Hepatitis C virus infection and insulin resistance

World J Diabetes. 2014 February 15; 5(1): 52-58.

Published online 2014 February 15. doi: 10.4239/wjd.v5.i1.52.

Copyright ©2014 Baishideng Publishing Group Co., Limited. All rights reserved.

Sandip K Bose and Ranjit Ray.

Sandip K Bose, Ranjit Ray, Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO 63104, United States

Ranjit Ray, Division of Infectious Diseases, Allergy and Immunology, Edward A Doisy Research Center, St. Louis, MO 63104, United States

Ranjit Ray, Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104, United States

Author contributions: Bose SK performed literature search and wrote the initial draft of the paper; Ray R edited the paper and made additional changes as needed.

Supported by The National Institutes of Health, NO. DK080812

Correspondence to: Ranjit Ray, PhD, Division of Infectious Diseases, Allergy and Immunology, Edward A Doisy Research Center, 1100 S. Grand Blvd., 8^th Floor, St. Louis, MO 63104, United States. rayr@slu.edu

Telephone: +1-314- 9779034 Fax: +1-314-7713816

Received November 9, 2013; Revised December 20, 2013; Accepted January 13, 2014;

Abstract

Approximately 170 million people worldwide are chronically infected with hepatitis C virus (HCV). Chronic HCV infection is the leading cause for the development of liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and is the primary cause for liver transplantation in the western world. Insulin resistance is one of the pathological features in patients with HCV infection and often leads to development of type II diabetes. Insulin resistance plays an important role in the development of various complications associated with HCV infection. Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis, steatosis, HCC and resistance to anti-viral treatment. Thus, HCV associated insulin resistance is a therapeutic target at any stage of HCV infection. HCV modulates normal cellular gene expression and interferes with the insulin signaling pathway. Various mechanisms have been proposed in regard to HCV mediated insulin resistance, involving up regulation of inflammatory cytokines, like tumor necrosis factor-α, phosphorylation of insulin-receptor substrate-1, Akt, up-regulation of gluconeogenic genes like glucose 6 phosphatase, phosphoenolpyruvate carboxykinase 2, and accumulation of lipid droplets. In this review, we summarize the available information on how HCV infection interferes with insulin signaling pathways resulting in insulin resistance.

Keywords: Hepatitis C virus, Insulin resistance, Insulin receptor substrate 1, Protein kinase B, mammalian target of rapamycin/S6K1, Suppressor of cytokine signaling 3, Glucose transporter-4, Lipid metabolism, Anti-viral therapy

Core tip: Insulin resistance is one of the pathological features in patients with hepatitis C virus (HCV) infection and often leads to development of type II diabetes. Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis, steatosis, hepatocellular carcinoma and resistance to anti-viral treatment. In this review, we summarize the available information on how HCV infection interferes with insulin signaling pathways.

INTRODUCTION

Hepatitis C virus (HCV) contains a positive sense single stranded RNA genome and belongs to the family Flaviviridae and genus Hepacivirus[¹]. HCV genome, 9.6 kb in length, is composed of a 5’ non-translated region (NTR), a long open reading frame (ORF) encoding a polyprotein and a 3’ NTR. The ORF encodes a polyprotein of about 3000 amino acids that is translated via an internal ribosome entry site at the 5’ NTR. The polyprotein is then cleaved by both cellular and viral proteases into at least 10 different proteins[¹]. These include three structural proteins namely, core and two envelope glycoproteins (E1 and E2). In addition, a protein called F or ARFP can be produced from a frame-shift of the core protein[²]. An ion channel protein p7 is formed by cleavage of E2[³]. Non structural proteins of HCV include NS2, NS3, NS4A, NS4B, NS5A, and NS5B.

The primary host cell for HCV is hepatocytes but replication may also occur in other cell types, such as peripheral blood mononuclear cells, as well as in B and T cell lines[^4,5]. HCV is a major cause of acute and chronic liver disease worldwide. More than 170 million people are currently infected with HCV[⁶]. Currently HCV vaccine is not available. Acute infection is usually asymptomatic, making early diagnosis difficult. Approximately 70% of acutely infected individuals fail to clear the virus and become chronically infected[⁷]. Chronic HCV infection is the leading cause for the development of liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and is the primary cause for liver transplantation in the western world. The sustained antiviral response rate in treatment of chronic HCV infection with interferon (IFN)-α with ribavirin is limited (about 30%-40%)[^8,9]. Boceprevir and telaprevir protease inhibitors, have been shown to exhibit significantly higher rates of sustained virologic response (SVR) against HCV genotype 1 (about 65%-75%) as compared with peginterferon-ribavirin alone[^10,11]. However, use of these antiviral agents display higher incidence of adverse events, such as rash, gastrointestinal disorders, and anemia.

Insulin resistance plays an important role in the development of various complications associated with HCV infection. Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis, steatosis, HCC and resistance to anti-viral treatment[¹²]. Thus, HCV associated insulin resistance is a therapeutic target at any stage of HCV infection. HCV modulates normal cellular gene expression and interferes with the insulin signaling pathway. The aim of this review is to summarize the currently available information on how chronic HCV infection interferes with insulin signaling pathways resulting in insulin resistance.

GLUCOSE UPTAKE AND INSULIN RESISTANCE

Glucose is a key metabolite essential for the production of energy (mostly ATP) which is required by cells. There are several mechanisms underlying increased glucose production. These include production of free glucose by increased glycogenolysis in the liver, increased gluconeogenesis, activation of forkhead box transcription factor (FoxO1) and improper insulin-glucagon hormonal balance, which stimulates increased glucose production[¹³]. Several factors contribute to elevated gluconeogenesis in diabetes, namely (1) increased supply of glucogenic precursors to the liver (glycerol, amino acids, free fatty acids), (2) increased lipid content, (3) increased cytokines and adipokines, and (4) decreased insulin receptor (IR) signaling in hepatocytes[¹³]. Glucose uptake into cells is regulated by the action of specific hormones, namely insulin and glucagon. Insulin is a peptide hormone secreted by the β-cells of the pancreatic islets of langerhans and maintains normal blood glucose levels by facilitating cellular glucose uptake, regulating carbohydrate, lipid and protein metabolism and promoting cell division and growth through its mitogenic effects[¹⁴]. The ability of insulin to stimulate glucose uptake into tissues is central to the maintenance of whole-body glucose homeostasis[¹⁵]. Type II diabetes mellitus (T2DM), occurs when the production of insulin is not sufficient to overcome a difficulty the body has in properly using insulin. This difficulty is called insulin resistance, resulting in increased glucose levels. Both forms of diabetes can pose an increased risk of major lifelong complications. In the case of insulin resistance, this includes a fivefold increased risk of coronary vascular disease, diabetic retinopathy and neuropathy[^16-19]. Fatty liver is relatively common in overweight and obese persons with T2DM and is an aspect of body composition related to severity of insulin resistance, dyslipidemia, and inflammatory markers[²⁰].

Glucose transporter-4 (GLUT-4) was shown to be the major isoform responsible for enhanced glucose uptake into muscle and adipose tissues following the secretion of insulin into the bloodstream[^21,22]. The process of glucose uptake by cells requires a series of events to take place in a timely manner. It involves the binding of insulin to the IR resulting in subsequent phosphorylation and activation of IR substrate 1 and 2 (IRS-1/IRS-2), central molecules of the insulin signaling cascade[^23,24]. This in turn activates protein kinase B (AKT) by phosphorylation of Ser⁴⁷³ and Thr³⁰⁸ residues. Activated AKT causes the translocation of GLUT-4 from intracellular compartments to the cell surface where it is required for glucose uptake[²⁵]. Any change in the signaling is likely to induce insulin resistance which is associated with a number of pathophysiological changes including glucose intolerance, obesity, dyslipidemia and hypertension. Insulin resistance is a physiological condition in which cells fail to respond to the normal actions of the hormone insulin. The body produces insulin, but the cells in the body become resistant to insulin and are unable to use it as effectively, resulting in an attenuated biological response, leading to hyperglycemia[²⁶]. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response pathway, and innate immune pathways have all been implicated in the pathogenesis of insulin resistance[²⁷]. During the course of insulin resistance several inflammatory cytokines and lipid metabolites, like free fatty acids, interrupt with the normal insulin signaling and promote T2DM.

CHRONIC HCV INFECTION AND INSULIN RESISTANCE

Epidemiological studies suggest that patients with chronic HCV infection have a significantly increased prevalence of T2DM as compared to hepatitis B virus infected patients[^28-30]. Both insulin resistance and diabetes can adversely affect the course of chronic hepatitis C (CHC), leading to enhanced steatohepatitis and liver fibrosis[^30-32]. Insulin resistance, associated with type 2 diabetes, can promote fatty liver, and excessive hepatic accumulation of fat may promote insulin resistance and therefore contribute to the pathogenesis of the metabolic syndrome[³³]. Insulin resistance is a critical component of type 2 diabetes mellitus pathogenesis. Several mechanisms are likely to be involved in the pathogenesis of HCV-related insulin resistance[³⁴]. Several cellular lesions have been associated with insulin resistance, but the precise mechanism by which HCV induces insulin resistance remains elusive with numerous viewpoints and opinions[³⁰].

Impairment of IRS-1 and IRS-2 expression has been observed in the liver of patients with chronic HCV infection, as well as in HCV core transgenic mice, and from in vitro cell culture system[^35-38]. HCV mediates dysfunction of the insulin signaling pathways via several distinct mechanisms, such as upregulating the expression of suppressors of cytokine signaling 3 expression[³⁵], down regulation of peroxisome proliferator-activated receptors gamma (PPARγ)[³⁶], activation of mammalian target of rapamycin (mTOR)/S6K1 pathway[³⁸], and increased tumor necrosis factor-α (TNF-α) secretion[³⁹].

