PRESS RELEASE: U.S. Food and Drug Administration Approves Gilead’s Sovaldi™ (Sofosbuvir) for the Treatment of Chronic Hepatitis C

– Sovaldi Approved for Use in Genotypes 1, 2, 3 or 4 –

– High Cure Rates (SVR12) and Shortened, 12-Week Course of Therapy for Many Patients –

– First Ever Oral Treatment Regimen for Genotypes 2 or 3 –

– First Regimen for Patients Awaiting Liver Transplantation to Prevent HCV Recurrence –

FOSTER CITY, Calif.--(BUSINESS WIRE)--Dec. 6, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved Sovaldi™ (sofosbuvir) 400 mg tablets, a once-daily oral nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. Sovaldi’s efficacy has been established in subjects with hepatitis C virus (HCV) genotypes 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection. Recommended regimens and treatment duration for Sovaldi combination therapy in HCV mono-infected or HCV/HIV-1 co-infected patients follows:

	Treatment					Duration
Genotype 1 or 4					Sovaldi + peg-interferon alfa + ribavirin					12 weeks
Genotype 2					Sovaldi + ribavirin					12 weeks
Genotype 3					Sovaldi + ribavirin					24 weeks

Sovaldi in combination with ribavirin for 24 weeks can be considered for CHC patients with genotype 1 infection who are interferon ineligible. Additionally, Sovaldi should be used in combination with ribavirin for treatment of CHC patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation to prevent post-transplant HCV infection. Treatment regimen, duration and response to Sovaldi are dependent on viral genotype and patient population, and associated baseline factors. Monotherapy is not recommended. Full Prescribing Information will be available on www.Gilead.com.

The FDA granted Sovaldi Priority Review and Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options.

“I believe that Sovaldi will have a major impact on public health by significantly increasing the number of Americans who are cured of hepatitis C,” said Ira Jacobson, MD, Chief of the Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York City and a principal investigator in the Sovaldi clinical trials. “In clinical studies, Sovaldi in combination with other agents achieved very high cure rates while shortening the duration of treatment to as little as 12 weeks and reducing or completely eliminating the need for interferon injections, depending on the viral genotype.”

Chronic hepatitis C affects an estimated 4 million people in the United States, the majority of whom are “baby boomers” – individuals born between 1945 and 1965. The disease is the nation’s leading cause of liver cancer and liver transplantation, and in recent years has surpassed HIV/AIDS as a cause of death. The current standard of care for HCV involves up to 48 weeks of therapy with a pegylated interferon (peg-IFN)/ribavirin (RBV)-containing regimen, which may not suitable for certain types of patients.

“It is our hope that Sovaldi will mark the beginning of a new era in hepatitis C treatment. Gilead is proud to have played a role in bringing about this important therapeutic advance and we would like to extend our thanks to the many patients and physicians who partnered with us on Sovaldi’s clinical studies,” said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences.

Sovaldi’s approval is supported primarily by data from four Phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION, which evaluated 12 or 16 weeks of treatment with Sovaldi combined with either RBV or RBV plus peg-IFN. Three of these studies evaluated Sovaldi plus RBV in genotype 2 or 3 patients who were either treatment-naïve (FISSION), treatment-experienced (FUSION) or peg-IFN intolerant, ineligible or unwilling (POSITRON). NEUTRINO evaluated Sovaldi in combination with Peg-IFN/RBV in treatment naïve patients with genotypes 1, 4, 5 or 6. In these studies, Sovaldi-based therapy was found to be superior to historical controls (NEUTRINO and FUSION) or to placebo (POSITRON), or non-inferior to currently available treatment options (FISSION) based on the proportion of patients who had a sustained virologic response (HCV undetectable) 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV. Trial participants taking Sovaldi-based therapy achieved SVR12 rates of 50-90 percent. For full study details, see the Clinical Studies section of the full Prescribing Information.

During the FDA’s review, data from two additional Phase 3 studies, VALENCE and PHOTON-1, were added to the NDA as a result of the Breakthrough Designation status. In the VALENCE study, patients with genotype 3 HCV infection were treated with Sovaldi and RBV for 24 weeks. Eighty-four percent of patients in this trial achieved SVR12. The PHOTON-1 study evaluated Sovaldi and RBV for 12 weeks in patients with genotype 2 HCV infection co-infected with HIV-1 and for 24 weeks in patients with genotypes 1 or 3 HCV co-infected with HIV-1. Trial participants achieved SVR12 rates of 76-92 percent. In all Phase 3 studies of Sovaldi, no viral resistance to the drug was detected among patients who relapsed following completion of therapy.

To date, nearly 3,000 patients have received at least one dose of Sovaldi in Phase 2 or 3 studies. Sovaldi combination therapy was well tolerated in clinical studies. Adverse events were generally mild and there were few treatment discontinuations due to adverse events. The most common adverse events occurring in at least 20 percent of patients receiving Sovaldi in combination with Peg-IFN/RBV were fatigue, headache, nausea, insomnia and anemia; see below for Important Safety Information regarding contraindications, warnings and precautions, adverse reactions and drug interactions.

On November 22, 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion on Gilead’s application for marketing authorization for Sovaldi. The CHMP opinion was adopted following an accelerated review procedure, which is reserved for medicinal products that are expected to be of major public health interest. This assessment does not guarantee marketing authorization by the European Commission. If approved, Sovaldi could be available in the European Union in the first quarter of 2014. Applications for marketing approval of Sovaldi are also pending in Australia, Canada, New Zealand, Switzerland and Turkey.

Dr. Jacobson is a paid consultant to Gilead.

The Wholesaler Acquisition Cost (WAC) of a 28-tablet bottle of Sovaldi in the United States is $28,000.

U.S. Patient Assistance Program

Gilead is committed to ensuring that people with hepatitis C can access Sovaldi and has launched Support Path™ (www.MySupportPath.com) to provide assistance to patients who are uninsured, underinsured or who need financial assistance to pay for the medicine. The program consists of an integrated offering of support services for patients and providers, including:

• Access to dedicated case managers to help patients and their providers with insurance-related needs, including identifying alternative coverage options such as federally-insured programs (e.g., Medicaid, Medicare) and health exchanges.
• Education and support, including a 24/7 nursing support service line and the ability to schedule an onsite visit from a clinical educator.
• The Sovaldi Co-pay Coupon Program, which provides co-pay assistance for eligible patients with private insurance who need assistance paying for out-of-pocket medication costs. Most patients will pay no more than $5 per co-pay. Co-pay assistance can also be applied toward deductibles and co-insurance obligations.
• Gilead will provide support to the Patient Access Network (PAN) Foundation, an independent non-profit organization that provides assistance for eligible federally-insured and privately-insured patients who need help covering out-of-pocket medication costs.
• The Support Path Patient Assistance Program will provide Sovaldi at no charge for eligible patients with no other insurance options.

Information about how to apply for any of these forms of assistance can be found at www.MySupportPath.com or by calling 1-855-7MyPath (1-855-769-7284) between 9 a.m. - 8 p.m. EST.

Global Availability

Gilead is committed to helping ensure access to Sovaldi in resource-limited settings. The company is developing a hepatitis C treatment access program, focusing on those countries with the greatest HCV burden. Full program details will be announced in the coming months.

About Sovaldi

Sovaldi is an oral nucleotide analog inhibitor of the HCV NS5B polymerase enzyme, which plays an essential role in HCV replication. Sovaldi is a direct-acting agent, meaning that it interferes directly with the HCV life cycle by suppressing viral replication. Treatment regimen and duration for Sovaldi are dependent on both viral genotype and patient population. Treatment response varies based on baseline host and viral factors. Monotherapy is not recommended for treatment of CHC.

IMPORTANT SAFETY INFORMATION

Contraindications

Sovaldi combination treatment with ribavirin or with peginterferon alfa plus ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risk for birth defects and fetal death associated with ribavirin. Contraindications to peginterferon alfa and ribavirin also apply to Sovaldi combination treatment. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.

