two log10 drop in HCV RNA level at week 12 of treatment (early virologic response, EVR, n=466), undetectable HCV RNA at week 20 of treatment (W20VR, n=320), and sustained virologic response (SVR, n=157) at week 72 (24 weeks after treatment completion).

Results: At baseline, coffee intake over the previous year was coded as none (n=133), < 1 cup (n=253), 1 to <3 cups (n=367), or 3 cups per day (N=132). Among non-coffee drinkers, the median log10 drop from baseline to week 12 was 1.7 (interquartile range (IQR): 0.7-3.6), whereas among those who drank >/= 3 cups per day, the median log10 drop was 3.7 (1.8-4.2) (p for trend across categories <0.0001). Highly statistically significant trends for the percent of patients with EVR, W20VR, and SVR were seen with increasing coffee consumption (Table) with an effect that was strongest for >/= 3 cups per day. Coffee intake at baseline was associated with Caucasian race, current alcohol drinking, rs12979860 (IL28B) genotype, tolerating the maximum dose of peginterferon alfa-2a during treatment, higher baseline log10 HCV RNA, hemoglobin, platelet, and neutrophil count, lower AST/ALT ratio, and less cirrhosis at biopsy (p<0.05 for all). In multivariate analysis which included these covariates, the association of coffee with outcomes was attenuated but remained for EVR (p=0.005), W20VR (p=0.006), and SVR (p=0.039).

Conclusion: Pre-treatment coffee intake was independently associated with improved virologic response during peginterferon alfa-2a and ribavirin in the HALT-C trial.

daily coffee consumption of 3 or more cups was associated with 25.8% SVR vs 20.7% for 1-<3 cups and 12.7% for <1 cup and these are all statistically significant. Coffee increased EVR & week20 responses too.

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Also See: AASLD: More Evidence Coffee May Slow Liver Disease
Reported by Jules Levin
AASLD Nov 2 2010 Boston

C.Koh; T.Heller; V.Haynes-Williams; K.Hara; J.Feld; Y.Rotman; M.G.Ghany; T.Liang; J.H.Hoofnagle Liver Diseases Branch, NIH-NIDDK, Bethesda, MD

Introduction: The short-term goal of therapy of hepatitis C is viral eradication; but the long-term goal is prevention of liver-related disability or death. Although the short-term benefits of an SVR after therapy are established, the long-term clinical benefits are less defined. Aims: To assess changes in non-invasive markers of disease activity and fibrosis in a cohort of pts followed for up to 22 yrs after SVR.

Methods: The first 103 patients (pts) to achieve SVR after being treated at the National Institutes of Health, starting in 1984, using standard or peginterferon with or without ribavirin were evaluated. Serum markers of hepatic inflammation, synthetic function and fibrosis before treatment and at the last visit were compared. Pts evaluated since 2007 underwent transient elastography.

Results: Three of the 103 pts relapsed; 0.7, 6.4 and 6.5 years after therapy (10-year relapse rate of 5.7% by Kaplan-Meier analysis). The 100 remaining pts included 56 men; 88 whites, 4 African Americans, 8 Asians; average age at last visit 56 years (range 17 - 84); HCV genotype 1 in 45%, 2 and 3 in 53%, other in 2%. Pretreatment liver histology (99 pts) showed mild fibrosis (Ishak score 0-2) in 64, moderate (3-4) in 25, and cirrhosis (5-6) in 10. After SVR, pts were followed for 0.5 to 22 (median = 7.6) yrs. There were no cases of hepatic decompensation or liver cancer. Serum markers improved in all long-term responders, including mean ALT (from 152 to 27 U/L), AST (86 to 24 U/L), alkaline phosphatase (78 to 69 U/L), globulin (3.2 to 2.8 gm/dL), IgG (1462 to 1113 mg/dL), alpha fetoprotein (4.6 to 2.9 ng/mL), GGT (47 to 28 U/L), rheumatoid factor (38% to 19% positive), platelet count (208,000 to 239,000/uL) and AST-platelet ratio index (APRI: 0.99 to 0.25) (p < 0.001 for all). Transient elastography was successful in 75 pts and was normal (< 7.0 kPa) in 60%; moderately elevated (7.1-13.8) in 31%; and in the cirrhotic range (> 13.8) in 9%. Of 7 pts with cirrhosis before therapy, 6 had abnormal elastography at follow up. Elastography readings but not serum markers at the time of last follow up correlated with pre-treatment liver fibrosis (p=<0.001).