MODULATION OF IR SUBSTRATE BY HCV

HCV modulates insulin signaling and IRS-1 via multiple mechanisms which have been presented in Figure 1. Ser/Thr phosphorylation of IRS-1 inhibits its association with the IR, which in turn inhibits tyrosine phosphorylation of IRS-1, required for its activation, and promotes degradation. Upregulation of serine phosphorylation of IRS-1 is a key negative feedback mechanism under physiological conditions to prevent the action of insulin. In an insulin-resistant state, an imbalance occurs between positive IRS-1 Tyr-phosphorylation and negative Ser-phosphorylation of IRS-1[⁴⁰]. HCV core protein expression in hepatocytes upregulates Ser³¹² phosphorylation status of IRS-1 and modulates downstream Akt activity by inhibiting Thr³⁰⁸ phosphorylation[³⁷]. Ser³¹² and Ser¹¹⁰¹ phosphorylation of IRS-1 inhibits its association with the IR and stimulates degradation. HCV core protein induces insulin resistance by increasing Ser³¹² and Ser ¹¹⁰¹ phosphorylation, marking its for degradation via the activated mTOR/S6K1 pathway[³⁸], and subsequently blocking Tyr- phosphorylation of IRS-1 and Thr³⁰⁸ phosphorylation of Akt for the inhibition of glucose uptake. Activation of mTOR signaling also plays a key role in modulating IRS-1 activity. HCV genotype 2a infection significantly downregulates the expression of TSC1/TSC2, which in turn results in activation of downstream mTOR and S6K1[³⁸]. Phosphorylation of IRS-1 at Ser¹¹⁰¹ via the mTOR-S6K1 pathway may release IRS-1 from intracellular complexes, thereby enabling its degradation[⁴¹]. HCV significantly increases Ser¹¹⁰¹ phosphorylation of IRS-1, which enables its degradation[³⁸].

Figure 1 Schematic showing the interference of Hepatitis C virus in the insulin signaling pathway. Hepatitis C virus (HCV) core protein is known to up regulate Ser³¹² phosphorylation of insulin receptor substrate (IRS)-1 leading to degradation of IRS-1, the key molecule involved in propagation of insulin signal downstream from the insulin receptor (IR). HCV infection is also known to down regulate TSC1/TSC2 complex, resulting in subsequent upregulation of mTOR/S6K1 which leads to Ser¹¹⁰¹ phosphorylation of IRS-1 and its subsequent degradation. A role of HCV mediated upregulation of SOCS3 and tumor necrosis factor-α (TNF-α) has also been proposed which leads to degradation and blocking of IRS-1 function. HCV also upregulates glucose 6 phosphatase (G6P), phosphoenolpyruvate carboxykinase 2 (PCK2) leading to increased glucose production, and down regulates glucose transporter (GLUT)-4, GLUT-2, leading to decreased glucose uptake by hepatocytes. Overall, these alterations lead to insulin resistance. mTOR: Mammalian target of rapamycin.

A decrease in expression of IRS-1 and IRS-2, in patients with HCV infection has also been reported[³⁵]. Down-regulation of IRS-1 and IRS-2 was also seen in HCV core-transgenic mice livers and HCV core-transfected human hepatoma cells[³⁵]. HCV core up-regulated suppressor of cytokine signaling 3 (SOCS3) and caused ubiquitination of IRS-1 and IRS-2. HCV core-induced down-regulation of IRS-1 and IRS-2 was not seen in SOCS3(-/-) mouse embryonic fibroblast cells, indicating the important role played by SOCS3 in mediating down regulation of IRS-1[³⁵]. There have been reports that HCV genotypes might play an important role in deciding the pathway by which it impairs insulin signaling. It has been shown that the core protein of HCV genotype 3a promoted IRS-1 degradation through the downregulation of PPARγ and by upregulating the SOCS7, the core protein of genotype 1b activated the mTOR[³⁶].

TNF-α, released in an excess may promote phosphorylation of serine residues of IRS-1 eventually leading to the downregulation of downstream insulin signaling molecule Akt. HCV core protein increases the expression level of TNF-α and promotes insulin resistance[⁴²].

IMPAIRED LIPID AND GLUCOSE METABOLISM BY HCV

Insulin resistance is strongly influenced by abnormalities in lipid metabolism. Any dysfunction of the lipid metabolism triggers lipotoxicity through the production of free fatty acids thereby promoting insulin resistance[⁴³]. HCV core protein down-regulates microsomal triglyceride transfer protein, an enzyme that mediates lipid translocation to the endoplasmic reticulum membrane and decreases the assembly of very low density lipoproteins[⁴⁴]. It has been observed that HCV promotes fatty acid synthesis by the upregulation of lipogenic gene sterol regulatory element binding protein 1c which promotes the transcriptional activation of other lipogenic genes like acetyl CoA carboxylase, ATP citrate lyase, hydroxymethylglutaryl CoA reductase[⁴⁵].

HCV infection promotes the expression of gluconeogenic genes namely, glucose 6 phosphatase (G6P) and phosphoenolpyruvate carboxykinase 2 (PCK2) resulting in increased glucose production and enhanced insulin resistance[^46,38]. HCV also down regulates the expression of GLUT4, which is necessary for uptake of glucose. This results in a decreased glucose uptake and increased plasma glucose, leading to development of insulin resistance[³⁸].

A schematic showing how HCV interferes with insulin signaling pathway, leading to insulin resistance is presented in (Figure 1). HCV modulates functioning of IRS-1 via multiple mechanisms, including up regulation of Ser³¹² or Ser¹¹⁰¹ phosphorylation which leads to degradation of IRS-1. HCV also upregulates SOCS3 and down regulates TSC1/TSC2 leading to blocking of insulin signaling. HCV infection leads to increased gluconeogenesis via up regulation of G6P and PCK2. GLUT-4, and GLUT-2 expression is also down regulated by HCV leading to decreased glucose uptake. Overall, all these alterations by HCV leads to development of insulin resistance.

INSULIN RESISTANCE AND LIVER DISEASE PROGRESSION

The metabolic syndrome is a constellation of problems that includes insulin resistance, obesity, hypertension, and hyperlipidemia[⁴⁷]. Increasingly, components of the metabolic syndrome are being linked to various forms of cancer, including the risk of developing HCC. IR is induced by HCV-4 irrespective of severity of liver disease. IR starts early in infection and facilitates progression of hepatic fibrosis and HCC development[⁴⁷]. HCC patients showed higher IR frequency, and moderate to high viral load associated with high HOMA-IR in CHC and HCC[⁴⁷]. Insulin resistance associates with a higher risk of HCC in cirrhotic HIV/HCV-co-infected patients also[⁴⁸]. There are many causes of HCC, and nonalcoholic fatty liver disease (NASH) is emerging as a leading risk factor owing to the epidemic of obesity and T2DM. The mechanisms leading to HCC in obesity and T2DM likely involve interactions between several signaling pathways, many of which are modulated by HCV infection, and also include oxidative stress, inflammation, oncogenes, adiponectins, and insulin resistance associated with visceral adiposity and diabetes[⁴⁹].

Insulin resistance and subsequent hyperinsulinemia are highly associated with fatty liver disease and is an important risk factor for the progression of fibrosis in CHC[^50,51]. From metabolic aspect, HCV infection resembles NASH in numerous features, such as the presence of steatosis, serum dyslipidemia, and oxidative stress in the liver[⁵²]. On the other hand, there are noticeable differences between hepatitis C and NASH, in the fact that HCV modulates cellular gene expression and intracellular signal transduction pathways, while such details have not been noted for NASH. HCV core protein expression leads to the development of progressive hepatic steatosis and HCC in transgenic mice[⁵³]. Hepatic steatosis is known to occur at a high rate (40%-86%) in chronic HCV patients, and a close relationship between steatosis and intrahepatic core protein expression has been noted[⁵⁴]. Insulin resistance is a prominent mechanism linking steatosis and fibrogenesis although this link is complex and not properly understood.

CLINICAL IMPLICATIONS OF HCV-MEDIATED INSULIN RESISTANCE

Several epidemiological, clinical and experimental data show that HCV plays a direct role in perturbing glucose metabolism, leading to both insulin resistance and diabetes[^28-30]. Curing HCV results in the amelioration of insulin resistance and decreased incidence of diabetes after the end of therapy[^55,56]. In the only trial that used the antidiabetic metformin[⁵⁷], only a marginal, nonsignificant increase of the SVR rate was observed, despite an increased virological response after 4 wk of triple therapy. The data reported in a study using different schedules containing the antiglycaemic PPAR-γ agonist pioglitazone[⁵⁸] are discouraging. Overall, the administration of insulin sensitizers together with the standard of care has not only failed to improve the virological response to therapy, but has also fallen short of providing much useful insight into the mechanisms linking reduced response to insulin resistance[⁵⁹]. Early sulfonylureas although useful in lowering blood glucose level, were associated with significant off-target effects, and the biguanide phenformin was discontinued due to adverse events[⁶⁰]. Although metformin is in the same drug class, it has a better safety profile and is now recommended as first-line treatment of diabetes during HCV infection.

THERAPEUTIC APPROACHES AND FUTURE GOALS

Treatment for HCV induced insulin resistance is highly linked with anti-viral treatment. Treatment of chronic HCV infection has 2 goals. The first is to achieve SVR (i.e., sustained eradication of HCV, which is defined as the persistent absence of HCV RNA in serum 6 mo or more after completing antiviral treatment). The second goal is to prevent progression to cirrhosis, HCC, and decompensated liver disease requiring liver transplantation. The treatment of HCV has evolved over the years. Current treatment options include combination therapy consisting of ribavirin and pegylated IFN. Protease inhibitors are emerging as a third feature of combination therapy. The sustained antiviral response rate in treatment of chronic HCV infection with IFN-α and ribavirin is limited (about 30%-40%)[^8,9]. Boceprevir and telaprevir protease inhibitors have been shown to exhibit significantly higher rates of SVR against HCV genotype 1 (65%-75%) as compared with peginterferon-ribavirin alone[^10,11]. More recently, sofosbuvir has also been used for treatment along with ribavirin, with significant increased SVR[⁶¹]. However, use of these antiviral agents display higher incidence of adverse events, such as rash, gastrointestinal disorders, and anemia. Thus, development of therapies with less side effects is desirable.

The prevalence of HCV antibodies in the type 2 diabetic population ranges between 1.78% and 12.1%[⁶²]. Several cross-sectional studies have found a higher prevalence of HCV antibodies in type 2 diabetic patients than expected in the general population[^62,63]. Early phase and total insulin secretion are determined using oral glucose tolerance testing (OGTT), Insulin sensitivity was measured directly by steady-state plasma glucose concentration during insulin suppression test. Fasting plasma glucose ≥ 126 mg/dL or 2-h plasma glucose > 200 mg/dL during OGTT are generally used as criteria for diagnosis of diabetes[⁶⁴]. Well controlled DM was defined when the HbA1c level was < 7%. Agents used in diabetic therapy include the following: sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, Meglitinide derivativesetc[⁶⁰]. Although effective in reducing blood glucose levels, early sulfonylureas were associated with significant off-target effects, and the biguanide phenformin was discontinued due to adverse events[⁶⁰]. Although metformin is in the same drug class, it has a better safety profile and is now recommended as first-line treatment. However, many patients require additional glucose control treatment with an agent that has a complementary mechanism of action like metformin. Some common drugs used for treatment of T2DM available in the market include metformin oral, actos oral, Byetta subQ, Januvia oral, etc.

