January 31, 2011

Hepatology. 2011 Jan;53(1):14-22. doi: 10.1002/hep.24056.

Darling JM, Aerssens J, Fanning G, McHutchison JG, Goldstein DB, Thompson AJ, Shianna KV, Afdhal NH, Hudson ML, Howell CD, Talloen W, Bollekens J, De Wit M, Scholliers A, Fried MW.

University of North Carolina, Chapel Hill, NC.

Abstract

Polymorphisms of the IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of interferon-γ-inducible protein-10 (IP-10) may also differentiate antiviral response. We evaluated IP-10 levels in pretreatment serum from 115 nonresponders and 157 sustained responders in the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African American (AA) and Caucasian American (CA) patients. Mean IP-10 was lower in sustained responders compared with nonresponders (437 ± 31 vs 704 ± 44 pg/mL, P < 0.001), both in AA and CA patients. The positive predictive value of low IP-10 levels (<600 pg/mL) for SVR was 69%, whereas the negative predictive value of high IP-10 levels (>600 pg/mL) was 67%. We assessed the combination of pretreatment IP-10 levels with IL28B genotype as predictors of treatment response. The IL28B polymorphism rs12979860 was tested in 210 participants. The CC, CT, and TT genotypes were found in 30%, 49%, and 21% of patients, respectively, with corresponding SVR rates of 87%, 50%, and 39% (P < 0.0001). Serum IP-10 levels within the IL28B genotype groups provided additional information regarding the likelihood of SVR (P < 0.0001). CT carriers with low IP-10 had 64% SVR versus 24% with high IP-10. Similarly, a higher SVR rate was identified for TT and CC carriers with low versus high IP-10 (TT, 48% versus 20%; CC, 89% versus 79%). IL28B genotype and baseline IP-10 levels were additive but independent when predicting SVR in both AA and CA patients. Conclusion: When IL28B genotype is combined with pretreatment serum IP-10 measurement, the predictive value for discrimination between SVR and nonresponse is significantly improved, especially in non-CC genotypes. This relationship warrants further investigation to elucidate the mechanisms of antiviral response and prospective validation. (Hepatology 2011;).

Copyright © 2010 American Association for the Study of Liver Diseases.

PMID: 21254158 [PubMed - in process]

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Hepatology. 2011 Jan;53(1):317-24. doi: 10.1002/hep.24074.

Charlton MR, Thompson A, Veldt BJ, Watt K, Tillmann H, Poterucha JJ, Heimbach JK, Goldstein D, McHutchison J.

Division of Gastroenterology and Hepatology and. charlton.michael@mayo.edu

Abstract

Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related). Conclusion: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection. (Hepatology 2011;).

Copyright © 2010 American Association for the Study of Liver Diseases.

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Eur J Gastroenterol Hepatol. 2011 Jan 20. [Epub ahead of print]

Singal AK, Sagi S, Kuo YF, Weinman S.

aDepartment of Internal Medicine, Division of Gastroenterology bDepartment of Internal Medicine cBiostatististics, Center for Aging, University of Texas Medical Branch, Galveston, Texas dLiver Center and Department of Internal Medicine, University of Kansas, Kansas City, Kansas, USA.

Abstract

BACKGROUND AND AIMS: Limited information is available on the impact of hepatitis C virus (HCV) infection on the clinical course and outcome of acute alcoholic hepatitis (AH), a condition with a significant mortality. We designed this retrospective study to assess effect of HCV on the outcome of patients with AH.

METHODS: Medical charts of patients with a discharge diagnosis of AH (defined using rigorous clinical criteria) were reviewed. Patients were stratified based on the presence or absence of concomitant HCV infection. The disease severity was estimated at admission and at day 7 using model for end-stage disease and discriminant function index scores. Patient survival at 6 months was confirmed with the county death registry. RESULTS : A total of 76 (29 HCV positive) AH cases were analyzed. At admission, disease severity was similar in both groups with severe disease in 53% (49% of AH alone and 59% of AH+HCV; P=0.18). Although severity scores at day 7 were not available for all patients, disease severity tended to be worse for patients with AH+HCV. Kaplan-Meier survival curves showed a poor survival for AH+HCV compared with AH alone (69 vs. 91%; log-rank P=0.015). Although patients with AH+HCV were treated less often compared with AH alone (27 vs. 54%; P=0.05), HCV emerged as an independent risk factor for a poor outcome at 6 months (Cox proportional hazard ratio 8.45; P=0.01) after controlling for patient demographics, disease severity at admission, and treatment.