Warnings and Precautions

• Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners must use two forms of non-hormonal contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the prescribing information for ribavirin.
• Use with Potent P-gp Inducers: Rifampin and St. John’s wort should not be used with Sovaldi as they may significantly decrease sofosbuvir plasma concentration, reducing its therapeutic effect.

Adverse Reactions

Most common (≥20%, all grades) adverse reactions for:

• Sovaldi + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia, and anemia
• Sovaldi + ribavirin combination therapy were fatigue, and headache

Drug Interactions

In addition to rifampin and St. John’s wort, coadministration of Sovaldi is not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of sofosbuvir, reducing its therapeutic effect.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that physicians and patients may not see advantages of Sovaldi over other therapies and may therefore be reluctant to prescribe the product, and the risk that public payers may be reluctant to approve or provide reimbursement for the product. In addition, pending marketing applications for Sovaldi in the European Union and other territories may not be approved in the currently anticipated timelines or at all, and marketing approval, if granted, may have significant limitations on its use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Sovaldi is available at www.Gilead.com

Sovaldi and Support Path are trademarks or registered trademarks of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

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Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)

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FDA approves Sovaldi (Sofosbuvir) for chronic hepatitis C

FDA NEWS RELEASE

For Immediate Release: Dec. 6, 2013

Media Inquiries: Stephanie Yao, 301-796-0394, stephanie.yao@fda.hhs.gov

Consumer Inquiries: 888-INFO-FDA

FDA approves Sovaldi for chronic hepatitis C

Drug is third with breakthrough therapy designation to receive FDA approval

The U.S. Food and Drug Administration today approved Sovaldi (sofosbuvir) to treat chronic hepatitis C virus (HCV) infection. Sovaldi is the first drug that has demonstrated safety and efficacy to treat certain types of HCV infection without the need for co-administration of interferon.

“Today’s approval represents a significant shift in the treatment paradigm for some patients with chronic hepatitis C,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Sovaldi is the second drug approved by the FDA in the past two weeks to treat chronic HCV infection. On November 22, the FDA approved Olysio (simeprevir).

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with HCV have no symptoms of the disease until liver damage becomes apparent, which may take several years. Some people with chronic HCV infection develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections or liver cancer. According to the Centers for Disease Control and Prevention, about 3.2 million Americans are infected with HCV.

Sovaldi is a nucleotide analog inhibitor that blocks a specific protein needed by the hepatitis C virus to replicate. Sovaldi is to be used as a component of a combination antiviral treatment regimen for chronic HCV infection. There are several different types of HCV infection. Depending on the type of HCV infection a patient has, the treatment regimen could include Sovaldi and ribavirin or Sovaldi, ribavirin and peginterferon-alfa. Ribavirin and peginterferon-alfa are two drugs also used to treat HCV infection.

Sovaldi’s effectiveness was evaluated in six clinical trials consisting of 1,947 participants who had not previously received treatment for their disease (treatment-naive) or had not responded to previous treatment (treatment-experienced), including participants co-infected with HCV and HIV. The trials were designed to measure whether the hepatitis C virus was no longer detected in the blood at least 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s HCV infection has been cured.

Results from all clinical trials showed a treatment regimen containing Sovaldi was effective in treating multiple types of the hepatitis C virus. Additionally, Sovaldi demonstrated efficacy in participants who could not tolerate or take an interferon-based treatment regimen and in participants with liver cancer awaiting liver transplantation, addressing unmet medical needs in these populations.

The most common side effects reported in clinical study participants treated with Sovaldi and ribavirin were fatigue and headache. In participants treated with Sovaldi, ribavirin and peginterferon-alfa, the most common side effects reported were fatigue, headache, nausea, insomnia and anemia.

Sovaldi is the third drug with breakthrough therapy designation to receive FDA approval. The FDA can designate a drug as a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may demonstrate a substantial improvement over available therapies for patients with serious or life-threatening diseases. Sovaldi was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness.

Sovaldi is marketed by Gilead, based in Foster City, Calif. Olysio is marketed by Raritan, N.J.-based Janssen Pharmaceuticals.

For more information:

FDA: Approved Drugs: Questions and Answers

FDA: Drug Innovation

FDA: What’s New at FDA in Hepatitis

CDC: Hepatitis C Information for the Public

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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Gilead’s (GILD) Blockbuster Hep C Drug Ready for Launch

Provided by Cabot Investing Advice

on December 06, 2013

Gilead Sciences' (GILD) hepatitis C treatment Sovaldi, formerly known as sofosbuvir, is one of the most anticipated new drugs in the industry in quite some time. Everyone and his mother expect the FDA to approve it by its Sunday deadline, thanks to the strong safety and efficacy data produced in its clinical trials.

Analysts are modeling an already-blockbuster $1.7 billion in sales next year, climbing to $8 billion in 2018, making it one of the best-selling drugs in the world.

Expectations are so high because Sovaldi promises substantial improvement on existing treatments for a serious disease. It's both more effective and has fewer side effects than the standard regimen of pegylated interferon, and it can be swallowed rather than injected.

The only live question at this point is where Gilead will price the drug. ISI Group analyst Mark Schoenebaum's informal survey of buy-side analysts last month found an average estimate of $85,000 for 12 weeks of treatment, but sell-side estimates have been running as high as $100,000. The price depends partly on how the FDA chooses to label the drug, which remains to be seen.
GILD is a Cabot Top Ten Trader stock.

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Prediction of Hepatic Fibrosis in Patients Coinfected With HIV and Hepatitis C Virus Based on Genetic Markers

J Acquir Immune Defic Syndr. 2013 Dec 15;64(5):434-42. doi: 10.1097/QAI.0b013e3182a06eb6.

Fernández-Rodríguez A, Berenguer J, Jiménez-Sousa MA, Guzmán-Fulgencio M, Micheloud D, Miralles P, López JC, Bellón JM, Aldamiz-Echevarria T,García-Broncano P, Carrero A, Alvarez E, Resino S.

*Viral Infection and Immunity Unit, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain; †Infectious Diseases and HIV Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain; ‡Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain; and Departments of §Internal Medicine; ‖Pathology, Hospital General Universitario, Gregorio Marañón, Madrid, Spain.

Abstract

OBJECTIVE: To assess the ability of the cirrhosis risk score (CRS) to predict liver fibrosis progression in HIV/hepatitis C virus (HCV)-coinfected patients.

DESIGN: Retrospective follow-up study.

METHODS: Based on a minimum follow-up time of 10 years with HCV infection, 190 HIV/HCV-coinfected patients were classified according to their METAVIR score: (1) 25 nonprogressor patients who did not develop fibrosis (F0) and (2) 165 progressor patients who developed fibrosis (F ≥ 1). Seven polymorphisms of CRS signature and IL28B genotype were performed using the GoldenGate assay. The CRS signature was calculated by naive Bayes formula as previously described.

RESULTS: Nonprogressors had CRS values significantly lower than progressors (0.61 versus 0.67; P = 0.043). Among the progressors, we observed similar CRS values through all the fibrosis stages (F1/F2/F3/F4). The percentage of patients with CRS > 0.70 (high risk of developing fibrosis) was higher in progressors than in nonprogressors; but the percentages with values between 0.50 and 0.70 (intermediate risk) and <0.50 (low risk) were quite similar for each of the fibrosis stages (P = 0.047). The area under the receiver-operating characteristic curve of CRS for discriminating nonprogressor versus progressor was 0.625 (P = 0.043). When clinical variables were considered (age at HCV infection, intravenous drug use, gender, IL28B, and HCV genotype), the area under the receiver-operating characteristic curve of CRS improved up to 0.739 (P < 0.001).

CONCLUSIONS: CRS itself seems not to be a good marker for identifying HIV/HCV-coinfected patients who are at high risk of developing liver fibrosis. However, CRS score coupled with clinical factors might help to distinguish between nonprogressors and progressors patients.