Another possible way of reversing insulin resistance would be via targeting the signaling components in the insulin signaling pathway modulated by HCV. For instance, we have shown that HCV up regulates phospho-S6K1, which stimulates degradation of IRS-1[³⁸]. Thus, targeting phospho-S6K1 would be a target against HCV induced insulin resistance. These studies have not been done yet, so at this time it will be difficult to comment on the predictive outcome on reversal of insulin resistance. Use of specific inhibitors of SOCS-3, which may become useful to correct resistance to both insulin and IFN-α, are not available for clinical use. Alternatively, one may envision inhibiting TNF-α by administering infliximab or similar agents. IR also results from uncontrolled diet and life style. Regulation of weight, diet, and life style management will also be key in managing IR.

ACKNOWLEDGMENTS

We thank and Lin Cowick for preparation of the manuscript.

Footnotes

P- Reviewers: Efanov AM, Teeter JG, Traub M, Vestergaard ET S- Editor: Zhai HH L- Editor: A E- Editor: Liu SQ

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Source

New pain pill's approval: 'Genuinely frightening'

By Stephanie Smith, CNN
updated 4:04 PM EST, Wed February 26, 2014

(CNN) -- A potent little painkiller is causing a big stir.

A coalition of more than 40 health care, consumer and addiction treatment groups is urging the Food and Drug Administration to revoke approval of the prescription drug Zohydro.

The hydrocodone-based drug is the latest in a long line of painkillers called opioid analgesics. The FDA approved the medication last fall to treat chronic pain, and it is set to become available to patients in March.

"In the midst of a severe drug epidemic fueled by overprescribing of opioids, the very last thing the country needs is a new, dangerous, high-dose opioid," the coalition wrote in a letter to FDA Commissioner Dr. Margaret Hamburg.

"Too many people have already become addicted to similar opioid medications, and too many lives have been lost."

One addiction expert who signed the letter was more forthright.

"It's a whopping dose of hydrocodone packed in an easy-to-crush capsule," said Dr. Andrew Kolodny, president of the advocacy group Physicians for Responsible Opioid Prescribing. "It will kill people as soon as it's released."

The letter is the latest in a series of entreaties to the FDA related to Zohydro.

In December, 29 state attorneys general sent a similar letter to the FDA. The month before, members of Congress asked the agency to review its decision to approve the drug.

The concerns echoed by all groups are broadly about the drug's potency and abuse potential. They say they fear that Zohydro -- especially at higher doses -- will amplify already-rising overdose numbers.

"This could be the next OxyContin," says a petition on Change.org asking the FDA to reconsider.

Report: States failing to curb prescription abuse

According to the Centers for Disease Control and Prevention, prescription opioid deaths more than quadrupled since 1999 -- there were 4,030 deaths involving the drugs in 1999, compared with 16,651 in 2010.

"You're talking about a drug that's somewhere in the neighborhood of five times more potent than what we're dealing with now," said Dr. Stephen Anderson, a Washington emergency room physician who is not part of the most recent petition to the FDA about the drug. "I'm five times more concerned, solely based on potency."

Both Zohydro's maker, Zogenix, and the FDA assert the drug's benefits outweigh its risks.

"We do not expect the introduction of Zohydro ER (extended release) to increase the overall use of opioids," said Dr. Brad Galer, executive vice president and chief medical officer at Zogenix, in an e-mail. "In fact, prescription data from the last five years shows that total use of ER opioids is constant and independent of new entrants to the market."

Galer said the company will focus its commercial efforts on a small group of doctors with good experience prescribing opioids, so that only appropriate chronic pain patients would receive the drug.

Advocates for pain patients say that concerns about abuse, while valid for some, are not necessarily an issue for those patients.

"We know that a person with pain is not a person who abuses medications," said Paul Gileno, founder and president of the U.S. Pain Foundation, a group that receives some funding in unrestricted grants from the pharmaceutical industry. "A person with pain is a person suffering to get pain relief in order to live a fulfilling life."

Opinion: How safe are your prescription drugs?

In their petition to the FDA for approval, Zogenix representatives cited examples of patients who might benefit from Zohydro: a 46-year-old male with chronic back and leg pain who had two failed back surgeries; a 52-year-old female with metastatic breast cancer experiencing diffuse pain; a 32-year-old woman with multiple orthopedic fractures.

If Zohydro follows in the footsteps of its opioid-containing predecessors, such a narrow, focused patient group may expand -- to patients with low back pain, fibromyalgia, arthritis or countless other chronic conditions.

"The problem is, it costs a lot of money bringing a drug through clinical trials and then bringing it to market," said Anderson, past president of the Washington chapter of the American College of Emergency Physicians. "You have to anticipate (the drug company) being able to market and get its money back.

"I see this as a marketing ploy where eventually it's 'I've got bigger, I've got stronger, why don't you prescribe this,' and I'm terrified of that."

Dr. Sanjay Gupta: Let's end the prescription drug death epidemic

Bigger, stronger opioids -- especially those containing hydrocodone -- are a concern. Hydrocodone (Zohydro's sole ingredient) is one of the most frequently prescribed -- and abused -- opioids.

For that reason, in October, the FDA said it intended to shift hydrocodone-containing drugs from Schedule III to Schedule II. That rescheduling (still pending approval by the Drug Enforcement Administration) would mean much stricter dispensing and prescribing rules for hydrocodone-containing products.

At the time of that recommendation, the FDA posted a statement on its website that it "... has become increasingly concerned about the abuse and misuse of opioid products, which have sadly reached epidemic proportions in certain parts of the United States."

A day after announcing the proposed drug schedule change for hydrocodone, the FDA announced Zohydro's approval. It was a confusing juxtaposition, some say.

"Shocking, outrageous and genuinely frightening," said Kolodny of the Physicians for Responsible Opioid Prescribing.

FDA spokeswoman Morgan Liscinsky said that Zohydro's approval was separate and distinct from the agency's recommendation about rescheduling hydrocodone-containing products.

"I find great difficulty (with) the wisdom of the FDA's approval in terms of protecting the public's health," said Dr. Alex Cahana, professor of pain medicine at the University of Washington in Seattle, who was not among those who signed the letter to the FDA. "Risk-benefit thinking suggests that not everything we can do, we should do."

Zohydro will enter the market already classified as a Schedule II -- one reason both the FDA and the drug's maker are confident it will not contribute to the broader overdose problem.

Zohydro's labeling will feature warnings about abuse, addiction and misuse, and Galer said Zogenix is working on an abuse-deterrent version of Zohydro that should become available in three years.

None of those precautions has assuaged concerns. Anderson said that while a small subset of patients may benefit from Zohydro, unleashing such a potent drug in the current environment is unsafe.

"Put more of this kind of drug out on the street and, I'll see more overdoses related to this, no question," Anderson said.

Source

Research: Fructose not responsible for increase in non-alcoholic fatty liver disease

PUBLIC RELEASE DATE: 26-Feb-2014

Contact: Leslie Shepherd
shepherdl@smh.ca
416-864-6094
St. Michael's Hospital

Excess consumption of calories can contribute to the disease

TORONTO, Feb. 26, 2014—Non-alcoholic fatty liver disease is the most common chronic liver disease in developed countries, affecting up to 30 per cent of their populations.

Since the disease is closely linked to obesity and Type 2 diabetes, there's a growing debate in the medical community about whether diet plays a role in its development, specifically the consumption of fructose.

The possible link to non-alcoholic fatty liver disease has become the main criticism against fructose among those who believe there is something unique about the fructose molecule or the way it is metabolized and blame it for the obesity epidemic.

A meta-analysis of all available human trials published today in the European Journal of Clinical Nutrition says fructose in and of itself is not to blame for the increase in non-alcoholic fatty liver disease.

But excess consumption of calories can contribute to the disease, regardless of whether those calories came from fructose or other carbohydrates, said the lead author, Dr. John Sievenpiper, a researcher in the Clinical Nutrition and Risk Factor Modification Centre of St. Michael's Hospital.

"The one thing fructose is supposed to do above all else is give you fatty liver disease, which some say is a starting point for metabolic syndrome--a term used to describe a group of conditions that puts people at higher risk of developing Type 2 diabetes, heart disease and other heart-related problems--and Type 2 diabetes itself," Dr. Sievenpiper said.

"But we found it behaves no differently than glucose or refined starches. It is only when you consume excess calories in the form of fructose that you see a signal for harm but no more harm than if you consume excess calories as glucose."

Fructose, which is naturally found in fruit, vegetables and honey, is a simple sugar that together with glucose forms sucrose, the basis of table sugar. It is also found in sucrose and high-fructose corn syrup, the two most common sweeteners in commercially prepared foods.

Non-alcoholic fatty liver disease is one cause of a fatty liver, occurring when fat is deposited in the liver. Unlike alcoholic liver disease, it is not due to excessive alcohol use.

Previous research by Dr. Sievenpiper has found that fructose by itself does not cause weight gain and does not itself have any impact on an emerging marker for the risk of cardiovascular disease known as postprandial triglycerides when it is substituted for other carbohydrates. It is when fructose is overconsumed providing excess calories that you see the adverse effects on health, but no more than when other carbohydrates are overconsumed.

A study he published in the February issue of Current Opinion in Lipidologyalso found no benefit in replacing fructose with glucose in commercially prepared foods. That research again showed that that when portion sizes and calories are the same, fructose does not cause any more harm than glucose.

"The debate over the role of fructose in obesity, fatty liver and other metabolic diseases has distracted us from the issue of overconsumption," Dr. Sievenpiper said. "Our data should serve to remind people that the excess calories, whether they are from fructose or other sources, are the issue."

###

The European Journal of Clinical Nutrition paper was funded by a Canadian Institutes of Health Research Knowledge Synthesis grant and a research grant from the Calorie Control Council.

About St. Michael's Hospital

St Michael's Hospital provides compassionate care to all who enter its doors. The hospital also provides outstanding medical education to future health care professionals in 27 academic disciplines. Critical care and trauma, heart disease, neurosurgery, diabetes, cancer care, care of the homeless and global health are among the hospital's recognized areas of expertise. Through the Keenan Research Centre and the Li Ka Shing International Healthcare Education Centre, which make up the Li Ka Shing Knowledge Institute, research and education at St. Michael's Hospital are recognized and make an impact around the world. Founded in 1892, the hospital is fully affiliated with the University of Toronto.

