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More patients relapse in Gilead hepatitis C (*) trial

Two more patients in a 10-patient segment of a mid-stage trial testing Gilead Sciences Inc's experimental hepatitis C drug GS-7977 had the virus return within four weeks of treatment, researchers said on Tuesday.

The company, which recently paid nearly $11 billion to acquire the drug and its developer, Pharmasset, said last month that six out of 10 patients with a prior "null response" to standard hepatitis C therapy saw the virus return within four weeks of treatment with a combination of GS-7977 and the antiviral drug ribavirin.

The latest results from the mid-stage trial bring to eight the number of patients who have relapsed.

One patient has not reached the four-week point and the other showed a response to the drug, Dr. Edward Gane from New Zealand's Auckland City Hospital and the study's lead investigator said here at the Conference on Retroviruses and Opportunistic Infections.

The trial segment he updated involved patients infected with genotype 1 hepatitis C -- the most common, but also the most difficult to treat, subset of the disease.

"The majority of null responders have relapsed post treatment," Dr. Gane said, adding that such patients will likely need either a longer duration of therapy or combination treatment with other direct-acting antiviral agents.

He said the relapsed patients will be offered a "rescue protocol" in the form of another trial of GS-7977 in combination with a different experimental drug.

Shares of Gilead have dropped 18 percent since the company's announcement of the trial results, which suggested that an all-oral treatment for hepatitis C may be further away than many had hoped.

Dr. Gane said ongoing pivotal-stage trials of GS-7977 "should establish that interferon-free treatment is not a dream. It's a reality that should be here within the next five years."

Current hepatitis C drug regimens require injections of interferon, which causes severe flu-like symptoms and cannot be tolerated by some patients.

GS-7977 is designed to block an enzyme essential to the replication of the hepatitis C virus. It is one of a new class of treatments designed to be given without injections of interferon, which helps boost the body's immune system but can also cause debilitating flu-like side effects.

Gilead has said it expects to announce at the end of this month results from a mid-stage trial of GS-7977 in previously untreated hepatitis C patients. (Reuter 06/03/2012)

(*)Hepatitis C is a liver-destroying disease that affects some 170 million people worldwide. Untreated, it can lead to cirrhosis, liver cancer and the need for a liver transplant.

New Direct-acting Antivirals in the Development for Hepatitis C Virus Infection

Paul J. Pockros, MD(*)

Posted: 01/26/2011; Ther Adv Gastroenterol. 2010;3(3):191-202. © 2010 Sage Publications, Inc.

Abstract

A large number of new therapies are in development for chronic hepatitis C including direct-acting antiviral drugs (DAA), which target specific hepatitis C virus enzymes. Two of these compounds have already advanced into phase 3 development in the USA and EU, and many more are in phase 2 trials and likely to advance. In this review, the results of recent studies on ribavirin analogues, nonstructural (NS) 3/4 serine protease inhibitors, NS5B polymerase inhibitors, cyclophilin inhibitors, silimarin components, and thiazolides have been updated. Each compound includes a brief summary of its proposed mechanism of action, results of early clinical trials, and more advanced trial data where available. These compounds are likely to be the first approved in the USA and EU and will initially be used in combination with the current standard of care. It is possible that future treatment paradigms with these agents will offer the potential of interferon-free regimens. It is most likely that patients for these new therapies will be selected carefully by identifying and treating first those who have excellent sustained virologic response rates with 24 weeks of pegylated interferon and ribavirin, the current standard of care. It is also likely that there will be a need to identify those patients who are not likely to have a sustained virologic response with the addition of a protease inhibitor to the current standard of care and delaying their therapy until combination viral suppression therapy becomes an option. The cost and side effects of the DAA will be important considerations for treating physicians. This review is current through 2009; however, data are rapidly changing.