PMID: 23797694 [PubMed - in process]

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Iron metabolic disorder in chronic hepatitis C: Mechanisms and relevance to hepatocarcinogenesis

Journal of Gastroenterology and Hepatology

Special Issue: Third Asian-Pacific Topic Conference (APTC2012): Nutrition-related disorders and digestive system. Organized by Japanese Society of Gastroenterology (JSGE) and Asian-Pacific Association of Gastroenterology (APAGE), Tokyo, Japan, November 2–3, 2012. Guest Editor: Soichiro Miura

Volume 28, Issue Supplement S4, pages 93–98, December 2013

Nutrition-Related Liver Disorders: NAFLD

You have free access to this content

Keisuke Hino^*, Sohji Nishina, Yuichi Hara

Article first published online: 19 NOV 2013

DOI: 10.1111/jgh.12243

© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

Keywords: hepatitis C;  hepcidin;  iron;  oxidative stress;  reactive oxygen species

Abstract

The liver is the major iron storage organ in the body, and therefore, iron metabolic disorder is sometimes involved in chronic liver diseases. Chronic hepatitis C is one of the liver diseases that show hepatic iron accumulation, even though its level should be recognized to be basically mild to moderate and sometimes within the normal range. The mechanisms underlying hepatic iron accumulation in chronic hepatitis C have not been fully elucidated. Reduction of the hepcidin transcription activity by hepatitis C virus (HCV)-induced reactive oxygen species may in part account for it, but the regulation of hepcidin is very complex and may depend on many variables, including the particular stage of the systemic and/or hepatic inflammatory conditions and the circulating transferrin-bound iron and intracellular iron stores. This might explain the variations in hepatic iron concentrations reported among patients with HCV-related chronic liver disease. However, even mild-to-moderate iron overload in the liver contributes to disease progression and hepatocarcinogenesis in chronic hepatitis C probably by reinforcing the HCV-induced oxidative stress through Fenton reaction. The present review highlights the current concept of hepatic iron overload status in chronic hepatitis C and discusses how iron metabolic disorder develops in this disease and the impact of hepatic iron overload on disease progression and its relevance to hepatocarcinogenesis.

Introduction

Approximately 170 million people worldwide are infected with hepatitis C virus (HCV).[1] HCV infection often remains asymptomatic but can lead to severe liver damage. However, how HCV causes liver injury and liver cancer is not fully understood. Histological examination has revealed that chronic inflammation seems to play an important role in the pathogenesis of chronic hepatitis C, and excess iron also is associated with increased morbidity and mortality.[2, 3] In addition, a study using electron microscopy and X-ray microanalysis demonstrated that almost all liver specimens from patients with chronic hepatitis C had at least some lysosomal iron deposits even when no iron deposit was evident with standard optical microscopy and Prussian Blue staining.[4] Elevated iron-related serum markers and increased hepatic iron accumulation are relatively common and correlate with the severity of hepatic inflammation and fibrosis in patients with chronic hepatitis C. Excess divalent iron can be highly toxic mainly via the Fenton reaction producing hydroxyl radicals.[5] This is particularly relevant for chronic hepatitis C, in which oxidative stress has been proposed as a major mechanism of liver injury. Oxidative stress and increased iron levels strongly favor DNA damage, genetic instability, and tumorgenesis. Indeed, a significant correlation between 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidatively generated DNA damage,[6] and hepatic iron excess has been shown in patients with chronic hepatitis C.[7] Kato et al. reported that phlebotomy lowered the risk of progression to hepatocellular carcinoma (HCC),[8, 9] which showed the critical role of iron in the development of HCC in patients with chronic hepatitis C. Thus, there is a critical interaction between HCV infection and hepatic iron overload in the progression of liver disease and the development of HCV-related HCC. However, the mechanisms underlying hepatic iron overload and its contribution to hepatocarcinogenesis in chronic hepatitis C are not fully elucidated. The present review highlights the current concept of hepatic iron overload status in chronic hepatitis C and discusses how iron metabolic disorder develops in chronic hepatitis C, the impact of hepatic iron overload on disease progression, and its relevance to hepatocarcinogenesis.

Regulation of systemic iron homeostasis

In normal adults, storage iron is deposited in hepatocytes and tissue macrophages and mobilized in response to acute need. Serum iron levels are determined both by intestinal absorption and macrophage recycling of iron from hemoglobin because there is no efficient pathway for iron excretion.[10] Regulatory effectors that modulate intestinal iron absorption probably also modulate the release of iron from tissue macrophages and hepatocytes. Hepcidin appears to be such a regulatory effector. It is a small, cysteine-rich peptide, cleaved from a larger precursor.[11-13] Hepcidin, which was originally isolated from human serum and urine as a peptide with antimicrobial activity,[11, 13] is a hormone exclusively synthesized in the liver and a soluble regulator that acts to attenuate both intestinal iron absorption and iron release from reticuloendothelial macrophages.[12, 14] Increased plasma iron from macrophage recycling of aged red blood cells or from intestinal absorption of iron stimulates hepatocytes through several signaling pathways to produce more hepcidin. Ferroportin is an iron exporter on the surface of absorptive intestinal enterocytes, macrophages, hepatocytes, and placental cells, all of which release iron into plasma.[15-17] Circulating hepcidin can bind to ferroportin, cause internalization, and trap iron in hepatocytes, macrophages, and absorptive enterocytes.[18] Thus, coupling the internalization of ferroportin to hepcidin levels generates a homeostatic loop regulating the iron plasma level and the tissue distribution of iron.

Transcriptional regulation of hepcidin

Knowledge of how hepcidin transcription is regulated within hepatocytes appears to be indispensable for understanding the mechanisms underlying hepatic iron overload in chronic hepatitis C because hepcidin is the central regulator of systemic iron homeostasis. Important elements of the signaling pathway present on the hepatic plasma membrane that affect hepcidin transcription include transferrin receptor 2 (TfR2),[19] HFE,[20] which is the protein affected in the most common form of genetic hemochromatosis, and hemojuverin (HJV),[21] a member of the bone morphogenetic protein (BMP) receptor family. The mechanisms by which TfR2, HFE, and HJV are linked to changes in hepcidin transcription are incompletely understood, but the discovery of HJV revealed that the well-known sons of mothers against decapentaplegic (SMAD) signal transduction pathway was important in this process.[22] Notably, animals that lack hepatocyte SMAD4, a protein that combines with other members of the SMAD family to regulate transcription of target genes, develop significant iron overload associated with a profound reduction in hepcidin expression.[23] Interleukin 6 (IL-6) activates hepcidin transcription through a pathway that involves janus kinase-signal transducer and activator of transcription (STAT) signaling and a binding site for the transcription factor STAT3.[24, 25] The transcription factor CCAAT/enhancer-binding protein α (C/EBPα) is also clearly involved in regulating hepcidin transcription.[26] C/EBPα knockout mice demonstrate decreased hepcidin expression and iron overload.[26]

The pathways described earlier activate hepcidin transcription, but only one pathway has been identified that represses hepcidin expression. The transmembrane serine protease (TMPRSS6) is part of the pathway that suppresses hepcidin expression as revealed in TMPRSS6 mutant mice.[27]

Hepatic iron accumulation in chronic hepatitis C

Based on the assumption that one-third of iron stores are normally in the liver, this would translate to a normal median hepatic iron content of 0.27 g for men and 0.13 g for women.[28] Extensive studies reported median hepatic iron concentrations of 396 (range 0–2105) and 458 (range 114–2190) μg/g dry weight liver tissue in patients with chronic hepatitis C.[29, 30] These results suggest that hepatic iron content in patients with chronic hepatitis C is approximately 0.50∼0.69 g, equivalent to two to five times the normal hepatic iron content if the liver weight is estimated to be 1500 g. In contrast, a hepatic iron index (μmol Fe/g liver tissue/patients age) of 1.9 or more has been reported to be typical of patients with hereditary hemochromatosis.[31] If the hepatic iron index of a patient aged 60 with hereditary hemochromatosis is 1.9, the hepatic iron concentration of this patient is assumed to be 6384 μg/g liver tissue. Thus, we should understand that hepatic iron content is much less in chronic hepatitis C than in hereditary hemochromatosis, even though it is recognized to be one of liver diseases that show hepatic iron accumulation.