Media contacts

For more information, or to arrange an interview with Dr. Sievenpiper, contact:

Leslie Shepherd
Manager, Media Strategy
St. Michael's Hospital
416-864-6094
shepherdl@smh.ca
Inspired Care. Inspiring Science.
http://www.stmichaelshospital.com
Follow us on Twitter: http://www.twitter.com/stmikeshospital

Source

Efficacy of Nucleotide Polymerase Inhibitor Sofosbuvir Plus the NS5A Inhibitor Ledipasvir or the NS5B Non-Nucleoside Inhibitor GS-9669 Against HCV Genotype 1

Gastroenterology
Volume 146, Issue 3 , Pages 736-743.e1, March 2014

Edward J. Gane, Catherine A. Stedman, Robert H. Hyland, Xiao Ding, Evguenia Svarovskaia, G. Mani Subramanian,William T. Symonds, John G. McHutchison, Phillip S. Pang

Received 3 October 2013; accepted 13 November 2013. published online 20 November 2013.

Abstract

Background & Aims
We evaluated an all-oral regimen comprising the nucleotide polymerase inhibitor sofosbuvir (SOF) with the NS5A inhibitor ledipasvir (LDV) or the NS5B non-nucleoside inhibitor GS-9669 in patients with genotype 1 hepatitis C virus (HCV) infection.

Methods
A total of 113 patients were enrolled. Sofosbuvir (400 mg once daily) and LDV (90 mg once daily) plus ribavirin (RBV) were given for 12 weeks to treatment-naïve (TN) patients (n = 25) and those who did not respond to previous therapy (prior null responders, n = 9). Sofosbuvir and GS-9669 (500 mg once daily) plus RBV were given for 12 weeks to TN patients (n = 25) and prior null responders (n = 10). Additionally, prior null responders with cirrhosis were randomly assigned to groups given a fixed-dose combination of SOF and LDV, with RBV (n = 9) or without RBV (n = 10). Finally, a group of TN patients received SOF, LDV, and RBV for 6 weeks (n = 25). The primary efficacy end point was sustained virologic response 12 weeks after therapy (SVR12).

Results
SVR12 was achieved by 25 of 25 (100%) TN patients receiving SOF, LDV, and RBV and 23 of 25 (92%) of those receiving SOF, GS-9669, and RBV. Of TN patients receiving 6 weeks of SOF, LDV, and RBV, 17 of 25 (68%) achieved SVR12. All noncirrhotic prior null responders receiving 12 weeks of SOF along with another direct-acting antiviral agent plus RBV achieved SVR12—9 of 9 (100%) of those receiving SOF, LDV, and RBV and 10 of 10 (100%) of those receiving SOF, GS-9669, and RBV. Among cirrhotic prior null responders, SVR12 was achieved by 9 (100%) of those receiving SOF, LDV, and RBV and 7 (70%) of those receiving SOF and LDVD without RBV. The most common reported adverse events were headache, fatigue, and nausea.

Conclusions
The combination of SOF and a second direct-acting antiviral agent is highly effective in TN patients with HCV genotype 1 infection and in patients that did not respond to previous treatment. ClinicalTrials.gov ID NCT01260350.

Keywords: DAA, Drug, Clinical Trial, Liver Cirrhosis

Abbreviations used in this paper: DAA, direct-acting antiviral, HCV, hepatitis C virus, LDV, ledipasvir, RBV, ribavirin, SOF, sofosbuvir,SVR12, sustained virologic response 12 weeks post therapy, TN, treatment-naïve

Source

Judge Orders Obamacare Insurers in Louisiana to Accept HIV Funds

Reuters Health Information

By Julie Steenhuysen
February 26, 2014

CHICAGO (Reuters) - A U.S. district court judge in Louisiana has temporarily barred Blue Cross and Blue Shield of Louisiana and two smaller insurers from rejecting payments from a federal program intended to help low-income HIV patients buy health insurance.

The insurers named in the case are Blue Cross and Blue Shield of Louisiana, Vantage Health Plan and Louisiana Health Cooperative. They are among a small handful of insurance companies in Louisiana that sell healthcare policies under President Barack Obama's healthcare law.

Blue Cross and Blue Shield of Louisiana, the state's largest insurer, said late last year that it would no longer accept federal Ryan White payments on behalf of individuals infected with the human immunodeficiency virus (HIV), which causes AIDS. Subsequently, the two smaller insurers followed suit.

Brian Jackson, chief judge of the U.S. District Court for the Middle District of Louisiana, on Monday issued a temporary restraining order that compels the three insurance companies to continue to accept federal Ryan White funds to pay insurance premiums on behalf of low-income individuals with HIV who bought one of the companies' plans on the federal health insurance exchanges.

The order expires in 14 days, but Jackson has scheduled a hearing to consider a preliminary injunction in the matter. If granted, the preliminary injunction would supplant the temporary restraining order, and would maintain insurance coverage for low-income Louisianans living with HIV.

"We are moving ahead in court to address the legalities of having them pull the rug out from under low-income people with HIV/AIDS," said Susan Sommer, director of constitutional litigation for Lambda Legal, which brought the lawsuit on behalf of John East, a plaintiff living with HIV.

For more than two decades, low-income individuals with HIV have used funds from the federal Ryan White HIV/AIDS Program to buy health insurance.

Late last year, Blue Cross and Blue Shield of Louisiana began rejecting Ryan White payments sent on behalf of impoverished HIV-AIDS patients who had enrolled in one of its Obamacare plans, as did Blue Cross Blue Shield of North Dakota.

The insurers told healthcare advocates that guidance issued by the Centers for Medicare and Medicaid Services, the lead Obamacare agency, prevented them from accepting third-party payments for the new health plans, even when the funds came from a government program.

Earlier this month, the CMS said that guidance did not apply to the Ryan White program. The federal agency also said that it is considering amending rules to require issuers to accept Ryan White payments.

Louisiana Blue, nevertheless, said it will stop honoring Ryan White and other third-party payments for premiums beginning March 1, a policy it said will "safeguard against" potential fraudulent activity from "people who want to game the system."

A spokesman for Blue Cross did not respond to a request for comment on the ruling.

Sommer said Lambda Legal is seeking to proceed as a class action on behalf of all affected people.

In his ruling, Jackson cited the grave risk and potential "irreparable injury" that would befall individuals with HIV who are unable to obtain insurance.

Source

HCV Genotype 3 is Associated with an Increased Risk of Cirrhosis and Hepatocellular Cancer in a National Sample of U.S. Veterans with HCV

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Research Article

Fasiha Kanwal^1,2,*, Jennifer R. Kramer^1,3,  Jawad Ilyas², Zhigang Duan³, Hashem B. El-Serag^1,2

DOI: 10.1002/hep.27095

Copyright © 2014 American Association for the Study of Liver Diseases

Publication History
Accepted manuscript online: 24 FEB 2014 09:44PM EST
Manuscript Accepted: 20 FEB 2014
Manuscript Revised: 4 FEB 2014
Manuscript Received: 19 NOV 2013

Keywords: Cohort;  longitudinal;  Veterans Administration;  viral factors;  association

ABSTRACT

Data show that viral genotype 1 may increase the risk of cirrhosis and hepatocellular carcinoma (HCC) compared to genotype 2 in patients with chronic hepatitis C virus (HCV) infection. However, the effect of HCV genotype 3 on cirrhosis and HCC risk is uncertain. We identified patients with active HCV infection, confirmed by positive PCR and a known HCV genotype, from the VA HCV Clinical Case Registry between 2000 and 2009. We examined the effect of HCV genotype on the risk of cirrhosis and HCC in a Cox proportional hazards model adjusting for patients’ age, period of service (World War I/II, Vietnam era, post-Vietnam era), race, gender, HIV infection,alcohol use, diabetes, body mass index, and antiviral treatment receipt. Of the 110,484 patients with active HCV viremia, 88,348 (79.9%) had genotype 1, 13,077 (11.8%) genotype 2, 8337 (7.5%) genotype 3, and 1082 (0.9%) patients had genotype 4 infection. Despite being younger, patients with genotype 3 had a higher risk of developing cirrhosis (unadjusted hazard ratio, HR=1.40, 95% CI=1.32-1.50) and HCC (unadjusted HR=1.66, 95% CI=1.48-1.85) than HCV genotype 1 patients. After adjustment for pre-specified demographic, clinical, and antiviral treatment factors, the risk of cirrhosis and HCC was 31% (adjusted HR=1.31, 95% CI=1.22-1.39) and 80% (adjusted HR=1.80, 95%CI=1.61-2.03) higher in patients with genotype 3 compared to genotype 1 infected patients. Conclusion: HCV genotype 3 is associated with a significantly increased risk of developing cirrhosis and HCC compared to HCV genotype 1. This association is independent of patients’ age, diabetes, body mass index, or antiviral treatment. (Hepatology 2014;)

Source

FDA Hepatitis Update - Changes to the Victrelis (boceprevir) label

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.

On February 24, 2014, FDA approved an update to the Victrelis (boceprevir) label to include a new virologic futility rule. Specifically Section 2, Dosage and Administration, Table 1 was revised to state: If a patient has HCV-RNA results greater than or equal to 1000 IU/mL at treatment week 8, then discontinue three-medicine regimen.

This statement is also reflected in subsection 2.4 Discontinuation of Dosing Based on Treatment Futility: Discontinuation of therapy is recommended in all patients with 1) HCV-RNA levels of greater than or equal to 1000 IU per mL at TW8 (treatment week 8); or 2) HCV-RNA levels of greater than or equal to 100 IU per mL at TW12 (treatment week 12); or 3) confirmed detectable HCV-RNA levels at TW24 (treatment week 24).

You can view the complete revised Victrelis label and Medication Guide at Drugs@FDA.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Manage your FDA Subscriptions:

• Update your preferences or unsubscribe
• Questions about this service? Please visit subscriberhelp.govdelivery.com
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------------------------------------------

Taking stress out of hepatitis C

by Opiferum
February 25, 2014

Stress is a part of life in today's fast lane. From sitting in traffic to spending too much time worrying about the future, there are plenty of forms of stress. As we all react to stress on an individual basis, what might be stressful to you is a very personal experience. Therefore, the way in which we recognize and manage stress is vital, especially if you live with hepatitis C. After all, the effects of stress on liver disease are numerous. They include decreased hepatic (liver) blood flow, severity of liver disease, elevated ALT levels, liver cell death and worsening of liver disease. Reading a long list of symptoms is stressful enough to read, so it is no wonder we can find ourselves suffering from stress without even realizing it. So ask yourself, do you know when was the last time you were stressed without realizing it? Identifying unrecognized stress is a task in itself, as it is so easy to push stressful thoughts into our subconscious where they will lay dormant. Sometimes, this is not only the most difficult form of stress to identify, but prevent. After all, it is impossible to guarantee when stress might strike. Self-awareness is a great way in which to realize for yourself how much unrecognized stress affects those of us living with the hepatitis C virus. Let's take a look at some ways in which to reduce stress.