(*) Paul J. Pockros, MD

Head, Division of Gastroenterology/Hepatology, Scripps Clinic, 10666 N Torrey Pines Road, La Jolla, CA 92037, USA pockros.paul@scrippshealth.org

Correspondence to
Paul J. Pockros, MD Head, Division of Gastroenterology/Hepatology, Scripps Clinic, 10666 N Torrey Pines Road, La Jolla, CA 92037, USA pockros.paul@scrippshealth.org

Source: www.medscape.com

Risk Factors for Hepatocellular Carcinoma in a Cohort Infected With Hepatitis B or C

Scott R Walter; Hla-Hla Thein; Heather F Gidding; Janaki Amin; Matthew G Law; Jacob George; Gregory J Dore

Posted: 12/28/2011; J Gastroenterol Hepatol. 2011;26(12):1757-1764. © 2011 Blackwell Publishing

Abstract

Background and Aim: The incidence of hepatocellular carcinoma (HCC) has increased in Australia in recent decades, a large and growing proportion of which occurs among a population chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). However, risk factors for HCC among these high-risk groups require further characterization.
Methods: We conducted a population-based cohort study using HBV and HCV cases notified to the New South Wales Health Department between 2000 and 2007. These were linked to cause of death data, HIV/AIDS notifications, and hospital records. Proportional hazards regression was used to identify significant risk factors for developing HCC.
Results: A total of 242 and 339 HCC cases were linked to HBV (n = 43 892) and HCV (n = 83 817) notifications, respectively. For both HBV and HCV groups, being male and increasing age were significantly associated with risk of HCC. Increasing comorbidity score indicated high risk, while living outside urban areas was associated with lower risk. Hazard ratios for males were two to three times those of females. For both HBV and HCV groups, cirrhosis, alcoholic liver disease, and the interaction between the two were associated with significantly and considerably elevated risk.
Conclusion: This large population-based study confirms known risk factors for HCC. The association with older age highlights the potential impact of HBV and HCV screening of at-risk groups and early clinical assessment. Additional research is required to evaluate the impact of improving antiviral therapy on HCC risk.

Source: www.medscape.com

Natural Variation in Drug Susceptibility to HCV Polymerase Inhibitors in Treatment-naïve HCV Patient Isolates

S.-C. C. Sun(*); A. Bae; X. Qi; J. Harris; K. A. Wong; M. D. Miller; H. Mo

Posted: 12/27/2011; J Viral Hepat. 2011;18(12):861-870. © 2011 Blackwell Publishing

Abstract

To assess the natural variation in drug susceptibility among treatment-naïve hepatitis C virus (HCV) patient isolates, the susceptibilities of chimeric replicons carrying the HCV NS5B polymerase from up to 51 patient isolates against a panel of diverse HCV nonnucleoside polymerase inhibitors were evaluated using a replicon-based transient replication assay. Some patient to patient variation in susceptibility to the panel of three HCV nonnucleoside polymerase inhibitors was observed. Linear regression and correlation analyses revealed no correlations among the susceptibilities to the polymerase inhibitors tested. Our results suggest that variable antiviral responses to HCV nonnucleoside polymerase inhibitors may be observed because of the natural variation in baseline susceptibility. In addition, the lack of correlation among the susceptibilities to three classes of HCV polymerase inhibitors evaluated here supports their possible combined use in a combination therapy strategy.

(*)S.-C. C. Sun, A. Bae, X. Qi, J. Harris, K. A. Wong, M. D. Miller and H. Mo

Department of Clinical Virology, Gilead Sciences, Inc., Foster City, CA, USA

Correspondence
Hongmei Mo, Department of Clinical Virology, Gilead Sciences, Inc., 333 Lakeside Dr, Foster City, CA 94404, USA. E-mail: Hongmei.Mo@gilead.com

ource: www.medscape.com

Understanding the Host Genetics of Chronic Hepatitis B and C

Mark Thursz, M.D (*)., F.R.C.P.; Leland Yee, Ph.D.; Salim Khakoo, M.D., F.R.C.P.