Conclusions: In long-term follow up, 97% of patients with an SVR maintained a virological response. No patients died of liver-related causes. Despite long-term SVR, patients with pre-existing cirrhosis still had evidence of hepatic fibrosis by transient elastography. Noninvasive markers of liver disease all improve over time. In chronic hepatitis C, SVR is associated with both short term and long-term benefits.
 
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Genetic Testing for Hepatitis C Virus Genotype 2 or 3 Infection

IL28B genotype was an independent predictor of sustained virologic response to HCV therapy.

Polymorphisms in the IL28B gene have been shown to play an important role in how patients infected with hepatitis C virus (HCV) genotype 1 develop chronic infection and respond to treatment (JW Gastroenterol Oct 16 2009). Now, researchers have evaluated the potential role of IL28B polymorphisms in patients infected with HCV genotype 2 or 3.

The study was a secondary analysis of a randomized trial in which 283 white patients with HCV genotype 2 or 3 received 12 or 24 weeks of peginterferon alfa-2b (1.0 µg/kg weekly) plus ribavirin (1000–1200 mg daily), depending on whether they had achieved rapid virologic response (RVR; undetectable viral load at 4 weeks; JW Gastroenterol Jul 26 2005). For the present analysis, 268 patients had available clinical, laboratory, and genetic data (IL28B genotyping of the rs12979860 single nucleotide polymorphism).

Of the 268 patients, 37% had IL28B genotype CC, 48% had genotype CT, and 15% had genotype TT. Sustained virologic response (SVR) was achieved by more genotype CC patients (82%) than genotype CT (75%) or TT (58%) patients (P=0.0046). However, this difference was evident only among patients who had not initially achieved RVR (87% SVR for CC vs. 67% for CT and 29% for TT; P=0.0002). In a multivariate analysis, IL28B genotype was a significant, independent predictor of SVR.

Comment: This analysis of previously well-characterized clinical-trial participants demonstrates the potential relevance of IL28B polymorphisms in HCV genotype 2 or 3 patients. The clinical value of genetic testing in HCV genotype 2 or 3 patients who achieve RVR is questionable, but it might be useful in patients who do not achieve RVR. Among non-RVR patients, the SVR rate was much lower for those with genotype TT than for patients with genotype CC or CT. Genotype TT patients might benefit from extended HCV therapy, possibly for 48 weeks. These preliminary, but clinically relevant, findings need to be validated in large prospective studies.

Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology November 5, 2010

Citation(s):

Mangia A et al. An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response. Gastroenterology 2010 Sep; 139:821.

Medline abstract (Free)

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Published on: 2010-11-05

There is a growing body of literature on the relationship of Hepatitis C virus infection (HCV) and type 2 diabetes mellitus (T2DM). However, there are certain gaps in literature and the data is inconclusive.

This study was, therefore, carried out to determine the prevalence of HCV infection in diabetic patients and to elucidate the presence of any possible relationship between HCV and T2DM in this region.

Methods: Serologic testing for anti-HCV antibody was done on a sample of 3000 individuals with T2DM visiting Diabetes Clinic of Nishtar Medical College Hospital, Multan and 10,000 volunteer blood donors visiting blood bank of the same hospital during the study period using Accurate rapid immunochromatographic kits which was later confirmed by using Chemelex S.A third generation ELISA kit for positive cases. Data about various variables was collected from diabetic patients using a structured questionnaire after taking informed consent.

Results: Prevalence rate of 13.7% for HCV infection was recorded among subjects having T2DM with seropositivity rate of 4.9% among the control group of volunteer blood donors without diabetes.