S - strive for flexibility;
T - take time to decide where your boundaries are in a relationship;
R - relax and take a deep breath, as sometimes, the time it takes to breathe is all it takes to realize that a step back is the safest place to be;
E - eat hep C friendly food, because it will put less stress on your liver;
S - sleep when your body is telling you it needs rest;
S - seek clarification, because we can make wrongful interpretations of a situation based on second-guessing what the other person is thinking (or doing).

Such simple steps might sound silly, but there is a lot to be said about “keeping things simple”. This is because stress is more often a build up of reactions we store without realizing. Now that social-media is a large part of our modern world, we are faced with more pressure than ever before. Red-flag alerts, notifications and spam now command our attention on the internet. We might spend more time making comments on social networking sites than taking the time to talk to our loved ones, face-to-face. As well, we are at risk of not feeling safe on the world wide web. Have you had a holiday from the internet recently? If not, take the challenge and you might discover just how much less stressful it is to keep up with the virtual world!

Stress is like a toxic weed, it can grow in any condition without any food or nutrients. All it needs is a person not to be aware of it. Sometimes, the best way to deal with stress is to tune into one's self and truly feel what it feels like, so as to know what it really is. Not knowing how stress feels is almost more stressful than stress itself! For those of us that live with the hepatitis C virus, our reactions to situations might be more sensitive. This can make us more vulnerable to stress, which is why knowing how stress affects you is a unique and wonderful way in which to help reduce it. With just a few minutes per day, it is possible to learn to live with stress in a healthier way. It might just be as simple as becoming more flexible, or eating healthier food: it just depends on YOU.

--------------------

Mixed genotype hepatitis C infections and implications for treatment

Hepatology

Volume 59, Issue 3, page 1209, March 2014

Correspondence

You have full text access to this OnlineOpen article

Anna L. McNaughton M.Sc.¹, Emma C. Thomson Ph.D., MRCP¹, Kate Templeton Ph.D.², Rory N. Gunson FRCPath³, E. Carol McWilliam Leitch Ph.D.¹

Article first published online: 13 JAN 2014

DOI: 10.1002/hep.26544

Copyright © 2013 Crown copyright. HEPATOLOGY Copyright © 2013 the American Association for the Study of Liver Diseases.

Potential conflict of interest: Nothing to report.

This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.

Supported by MRC grant 63785.

To the Editor:

The recently licensed direct-acting antivirals (DAAs) boceprevir and telaprevir used to treat hepatitis C virus (HCV) infection act in a genotype-specific manner. The potential outcome of DAA treatment regimes on mixed HCV infections, consisting of concurrent infection with more than one HCV genotype, has not been considered. Standard genotyping methods are only capable of identifying the dominant genotype present within a mixed infection sample, leaving minor genotypes undetected. We propose that DAA treatment of mixed infections may be associated with the occurrence of genotype switching, whereby a previously undetected minority variant drug-resistant genotype expands to replace the successfully treated majority variant genotype. Such genotype switching could in some cases result in nonresponse to DAA treatment and could also be incorrectly interpreted as reinfection if genotyping is not repeated following treatment failure. As a matter of urgency, there is a need to assess the prevalence and clinical impact of mixed HCV infections.

To determine the prevalence of mixed HCV infections in a cohort of patients infected with genotype (gt) 3a (n = 47) or 1a (n = 48), we designed gt1a- and gt3a-specific primers providing partial coverage of the envelope genes E1 and E2 of HCV. Nested reverse transcription (RT) polymerase chain reaction (PCR) reactions were performed using gt1a primers with gt3a-infected samples and vice versa. Amplicons were sequenced and used to construct maximum likelihood phylogenetic trees using the MEGA 5.0 software package to confirm genotype.

The sensitivity of the RT-PCR reactions, as determined by 90% detection limits calculated from serial endpoint dilution RT-PCR and probit analysis, was nine copies/reaction. Of the gt3a-infected patient samples, 10.6% (5/47) harbored minority variant gt1a strains, whereas none of the gt1a-infected patient samples contained gt3a as a minority strain.

These findings are in keeping with other studies that found mixed HCV infections at rates of 5%-25.3%.[1-3] Further work is required to assess the impact of minority variant strains on patients treated with DAA therapy. If relapse following dual therapy for gt3 infection is associated with emerging dominance of preexisting gt1 strains, screening of baseline patient samples using genotype-specific methods could result in improved treatment strategies; for example, the prescription of triple rather than dual antiviral therapy. More work is required to assess the impact of multiple genotype infection on clinical outcome, and this work is more pressing in the DAA era.

Anna L. McNaughton, M.Sc.¹
Emma C. Thomson, Ph.D., MRCP¹
Kate Templeton, Ph.D.²
Rory N. Gunson, FRCPath³
E. Carol McWilliam Leitch, Ph.D.^1
1 MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
² Edinburgh Specialist Virology Centre, Edinburgh, UK
³ West of Scotland Specialist Virology Centre, Glasgow, UK

References

1. Pham ST, Bull RA, Bennett JM, Rawlinson WD, Dore GJ, Lloyd AR, et al. Frequent multiple hepatitis C virus infections among injection drug users in a prison setting. Hepatology 2010;52:1564-1572. Abstract Full Article (HTML) PDF(325K) References Web of Science® Times Cited: 21
2. Yun H, Kim D, Kim S, Kang S, Jeong S, Cheon Y, et al. High prevalence of HBV and HCV infection among intravenous drug users in Korea. J Med Virol 2008;80:1570-1575. Abstract PDF(114K) References Web of Science® Times Cited: 5
3. Thomson, EC, Fleming VM, Main J, Klenerman P, Weber J, Eliahoo J, et al. Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men. Gut 2011;60:837-845. CrossRef,  Web of Science® Times Cited: 24

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Boceprevir and telaprevir-based triple therapy for chronic hepatitis C: virological efficacy and impact on kidney function and MELD score

Journal of Viral Hepatitis

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

V. Virlogeux^1,2,3,4, P. Pradat^1,2,3, F. Bailly^1,2,3, G. Funingana¹, F. Gonçalves¹, M. Maynard¹, K. Hartig-Lavie¹, M. Amiri¹, F. Zoulim^1,2,3,5,*

Article first published online: 25 FEB 2014

DOI: 10.1111/jvh.12237

© 2014 John Wiley & Sons Ltd

Keywords: glomerular filtration rate;  hepatitis C virus;  pegylated interferon;  protease inhibitor;  renal function;  ribavirin; triple therapy; virological response

Abstract

Summary

Triple therapy using telaprevir or boceprevir [hepatitis C virus (HCV)-NS3/NS4A protease inhibitors (PI)] in association with PEG-IFN/ribavirin has recently become the new standard of care (SOC) for treatment of HCV genotype 1 patients. Our objective was to assess the efficacy and tolerance of triple therapy in routine clinical practice. A total of 186 consecutive HCV patients initiating triple therapy were enrolled in a single centre study. Clinical, biological and virological data were collected at baseline and during follow-up as well as tolerance and side effect details. Among 186 HCV patients initiating triple therapy, 69% received telaprevir and 31% boceprevir. Sixty-one per cent of patients had cirrhosis. The overall extended rapid virological response (eRVR) rate and sustained virological response (SVR) rate were 57.0% and 59.7%, respectively. IL28B CC phenotype was associated with increased probability of achieving eRVR and SVR, whereas previous non-response was associated with low eRVR and SVR rates. The SVR rate increased from 30.8% in previously non-responders to 59.1% in partial non-responders and 75% in relapsers. SVR rate in naive patients was 62.5%. Glomerular filtration rate assessed by MDRD after 12 weeks of therapy was significantly reduced for both PI (P < 0.001). The model for end-stage liver disease(MELD) score was significantly increased at W12 for telaprevir (P = 0.008) and at W24 for boceprevir (P = 0.027). PI-based triple therapy leads to high rates of virological response even in previously non-responder patients. Renal function after triple therapy is impaired as well as MELD score in all patients. Cautious clinical monitoring should focus not only on haematological and dermatological side effects but also on renal function.

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Glycerol phenylbutyrate reduces hepatic encephalopathy events And ammonia levels compared to placebo

PUBLIC RELEASE DATE: 25-Feb-2014]

Contact: Dawn Peters
sciencenewsroom@wiley.com
781-388-8408
Wiley

Phase 2 trial results published in the March issue of Hepatology, a journal of the American Association for the Study of Liver Diseases, suggests the potential for Glycerol Phenylbutyrate (GPB) to reduce hepatic encephalopathy episodes in patients with cirrhosis, with a safety profile similar to placebo.

Patients with hepatic encephalopathy experience neuropsychiatric symptoms that may range from mild confusion to coma. There is conflicting evidence on the link between elevated blood ammonia and hepatic encephalopathy. Poorly-absorbable disaccharides and antibiotics are currently used to treat encephalopathy and are generally believed to act by reducing ammonia production in the intestine.

"GPB is approved to treat urea cycle defects that prevent the removal of ammonia from the body," explains Dr. Bruce F. Scharschmidt, Sr. VP & Chief Medical Officer with Hyperion Therapeutics in San Francisco, CA. "Our trial was the first to investigate the efficacy of a direct ammonia lowering agent in patients with cirrhosis and hepatic encephalopathy."

This phase 2 clinical trial enrolled 178 cirrhosis patients, including 59 who were already taking rifaximin. Participants who had two or more hepatic encephalopathy events within the six months prior to the trial were included. The trial aim was to determine the proportion of patients with hepatic encephalopathy taking 6mL GBP twice daily compared to placebo.

Results show that the percentage of patients who experienced hepatic encephalopathy events was significantly reduced among patients randomized to GPB versus placebo at 21% vs. 36%, respectively. Total hepatic encephalopathy events were lower in patients taking the medication (35) versus placebo (57). Hospitalizations due to hepatic encephalopathy tended to be less frequent among patients taking GPB at 13 compared to those in the placebo group at 25.

The trial results also indicate that ammonia levels in the blood of patients on GPB were lower than subjects not taking the medication. "Our findings provide evidence that elevated blood ammonia plays an important role in the development of hepatic encephalopathy," concludes Dr. Scharschmidt. "GPB reduced the risk of hepatic encephalopathy in patients with cirrhosis and further investigation of its therapeutic potential for patients with hepatic encephalopathy is warranted."

In a related editorial published in Hepatology, Dr. Meritxell Ventura-Cots with the Hospital Vall Hebron in Barcelona, Spain writes, "The study by Rockey et al. shows that GPB improves the outcome among cirrhotic patients with highly recurrent hepatic encephalopathy. The new drug avoids the risk of sodium overload, was well tolerated and had a good safety profile."

