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2011 EASL; Easy To Understand Summary of the investigational Hepatitis C drugs
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From NATAP
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Factors affecting HCV viral load response to the non-nucleoside polymerase inhibitors ABT-072 and ABT-333 -
Adherence To Assigned Dosing Regimen and Sustained Virologic Response Among Hepatitis C-Genotype 1 Previously Untreated and Peginterferon/Ribavirin Treatment-Failure Patients Treated With Boceprevir Plus Peginterferon Alfa-2b/Ribavirin (patients with >80% adherence to all dosing achieved 90% cure rates. My guess is if adherence is 100% SVR rates will be higher)
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Four-Week Treatment with GS-9256 and Tegobuvir (GS-9190) +/- RBV +/- PEG, Results in Enhanced Viral Suppression on Follow-up PEG/RBV Therapy, in Genotype 1a/1b HCV Patients -
Genotypic and Phenotypic Characterization of NS3 Variants Selected in HCV-Infected Patients Treated with ABT-450 -
Characterization of Virologic Escape in HCV Genotype 1 Null Responders Receiving a Combination of the NS3 Protease Inhibitor BMS-650032 and NS5A Inhibitor BMS-790052 -
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Among 1 Genotype HCV–Infected Patients Not Achieving SVR With Boceprevir-Based Regimen, Resistance-Associated Variants More Common in Those With Poor Response to 4-Week PegIFN/RBV Lead-in
SOCRATES: Combining Sorafenib and TACE for Treatment of Advanced Hepatocellular Carcinoma Yields Promising Efficacy Results
ZENITH Interim Results: Potent Antiviral Activity With 12 Weeks of VX-222 + Telaprevir + PegIFN/RBV Quad Therapy, but Virologic Breakthrough Common With VX-222 + Telaprevir Dual Therapy
From Medscape Medical News
Telaprevir Add-On Effective After Initial HCV Therapy Fails
Daniel M. Keller, PhD
April 6, 2011 (Berlin, Germany) — Telaprevir added to standard pegylated interferon alfa-2a/ribavirin (peg-IFN/RBV) therapy for hepatitis C virus (HCV) infection was superior to retreatment with peg-IFN/RBV plus placebo in patients for whom standard therapy had failed in the past, researchers announced here at the European Association for the Study of the Liver (EASL) 46th Annual Meeting.
The safety and tolerability of adding telaprevir were similar to results seen in previous trials. Adverse events leading to permanent discontinuation of the drugs consisted mainly of anemia and rash, and were more prevalent in the telaprevir groups than in the control group.
Standard combination therapy with peg-IFN/RBV fails in approximately 60% of patients with HCV genotype 1, which is one of the more difficult genotypes to eradicate, noted Stefan Zeuzem, MD, chief of the Department of Medicine and professor of medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, who presented the study results.
The aim of the Re-Treatment of Patients With Telaprevir-Based Regimen to Optimize Outcomes (REALIZE) trial was to test the addition of telaprevir, a new small-molecule HCV protease inhibitor, to peg-IFN/RBV in 662 patients with HCV genotype 1 for whom peg-IFN/RBV had previously failed to produce sufficient and sustained viral suppression.
The primary objective of this pivotal phase 3 international, multicenter, double-blind, placebo-controlled trial was to compare the proportion of patients achieving a sustained virologic response (SVR) with telaprevir plus peg-IFN/RBV and the proportion achieving an SVR with placebo plus peg-IFN/RBV. All SVRs were below 25 IU HCV RNA (undetectable level).
Patients were divided into 3 categories: null responders did not show at least a 2 log
10 drop in serum HCV RNA at week 12 of previous standard therapy; partial responders experienced at least a 2 log
10 drop at week 12 of previous therapy but still had detectable HCV RNA in the blood at week 24; and relapsers achieved viral levels below the limit of detection at 42 weeks but then had a recurrence of detectable virus.
The groups were well matched at baseline. Approximately 70% were men, median age was approximately 50 years, 93% were white, HCV RNA was above 800,000 IU/mL in 86% to 89%, and almost 60% were in the advanced stages of disease with bridging fibrosis or cirrhosis (26%). About half were infected with genotype 1a and about half with genotype 1b. About 30% were previous nonresponders, 20% were partial responders, and 50% were previous relapsers.
Patients were randomly assigned to 1 of 3 treatment groups: 266 patients received telaprevir + peg-IFN/RBV for 12 weeks, then placebo + peg-IFN/RBV for 4 weeks (T12/PR48); 264 patients received a lead-in of placebo + peg-IFN/RBV for 4 weeks, then telaprevir + peg-IFN/RBV for 12 weeks (lead-in T12/PR48); and 132 patients received placebo + peg-IFN/RBV for 16 weeks (placebo/PR48).