The patients with T2DM were more likely to have HCV infection as compared to the control group (OR= 3.03, 95%CI= 2.64-3.48, p= 0.001). Diabetic patients with age above 55 years had higher prevalence rate as compared to younger individuals.

Male patients had significantly high seropositivity as compared to female patients (15.3% vs. 12.4%, p=0.02).

Those with duration of diabetes 11 years and above and the ones with good glycemic control had higher seroprevalence rates of 18.2% and 18.7% respectively. There was no statistically significant difference among subjects when the distribution of HCV was studied on the basis of marital status, locality, or family history of diabetes.

Conclusions: The results show that there is a strong association between HCV and T2DM in the region as evident from significantly higher prevalence of HCV infection in diabetics as compared to the control group in the present study.

Author: Nauman JadoonMohammad ShahzadRehan YaqoobMansoor HussainNaseema Ali

Credits/Source: Virology Journal 2010, 7:304

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By Cheryl Lathrop

BOSTON -- November 5, 2010 -- Adding the probiotic VSL#3 to propranolol reduced the hepatic venous pressure gradient (HVPG) in patients with cirrhosis with large varices, according to a study presented here at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

"This novel therapy might provide alternative or adjunct therapy to beta-blockers in the management of patients with portal hypertension," said Nitin Gupta, MD, Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India, on November 1.

For the study, the researchers randomised 87 patients with cirrhosis and portal hypertension with large oesophageal varices (nonbleeders) to receive either propranolol plus placebo (group 1; n = 30); propranolol plus norfloxacin (group 2; n = 27) or propranolol + VSL#3 (group 3; n = 30).

Of these, 75 patients underwent the follow-up hepatic vein pressure gradient (HVPG) measurement, and thus completed the study: group 1 (n = 26), group 2 (n = 24), and group 3 (n = 25).

Propranolol was titrated to achieve a heart rate of 55 bpm or a maximum of 320 mg/day. The researchers studied splanchnic haemodynamics before and after 2 months of either treatment.

The primary endpoint was the change in HVPG compared with baseline; the secondary end point was the number of adverse events with therapy.

Addition of VSL#3 to propranolol synergistically increased the degree of reduction of HVPG in patients with cirrhosis with large varices. Responders were 31% in group 1, 46% in group 2, and 60% in group 3 (P =.046). The fall (comparison of change) in HVPG was 2.1 mm Hg in group 1, 3.3 mm Hg in group 2, and 3.7 mm Hg in group 3.

VSL#3 was well tolerated without significant side effects. The number of patients with adverse events did not differ significantly between the groups.

[Presentation title: Addition of Probiotics to Propranolol Improves Response for Primary Prophylaxis of Variceal Bleeding in Patients With Cirrhosis and Large Esophageal Varices. Abstract 1556]

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Better Hepatitis C Surveillance Helps Public, CDC Finds

Health departments' program seems to provide more accurate, timely reporting

Posted: November 5, 2010

FRIDAY, Nov. 5 (HealthDay News) -- Enhanced surveillance of acute hepatitis C infections in the United States offers more timely and complete case reporting that provides greater benefits to public health, a new study concludes.

Each year in the United States, HCV infection affects nearly 4 million people and causes about 12,000 deaths, and the U.S. Institute of Medicine recently recommended a comprehensive evaluation of the nation's hepatitis B and C surveillance system.

Researchers at the U.S. Centers for Disease Control and Prevention (CDC) compared 2008 data on acute hepatitis C (HCV) collected from two sources: the National Notifiable Diseases Surveillance System (the CDC's nationwide system for disease reporting) and the Emerging Infections Program (EIP), a CDC-funded network of health departments in selected states that gathers detailed information meant to improve public health responses to emerging infectious diseases.

EIP sites reported 26 (22 percent ) more acute HCV cases than the 94 cases reported by NNDSS. Information on race and major HCV risk factors was absent from 22 percent and 60 percent of NNDSS reports, respectively, compared with 8 percent and 25 percent of EIP reports, respectively.