There also remains uncertainty as to whether iron predominantly accumulates in hepatocytes or the reticuloendothelial system, mainly Kupffer cells, in patients with chronic hepatitis C. Some clinical studies showed that iron was mainly localized in the reticuloendothelial system,[32, 33] whereas others reported its localization in hepatocytes.[34] Interestingly, Fiel et al. documented that even ribavirin-associated hemolysis deposited iron preferentially in hepatocytes in patients with chronic hepatitis C.[35] Hepatocytic iron accumulation may indicate potential DNA damage and genetic instability in association with HCV-induced oxidative stress, whereas iron deposition in Kupffer cells may contribute to cytokine release leading to inflammation or fibrosis. However, further investigations are needed to clarify this issue.\

Mechanisms underlying hepatic iron accumulation in chronic hepatitis C

HFE is a major histocompatibility class I-like (MHC) molecule that, unlike other known classical and non-classical MHC proteins, has a regulatory role in the functions of iron metabolism in cells and the body. A homozygous mutation in the HFE protein in humans that changes cysteine at position 282 to tyrosine is responsible for iron overload and organ damage resulting in hemochromatosis.[36] The role of HFE mutations in chronic hepatitis C has been well reviewed.[37] In general, patients with chronic hepatitis C seem to have no difference in the prevalence of heterozygosity for HFE mutations as compared with a control population. It is still controversial as to whether HFE mutations are associated with hepatic iron overload in chronic hepatitis C probably because of the different methodologies used to measure hepatic iron and/or confounding variables such as demographic parameters, environmental factors, hepatic inflammatory activity, and the duration of HCV infection among the reported studies. In addition, HFE mutations are seemingly not associated with the progression of liver disease in chronic hepatitis C patients even though HFE may affect Kupffer cells or interact with immune cells.

Fujita et al. showed for the first time that hepatic hepcidin messenger RNA (mRNA) levels adjusted by serum ferritin values were significantly lower in patients with chronic hepatitis C than in those with chronic hepatitis B or those without hepatitis B virus (HBV) or HCV infection.[38] Of note, the relative expression of hepcidin for iron stores was lower in chronic hepatitis C than in chronic hepatitis B or chronic liver diseases without HBV or HCV infection, even though hepcidin expression levels were strongly correlated with serum ferritin and the degree of hepatic iron deposition. These results suggested that hepcidin might play a pivotal role in iron overload in patients with chronic hepatitis C. A recent study using a validated immunoassay of the 25 amino acid bioactive hepcidin in serum also revealed that serum hepcidin levels were lower in patients with chronic hepatitis C than in controls despite a significant correlation between hepcidin and serum ferritin or the histological iron score in both groups.[39] Thus, the relatively decreased synthesis of hepcidin in chronic hepatitis C contrasts with the absolute deficit or lack in hepcidin synthesis observed in hereditary hemochromatosis and may account for the mild-to-moderate hepatic iron overload observed in some patients with chronic hepatitis C.

Regulation of hepcidin transcription by HCV, iron overload, and inflammation

The next question is how hepcidin transcription is suppressed in the presence of HCV infection. Which pathway for regulating hepcidin transcription is affected? Oxidative stress is present in chronic hepatitis C to a greater degree than in other inflammatory liver diseases.[32] The HCV core protein induces the production of reactive oxygen species (ROS) through inhibition of mitochondrial electron transport.[40] Interestingly, alcohol metabolism-mediated ROS were shown to suppress hepcidin transcription via C/EBPα.[41] Therefore, we investigated the mechanisms underlying hepcidin transcription inhibited by HCV focusing on ROS production, which plays a critical role in the pathogenesis of both alcoholic liver disease and chronic hepatitis C. Hepcidin promoter activity and the DNA binding activity of C/EBPα were downregulated concomitant with increased expression of C/EBP homology protein, an inhibitor of C/EBP DNA binding activity, and with increased levels of ROS in transgenic mice expressing the HCV polyprotein[42] (Fig. 1). Thus, the mechanisms underlying HCV-related hepatic iron overload appear to have some similarities with alcohol-induced iron overload in terms of disrupted hepcidin transcription through suppressed activity of C/EBPα. In agreement with our observation, an in vitro study by Miura et al. using hepatoma cells showed that HCV-induced ROS inhibited the binding activity of C/EBPα to the hepcidin promoter through increased histone deacetylase activity.[43]

Figure 1. Schematic diagram depicting the mechanisms underlying the hepatic iron accumulation in transgenic mice expressing the hepatitis C virus (HCV) polyprotein. HCV protein-induced reactive oxygen species (ROS) increase hepatic expression of CCAAT/enhancer-binding protein (C/EBP) homology protein (CHOP) and subsequently reduce DNA binding activity of C/EBPα, which leads to reduction of hepcidin transcription. Decreased hepcidin expression increases ferroportin (FPN) expression in the enterocytes and reticuloendothelial macrophages resulting in increased duodenal iron transport and macrophage iron release, which lead to hepatic iron accumulation.

Hepcidin is also regulated by both circulating transferrin-bound iron and intracellular iron stores. The exact mechanism is still unknown but seems to involve the BMP/SMAD pathway. As yet, there is no convincing evidence that accounts for the suppressive transcription of hepcidin through the BMP/SMAD cascade in chronic hepatitis C. Taking into account the significant correlation between hepcidin and serum ferritin, or the histological iron score, hepcidin transcription seems to be properly regulated in response to the iron concentration in chronic hepatitis C. Thus, the opposing effects of HCV-induced hepcidin-suppressive factors and iron load-induced hepcidin-stimulation factors potentially regulate hepcidin transcription in chronic hepatitis C. As suggested by Girelli et al.,[39] in the early phase of chronic hepatitis C hepcidin may be prominently suppressed by HCV, but as iron accumulates, the negative influence of viral factors may be masked by the positive stimulation of iron.

Inflammation also regulates hepcidin transcription. Pro-inflammatory cytokines such as IL-6 mediate this response by inducing transcription of hepcidin mRNA via STAT3, which binds to a STAT-responsive element within the hepcidin promoter.[24, 25] Our transgenic mice expressing the HCV polyprotein did not show any inflammation in the liver. A possible pitfall in this experimental model was that we could not take the inflammatory effect on hepcidin regulation into account, which is different from what is observed in patients with chronic hepatitis C. Serum levels of IL-6 have been shown to be elevated in patients with HCV-related chronic liver disease,[44] which raises the possibility that IL-6 acts to stimulate hepcidin expression through the STAT3 pathway. This would be expected to counteract the decrease in hepcidin transcription caused by HCV-induced ROS. However, no significant relationship has been found between serum IL-6 and hepcidin in patients with chronic hepatitis C,[39, 45] even though a paracrine effect of local IL-6 release on hepcidin transcription in the liver cannot be excluded. On the other hand, chronic inflammation with production of pro-inflammatory cytokines has the potential to deliver an additional burden of ROS, which would be expected to reinforce the decrease in hepcidin transcription. Most likely, during chronic inflammation states in vivo like chronic hepatitis C, the regulation of hepcidin is more complex and may depend on many variables, including the particular stage of systemic and/or hepatic inflammatory disease. This might explain the variations in hepatic iron concentrations reported among patients with HCV-related chronic liver disease. The schematic outline in Figure 2 depicts the assumed mechanisms underlying the hepatic iron accumulation in chronic hepatitis C.

Figure 2. Schematic diagram depicting the assumed mechanisms underlying the hepatic iron accumulation in patients with chronic hepatitis C. Hepcidin transcription in chronic hepatitis C may be potentially regulated by the opposing effects of hepatitis C virus (HCV)-related reactive oxygen species (ROS)-induced hepcidin suppression and iron load-induced hepcidin stimulation. Inflammation may also have the opposing effects of stimulation and suppression of hepcidin transcription through the interleukin (IL)-6/signal transducer and activator of transcription (STAT) pathway and ROS pathway, respectively. Consequent relative suppression of hepcidin expression is potentially one of the mechanisms underlying the hepatic iron accumulation in patients with chronic hepatitis C. BMP, bone morphogenetic protein; SMAD, sons of mothers against decapentaplegic.