CONCLUSION: HCV may be a risk factor for patients with AH with a worse outcome at 6 months. If our findings are confirmed in larger databases, prospective studies are needed to examine mechanisms for this effect of HCV on the outcome of AH.

PMID: 21258239 [PubMed - as supplied by publisher]

Source
Public release date: 31-Jan-2011

Contact: John Heys
jheys@idsociety.org
703-299-0412
Infectious Diseases Society of America

Research suggests improvements in prevention and treatment efforts needed

[EMBARGOED FOR JAN. 31, 2011] A recent 20-year study of injection drug users (IDUs) in Baltimore found a significant decline in new cases of HIV infection but only a slight decline in new cases of hepatitis C virus (HCV) infection. The findings suggest that efforts to curb blood-borne transmission of these viral infections have had success but must be expanded against the highly transmissible HCV. Researchers from Johns Hopkins School of Public Health and other centers, led by Shruti H. Mehta, PhD, MPH, report the findings in the March 1 issue of The Journal of Infectious Diseases, now available online. (Please see below for a link to the embargoed study online.)

Previous data had suggested that HIV incidence among IDUs has declined. This trend is often attributed in part to harm reduction measures, including needle exchange programs and substance abuse treatment. However, these measures have not been as successful in lowering the rates of HCV incidence and prevalence. For example, HCV infection is nearly 10 times more transmissible by sharing needles than is HIV infection. Sharing a needle even once can be enough to transmit HCV.

The investigators found that new cases of HIV infection declined dramatically across four different time periods during the past 20 years, from 5.5 per 100 person-years (PY) in 1988-'89, to two per 100 PY in 1994-'95, and to zero cases in 1998 and 2005-'08. While researchers also observed reductions in new cases of HCV infection, these were not nearly as substantial: from 22 per 100 PY in 1988-'89, to 17.2 per 100 PY in 1994-'95, to 17.9 in 1998, and to 7.8 per 100 PY in 2005-'08. Overall, cases appeared to decline only among younger IDUs, who had started injecting drugs recently.

According to researchers, these data suggest that "current prevention efforts delay but do not prevent HCV at the population level and will need to be further intensified to reduce risk of HCV infection to the level of HIV." Efforts on both the prevention and the treatment fronts to reduce the reservoir of HCV-infected IDUs will have to be expanded, the investigators concluded.

In an accompanying editorial, Jason Grebeley, PhD, and Gregory J. Dore, MB BS, MPH, PhD, of the University of New South Wales in Australia, agreed that higher prevalence of HCV infection and greater transmission risk following an injection with a contaminated syringe as compared to HIV have hampered harm reduction measures. They also noted that current implementation of harm reduction measures in most settings is inadequate. Rates of equipment sharing remain high, and access to opioid substitution therapy and other drug treatment programs is limited.

The editorial authors also pointed out the impact that an HCV vaccine could have on new cases of HCV infection. Though a highly efficacious vaccine has not yet been discovered, efforts to do so are crucial. They suggested that even though the window for preventing HCV may be small, improvements in HCV prevention are feasible.

###

Fast Facts:

1) Among the community of injection drug users (IDUs) in Baltimore, HIV incidence declined dramatically over 20 years, while new cases of hepatitis C virus (HCV) infection declined only slightly.

2) HIV incidence decreased from 5.5 per 100 person-years (PY) in 1988-'89, to two per 100 PY in 1994-'95, and to zero in 1998 and 2005-'08. The declines in HCV infection were not nearly as substantial: from 22 per 100 PY in 1988-'89, to 17.2 per 100 PY in 1994-'95, to 17.9 in 1998, and to 7.8 per 100 PY in 2005-'08.

3) Prevention and treatment efforts must be expanded to reduce the number of HCV infections among IDUs.