###

This study and editorial are published in Hepatology. Media wishing to receive a PDF of the articles may contact sciencenewsroom@wiley.com.

Full citations: "Randomized, Double-Blind, Controlled Study of Glycerol Phenylbutyrate in Hepatic Encephalopathy." Don C. Rockey, John M.Vierling, Parvez Mantry, Marwan Ghabril, Robert S. Brown Jr., Olga Alexeeva, Igor A. Zupanets, Vladimir Grinevich, Andrey Baranovsky, Larysa Dudar, Galyna Fadieienko, Nataliya Kharchenko, Iryna Klaryts'ka, Vyacheslav Morozov, Priya Grewal, Timothy McCashland, K. Gautham Reddy, K. Rajender Reddy, Vasyl Syplyviy, Nathan M. Bass, Klara Dickinson, Catherine Norris, Dion Coakley, Masoud Mokhtarani and Bruce F. Scharschmidt for the HALT-HE Study Group.Hepatology; (DOI: 10.1002/hep.26611) Print Issue Date: March, 2014.

URL: http://doi.wiley.com/10.1002/hep.26611

Editorial: "Drug-Induced Removal of Nitrogen Derivatives in Urine: A New Concept Whose Time Has Come." Juan Cordoba and Meritxell Ventura-Cots. Hepatology; (DOI: 10.1002/hep.26789) Print Issue Date: March, 2014.

URL: http://doi.wiley.com/10.1002/hep.26789

Author Contact: Media wishing to speak with Dr. Scharschmidt may contact Sylvia Wheeler with Hyperion Therapeutics at Sylvia.Wheeler@hyperiontx.com.

About the Journal

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

About Wiley

Wiley is a global provider of content-enabled solutions that improve outcomes in research, education, and professional practice. Our core businesses produce scientific, technical, medical, and scholarly journals, reference works, books, database services, and advertising; professional books, subscription products, certification and training services and online applications; and education content and services including integrated online teaching and learning resources for undergraduate and graduate students and lifelong learners.

Founded in 1807, John Wiley & Sons, Inc. (NYSE: JWa, JWb), has been a valued source of information and understanding for more than 200 years, helping people around the world meet their needs and fulfill their aspirations. Wiley and its acquired companies have published the works of more than 450 Nobel laureates in all categories: Literature, Economics, Physiology or Medicine, Physics, Chemistry, and Peace. Wiley's global headquarters are located in Hoboken, New Jersey, with operations in the U.S., Europe, Asia, Canada, and Australia. The Company's website can be accessed at http://www.wiley.com.

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Gilead – “Forget Me Not” HCV Disease Activation Commercial

 Gilead – “Forget Me Not” HCV Disease Activation Commercial from Gilead on Vimeo.

 

“Gilead is first to throw its hat into direct to consumer marketing for hepatitis C.”

 

This commercial (and campaign) is designed to get diagnosed patients to rethink treating their hepatitis C. And through empathy and understanding, we connect with hepatitis C patients and encourage them to take action by registering online at HepcHope.com and to talk to their gastroenterologist about scientific advances that may help them move on from hepatitis C.

 

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Celsion Announces FDA Clearance of the OPTIMA Study - A Pivotal Phase III Trial of ThermoDox in Primary Liver Cancer

PRESS RELEASE

Feb. 24, 2014, 8:00 a.m. EST

--Study Developed in Consultation with Clinical Advisors, Statistical Experts and FDA --Compelling Survival Data Supports Development --Trial Advances Global Regulatory Strategy in Key Markets

LAWRENCEVILLE, N.J., Feb. 24, 2014 /PRNewswire/ -- Celsion Corporation CLSN -0.27% announced today that the U.S. Food and Drug Administration (FDA) has reviewed and provided clearance for the Company's planned pivotal, double-blind, placebo-controlled Phase III trial of ThermoDox®, its proprietary heat-activated liposomal encapsulation of doxorubicin in combination with radio frequency ablation (RFA) in primary liver cancer, also known as hepatocellular carcinoma (HCC). The trial design is based on a comprehensive analysis of data from the Company's Phase III HEAT Study, which demonstrated that treatment with ThermoDox resulted in a 55% improvement in overall survival in a substantial number of HCC patients that received an optimized RFA treatment.  Celsion expects to launch the study in the first half of 2014.

The Phase III trial, known as the OPTIMA Study, was designed with extensive input from globally recognized HCC researchers and clinicians, and after formal consultation with FDA. The OPTIMA Study is expected to enroll 550 patients globally, with up to 100 sites in the United States, Europe, China and Asia Pacific and will evaluate ThermoDox in combination with RFA, which will be standardized to a minimum of 45 minutes across all investigators and sites for treating lesions 3 to 7 centimeters, versus standardized RFA alone. The primary endpoint for the trial is overall survival (OS).  The statistical plan calls for two interim efficacy analyses by an independent Data Monitoring Committee (iDMC).

"ThermoDox appears to hold great promise as a first-line treatment when used in combination with  optimized RFA, for primary liver cancer, one of the most deadly and prevalent forms of cancer worldwide," stated Nicholas Borys, MD, Celsion's Chief Medical Officer. "Consistency of the retrospective data emerging from the HEAT Study over the past year has been remarkable, and underscores the potential of ThermoDox to extend survival in primary liver cancer patients. Now informed by critical insights from our HEAT Study, I am confident that the OPTIMA Study is robust, well-designed and well-supported by HCC researchers worldwide.  We look forward to initiation and timely completion of this important study."

As reported in January 2014, post-hoc data from the Company's  HEAT Study demonstrate that the patient subgroup in the ThermoDox arm whose RFA procedure lasted longer than 45 minutes (285 patients or 63% of single lesion patients), experienced a 55% improvement in overall survival, with a Hazard Ratio of 0.64 (95% CI 0.41 - 1.00) and a P-value = 0.0495. Median overall survival for this subgroup has not yet been reached. Celsion will continue to follow patients in the HEAT Study on a quarterly basis.

"FDA allowance of the Phase III OPTIMA Study represents a significant step forward in our global development strategy for ThermoDox and establishes a clear regulatory pathway that advances our goal of delivering a new treatment option to patients with this devastating and underserved disease," stated Michael H. Tardugno, Celsion's President and CEO. "In parallel with our efforts in the United States, we continue to advance discussions with regulators in other important global markets, including a recent positive meeting with China FDA (CFDA) and near-term plans to meet with European regulatory authorities."

In support of the Company's global regulatory efforts, Celsion recently met with CFDA to discuss the Phase III trial, including minimum patient enrollment requirements supporting ThermoDox's registration in China. Based on those discussions, Celsion is submitting an application for accelerated approval of the study in China. Celsion will expand its clinical site footprint in Europe and plans to meet with the European Medicines Agency (EMA) in the first half of 2014.

The HEAT Study and prior post-hoc analyses were presented at three medical conferences in 2013, including the World Conference on Interventional Oncology in May; the European Conference on Interventional Oncology in June and the International Liver Cancer Association Annual Conference in September.  Presentations were made by some of the most highly recognized liver cancer researchers and key HEAT Study investigators.  Quarterly overall survival data analyses have been conducted with the full support of these researchers and clinical investigators.

About Celsion Corporation

Celsion is dedicated to the development and commercialization of innovative cancer drugs, including tumor-targeting treatments using focused heat energy in combination with heat-activated liposomal drug technology.  Celsion has research, license or commercialization agreements with leading institutions, including the National Institutes of Health, Duke University Medical Center, University of Hong Kong, the University of Pisa, the UCLA Department of Medicine, the Kyungpook National University Hospital, the Beijing Cancer Hospital and the University of Oxford.  For more information on Celsion, visit our website: http://www.celsion.com .

Celsion wishes to inform readers that forward-looking statements in this release are made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995.  Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, unforeseen changes in the course of research and development activities and in clinical trials; the uncertainties of and difficulties in analyzing interim clinical data, particularly in small subgroups; FDA and regulatory uncertainties and risks; the significant expense, time, and risk of failure of conducting clinical trials; HEAT Study data is subject to further verification and review by the HEAT Study Data Management Committee; the need for Celsion to evaluate its future development plans; possible acquisitions or licenses of other technologies, assets or businesses or the possible failure to make such acquisitions or licenses; possible actions by customers, suppliers, competitors, regulatory authorities; and other risks detailed from time to time in the Celsion's periodic reports and prospectuses filed with the Securities and Exchange Commission.  Celsion assumes no obligation to update or supplement forward-looking statements that become untrue because of subsequent events, new information or otherwise.

Celsion Investor Contact Jeffrey W. ChurchSr. Vice President and CFO609-482-2455jchurch@celsion.com

SOURCE Celsion Corporation

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Scientists Transform Skin Cells into Functioning Liver Cells

Joint Gladstone-UCSF Study Highlights Novel Reprogramming Method, Offers New Hope for Treating Liver Failure

By Jeff Norris and Anne Holden on February 23, 2014

The power of regenerative medicine now allows scientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and even neurons. However, a method to generate cells that are fully mature—a crucial prerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the Gladstone Institutes and UC San Francisco have made an important breakthrough: they have discovered a way to transform skin cells into mature, fully functioning liver cells that flourish on their own, even after being transplanted into laboratory animals modified to mimic liver failure.

Holger Willenbring, MD, PhD

In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cell-derived liver cells to survive once being transplanted into existing liver tissue. But the Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the journal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding, PhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular reprogramming method that transforms human skin cells into liver cells that are virtually indistinguishable from the cells that make up native liver tissue.

These results offer new hope for the millions of people suffering from, or at risk of developing, liver failure—an increasingly common condition that results in progressive and irreversible loss of liver function. At present, the only option is a costly liver transplant. So, scientists have long looked to stem cell technology as a potential alternative. But thus far they have come up largely empty-handed.

Sheng Ding, PhD

“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order to then grow liver cells,” explained Ding, one of the paper’s senior authors, who is also a professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However, generating these so-called induced pluripotent stem cells, or iPS cells, and then transforming them into liver cells wasn’t always resulting in complete transformation. So we thought that, rather than taking these skin cells all the way back to a pluripotent, stem cell-like state, perhaps we could take them to an intermediate phase.”

This research, which was performed jointly at the Roddenberry Center for Stem Cell Research at Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, involved using a ‘cocktail’ of reprogramming genes and chemical compounds to transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells that eventually mature into many of the body’s major organs—including the liver.

“Instead of taking the skin cells back to the beginning, we took them only part way, creating endoderm-like cells,” added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one of the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that could more readily be coaxed into becoming liver cells.”