Relevance of hepatic iron overload to hepatocarcinogenesis

Studies in HCV-infected and uninfected chimpanzees demonstrated that iron loading did exacerbate liver injury in HCV-infected chimpanzees and that HCV infection increased the susceptibility of the liver to injury following iron loading.[46] Increased hepatic iron deposition is reported to be associated with more advanced liver fibrosis in patients with chronic hepatitis C.[47] Recently, it has been prospectively shown in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial cohort that stainable iron in hepatocytes and portal tract cells predicts progression and outcomes (Child–Pugh score > 7, ascites, encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, HCC, and death) in advanced chronic hepatitis C.[48] Thus, iron is a cofactor that influences the severity and progression of chronic hepatitis C.

Although the association of markedly increased iron accumulation in the liver with hepatocarcinogenesis in hereditary hemochromatosis has been well described,[49] it remains to be elucidated whether mild-to-moderate increases in hepatic iron accumulation contribute to the development of HCC in patients with HCV-associated chronic liver diseases. Nevertheless, there are several lines of evidence that suggest the association of hepatic iron overload with hepatocarcinogenesis in chronic hepatitis C. It has been reported that hepatic iron storage is strongly correlated with hepatic 8-OHdG levels and that subsequent oxidative DNA damage in the liver is associated with an increased risk of HCC development.[2] In addition, the decrease in hepatic 8-OHdG content caused by phlebotomy lowers the risk of progression to HCC, which indeed shows the critical role of the iron-overload state in the development of HCC in patients with chronic hepatitis C.[8, 9]

We investigated whether mild iron overload actually induced HCC in the presence of HCV protein using transgenic mice expressing the HCV polyprotein. Transgenic mice fed an excess-iron diet showed marked hepatic steatosis, including the centrilobular microvesicular type, ultrastructural alterations of the mitochondria and decreased degradation activity of fatty acid at 6 months, as well as hepatic accumulation of lipid peroxidation products and 8-OHdG at 12 months after the initiation of feeding. Of note, hepatic tumors including HCC developed in 5 of 11 (45%) transgenic mice fed the excess-iron diet at 12 months after the initiation of feeding but did not in control mice or transgenic mice fed the control diet.[50] These results indicate the importance of oxidative stress and subsequent mitochondrial injury synergistically induced by iron loading and HCV proteins in the development of HCC. Thus, there seems to be a close relationship between the development of HCC and oxidative DNA damage synergistically induced by hepatic iron accumulation and HCV proteins. However, further investigations are needed to clarify the detailed mechanisms by which hepatic iron accumulation results in the development of HCC in chronic hepatitis C.

Acknowledgments

This research was supported by a Grant-in-Aid for Scientific Research (B) (23390201) from the Japan Society for the Promotion of Science, by a Health and Labor Sciences Research Grant for Research on Hepatitis from the Ministry of Health, Labor and Welfare of Japan and by a Research Project Grant P2 from Kawasaki Medical School.

References

Source

Excitement Mounting That Radiation Will Eliminate HIV

Medscape Medical News from the: Radiological Society of North America (RSNA) 99th Scientific Assembly and Annual Meeting

This coverage is not sanctioned by, nor a part of, the Radiological Society of North America.

Lara C. Pullen, PhD
December 04, 2013

CHICAGO — Radioimmunotherapy in conjunction with antiretroviral triple therapy can effectively kill HIV-infected cells from patients, a new study has shown.

"The cells are being steadily killed by a dose of radiation," explained Ekaterina Dadachova, PhD, professor of radiology, microbiology, and immunology at the Albert Einstein College of Medicine in the Bronx, New York.

Dr. Dadachova presented the research to an excited audience here at the Radiological Society of North America 99th Scientific Assembly and Annual Meeting. She began her talk by reminding the audience that the conference started on December 1, World AIDS Day.

The safety of radioimmunotherapy is well established in the field of oncology, where tumor cell burdens are approximately 1000 times greater than those seen in HIV patients being treated with triple therapy. This makes HIV a comparatively light load for radioimmunotherapy, according to those most familiar with the technique.

Current treatment options for HIV include antiretrovirals, which can dramatically increase a patient's lifespan and has transformed HIV from an acute disease. "HIV is now a chronic disease, but people are still dying from it and there is still no cure," Dr. Dadachova said.

Medications suppress viral reproduction, but they do not kill infected cells. Antiretrovirals also have a host of problems, including high cost, toxicity, nonadherence, and drug resistance.

Most important, viremia returns after treatment cessation. This is because both cellular and anatomic reservoirs of HIV in the body maintain the infection.

“It has fantastic potential.”

At the cellular level, even with antiretrovirals, the patient's body contains long-lived cell populations that are infected with HIV and are capable of surviving for prolonged periods of time. Resting CD4+ T-cells, macrophages, dendritic cells, and hematopoietic cells can all serve as reservoirs for HIV.

Anatomically, HIV also persists in the brain, and this has traditionally been a very difficult area for HIV therapeutics to access.

The world needs a strategy for eradicating HIV, said Dr. Dadachova. She then proceeded to describe her team's strategy using radioimmunotherapy.

The approach is effective against HIV-infected cells because it binds to a specific antigen and kills the cells. To be successful as a therapy, it requires an antigen target that in no way resembles a human antigen. If such an antigen can be found, then "1 or 2 hits per cell is enough to destroy the cell," explained Dr. Dadachova.

Her team used the HIV antigen gp41 to generate the 2556 antibody that binds specifically to HIV-infected cells.

Radiolabeled human antibody binds to the viral gp41 protein expressed on the surface of the HIV-infected lymphocyte and the cell is killed with alpha radiation.

The researchers previously used gp41 radioimmunotherapy in mice with severe combined immunodeficiency that were injected with infected human cells (PLoS One.2012;7:e31866). "We are basically able to eliminate the HIV-infected cells in those mice," Dr. Dadachova said enthusiastically. More important, they were able to eliminate HIV-infected cells in the brains of the mice.

Although the team's success with mice was exciting, she noted that they still did not know whether radioimmunotherapy would work in patients being treated with antiretroviral therapy. No one could say what the interaction between radioimmunotherapy, HIV, and antiretrovirals would look like. Would the suppressed viral replication also suppress the expression of gp41 below the level needed for radioimmunotherapy?

"That's where the Bill and Melinda Gates Foundation came in," she said. "They funded our study."

This year, Dr. Dadachova and her team performed an ex vivo study on clinical samples. They found that radioimmunotherapy killed the infected patient's lymphocytes over a full range of doses.

They also used an in vitro model to demonstrate that the radiolabeled antibody crosses the blood–brain barrier without disturbing the tight junctions of the cells.

"It has fantastic potential," said Gary Whitman, MD, professor of radiology at the University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Dadachova will next be partnering with physicians in South Africa to enroll patients there in the first radioimmunotherapy clinical trial. She said she expects the first results by the end of 2014. She also reported that she is applying to the National Institutes of Health for funding to continue the research in the United States.

The treatment regimen will likely consist of a single injection of radioimmunotherapy, she explained. Because bismuth-213 is a very short-lived isotope, all radioactivity will be gone from the patient in 4 hours. Follow-up testing will reveal whether the patient rebounds and requires another treatment.

Many in the room said the precedence of radioimmunotherapy in the treatment of cancer fuels their hope that people will truly have something to celebrate next World AIDS Day.

Dr. Dadachova and Dr. Whitman have disclosed no relevant financial relationships.

Radiological Society of North America (RSNA) 99th Scientific Assembly and Annual Meeting: Abstract SSK12. Presented December 3, 2013.

Source

HIV returns in "cured" Boston patients

ByMICHELLE CASTILLO CBS NEWS December 6, 2013, 12: 42 PM

Researchers announced today that two men they previously believed to be “cured” of HIV are now showing traces of the virus in their blood.

