News Ticker:Serum Vitamin D Levels Are Not Predictive of the Progression of Chronic Liver Disease in Hepatitis C Patients with Advanced Fibrosis

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HepCBC hosts educational forum

New U.S. statistics show that viral hepatitis deaths are surpassing those from HIV – the virus that leads to AIDS.

This stirring news has helped lead HepCBC Hepatitis C Education and Prevention Society to host a forum to discuss new guidelines for the management of hepatitis C and B recommended by liver specialists.

The forum is being held Friday, March 2 from 9 a.m. to 4 p.m. at Royal Jubilee Hospital’s Begbie Hall, 2101 Richmond Ave.

Five Canadian liver specialists will present new recommended guidelines for managing HCV. Each of their presentations will be followed by a public question and answer and comment period. The public is invited, but as seating is limited, online pre-registration is required via www.hepcbc.ca.


China investigating hepatitis C outbreak in south
The Associated Press
Published: Monday, Feb. 27, 2012 - 5:48 am

BEIJING -- China says it is sending medical experts to investigate an outbreak of hepatitis C among more than 200 people in the southern province of Guangdong.

Ministry of Health spokesman Deng Haihua said Monday that mistakes in medical procedures may have caused the infections in the province's Zijin county. Deng said strengthened preventative measures were ordered at clinics and hospitals in the area to prevent the further spread of the virus.
Hepatitis C is spread primarily through blood and can lead to life-threatening liver damage. Infection can occur through blood transfusions, poorly sterilized equipment or the sharing of intravenous drug needles.
Use of contaminated needles has been blamed in previous outbreaks in China.

 Answering the Call

Research

Serum Vitamin D Levels Are Not Predictive of the Progression of Chronic Liver Disease in Hepatitis C Patients with Advanced Fibrosis
Source PloS One

Introduction Only

Hepatic fibrosis results from wound healing following acute and chronic liver injury. In response to chronic hepatic inflammation, parenchymal cells release extracellular matrix proteins including type I collagen, resulting in the progressive deposition of, and accumulation of, fibrosis. Ultimately, fibrotic tissue can replace hepatocytes and disrupt lobular architecture, the hallmark of cirrhosis, which, in turn, results eventually in hepatic dysfunction. [1]
Emerging data suggest that vitamin D is an important modulator of both the inflammatory response and wound healing. [2], [3] Vitamin D may modulate the inflammatory response and subsequent fibrosis via inhibition of TNF-α, a cytokine that plays a central role in the regulation of the immune response [4], [5] and by inhibiting the development of fibrosis directly through suppression of TGF-β, a multifunctional cytokine that may influence fibrosis progression [6].[7].[8].

The importance of vitamin D in immune modulation and deposition of fibrosis may extend to the liver, which plays an important role in vitamin D homeostasis. The liver is the site of the conversion of vitamin D3 to 25-hydroxy-vitamin D (25-OH-vitamin D) and may be a site of vitamin D storage. [9] In addition, vitamin D receptors exist on hepatocytes and other hepatic parenchymal cells, including hepatic stellate cells. As in the kidney, vitamin D is postulated to play an antiinflammatory and antifibrotic role in the liver via binding to promoters of target genes, leading to down-regulation of TNF-α and TGF-β production.

Cross-sectional population data suggest that vitamin D deficiency is common in persons with advanced liver disease. [10], [11] For example, Fisher et al. [12] evaluated vitamin D levels in 100 patients with liver disease, 51 with cirrhosis and 49 without cirrhosis, including 38 patients with chronic hepatitis C. The prevalence of vitamin D deficiency was significantly higher in cirrhotic than noncirrhotic subjects (86.3% versus 49.0%, p = 0.0001). Moreover, vitamin D levels decreased with advancing Child class; vitamin D levels were significantly lower in subjects with Child class C (22.7 nmol/L) than in those with Child class A (45.8 nmol/L, p<0.001). Such studies, however, are limited by their cross-sectional nature. Thus, while an association between vitamin D deficiency and advancing liver disease has been noted, the potential that vitamin D deficiency could be a predictor for progressive liver disease has not been explored.

Recently, vitamin D has been evaluated as a potential immunomodulator of hepatitis C virus (HCV), and preliminary data suggest that the addition of vitamin D to standard antiviral therapy may improve treatment response rates. [13] This observation lends further weight to the potential immunomodulatory role of vitamin D in liver disease.