Next, the researchers discovered a set of genes and compounds that can transform these cells into functioning liver cells. And after just a few weeks, the team began to notice a transformation.

“The cells began to take on the shape of liver cells, and even started to perform regular liver-cell functions,” said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper’s other lead author. “They weren’t fully mature cells yet—but they were on their way.”

Now that the team was encouraged by these initial results in a dish, they wanted to see what would happen in an actual liver. So, they transplanted these early-stage liver cells into the livers of mice. Over a period of nine months, the team monitored cell function and growth by measuring levels of liver-specific proteins and genes.

Two months post-transplantation, the team noticed a boost in human liver protein levels in the mice, an indication that the transplanted cells were becoming mature, functional liver cells. Nine months later, cell growth had shown no signs of slowing down. These results indicate that the researchers have found the factors required to successfully regenerate liver tissue.

“Many questions remain, but the fact that these cells can fully mature and grow for months post-transplantation is extremely promising,” added Willenbring, associate director of the UCSF Liver Center and the paper’s other senior author. “In the future, our technique could serve as an alternative for liver-failure patients who don’t require full-organ replacement, or who don’t have access to a transplant due to limited donor organ availability.”

Other scientists who participated in this research include UCSF researchers Jack Harbell, MD, also a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet, PhD. Funding was provided by the following: the California Institute for Regenerative Medicine, the National Institutes of Health, the German Academic Exchange Service, and the Society of University Surgeons.

About the Gladstone Institutes

Gladstone is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and innovation to prevent, treat and cure cardiovascular, viral and neurological diseases. Gladstone is affiliated with UCSF.

About UCSF

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital.

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Hepatitis C to Share Spotlight at HIV Conference

Medscape Medical News > Conference News

Marcia Frellick

February 24, 2014

BOSTON — Although HIV will dominate the agenda at the 2014 Conference on Retroviruses and Opportunistic Infections (CROI), related viruses and infections will also be in the limelight.

Several presentations at the conference, being held from March 3 to 6, will focus on advances in the treatment of hepatitis C virus and the barriers to delivery, and the latest developments in tuberculosis (TB) and human papillomavirus.

Lynn Taylor, MD, from the division of infectious diseases at Miriam Hospital, Brown Medical School, in Providence, Rhode Island, told Medscape Medical News that developments in drugs and policy on the hepatitis C front make this year's discussion particularly important.

"We have seen extraordinary, unprecedented improvement in therapies to cure hep C," she said. "We have the potential to eradicate hep C locally, nationally, globally. The focus of our panel is that there's nothing in place yet, on any significant scale, to enhance delivery."

Dr. Taylor described a "crisis" in the United States because baby boomers who never knew they were infected are now discovering it in advanced form. "Seventy-five percent of Americans who have hep C don't even know they have it," she said.

“Ten years ago, you were considered a charlatan if you said hep C was curable.”

Last year, because of the prevalence of hepatitis C in baby boomers, the Centers for Disease Control and Prevention revised its guidelines to recommend a 1-time screening for everyone born from 1945 to 1965, in addition to risk-based screening. In December 2013, the European Association for the Study of the Liver revised its clinical practice guidelines on the management of hepatitis C; they will be presented in April before the International Liver Congress.

Dr. Taylor said she is "thrilled" to see the increased attention on hepatitis C at the conference.

"Ten years ago, you were considered a charlatan if you said hep C was curable," she said.

The conference, the most significant HIV research meeting in the world, will attract more than 4000 leading international HIV/AIDS researchers. The goal is to provide a forum for researchers to translate their findings into direct progress in HIV.

Conference to Draw More Than 4000 Researchers

Last year's conference was abuzz with the news that a 2-year-old Mississippi girl, born with HIV and treated early with antiretroviral drugs, had been functionally cured and no longer had detectable levels of the virus, despite not taking medication for 10 months.

This year, speakers will provide updates on the progress toward a cure for HIV, and look at what is standing in the way of getting there.

Adeeba Kamarulzaman, MBBS, from the University of Malaya in Kuala Lumpur, Malaysia, said she will explain some positive changes for drug users in the HIV fight in countries such as Malaysia.

She will also speak about the impact of the "epidemic of incarceration" and its effects on HIV, as well as coinfection with TB and hepatitis C, she told Medscape Medical News. She will highlight the increase in methamphetamine use and its relation to HIV risk behaviors, particularly in men who have sex with men.

TB is also getting attention at the conference. There will be presentations on the resistance, persistence, monitoring, and control of the disease; the use of novel imaging technology to monitor treatment response; and population-level control of HIV-related TB.

The prevention and treatment of HIV infection in infants will be addressed, as will the short- and long-term consequences of antiretroviral exposure during pregnancy and breast-feeding.

In addition, the outbreak of invasive meningococcal disease that affected men who have sex with men in New York City from 2010 to 2013 will be discussed.

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The Rise of Sofosbuvir

Infectious Disease Special Edition
ISSUE: FEBRUARY 2014 | VOLUME: 1

by Kate O'Rourke

Many clinicians are ecstatic about the recent approval of sofosbuvir (Sovaldi, Gilead Sciences) for patients with hepatitis C virus (HCV) infection. At The Liver Meeting 2013, several presentations provided new insight into just how sofosbuvir will perform in clinical practice.

“I think sofosbuvir is the cat’s meow,” said Sammy Saab, MD, MPH, professor of medicine and surgery and head of outcomes research in hepatology at the David Geffen School of Medicine, University of California, Los Angeles.

“It’s a drug that has no resistance or incremental adverse effects. It is very well tolerated, very safe, very efficacious and there are no significant drug interactions with it. I think it is going to revolutionize the way we treat hepatitis in this country and around the world.”

Traditional Risk Factors Fade Away

According to studies presented at The Liver Meeting, many factors traditionally thought to portend poor outcomes in HCV patients may not have an effect with sofosbuvir. One study was a retrospective analysis of 982 patients with HCV infection (genotypes 1-6) in four Phase III trials: FISSION, POSITRON, FUSION and NEUTRINO. Patients were treated with sofosbuvir plus ribavirin, with or without pegylated interferon (IFN). Sustained virologic response (SVR) rates were analyzed according to gender, age (<65 vs. ≥65 years), interleukin-28 B (IL28B) genotype, body mass index (<30 vs. ≥30 kg/m²), race (black vs. non-black), viral load (HCV RNA <10⁷ vs. ≥10⁷ copies/mL), opiate replacement status and cirrhosis. Of these factors, only male gender and the presence of cirrhosis were consistently predictive of worse outcomes; the difference between cirrhotics and noncirrhotics existed but was not large. In the NEUTRINO trial, for example, 80% of cirrhotics versus 92% of noncirrhotics achieved SVR at week 12. Also, IL28B genotype status was only predictive of SVR in the NEUTRINO trial.

HIV Coinfection

Sofosbuvir in combination with ribavirin also works well and causes less toxicity than IFN-based regimens in HCV patients who are coinfected with HIV. In the PHOTON-1 trial, 182 treatment-naive patients with HCV genotype 1, 2 or 3 and stable HIV disease, some of whom had cirrhosis, were evaluated. SVR rates at week 12 were 81% in HCV genotype 2 patients and 67% in HCV genotype 3 patients. Among the 19 patients not acheiving SVR at week 12, relapse was confirmed in 12 patients and data were missing for six patients. HCV genotype 1 patients received 24 weeks of treatment and had an SVR rate of 76%. Sofosbuvir was coadministered effectively with multiple HIV antiretroviral regimens, including inhibitors of HIV-1 protease, reverse transcriptase and integrase; it had no adverse effect on HIV status or antiretroviral therapy.

“The IFN-free regimen of sofosbuvir plus ribavirin resulted in high SVR 12 rates in HCV treatment-naive, HIV-infected patients with HCV genotype 1, 2 or 3 coinfection,” said Mark Sulkowski, MD, medical director of the Viral Hepatitis Center in the Divisions of Infectious Diseases and Gastroenterology & Hepatology, and professor of medicine at the Johns Hopkins School of Medicine, in Baltimore, who presented the study. “SVR 12 rates were similar to those observed in patients with HCV mono-infection.”

Null Responders

Data from the COSMOS trial suggested that HCV genotype 1 null responders may be a lot easier to treat with the combination of sofosbuvir plus simeprevir (Olysio, Janssen) than with first-generation direct-acting antiviral agents. In this Phase II trial, investigators evaluated 167 patients in two cohorts. In cohort 1, patients with METAVIR scores of F0 to F2 who were prior null responders to IFN with ribavirin received 12 or 24 weeks of treatment with sofosbuvir plus simeprevir, with or without ribavirin. In an intent-to-treat (ITT) analysis of the data, these patients achieved SVR rates at week 12 of 79% to 96%. Cohort 2 included treatment-naive patients and prior null responders with METAVIR scores of F3 to F4; they received 12 weeks of treatment with sofosbuvir plus simeprevir, with or without ribavirin. These patients achieved SVR rates at week 4 of 96% to 100%, based on an ITT analysis. The treatments were characterized as generally well tolerated.

“The findings in this interim analysis suggest that the addition of ribavirin to simeprevir plus sofosbuvir may not be needed to achieve high rates of SVR in this patient population,” said Ira Jacobson, MD, chief of the Division of Gastroenterology and Hepatology at Weill Cornell Medical College, New York City, who presented the data. “Anemia and bilirubin increases were predominantly limited to the ribavirin-containing treatment arms.”

Cirrhosis

Results from the LONESTAR-2 trial echoed results of other trials showing the high efficacy of sofosbuvir in prior null responders and patients with cirrhosis. This trial tested 12 weeks of treatment with sofosbuvir plus pegylated IFN and ribavirin in treatment-experienced patients with HCV genotype 2 or 3 infection. HIV and HBV coinfected patients were excluded from the trial, but 50% of the study population had compensated cirrhosis. In patients with HCV genotype 2 (n=23), 93% of cirrhotics and 100% of noncirrhotics achieved SVR at week 12. In HCV genotype 3 patients, the presence of cirrhosis did not affect outcomes, and 83% of patients achieved SVR at week 12.

“Sofosbuvir plus pegylated IFN/ribavirin for 12 weeks demonstrated high efficacy in treatment-experienced genotype 2/3 patients who have historically low response rates and limited treatment options,” said Eric Lawitz, MD, vice president of scientific and research development at The Texas Liver Institute and clinical professor of medicine at the San Antonio University of Texas Health Science Center, who presented the study. “SVR rates were similar in patients with and without cirrhosis.”