The average length of time between diagnosis and reporting of acute HCV cases to the state health department was 30 days (range 0 to 298 days) in NNDSS, compared with 19 days (range 0 to 350 days) in EIP sites, the study found.

"These findings underscore that enhanced surveillance for acute hepatitis C improves the completeness and timeliness of the data," the researchers wrote.

Between 2010 and 2019, the direct medical cost of chronic HCV infection could exceed $10.7 billion, the cost of HCV-related premature death could be $54.2 billion, and the cost of HCV-related disability could be $21.3 billion, according to the study.

The study appears in the latest issue of Morbidity and Mortality Weekly Report, published by the CDC.

More information
The American Academy of Family Physicians has more about hepatitis C.

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Nov. 5, 2010, 8:00 a.m. EDT

OCEANSIDE, Calif., Nov 05, 2010 (BUSINESS WIRE) -- International Stem Cell Corporation /quotes/comstock/11k!isco (ISCO 1.45, -0.02, -1.36%) , www.internationalstemcell.com, announced today that the recent presentation entitled "Hepatocyte-like cells derived from patient-specific human parthenogenetic stem cells possess functions of mature human hepatocytes including P450 activity" has been identified as an "AASLD Presidential Poster of Distinction" in the Stem Cells session of The Liver Meeting, the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), in Boston, MA, one of the most prestigious annual medical and scientific conferences. The abstract of the presentation is published in the peer-reviewed supplement to Hepatology, volume 52, number 4 (SUPPL), Oct. 2010, pg 965A, the official journal of the AASLD.

ISCO's CEO Andrey Semechkin, Ph.D., said, "For our cell biologists to have received this award from the leading society in the U.S. focused on treating liver diseases, demonstrates the high caliber of research being carried out at ISCO, and that human parthenogenetic stem cells and their differentiated derivatives are becoming of greater interest to the medical research community as a potential source of therapeutically valuable cells."

ISCO also announced today the initiation of the first in a series of animal studies designed to demonstrate whether hepatocytes and their progenitors derived from the human parthenogenetic stem cells show any disease modifying activity in vivo.

Dr. Nikolay Turovets, ISCO's Director of Research and Therapeutic Development said, "ISCO's continued focus on therapeutic development is critical to show that hepatocytes derived from stem cells can reproduce missing liver function in a diseased organism. Our first series of experiments are designed to test the ability of our cells to engraft and survive in vivo. A second set of experiments will investigate the functional activity of successfully engrafted cells. Data from these studies will also be used to guide the development of future IND submissions."

In other research news, ISCO announced that a grant in which ISCO is a partner, was recently funded by the Qualified Therapeutic Discovery Project Grants Program created under the healthcare reform legislation enacted last March. The study is led by Paul H. Chen, M.D. to investigate healing after corneal surgery using ISCO's corneal epithelial cells developed by ISCO's wholly-owned subsidiary Lifeline Cell Technology. ISCO's cells, combined with a proprietary surgical device developed by Dr. Chen, may provide safer and better long term results than LASIK. By utilizing ISCO's human corneal cells, ISCO and Dr. Chen believe that cellular enhanced PRK could eventually replace LASIK for many of the hundreds of thousands of patients who require corrective eye surgery.

According to Dr. Chen, "This collaborative work with ISCO could lead to a safer and more effective treatment that hopefully will provide quicker visual recovery, less pain, and an improved refractive correction outcome."

ABOUT INTERNATIONAL STEM CELL CORPORATION (ISCO.OB)

International Stem Cell Corporation is a California-based biotechnology company focused on therapeutic and research products. ISCO's core technology, parthenogenesis, results in creation of pluripotent human stem cells from unfertilized oocytes (eggs). These proprietary cells avoid ethical issues associated with use or destruction of viable human embryos and, unlike most other major stem cell types, can be immune matched and be a source of therapeutic cells with minimal rejection after transplantation into hundreds of millions of individuals of differing racial groups. ISCO also produces and markets specialized cells and growth media for therapeutic research worldwide through its subsidiary, Lifeline Cell Technology, and is developing a line of cosmeceutical products via its subsidiary, Lifeline Skin Care. ISCO is advancing novel human stem cell-based therapies where cells have been proven to be efficacious but traditional small molecule and protein therapeutics have not. More information is available on ISCO's website, http://www.internationalstemcell.com/.