The progression of hepatic fibrosis occurs over years, hampering the study of processes that affect fibrosis. On the other hand, the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial provided a unique opportunity to study fibrosis longitudinally over several years. [14] The HALT-C Trial was a 10-clinical center randomized, controlled trial to evaluate the benefit of long-term (3.5-years) peginterferon therapy in patients with histologically advanced (Ishak fibrosis stage ≥3) but clinically compensated chronic hepatitis C who had failed to respond previously to antiviral therapy. While the HALT-C Trial was a negative study, showing that such maintenance antiviral therapy was ineffective, the trial's study design, including sequential liver biopsies spanning 4 years rendered the trial population ideally suited for the study factors that might influence fibrosis progression. Therefore, we conducted a nested case-control study of vitamin D levels in subjects with and without liver histologic progression or clinical decompensation over the course of the HALT-C Trial.

Abstracts 

Source: Gastrohep News

Genetic mutations that protect against fibrosis in HCV
IL28B alleles associated with poor hepatitis C virus clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes, reports the latest issue of Hepatology.

Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV), 2 processes that require the appropriate activation of the host immune responses.

Intrahepatic inflammation is believed to mirror such activation, but its relationship with IL28B polymorphisms has yet to be fully appreciated.

Dr Francesco Negro and colleagues from Switzerland analyzed the association of IL28B polymorphisms with histological, and follow-up features in 2335 chronically HCV-infected Caucasian patients.

The G allele at IL28B marker rs8099917 was associated with lower fibrosis
Hepatology
Assessable phenotypes before any antiviral treatment included necroinflammatory activity, fibrosis, fibrosis progression rate, and hepatocellular carcinoma development.

The team evaluated associations of alleles with the phenotypes by univariate analysis and multivariate logistic regression, accounting for all relevant covariates.

The researchers found that the rare G allele at IL28B marker rs8099917 was associated with lower activity, lower fibrosis with a trend toward lower fibrosis progression rate.

When stratified according to HCV genotype, most significant associations were observed in patients infected with non-1 genotypes, where the odds ratio of having necroinflammation or rapid fibrosis progression for patients with IL28B genotypes TG or GG versus TT were 0.48, and 0.56, respectively.

The research team noted that IL28B polymorphisms were not predictive of the development of hepatocellular carcinoma.

De Negro's team concludes, "In chronic hepatitis C, IL28B variants associated with poor response to interferon therapy may predict slower fibrosis progression, especially in patients infected with non-1 HCV genotypes."

Big Pharma  

INTERVIEW: Medivir Vies For Spot In Narrow Hepatitis C Market
By Simon Varcoe

LONDON (Dow Jones)--Hepatitis C, a harrowing infection that leads to the inflammation of the liver, is a virus of pandemic size that has attracted the attention of some of the world's biggest drug makers.
But Sweden's small biotech Medivir AB (MVIR-B.SK) says it intends to be a major player in treating the disease, and predicts the market will ultimately have room for just four or five products.

"It is simply a question of which drug will have the biggest share of the market", Medivir's executive vice-president of corporate affairs Rein Piir told Dow Jones Newswires in an interview.

And in protease inhibitor TMC435, Piir believes Medivir has found its winner.

Piir says there is nothing in development that's better than TMC435, which is currently in global Phase III trials and which Medivir expects to launch by the end of next year.
Danske Banke analyst Hans Jeppsson agrees.

Jeppsson regards TMC435 as being the best-in-class protease inhibitor, which prevents viral replication by inhibiting the activity of protease enzymes. Final judgment will need to await results from two combination trials the drug is currently undergoing, he adds.

Around 170 million people are infected worldwide with Hepatitis C, a disease that can be transmitted sexually, through shared needles or through infected blood transfusions.

Thousands of people in Japan were infected with Hepatitis C between the 1970s and 1990s due to tainted blood clotting agents and the country remains one of the most hepatitis C-dense in the world. Due to the high numbers of hepatitis C sufferers in Japan, the country is "as important commercially" to Medivir as Europe, Piir says.

Other countries with a high prevalence of Hepatitis C include Egypt, where around 20% of blood donors are anti-HCV positive, and areas of Italy.

Medivir's Piir believes that the future treatment of Hepatitis C will involve a combination of protease inhibitors; inhibitors of nucleotides, which are molecules that, when joined together, make up the structural units of RNA and DNA; and inhibitors of NS5A, a non structural viral protein found in Hepatitis C.

NS5A inhibitors currently in development include Bristol-Myers Squibb's (BMY) BMS790052, and Gilead Sciences Inc's (GILD) GS-7977. However, Gilead recently reported that a majority of patients in a clinical trial of GS-7977 had experienced a relapse in their disease after being treated with the product, raising questions about the market potential of the drug and the wider class of NS5A inhibitors.

A protease inhibitor currently used to treat HCV genotype 1 infection, the most common and hardest-to-treat type of Hepatitis C is Vertex Pharmaceuticals' (VRTX) and Johnson & Johnson's (JNJ) telaprevir, though, unlike TMC435, it must be administered in combination with pegylated interferon alpha and the antiviral drug ribavirin. Its safety profile has also been criticized, whereas TMC435 has to-date been generally safe and well tolerated, according to Medivir.