Posted: 07/05/2011; Semin Liver Dis. 2011;31(2):115-127. © 2011 Thieme Medical Publishers

Abstract

The outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are heterogeneous, ranging from an asymptomatic self-limiting infection to cirrhosis and hepatocellular carcinoma. Several viral environmental and demographic variables have been identified as determinants of disease outcome, but these fail to explain a large proportion of the variability. Evidence from twin studies suggests that the host genetic background is an important contributor to disease outcome. Identification of genes that influence the outcome of infection has been attempted using a wide spectrum of approaches including candidate gene disease association studies, genome-wide scanning in affected sibling pairs and most recently genome-wide association studies. We summarize the main findings from a large number of studies in this review. Many studies have focused on the MHC loci from which several reproducible disease associations have been identified. More recently, genome-wide association studies have identified an important locus within the IL-28 - Il-29 region on chromosome 29, which appears to be a major determinant of the treatment response in patients infected with HCV and also a determinant of spontaneous resolution of infection. Translation of the genetic architecture of chronic viral hepatitis into therapeutic opportunities has been slow to proceed. One clinical trial and one drug development program have been based on genetic discoveries. The use of IL-28B genotyping to predict the response to pegylated interferon and ribavirin may also find its way into clinical practice. Indeed, stratification of clinical trial populations based on IL-28B genotype is already considered mandatory.

(*)Mark Thursz, M.D., F.R.C.P.,1 Leland Yee, Ph.D.,2 and Salim Khakoo, M.D., F.R.C.P.1

1Hepatology and Gastroenterology Section, Department of Medicine, Imperial College, London, United Kingdom; 2Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Address for correspondence and reprint requests
Mark Thursz, M.D., F.R.C.P., Professor, Imperial College, St Mary's Hospital Campus, Norfolk Place, London W2 1NY, United Kingdom (e-mail: m.thursz@ac.uk).

Dissecting the Genetic Contribution to Liver Disease; Guest Editors, Tom H. Karlsen, M.D., and Konstantinos N. Lazaridis, M.D.

Genes and Hepatitis C

Susceptibility, Fibrosis Progression and Response to Treatment

Manuel Romero-Gomez; Mohamed Eslam; Agustín Ruiz; Marta Maraver

Posted: 04/28/2011; Liver International. 2011;31(4):443-460. © 2011 Blackwell Publishing

Abstract

Hepatitis C virus contact and infection show three different phenotypes: spontaneous viral clearance (SVC), chronic hepatitis C (CHC) and sustained virological response (SVR) following antiviral treatment. Many factors, including genetics, influence the evolution of these three phenotypes. We performed a literature search (PubMed) up to 31 January 2010 without language restriction to identify relevant studies on genes and hepatitis C. Additional studies were sought by reviewing the reference lists of the identified articles. Meta-analysis (using Meta-disk 1.4) was conducted to evaluate the association of single nucleotide polymorphism (SNP) in the IL28B region and SVR. The candidate gene approach showed strong relationships between human leucocyte antigen class II (DQB1*0301 and DRB1*1101) and SVC. A cirrhosis risk score involving 7 SNPs has been validated recently. The set of odds ratios of studies demonstrated an association between SNP (rs12987960/rs8099917) in the IL28B and SVR in CHC treated with peginterferon plus ribavirin (OR: 4.6; 95% CI: 2.9–7.3). The overall distribution of protective allele correlated with ethnic differences in SVR (Asians, Europeans, Hispanic and Afro-Americans) together with SVC, but not with fibrosis stage or viral load. These polymorphisms did not influence SVR in very-easy-to-treat patients such as genotype 2/3, rapid virological responders or patients with acute hepatitis C. While the genetic fingerprint for fibrosis progression remains elusive, IL28b polymorphism predicts SVC and SVR. However, nearly half of patients achieving SVR did not show favourable genotype. Further genetic signals are warranted to complete the puzzle of factors influencing hepatitis C.

Manuel Romero-Gomez1, Mohamed Eslam1, Agustín Ruiz2 and Marta Maraver1

1 Unit for the Clinical Management of Digestive Diseases and Ciberehd, Hospital Universitario de Valme, Sevilla, Spain
2 Department of Structural Genetics, Neocodex S.A., Sevilla, Spain

Correspondence
Manuel Romero-Gómez, MD, PhD, Unit for the Clinical Management of Digestive Diseases and Ciberehd, Hospital Universitario de Valme, Universidad de Sevilla, 41014 Sevilla, Spain Tel: 134 955 01 57 61 Fax: 134 955 01 58 99 E-mail: mromerogomez@us.es

Source: www.medscape.com

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