Dr. Timothy Henrich, associate professor of infectious diseases at Brigham and Women’s Hospital in Boston, announced the resurgence of the virus at an international conference on AIDS research in Florida Thursday, the Boston Globe reported. He said the fact that these two men were showing signs of HIV means that the virus can lurk in places in the body where it is hard to find.

“This suggests that we need to look deeper, or we need to be looking in other tissues . . . the liver, gut, and brain,” Henrich said. “These are all potential sources, but it’s very difficult to obtain tissue from these places so we don’t do that routinely.”

The two HIV-positive men previously made headlines in July, when Henrich announced that they were no longer showing any detectable traces of HIV in their body. The patients had received stem cell transplants after they had been diagnosed with Hodgkin’s lymphoma, a type of blood cancer, and doctors believed this transplant had allowed their body to get rid of the virus. They had stopped taking antiretroviral medications for 15 weeks and seven weeks respectively at the time of the announcement.

The second patient decided to stay off the medication, but eight months after he had been “cured” the doctors found traces of HIV. He was placed on antiretrovirals again.
According to government estimates, about 1,148,200 persons 13 and older were infected with HIV in the U.S. in 2009. Around 18.1 percent of those people had not been diagnosed yet.
Another man, Timothy Ray Brown, similarly announced that he had been “cured” of HIV when he received a stem cell transplant. Brown, who had leukemia, received a donation from a person with a genetic mutation called CCR5-delta32, which made them HIV-resistant.

Researchers said in July 2012 that they found traces of HIV in Brown’s blood, but the patient claims those viruses are dead and cannot replicate.

The Boston men's stem cell donors did not have the CCR5-delta32mutation.

A Mississippi baby born HIV-positive was also determined to be "cured" of the virus. Instead of receiving a stem cell transplant, she was given powerful three-drug infusion within 30 hours after birth. The mother had not been diagnosed with HIV until she was in labor, and did not receive any prenatal treatments to prevent the spread of the virus to her baby.

Researchers said in Oct. the baby still appears to be HIV-free.

Henrich said that despite the failure to eradicate HIV from the two men, researchers learned a lot that would allow them to make improvements for future treatments.

“We go back to the drawing board,” Henrich said. “It’s exciting science, even if it’s not the outcome we would have liked.”

© 2013 CBS Interactive Inc. All Rights Reserved.

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Effects of Ribavirin Dose Reduction vs Erythropoietin for Boceprevir-Related Anemia in Patients With Chronic Hepatitis C Virus Genotype 1 Infection

Gastroenterology

A Randomized Trial

Fred Poordad, Eric Lawitz, K. Rajender Reddy, Nezam H. Afdhal, Christophe Hézode, Stefan Zeuzem, Samuel S. Lee, Jose Luis Calleja, Robert S. Brown, JR., Antonio Craxi, Heiner Wedemeyer, Lisa Nyberg, David R. Nelson, Lorenzo Rossaro, Luis Balart, Timothy R. Morgan, Bruce R. Bacon, Steven L. Flamm, Kris V. Kowdley, Weiping Deng, Kenneth J. Koury, Lisa D. Pedicone, Frank J. Dutko, Margaret H. Burroughs, Katia Alves, Janice Wahl, Clifford A. Brass, Janice K. Albrecht, and Mark S. Sulkowski

Gastroenterology. 2013;145(5):1035-1044.

Abstract and Introduction

Abstract

Background & Aims Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety.
Methods Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251).
Results Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin.
Conclusions Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035.

Introduction

Anemia is a well-established adverse event with both pegylated interferon alfa (peginterferon) and ribavirin (RBV) in the treatment of chronic hepatitis C virus (HCV), particularly when these compounds are used in combination.^[1-3] The mechanism of anemia with RBV is hemolysis-associated, peginterferon suppresses bone marrow, and the mechanism of anemia with boceprevir is unknown. The relative contribution of each to the degree of anemia varies by patient, and depends on renal function, RBV exposure, body mass, and degree of liver fibrosis. Roughly 30% of patients in the large phase 3 clinical trials of peginterferon/RBV experienced hemoglobin declines below 10 g/dL^[4,5] and this threshold has been largely recommended in practice guidelines as defining clinically meaningful anemia and the threshold for anemia management.^[6,7]

Chief among the clinical management paradigms that had been developed based on peginterferon/RBV therapy was the dosage-reduction scheme for RBV because data supported the concept that a minimum of 60%−80% of intended RBV dosing and duration was required to achieve optimal rates of sustained virologic response (SVR).^[8,9] These various reports that probability of response was correlated with RBV dosing and that higher dosages of RBV were more effective led many to speculate that RBV dosing should be maintained at all cost. This led to the use of erythropoietin (EPO) and blood transfusions to support anemic patients on therapy to allow for minimal and brief reductions in RBV dosing.

The contribution of EPO in achieving SVR has never been formally studied in a randomized manner in HCV therapy, including its use with the newly approved protease inhibitors.^[10-13] In a phase 3 clinical trial of boceprevir in previously untreated patients with HCV genotype-1, it was noted that patients who became anemic but did not receive EPO had similar SVR rates to those patients who were given the growth factor.^[14] Given the high cost of EPO and potential safety concerns with its off-label use with HCV treatment-induced anemia, there remains a need to assess the utility of EPO vs RBV dosage reduction as the primary anemia-management intervention with current HCV therapy. This study was designed to determine the relative efficacy and safety of RBV dosage reduction vs EPO as the primary anemia management strategy among previously untreated patients with chronic HCV genotype-1 infection who were treated with boceprevir plus peginterferon/RBV.

Methods

Study Design

This randomized, multi-center, open-label clinical trial was designed to compare 2 strategies for the management of anemia (RBV dosage reduction vs EPO use) in adult patients with previously untreated chronic HCV genotype-1 infection who became anemic (hemoglobin ≤10 g/L) during therapy with boceprevir (VICTRELIS, 800 mg 3 times daily; Merck Sharp & Dohme Corp., Whitehouse Station, NJ) plus peginterferon alfa-2b (PegIntron, 1.5 μg/kg/wk; Merck Sharp & Dohme Corp.)/RBV (600−1400 mg/d, based on weight). The study was conducted between December 2009 and October 2011 in accordance with the principles of good clinical practice and was approved by the appropriate Institutional Review Boards and regulatory agencies. All patients provided written informed consent. Patients (n = 687) were enrolled into this study and received 4 weeks of peginterferon/RBV followed by 24 or 44 weeks of boceprevir plus peginterferon/RBV (Supplementary Figure 1). Patients in cohort 1 (n = 111) received 44 weeks of boceprevir/peginterferon/RBV. After a protocol amendment, patients in cohort 2 (n = 576) were eligible to receive response-guided therapy due to the equivalent efficacy, which had been demonstrated in an earlier pivotal phase 3 trial (either 24 weeks of boceprevir/peginterferon/RBV if HCV RNA was undetectable at treatment week 8 and below the lower limit of quantitation [<25 IU/mL] at all subsequent time points, or 44 weeks of boceprevir/peginterferon/RBV if HCV RNA was detectable at treatment week 8 or ≥25 IU/mL at any subsequent time point). Patients with detectable HCV RNA (≥25 IU/mL) and a <2 log₁₀ decline from baseline HCV RNA levels at treatment week 12 discontinued treatment, as did patients with HCV RNA ≥25 IU/mL at treatment week 24. Patients (n = 500) who became anemic (hemoglobin ≤10 g/dL, or if the rate of hemoglobin decline suggested that the value would be ≤10 g/dL before the next protocol-specified visit and the value was <11 g/dL) during the 4-week lead-in phase with peginterferon/RBV or during study treatment with boceprevir/peginterferon/RBV were randomized in a 1:1 ratio to RBV dosage reduction or EPO use for primary anemia management. The randomized treatment was stratified by time to development of anemia (≤16 vs >16 weeks after starting peginterferon/RBV) and by race (black vs non-black). Patients remained in the Treated/Not Randomized arm (n = 187) if they never met the protocol definition of anemia, discontinued treatment before randomization, or if their first hemoglobin value was ≤8.5 g/dL and treatment was continued at the investigator's discretion.