The Swedish biotech floated on the Nasdaq OMX Stockholm index in 1996 and currently has a market capitalization of around SEK2.1 billion ($320.2 million).

-By Simon Varcoe, Dow Jones Newswires; +44-20-7842-9449; simon.varcoe@dowjones.com 

Related @ NATAP- Download PDF here
Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2 to 6: TMC435-C202, a phase IIa, open-label study - Article in Press.



Hepatitis C Remains A Hot Play
Novartis (NVS) is preparing to enter the thriving hepatitis C market by licensing rights to Enanta Pharmaceuticals’ lead experimental HCV inhibitor
“We believe EDP-239 has great potential as a potent ingredient in combination drug therapy, and our preclinical studies have demonstrated high potency against multiple genotypes of the virus, excellent safety profile, and a preclinical pharmacokinetic profile amenable to once-a-day dosing in humans,” said Jay Luly, president and CEO of Enanta Pharmaceuticals.

Source-Pharmalot

Read more here: http://www.sacbee.com/2012/02/27/4294139/china-investigating-hepatitis.html#storylink=cpy
A new study suggests that research funded by drugmakers is no more biased in favor of new medicines than studies that are funded by the federal government or non-profit foundations.

 Diabetes

Diabetes drug improves glucose control without increasing risk of hypoglycemia
University of Michigan leads study showing TAK-875 helps control blood sugar in type 2 diabetes by boosting insulin

TAK-875, a new treatment for type 2 diabetes, improves blood sugar control and is equally effective as glimepiride, but has a significantly lower risk of creating a dangerous drop in blood sugar, called hypoglycemia, according to a new study.

The results of the phase 2 randomized trial were published Online First Sunday in The Lancet.
Type 2 diabetes is the most common form of diabetes accounting for 90 percent of the 150 million people in the United States currently living with the disease. It is primarily caused by a lack of response to insulin which leads to high blood sugar and a variety of chronic conditions.
Free fatty acid receptor 1, also known as G protein-coupled receptor 40, or GPR40, plays a vital role in stimulating and regulating the production of insulin.

It works by boosting the release of insulin from pancreatic β-cells when glucose and fatty acids rise in the blood, such as after a meal, which results in a fall in blood glucose levels. Drugs that activate the FFAR1 receptor have the potential to help diabetics release more insulin and improve control of blood glucose levels.

TAK-875 is a novel oral medication designed to enhance insulin secretion in a glucose-dependant manner, which means that it has no effect on insulin secretion when glucose levels are normal, and as such has the potential to improve the control of blood sugar levels without the risk of hypoglycemia.
In the study, Charles Burant, M.D., Ph.D., professor of internal medicine at the University of Michigan Health System, and colleagues randomly assigned 426 patients with type 2 diabetes who were not achieving adequate glucose control through diet, exercise or metformin treatment to one of five doses of TAK-875, a placebo, or glimepiride, a conventional diabetes treatment. The primary outcome was change in hemogloblin A1c from the start of the study.

At 12 weeks, all doses of TAK-875 resulted in significant drops in HbA1c compared with placebo. A similar reduction occurred in patients given glimepiride.

At a TAK-875 dose of 25 mg or higher, about twice as many patients (33 to 48 percent) reached the American Diabetics Association target of HbA1c less than 7 percent within 12 weeks, compared with placebo (19 percent) and was similar to glimepiride (40 percent).
TAK-875 was generally well-tolerated. The incidence of hypoglycaemia was significantly lower for all doses of TAK-875 compared with glimepiride (2 percent compared to 19 percent), and was similar to placebo which was 2 percent.

The overall incidence of treatment-related side effects was similar for the TAK-875 groups and placebo groups (49 percent; all TAK-875 groups vs 48 percent), but higher in the glimepiride group (61 percent) because of the increased risk of hypoglycaemia.

The authors say: “In view of the frequent hypoglycemia after treatment with sulfonylureas,the low-risk of hypoglycaemia after treatment with TAK-875 suggests that there may be therapeutic advantage of targeting FFAR1 in treating people with type 2 diabetes.”
They conclude:“We are truly excited about the potential of TAK-875 and are eager to conduct larger trials to find out how well this drug works, how safe it is and what its place is in the treatment of diabetes.

“TAK-875 significantly improved glycemic control in patients with type 2 diabetes with minimum risk of hypoglycemia. The results show that activation of FFAR1 is a viable therapeutic target for treatment of type 2 diabetes,” authors say.

Disclosure: Burant is an unpaid consultant and advisor to Takeda Global Research and Development which discovered TAK-875.

Reference: To see the abstract online go to http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61879-5/abstract
Press release courtesy The Lancet

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