NOTE: The study and the accompanying editorial are available online. They are embargoed until 12:01 a.m. EST on Monday, Jan. 31, 2011:

"Changes in Blood-borne Infection Risk Among Injection Drug Users" http://www.oxfordjournals.org/our_journals/jid/jiq112.pdf

"Prevention of Hepatitis C Virus in Injecting Drug Users: A Narrow Window of Opportunity" http://www.oxfordjournals.org/our_journals/jid/jiq111.pdf

Founded in 1904, The Journal of Infectious Diseases is the premier publication in the Western Hemisphere for original research on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune mechanisms. Articles in JID include research results from microbiology, immunology, epidemiology, and related disciplines. JID is published under the auspices of the Infectious Diseases Society of America (IDSA). Based in Arlington, Va., IDSA is a professional society representing more than 9,000 physicians and scientists who specialize in infectious diseases. For more information, visit http://www.idsociety.org/.

Source
J Gastroenterol Hepatol. 2011 Feb;26(2):228-39. doi: 10.1111/j.1440-1746.2010.06488.x.

Liu CH, Kao JH.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.

Abstract

Hepatitis C virus (HCV) infection is a major health problem in patients with end-stage renal disease (ESRD). The incidence of acute HCV infection during maintenance dialysis is much higher than that in the general population because of the risk of nosocomial transmission. Following acute HCV infection, most patients develop chronic HCV infection, and a significant proportion develop chronic hepatitis, cirrhosis, and even hepatocellular carcinoma. Overall, chronic hepatitis C patients on hemodialysis bear an increased risk of liver-related morbidity and mortality, either during dialysis or after renal transplantation. Interferon (IFN) therapy is modestly effective for the treatment of HCV infection in ESRD patients. Conventional or pegylated IFN monotherapy has been used to treat acute hepatitis C in ESRD patients with excellent safety and efficacy. Regarding chronic hepatitis C, approximately one-third of patients can achieve a sustained virological response (SVR) after conventional or pegylated IFN monotherapy. The combination of low-dose ribavirin and conventional or pegylated IFN has further improved the SVR rate in treatment-naïve or retreated ESRD patients in clinical trials. Similar to the treatment of patients with normal renal function, baseline and on-treatment HCV virokinetics are useful to guide optimized therapy in ESRD patients. Of particular note, IFN-based therapy is not recommended at the post-renal transplantation stage because of the low SVR rate and risk of acute graft rejection. In conclusion, ESRD patients with HCV infection should be encouraged to receive antiviral therapy, and those who achieve an SVR usually have long-term, durable, virological, biochemical, and histological responses.

© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

PMID: 21261711 [PubMed - in process]

Source

Chemoprevention of hepatocellular carcinoma in chronic hepatitis C

Recent Results Cancer Res. 2011;188:85-99.

Morgan TR.

Gastroenterology Section, VA Long Beach Healthcare System, 5901 E. Seventh Street - 11, Long Beach, CA, 90822, USA, timothy.morgan@va.gov.

Abstract

Hepatitis C virus (HCV) infection causes chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma (HCC). The incidence of hepatocellular carcinoma in the United States tripled between 1975 and 2005, and is expected to increase further, and to remain elevated for more than 20 years. Curing hepatitis C infection in patients with cirrhosis through treatment with peginterferon and ribavirin reduces the risk of developing hepatocellular carcinoma. Several noncurative treatments also appear to reduce the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Prospective studies report a reduced incidence of hepatocellular carcinoma among patients treated with a mixture of carotenoids with or without myo-inositol, with vitamin K(2), or with polyprenoic acid (an acyclic retinoid). Uncontrolled and/or retrospective studies have reported beneficial effects of treatment with Sho-saiko-to, glycyrrhizin and ursodeoxycholic acid on hepatocellular carcinoma incidence. Meta-analyses of epidemiologic studies show a reduced risk of hepatocellular carcinoma among liver disease patients who drink two or more cups of coffee per day. Numerous agents prevent or reduce hepatocarcinogenesis in animal models. An ongoing Phase II clinical trial is evaluating S-adenosylmethionine (SAMe) as a potential chemopreventive agent in hepatitis C cirrhosis. Overall, these data suggest that chemoprevention of hepatocellular carcinoma in patients with chronic hepatitis C is an achievable objective.