To subscribe to receive ongoing corporate communications please click on the following link: http://www.b2i.us/irpass.asp?BzID=1468&to=ea&s=0.

FORWARD-LOOKING STATEMENTS

Statements pertaining to anticipated developments and therapeutic applications, the potential benefits of collaborations, affiliations, and other opportunities for the company and its subsidiaries, along with other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management constitute forward-looking statements. Any statements that are not historical fact (including, but not limited to statements that contain words such as" could", "will," "believes," "plans," "anticipates," "expects," "estimates,") should also be considered to be forward-looking statements. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential products and the management of collaborations, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital, application of capital resources among competing uses, and maintenance of intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the company's business, particularly those mentioned in the cautionary statements found in the company's Securities and Exchange Commission filings. The company disclaims any intent or obligation to update forward-looking statements.

Key Words: Stem cells, parthenogenesis, biotechnology, hepatocytes, liver disease

SOURCE: International Stem Cell Corporation

International Stem Cell Corporation
Jeffrey D. Janus
Sr. Vice President, Operations
1-760-940-6383
jjanus@intlstemcell.com
or
Nikolay Turovets, Ph.D.
Director of Research and Therapeutic Development
nturovets@intlstemcell.com

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Studies Assess Genes in Ribavirin-Induced Anemia

Two variants in the ITPA gene that cause inosine triphosphatase deficiency are linked to protection from ribavirin-induced hemolytic anemia in patients with hepatitis C virus, and a missense substitution on the ITPA gene influences ribavirin-induced anemia in Japanese patients with the virus, according to two studies published in the October issue of Gastroenterology.

THURSDAY, Nov. 4 (HealthDay News) -- Two variants in the ITPA gene that cause inosine triphosphatase (ITPase) deficiency are linked to protection from ribavirin-induced hemolytic anemia in patients with hepatitis C virus (HCV), and a missense substitution on the ITPA gene influences ribavirin-induced anemia in Japanese patients with the virus, according to two studies published in the October issue of Gastroenterology.

In the first study, Alexander J. Thompson, M.D., of the Duke Clinical Research Institute in Durham, N.C., and colleagues analyzed data from 304 patients with genotype 1 HCV who were treated with pegylated interferon and ribavirin. Two ITPA variants were associated with hemoglobin reduction at week four. The minor alleles of each were linked to protection from the reduction. An ITPase deficiency variable -- combining both ITPA variants -- was linked to lower rates of anemia over the 48-week treatment period and a lower rate of ribavirin dose reduction for anemia.

In the second study, Hidenori Ochi, of the RIKEN Center for Genomic Medicine in Hiroshima, Japan, and colleagues analyzed data from 923 patients with HCV-1b also treated with pegylated interferon and ribavirin. They found that hemoglobin decline wasn't correlated with ITPA expression level, indicating that the single nucleotide polymorphism rs1127354 is a single causal variant linked to ribavirin-induced anemia in Japanese patients with HCV.

This research "suggests that rs1127354 would be a useful marker for prediction of ribavirin-induced anemia. Moreover, genetic testing of ITPA variants might be applied to establish personalized dosages in pegylated-interferon and ribavirin combined therapy," Ochi and colleagues conclude.

Several co-authors of the first study disclosed a patent application based on the ITPA discovery. The second study was partly supported by Dainippon Sumitomo Pharma Co. Ltd. and RIKEN.

Abstract - Thompson
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Abstract - Ochi
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Bob Roehr

November 4, 2010 (Boston, Massachusetts) — A 4-week lead in the dosing of 2 oral small-molecule drugs was able to reduce the level of hepatitis C virus (HCV) RNA to undetectable levels in a small number of patients before either ribavirin (RBV) or an interferon/RBV combination was added to the regimen.