Different Treatment Duration for Patients With HCV Genotypes 2 and 3

Although many of the traditional factors that predict treatment response in HCV patients do not seem to apply to sofosbuvir, there does seem to be a difference in response among HCV genotypes. In general, clinicians are accustomed to treating patients with HCV genotype 2 or 3 similarly, but these two groups respond differently to sofosbuvir.

In Phase III trials, response rates have been higher in patients with HCV genotype 2 after 12 weeks of treatment with sofosbuvir plus ribavirin. The VALENCE trial originally set out to test 12 weeks of treatment with sofosbuvir plus ribavirin in patients with HCV genotype 2/3, but investigators amended the trial after recognizing that the two types of patients might respond to treatment differently; the 250 patients with HCV genotype 3 ultimately received 24 weeks of treatment. Among genotype 3 patients without cirrhosis, response rates were 94% in treatment-naive patients and 87% in treatment-experienced patients; genotype 3 patients with cirrhosis had response rates of 60%.

More evidence that longer therapy is better for HCV genotype 3 patients came from data presented at a meeting of the FDA Sofosbuvir Review team on Oct. 25.

“The FDA did an elegant analysis of the effect of treatment duration with sofosbuvir–ribavirin in genotype 3–infected patients,” Dr. Sulkowski said. “[They] presented very convincing data that a 24-week duration of sofosbuvir–ribavirin should be the standard for all genotype 3–infected patients.”

The FDA analysis combined data from the FISSION, POSITRON, FUSION and VALENCE trials. In both treatment-naive and treatment-experienced patients with HCV genotype 3, SVR rates dramatically rose and relapse rates fell when treatment was increased from 12 weeks to 24 weeks (Table).

As a result, when the FDA approved sofosbuvir in December, the agency approved a 12-week treatment regimen in patients with HCV genotype 2 and a 24-week regimen in patients with genotype 3, both in combination with ribavirin. The FDA also approved a 12-week regimen of sofosbuvir in combination with ribavirin and IFN for patients with HCV genotypes 1 and 4.

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Dr. Saab has served as a consultant and on the speakers’ bureaus for Boehringer Ingelheim, Genentech, Gilead Sciences, Janssen, Merck, and Vertex Pharmaceuticals. Dr. Sulkowski has received consulting fees from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck and Vertex. Dr. Jacobson has received grants or research support and has served as a member of a speaker’s bureau or as a consultant/advisor for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Idenix Pharmaceuticals, Janssen, Merck, Novartis, Roche/Genentech and Vertex. Dr. Lawitz has served on advisory committees or review panels for AbbVie, Achillion, BioCryst Pharmaceuticals, Biotica, Enanta, Idenix, Janssen, Merck, Novartis, Santaris, Theravance and Vertex; he has received grant and research support form AbbVie, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Idenix, Intercept, Janssen, Merck, Novartis, Presidio, Roche, Santaris Pharma and Vertex.

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Bristol-Myers Squibb Receives U.S. FDA Breakthrough Therapy Designation for All-Oral Daclatasvir Dual Investigational Regimen for Chronic Hepatitis C

• FDA grants Designation request for investigational daclatasvir (DCV) and asunaprevir (ASV) combination therapy for treatment of genotype 1b chronic hepatitis C (HCV) infection
• Marks second Breakthrough Therapy Designation for a daclatasvir-based regimen; 3DAA regimen granted Designation in 2013

Monday, February 24, 2014 8:30 am EST

"The FDA’s decision to grant Breakthrough Therapy Designation for our DCV Dual Regimen (daclatasvir and asunaprevir combination therapy) marks the second time that the FDA has granted the Designation to a daclatasvir-based regimen, further underscoring its potential to help address the high unmet needs of the HCV patient population"

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced that the U.S. Food and Drug Administration (FDA) has granted its investigational DCV Dual Regimen (daclatasvir and asunaprevir) Breakthrough Therapy Designation for use as a combination therapy in the treatment of genotype 1b chronic hepatitis C infection (HCV). The designation is based on data from the company’s ongoing Phase III clinical trial program evaluating the all-oral combination regimen of DCV, an investigational NS5A replication complex inhibitor, and ASV, an investigational NS3 protease inhibitor, without ribavirin.

According to the FDA, Breakthrough Therapy Designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for Breakthrough Therapy Designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.

“The FDA’s decision to grant Breakthrough Therapy Designation for our DCV Dual Regimen (daclatasvir and asunaprevir combination therapy) marks the second time that the FDA has granted the Designation to a daclatasvir-based regimen, further underscoring its potential to help address the high unmet needs of the HCV patient population,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “This is an important milestone for Bristol-Myers Squibb as we continue our strategic focus on the development of innovative medicines to address areas of high unmet medical need, where potential expedited review can make a critical difference for patients.”

Approximately 170 million people worldwide are infected with hepatitis C, with an estimated 2.7–3.9 million chronically infected in the U.S. Many of these people have been living with HCV for decades, putting them at heightened risk for developing serious, potentially life-threatening liver disease.

New data from Bristol-Myers Squibb’s ongoing Phase III clinical program studying the DCV Dual Regimen is anticipated to be presented at an upcoming scientific forum. Data from a separate daclatasvir and asunaprevir Phase III trial in Japanese patients with HCV genotype 1b who were either interferon-ineligible/intolerant or non-responders (null and partial) to interferon-based therapies served as the basis for a regulatory filing in Japan in October 2013.

Bristol-Myers Squibb also recently announced that the European Medicines Agency (EMA) validated the company’s marketing authorization application (MAA) for the use of daclatasvir for the treatment of adults with HCV with compensated liver disease, including genotypes 1, 2, 3, and 4. The application seeks the approval of daclatasvir for use in combination with other agents for the treatment of chronic hepatitis C and will be reviewed under an accelerated regulatory review.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. Up to 90 percent of those infected with hepatitis C will not spontaneously clear the virus and will become chronically infected. According to the World Health Organization, 20 percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer.

About Bristol-Myers Squibb’s HCV Portfolio

Bristol-Myers Squibb’s research efforts are focused on advancing late-stage compounds to deliver the most value to patients with hepatitis C. At the core of our pipeline is daclatasvir, an investigational NS5A replication complex inhibitor that has been studied in more than 5,500 patients as a foundational agent for multiple direct-acting antiviral (DAA) based combination therapies.

In 2013, Bristol-Myers Squibb’s investigational all-oral 3DAA Regimen (daclatasvir/ asunaprevir/BMS-791325) received FDA Breakthrough Therapy Designation, which helped to expedite the start of the ongoing Phase III UNITY Program. Study populations include non-cirrhotic treatment naïve and experienced patients, as well as cirrhotic treatment naïve and experienced patients. The daclatasvir 3DAA regimen is being studied as a fixed-dose-combination treatment with twice daily dosing.

In addition, enrollment has begun for the Phase III ALLY Program, in which daclatasvir in combination with sofosbuvir, is being studied in high unmet need patients, such as pre- and post-transplant patients, HIV/HCV co-infected patients and patients infected with HCV genotype 3.

Other compounds in the pipeline include:

• Asunaprevir (ASV) is an investigational NS3 protease inhibitor for hepatitis C which has been studied as a component of DCV-based treatment regimens
• BMS-791325 is a non-nucleoside inhibitor of the NS5B polymerase, currently in Phase III development for hepatitis C as a component of DCV-based treatment regimens
• Peginterferon lambda is an investigational type III interferon that has the potential to offer an alternative to peginterferon alfa in patients for whom an interferon-based regimen is required or preferred

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that DCV or any other compounds mentioned in this release will receive regulatory approval or, if approved, that they will become commercially successful products. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2013, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Contact:

Bristol-Myers Squibb Company
Media:
Carrie Fernandez
Office: 609-252-4831
Cell: 215-859-2605
carrie.fernandez@bms.com
or
Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
or
Ryan Asay, 609-252-5020
ryan.asay@bms.com

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Impact of interferon free regimens on clinical and cost outcomes for chronic hepatitis C genotype 1 patients

J Hepatol. 2014 Mar;60(3):530-7. doi: 10.1016/j.jhep.2013.11.009. Epub 2013 Nov 19.

Younossi ZM¹, Singer ME², Mir HM³, Henry L⁴, Hunt S⁴.

Abstract

BACKGROUND & AIMS: Hepatitis C (HCV) is a common cause of chronic liver disease worldwide. Current standard treatment for genotype-1 patients uses a triple combination of pegylated-interferon alpha (IFN), ribavirin (RBV) and a direct-acting antiviral agent (DAA) with 75-80% sustained virologic response (SVR) rates. The aim is to determine cost-effectiveness of staging-guided vs. treat all HCV genotype-1 patients with interferon-based vs. interferon-free regimens.

METHODS: A decision analytic Markov model simulating patients until death compared four strategies for treating HCV genotype-1: Triple therapy (IFN, RBV, DAA) with staging-guidance or treat all, and oral IFN-free regimen with staging-guidance or treat all. Strategies with staging initiated treatment at fibrosis stages F2-F4, with staging repeated every 5years until age 70. The reference case was a treatment-naïve 50-year-old. Analysis was repeated for 50% increase in cost of oral therapy. Effectiveness was measured in quality-adjusted life years (QALYs).

RESULTS: Treatment of all patients with oral IFN-free regimen was the most cost-effective strategy, with an ICER of $15,709/QALY at baseline cost of oral therapy. The ICER remained below $50,000/QALY in sensitivity analyses for baseline and +50% cost of oral therapy scenarios. The treat all strategy was also the most effective strategy; associated with the lowest risk of developing advanced liver disease.

CONCLUSIONS: Treating all HCV patients with oral IFN-free regimen reduced the number of patients developing advanced liver disease and increased life expectancy. Additionally, IFN-free regimen without staging may be the most cost-effective approach for treating HCV genotype-1 patients. The efficacy and safety of these regimens must be confirmed using randomized clinical trials.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: BOC, CHC, CMS, Centers for Medicare and Medicaid Services, Cost-effectiveness analysis, DAA, F0, F1, F2 or F4, GT, HCV, HIV, ICER, IFN, IFN, BV, DAA, Interferon-free oral treatment, Markov model, NADAC, National Average Drug Acquisition Cost, QALYs, RBV, SVR, TVR, Triple therapy, WAC, boceprevir, chronic hepatitis C, direct, acting antiviral agent, genotype, hepatitis C, immunodeficiency virus, incremental cost, effectiveness analysis, mild fibrosis, moderate or advanced fibrosis, pegylated, interferon alpha, quality, adjusted life years (a standard metric that incorporates both length and quality of life), ribavirin, sustained virologic response, telaprevir, wholesale acquisition cost

PMID: 24269472 [PubMed - in process]

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