PMID: 21253791 [PubMed - in process]

Source
Jan 31, 2011 08:00 ET

Clinical Data From Targeted Antibody Bavituximab Expected in 2Q11

TUSTIN, CA--(Marketwire - January 31, 2011) - Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), a clinical-stage biopharmaceutical company developing first-in-class monoclonal antibodies for the treatment of cancer and viral infections, today announced the completion of enrollment in the company's Phase Ib dose escalation safety study of bavituximab in patients coinfected with chronic hepatitis C virus (HCV) and HIV. Previously this month, Peregrine initiated a randomized Phase II HCV trial to evaluate 12 weeks of therapy with bavituximab, a phosphatidylserine (PS)-targeting monoclonal antibody with immune-modulating potential, in combination with the antiviral drug ribavirin versus standard of care, pegylated interferon alpha 2a and ribavirin.

"Completion of enrollment in our third Phase I HCV trial is an important milestone for our bavituximab antiviral program, and sets the stage for reporting clinical data at a medical conference in the second quarter of this year while we begin to evaluate combination treatment with the antiviral agent ribavirin in a recently initiated study," said Steven W. King, president and chief executive officer of Peregrine. "Though standard treatment for chronic HCV may soon evolve with the introduction of new targeted antiviral drug candidates, immune stimulation with interferon remains a critical component of therapy. Preclinical data support the potential combination of bavituximab and ribavirin and we look forward to seeing how this combination initially compares to standard interferon and ribavirin treatment for 12 weeks in our Phase II study for patients infected with HCV."

In prior HCV clinical trials, bavituximab administered as monotherapy in single and multiple doses demonstrated a positive safety profile with no dose-limiting toxicities or serious adverse events. Bavituximab as a monotherapy also showed promising on therapy antiviral activity of up to 1.5 log viral load reduction.

Bavituximab may address a fundamental "immune evasion" mechanism exploited by many infectious pathogens. A growing body of published data from researchers worldwide shows that bavituximab's PS target, exposed on the surface of cells infected by viruses and protozoan parasites, suppresses the immune system's ability to fight disease. PS-targeting antibodies such as bavituximab bind to PS and block the immunosuppressive signals created by the target, thereby allowing the immune system to mount a robust immune response against the pathogen.

About the Phase Ib HCV Trial

Peregrine's open-label, dose escalation safety study is designed to assess the safety and of bavituximab in up to 24 patients chronically infected with HCV and HIV. Patient cohorts received ascending dose levels of bavituximab weekly for up to 8 weeks. Primary endpoints include safety and pharmacokinetics, and secondary endpoints will measure HCV and HIV RNA by PCR. For further information about Peregrine's HCV trials, please visit http://www.peregrinetrials.com/ or http://www.clinicaltrials.gov/ct2/results?term=bavituximab.

About HCV

According to the U.S. Centers for Disease Control and Prevention, an estimated 3.2 million individuals in the United States have chronic hepatitis C virus (HCV) infection. Chronic HCV infection is a serious disease that can result in long-term health problems, including liver damage, liver failure, liver cancer, or death. It is the leading cause of cirrhosis and liver cancer and the most common reason for liver transplant in the United States. Approximately 8,000 to 10,000 people die every year from HCV-related liver disease.

About Bavituximab's Antiviral Approach

Bavituximab is the first in a new class of patented antibody therapeutics that target and bind to phosphatidylserine (PS), a specific phospholipid component of cell membranes. Bavituximab helps reactivate and direct the body's immune system to destroy infected cells and virus particles that exhibit this specific phospholipid on their surface. Since their target is host-derived rather than pathogen-derived, PS-targeting antibodies have the potential for broad-spectrum antiviral activity and are also expected to be much less susceptible to the viral mutations that often lead to drug resistance.

Researchers have found that PS is exposed on the outer membrane of cells infected with HCV, HIV, influenza, herpes viruses, hemorrhagic fever viruses, respiratory syncytial virus, measles as well as other viruses. A growing body of scientific publications, including Nature Medicine and The Journal of Experimental Medicine, has highlighted data on the role of PS and Peregrine's PS-targeting therapies in infectious diseases.