Supplementary Figure 1. Supplementary Figure 1 Study design and patient disposition. Patients (N = 1154) were assessed for eligibility. Eligible patients (n = 687) received 4 weeks of peginterferon/RBV followed by 24 or 44 weeks of boceprevir (800 mg 3 times a day) plus peginterferon/RBV. The study was projected to enroll a sample size of 660 patients to be treated with boceprevir/peginterferon/RBV. Approximately 60% (400 patients) were expected to develop anemia. The precision of the 95% CI for the true difference in SVR rates between the treatments was expected to be approximately ±10%. Patients with detectable HCV RNA (≥25 IU/mL) and a <2 log₁₀ decline from baseline HCV RNA levels at treatment week 12 discontinued treatment, as did patients with HCV RNA ≥25 IU/mL at treatment week 24. Patients remained in the Treated/Not Randomized arm (n = 187) if their hemoglobin values remained >10 g/dL throughout the 28-week or 48-week treatment period or they discontinued treatment before randomization. Patients with hemoglobin ≤10 g/dL during the lead-in phase with peginterferon/RBV or who became anemic (hemoglobin ≤10 g/dL) during study treatment were randomized in a 1:1 ratio to RBV dosage reduction (RBV DR) or EPO use. If the rate of hemoglobin decline suggested that the value would be ≤10 g/dL before the next protocol-specified visit and the value was <11g/dL, then the patient could be randomized to RBV dosage reduction or EPO use. Patients randomized during the lead-in period with peginterferon/RBV might have delayed initiation of boceprevir for up to 2 weeks at the discretion of the investigator if the anemia was significant.

The initial dosage reduction of RBV was 200 mg/d (or 400 mg/d if initial RBV dosage was 1400 mg/d) with a follow-up assessment at 2 weeks. If further dosage reduction of RBV was required, additional steps of RBV dosage reduction (by 200 mg/d) were performed. EPO was provided by the sponsor and was administered subcutaneously at 40,000 IU/wk. Secondary interventions for anemia (use of EPO in the RBV dosage-reduction arm; RBV dosage reduction in the EPO arm) were permitted for hemoglobin ≤8.5 g/dL. Packed red cell transfusions were allowed at the investigators' discretion. Patients were discontinued from the study if the hemoglobin level was ≤7.5 g/dL.

Selection of Patients

Eligibility criteria included no previous treatment for HCV infection, age older than 18 years, weight of 40−125 kg, HCV genotype-1, plasma HCV RNA level ≥10,000 IU/mL, hemoglobin ≤15 g/dL, and no contraindications for the use of EPO. Exclusion criteria were liver disease of cause other than HCV, decompensated liver disease, renal insufficiency, HIV or hepatitis B infection, pregnancy or current breastfeeding, diabetes, hypertension, pre-existing psychiatric conditions, and active or suspected malignancy. Laboratory exclusion criteria were hemoglobin <12 g/dL for females (males: <13 g/dL), neutrophils <1500/mm³ (blacks/African Americans: <1200/mm³), and platelets <100,000/mm³.

Efficacy

The primary efficacy end point was SVR (undetectable plasma HCV RNA at 24 weeks after the end of treatment) for both the RBV dosage-reduction and EPO arms. Plasma HCV RNA levels were measured with the TaqMan 2.0 assay (Roche Diagnostics, Indianapolis, IN), which had a lower limit of quantification of 25 IU/mL and lower limit of detection of 9.3 IU/mL. The lower limit of detection was used for decision making at various points throughout the study.

Safety

Safety analyses were based on all patients who were treated with any study medication. The proportion of patients with dosage modification/discontinuation due to adverse events, treatment-related serious adverse events, World Health Organization grade 3/4 neutropenia, and hemoglobin <10 g/dL were summarized by treatment. An adverse event was considered common if it occurred in a frequency ≥25% in either study arm. An exploratory analysis also examined safety in cirrhotic patients.

Statistical Analysis

The primary objective was to compare the effect on SVR of the 2 anemia management strategies. Key secondary objectives were to determine the safety and tolerability of EPO use vs RBV dosage reduction and to define predictors of SVR.

For the primary efficacy comparison, a 95% confidence interval (CI) for the difference in the SVR rates between the 2 treatment arms was computed using a Mantel-Haenszel approach adjusting for stratification factors as well as protocol amendment cohort. SVR rates were summarized for various subgroups using descriptive statistics (number and percentage) and exact 95% CIs. Exploratory analyses included calculation of P values using the χ² test to compare SVR rates in some subgroups and the proportions of requiring secondary anemia intervention, and the Cochran-Armitage trend test for SVR rates by total RBV dosage. For safety analyses, adverse events were summarized using descriptive statistics (number and percentage).

All authors were involved in the collection, analysis, or interpretation of the data; revision of the manuscript; and the decision to submit the manuscript for publication. All authors had access to the study data, and reviewed and approved the final manuscript. All authors vouch for the completeness and accuracy of the data and analyses, as well as the fidelity of the study to the protocol.

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Von Willebrand Factor as a new marker for non-invasive assessment of liver fibrosis and cirrhosis in patients with chronic hepatitis C

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

Original Article

You have free access to this content

A. Maieron^1,2, P. Salzl², M. Peck-Radosavljevic², M. Trauner², S. Hametner¹, R. Schöfl¹, P. Ferenci², M. Ferlitsch^2,*

Article first published online: 5 DEC 2013

DOI: 10.1111/apt.12564

© 2013 John Wiley & Sons Ltd

Abstract

Summary

Background

Staging of liver fibrosis in patients with chronic hepatitis C (CHC) is recommended prior to anti-viral therapy. As vWF-Ag was shown as a predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis, we performed this study to investigate if vWF-Ag is able to predict different fibrosis stages and if it is comparable to other fibrosis scores.

Aim

To investigate if vWF-Ag is able to predict different fibrosis stages and if it is comparable to other fibrosis scores.

Methods

We analysed 294 patients with chronic hepatitis C who underwent biopsy. We assessed stage of liver fibrosis according to Metavir, measured vWF-Ag and calculated different fibrosis scores (APRI, FCI, FORNS, FI, Fib-4) and compared them by AUCs. We also calculated a new score: vWF-Ag/thrombocytes (VITRO score) for prediction of fibrosis.

Results

vWF-Ag levels were increasing with stage of fibrosis: F0: vWF-Ag was median 136.5%, FI 140.6%, FII 157.5%, FIII 171.0%, FIV 252.0%;P < 0.001. vWF-Ag and VITRO score produced AUCs of 0.7 and 0.72 for ≥F2, comparable to the AUCs of APRI, Fib-4, FORNS with 0.75, 0.65 and 0.64 (P > 0.05). For ≥F3 AUCs were 0.79 and 0.86 for vWF-Ag and VITRO score, comparable with AUCs of 0.79, 0.86 and 0.87 for APRI, Fib-4 and FORNS. Cirrhosis shows AUCs of 0.84 and 0.89 for vWF-Ag and VITRO score, APRI, Fib-4 and FORNS showed similar results with AUCs of 0.82, 0.88 and 0.87.

Conclusions

vWF-Ag and VITRO score offer an easy possibility to evaluate the stage of fibrosis to diagnose subclinical cirrhosis in patients with chronic hepatitis C. Both vWF-Ag and VITRO score show equal performance in comparison to other fibrosis scores assessed in our study.

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What Everybody Ought to Know About Gilead and Johnson & Johnson's New Hepatitis C Drugs

Provided by The Motley Fool

By Todd Campbell | More Articles
December 6, 2013 | Comments

A new class of oral drugs for curing hepatits C is hitting the markets this winter, displacing injectible predecessors and ushering in treatments that are shorter and in some cases avoid side-affect riddled interferon.

With Johnson & Johnson's (NYSE: JNJ ) Olysio already winning FDA approval in November, Gilead Sciences's (NASDAQ: GILD ) sofosbuvir set to get the nod next week, and a range of competing drugs from AbbVie (NYSE: ABBV ) , Bristol-Myers Squibb(NYSE: BMY ) and Merck (NYSE: MRK ) coming along quickly, here's what you need to know about them.