Results from the phase 2 pilot study were presented by Stefan Zeuzem, MD, from the Goethe University Hospital in Frankfurt, Germany, here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting. It involved 2 compounds in development by Gilead Sciences.

GS-9256 targets the serine NS3 protease. In an earlier 3-day trial, it showed a 2.9-log mean maximal reduction in HCV RNA levels at a dose of 75 mg taken twice daily. GS-9190 (tegobuvir) is a nonnucleoside polymerase inhibitor that targets the NS5B region of the viral RNA, and in earlier studies it has shown a 1.6-log maximum reduction during 1 week at a dose of 40 mg taken twice daily, Dr. Zeuzem explained.

The researchers enrolled treatment-naive genotype 1 patients with HCV RNA levels greater than 1000 IU/mL and randomly assigned them to 3 groups:

• 9256 75 mg taken twice daily + 9190 40 mg taken twice daily (n = 16),

• 9256 75 mg taken twice daily + 9190 40 mg taken twice daily + weight-based RBV (n = 15), and

• 9256 75 mg taken twice daily + 9190 40 mg taken twice daily + weight-based RBV + pegylated interferon 180 μg every week (n = 15).

At the end of 4 weeks, all patients were continued on standard of care (SOC), consisting of pegylated interferon ± RBV. Patients in the first 2 groups who did not show at least a 2-log decline in HCV RNA levels by day 5 or who experienced viral breakthrough and relapse at any point during the first 4 weeks of the study could, at the discretion of the treating physician, immediately initiate SOC.

"The virologic response showed a median maximal change from baseline of 4.1, 5.1, and 5.7 log10 IU/mL decline in HCV RNA, respectively," said Dr. Zeuzem. "At day 14 of treatment, HCV RNA levels were below 25 in 1, 6, and 10 patients in the respective groups." At day 28, the numbers were 1/15, 5/13, and 14/14, respectively.

A significant portion of patients in the first group experienced viral breakthrough and were switched to SOC. Addition of RBV resulted in "a somewhat more profound" initial steep decline in viremia: "[C]learly the addition of ribavirin prevented the breakthrough in the majority of patients." The group using all 4 drugs did not experience viral breakthrough.

"The vast majority of patients, 11 of 15, rapidly selected for mutants in the protease region, typically at positions 168 and 155 [D168V/E/N, and/or R155K], as well as in the NS5B region at positions 445 and 448 [Y445H and Y448H]," Dr. Zeuzem said.

Adverse effects were most common in the group containing SOC. The maximum increase in bilirubin was 1.3, 1.6, and 3.0 times the upper limit of normal in the respective groups.

Dr. Zeuzem said the new drug combination "had robust antiviral activity. Interestingly, and perhaps also surprisingly, the addition of ribavirin demonstrated a substantially greater viral suppression," reduced the emergence of resistance, and was well tolerated. "The quad combination achieved 100% [rapid viral response] rates without breakthroughs."

During discussion, Dr. Zeuzem said this study supports the hypothesis that at least 1 mechanism of action of ribavirin is a direct antiviral effect on HCV, and that it does not work simply by modulating gene expression for production of interferon.

Evaluation of a 16-week course of the 4-drug combination is ongoing.

Responding to a question from the audience, Dr. Zeuzem said "the trough levels of the compounds were 40 to 50 times higher than the EC50, which is required for these compounds in vivo — well above what is required to maintain constant suppression of viral replication." There is no need to boost them, as is being considered with some other protease inhibitors, he added.

Session cochair Douglas R. LaBrecque, MD, director of Liver Services at University of Iowa Health Care, Iowa City, called the results promising but cautioned that the study was quite small and preliminary. It is likely to take several years before phase 3 data become available.

Gilead Sciences supported the study. Dr. Zeuzem is an academic investigator who participated in the study and has ongoing consulting and speaking arrangements with the company. Dr. LaBrecque has disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting: Late-Breaking Abstract 1. Presented November 1, 2010.

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