About Peregrine Pharmaceuticals

Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials for the treatment of cancer and serious viral infections. The company is pursuing multiple clinical programs in cancer and hepatitis C virus infection with its lead product candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. (www.avidbio.com), which provides development and biomanufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at http://www.peregrineinc.com/.

Safe Harbor Statement: Statements in this press release which are not purely historical, including statements regarding Peregrine Pharmaceuticals' intentions, hopes, beliefs, expectations, representations, projections, plans or predictions of the future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The forward-looking statements involve risks and uncertainties including, but not limited to, the risk that results from the Phase Ib or Phase II HCV trials will not be consistent with results experienced in earlier HCV clinical trials and preclinical studies, the risk that investigators may experience delays in patient enrollment, risk that results may not support registration filings with the U.S. Food and Drug Administration, and the risk that Peregrine may not have or raise adequate financial resources to complete the planned clinical programs. Factors that could cause actual results to differ materially or otherwise adversely impact the company's ability to obtain regulatory approval for its product candidates include, but are not limited to, uncertainties associated with completing preclinical and clinical trials for our technologies; the early stage of product development; the significant costs to develop our products as all of our products are currently in development, preclinical studies or clinical trials; obtaining additional financing to support our operations and the development of our products; obtaining regulatory approval for our technologies; anticipated timing of regulatory filings and the potential success in gaining regulatory approval and complying with governmental regulations applicable to our business. Our business could be affected by a number of other factors, including the risk factors listed from time to time in the company's SEC reports including, but not limited to, the annual report on Form 10-K for the year ended April 30, 2010 and the quarterly report on Form 10-Q for the quarter ended October 31, 2010. The company cautions investors not to place undue reliance on the forward-looking statements contained in this press release. Peregrine Pharmaceuticals, Inc. disclaims any obligation, and does not undertake to update or revise any forward-looking statements in this press release.

Peregrine Contact:
Amy Figueroa
Peregrine Pharmaceuticals
(800) 987-8256
info@peregrineinc.com

Source

Hepatitis C virus Resistance to Protease Inhibitors

Philippe Halfon a, Stephen Locarnini b

Received 13 December 2010; received in revised form 20 January 2011; accepted 20 January 2011. published online 31 January 2011.
Accepted Manuscript

Abstract

Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA) against HCV, include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase and NS5A inhibitors at various stages of clinical development. The rapid replication rate of HCV, along with the low fidelity of its polymerase, gives rise to the generation of mutations throughout the viral genome resulting in remarkable sequence variation in the HCV population, known as a quasispecies. The efficacy of DAAs is limited by the presence of these mutations resulting in amino-acid substitutions within the targeted proteins which affect viral sensitivity to these compounds. Thus, due to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Not surprisingly then, these changes are selected in patients either breaking through or not responding to potent DAA treatment. Six major position mutations in the NS3 HCV Protease (36, 54, 155, 156, 168, and 170) have now been reported in vitro or in vivo associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/ subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA sensitivity. Different amino acid diversity profiles for HCV genotypes/subtypes suggest differences in the position/ type of immune escape and drug resistance mutations. Also, different pathways of resistance profiles based on the chemical scaffold (linear or macrocyclic) of the protease inhibitors have been described. This review first describes how resistance to a protease inhibitor can develop and then provides an overview of the mechanism of how particular mutations confer varying levels of resistance to protease inhibitor, which have been identified and characterized using both genotypic and phenotypic tools. Future potential therapeutic strategies to assist patients who do develop resistance to protease inhibitors are also outlined. The challenge developing new HCV protease inhibitors should take in consideration not only the antiviral potency of the drugs, the occurrence and importance of side effects, the frequency of oral administration, but also the resistance profiles of these agents

a Virological Departement Laboratoire Alphabio, Hôpital Ambroise Paré, Marseille, France
b Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia

PII: S0168-8278(11)00079-1
doi:10.1016/j.jhep.2011.01.011
© 2011 Published by Elsevier Inc.

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