1. They work better, but not for everyone
This new class of drugs is more effective than the prior-generation injectibles, which include Incivek, now fully controlled by Johnson following Vertex's exit, and Victrelis, made by Merck. Both Gilead and J&J's new drugs are approved for 12-week treatment courses, far shorter than the 24- to 48-week courses for those predecessors. But both Gilead's and J&J's drugs don't cure everyone.

In studies, Gilead's sofosbuvir, which will likely be approved as a combination therapy alongside ribavirin, cured roughly 89% of patients with genotype 1, the most common genotype in America. Based on Phase 3 results, J&J's Olysio cures 84% of cases, but stumbles in patients with the Q80K polymorphism, curing just 58%.

"Given the high frequency of the Q80K polymorphism in the U.S. population and its significant impact on rates of SVR12, DAVP is recommending that all GT1a patients be screened for the Q80K polymorphism. Alternative treatment options should be considered for patients found to be infected with this polymorphic variant," according to the FDA's advisory panel committee recommendation.

That should significantly reduce Olysio's appeal, given that nearly 50% of those with hepatitis C, genotype 1 have Q80K.

2. They come with fewer side effects, but still rely on interferon and ribavirin
The target for all of these drugmakers remains a therapy that is free of side-effect laden interferon and ribavirin. If approved on Dec. 8, Gilead's drug will do away with interferon in treating patients with hepatitis genotypes 2 and 3, but interferon will still be dosed alongside ribavirin for the majority of Americans. Meanwhile, J&J's Olysio still relies on both interferon and ribavirin.

One of the closest to a truly interferon- and ribavirin-free therapy appears to be Bristol. Bristol's drug daclatasvir is being considered for approval in Japan for use in combination with Bristol's asunaprevir for the tough-to-treat genotype 1b population. That population accounts for 70% of Japanese hepatitis cases. and Bristol's interferon- and ribavirin-free, two-drug combination cleared the disease nearly 85% of the time.

3. Fewer pills, easier regimen
It's not just interferon and ribavirin that make it tough for patients to stick to their drug regimen -- it's the dosing, too. The dosing of multiple drugs and injections with varying treatment schedules makes it hard for patients to adhere to protocols. That can cause them to drop out of treatment, fail to clear the disease, or worse, choose to avoid treatment altogether. As a result, drugmakers are focusing on one-pill solutions.

Unfortunately, current treatments from Gilead and J&J are multi-pill, which is better, but not ideal. However, one pill treatments should be coming soon. In November, Gilead reported data from a Phase 2 trial showing that 95% of patients were cured by a single, once-daily pill combining sofosbuvir and another Gilead drug, ledipasvir.

4.  Increasingly expensive treatment
Some doctors will embrace off-label combinations of sofosbuvir with either daclatasvir or Olysio. Those combinations have shown impressive results in phase 2 -- so impressive that European regulators have given the nod for compassionate use of daclatasvir, despite Bristol not yet filing for EU approval.

Interim data from a phase 2 trial combining Olysio with sofosbuvir in patients with liver disease who had failed prior treatment are also remarkable. In that study, the combination delivered a 100% cure rate four weeks following a 12-week course of treatment.

While those combinations offer hope for the most critical cases, they pose a big question for patients and insurers. Analysts peg pricing of Olysio at $67,000 for 12 weeks, and estimates for sofosbuvir are running as high as $100,000 for 12 weeks. For comparison, the cost to treat patients with an interferon and ribavirin combination runs roughly $15,000 to $20,000.

5.  Hypercompetitive marketplace
Gilead, J&J, and Bristol are looking over their shoulders at AbbVie and Merck. Both companies have promising late-stage trials ongoing for treating hepatitis C, with AbbVie guiding for a Q2, 2014 filing with the FDA. In a Phase 3 trial, AbbVie's 3 drug, non-interferon, combination cured 95% of patients with genotype 1. And Merck's MK-5172, combined with MK-8742, produced a cure rate between 96% and 100% in a small Phase 2 trial, prompting the FDA to grant the therapy breakthrough status.

That means investors, patients, and doctors have a lot to consider over the coming year as all these contenders vie for a share of a market Express Scripts thinks will quadruple by the end of 2015.

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Todd Campbell has no position in any stocks mentioned.  Todd owns E.B. Capital Markets, LLC.  E.B. Capital's clients may or may not have positions in the companies mentioned.  Todd also owns Gundalow Advisors, LLC.  Gundalow's clients do not have positions in the companies mentioned.  The Motley Fool recommends Gilead Sciences and Johnson & Johnson. The Motley Fool owns shares of Johnson & Johnson. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

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How Europe's Compassion for Hepatitis C Patients Helps Bristol-Myers

Provided by The Motley Fool

By Todd Campbell | More Articles
December 5, 2013 | Comments

Sometimes a drug comes along that's special enough to capture regulators attention before it's submitted for approval. That's what appears to have happened in Europe for Bristol-Myers Squibb's promising hepatitis C drug daclatasvir. The drug won regulator support as part of combination treatment with Gilead Sciences's  sofosbuvir for compassionate use in critical patients.

Combining for a cure
Despite Bristol having only filed the drug for approval in Japan, the European Medicines Agency, or EMA, has stepped up to recommend its use for EU patients who would otherwise succumb to liver failure without the treatment.

In a late November press release, the EMA's Committee for Medicinal Products for Human Use, or CHMP, issued a positive opinion for compassionate use of a combination therapy consisting of Bristol's daclatasvir and Gilead's sofosbuvir -- a much more widely anticipated drug.

Gilead captured widespread attention when it secured sofosbuvir in an $11.2 billion acquisition of Pharmasset in 2011. Doctors and patients have eagerly anticipated sofosbuvir's commercialization ever since, and their patience is likely to be rewarded soon given that the FDA has set a Dec. 8 decision date for sofosbuvir and that the CHMP in Europe issued a positive opinion for the drug in November.

Prompting by the Norse
The issue of compassionate use for Bristol's drug was brought to CHMP by Sweden, which requested that CHMP consider the drug combination for the hardest-to-treat patients. As a result, CHMP is backing the use of Bristol's drug in adults with the genotype 1 version of hepatitis C who would otherwise be expected to die within a year if left untreated.

CHMP's special designation was based on a combination study in which the two drugs successfully treated hepatitis C, even in cases where patients had previously failed to respond to sofosbuvir.

The results from that combination trial were as impressive as any seen so far. In phase 2, combining daclatasvir with sofosbuvir cured 100% of patients after 12 weeks. That's significant considering that the 40 patients in the trial had all failed to respond to Vertex's Incivek and Merck's Victrelis -- two drugs that hit the market to fanfare in 2010.  

This marks just the fourth time the CHMP has offered a compassionate use opinion, and it sets the stage for a new wave of combination therapies that cut across manufacturers and displace side affect laden ribavirin and interferon.

Walking away from the relationship
CHMP's decision doesn't give daclatasvir a free pass for use in Europe. It will only reach the most challenged patients and only if both doctors and their individual member states approve it. But it may indicate a willingness in Europe to embrace the drug for more widespread use, suggesting that Bristol may consider filing sooner rather than later.

It's likely disappointing to many that Gilead chose to abandon going forward with an important phase 3 trial with Bristol on the combination therapy. Instead, Gilead chose to focus on ushering its own combination remedy through clinic. It's hard to imagine that Gilead could hope to achieve 100% cure rates with its sofosbuvir and ledipasvir pair, but coming close appears good enough for Gilead. Particularly, since it can capture the entire revenue stream rather than share it with Bristol.

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Todd Campbell has no position in any stocks mentioned. Todd owns E.B. Capital Markets, LLC.  E.B. Capital's clients may or may not have positions in the companies mentioned.  Todd also owns Gundalow Advisors, LLC.  Gundalow's clients do not have positions in the companies mentioned. The Motley Fool recommends Gilead Sciences. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe thatc onsidering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

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