In these 3 groups, drug doses were as follows: telaprevir 750 mg every 8 hours; peg-IFN 180 µg/week; and RBV 1000 to 1200 mg/day. The groups were followed-up and assessed for SVR at week 72. The primary statistical calculations were on previous relapsers and on previous nonresponders (a combination of previous partial responders and null responders).
Dr. Zeuzem reported that among previous relapsers, 83% to 88% achieved an SVR when treated with telaprevir plus peg-IFN/RBV. Less than 10% of them relapsed by week 72. In contrast, only 41% of previous nonresponders achieved an SVR with telaprevir, but this figure was still a 4-fold increase over the proportion with an SVR when retreated with peg-IFN/RBV and placebo. Overall, about 35% of patients in the 2 telaprevir groups failed to achieve an SVR; those failures occurred mainly among previous partial and previous null responders.
Addition of Telaprevir to Peg-IFN/RBV Enhances SVR Rates
Patient Group |
T12/PR48,
% (n/N) |
Lead-in T12/PR48,
% (n/N) |
Placebo/PR48,
% (n/N) |
Previous Relapsers | | | |
| SVRa | 83 (121/145)c | 88 (124/141)c | 24 (16/68) |
| Relapseb | 7 (10/135) | 7 (9/138) | 65 (30/46) |
Previous Nonresponders | | | |
| SVRa | 41 (50/121)c | 41 (51/123)c | 9 (6/64) |
| Relapseb | 23 (16/69) | 25 (18/72) | 33 (3/9) |
aSVR assessed 24 weeks after planned treatment completion
bRelapse: detectable virus at week 72 in patients with undetectable HCV RNA at end of assigned treatment
c
P < .001, comparison vs placebo/PR48
"The SVR rates tended to be higher in genotype 1b–infected patients, in particular in prior partial responders and prior null responders," Dr. Zeuzem reported. "The lead-in phase [group] showed numerically slightly higher [SVR] rates in the prior relapsers and the prior nonresponders, but there was an opposite trend for the prior partial responders."
When the data were analyzed by the degree of baseline fibrosis, all subgroups of patients responded better to telaprevir than to peg-IFN/RBV plus placebo. For example, among previous relapsers, 86%, 85%, and 84% achieved an SVR with telaprevir if they had no fibrosis, bridging fibrosis, or cirrhosis, respectively, compared with 32%, 13%, and 13%, respectively, with peg-IFN/RBV plus placebo. The addition of telaprevir added little or no benefit over peg-IFN/RBV alone for previous partial or null responders with cirrhosis.
Dr. Zeuzem noted that adverse events, which occurred at least 10% more frequently in the telaprevir groups than in the placebo group, were fatigue, pruritis, rash, anemia, nausea, diarrhea, and anorectal symptoms (described as pruritis, discomfort, or hemorrhoids).
The majority of adverse effects were grade 1 or 2, with some grade 3 rash in the pooled telaprevir groups. Rash was primarily eczematous, which resolved when therapy ended. Anemia was managed with RBV dose reduction when necessary, which occurred in 25% of the telaprevir-treated patients. Per protocol, erythropoiesis-stimulating agents were not permitted. In the telaprevir groups, 11% to 15% discontinued treatment because of adverse events; in the placebo group, 3% did.
Dr. Zeuzem concluded that "telaprevir/peg-interferon-ribavirin triple therapy was clearly superior to the standard peg-interferon/ribavirin treatment alone" in all 3 treatment-experienced populations."
He said a 4-week lead-in phase with peg-IFN/RBV did not reduce virologic failure or relapse rates and did not improve SVR rates. He noted that the safety of telaprevir was similar to that observed in previous studies. Adverse events, mainly anemia and rash, led to permanent discontinuation of study drugs more frequently in the telaprevir groups than in the control group.
Mark Thursz, MD, professor of hepatology at Imperial College, London, United Kingdom, and vice secretary of EASL, said: "I think these are very responsible conclusions . . . and I feel that the data that are coming out on this particularly difficult-to-treat group of patients — those who had previous treatment and failed — these are really exciting results. Overall, something like 60% of patients were successfully treated [and] reached an SVR in the REALIZE trial." He added that "partial responders [did] so-so; null responders, not so good. This is disappointing but not entirely surprising. They are particularly difficult groups to treat."
Dr. Thursz, who was not involved in the REALIZE trial, said that for patients for whom previous therapy has failed, "now we have treatment options to offer them, assuming that the commissioning authorities will pay for [the drugs] for those who don't pay for their own therapy."
In response to a question from the audience about the rashes and the possibility of Stevens–Johnson syndrome, Dr. Zeuzem said that of the several thousand people exposed to telaprevir, "to the very best of my knowledge, there is only 1 case of Stevens–Johnson syndrome described, but this case occurred after telaprevir was already discontinued, so a causal relationship cannot be justified from this single case. But I know that this single case has made many people very nervous."
Although anemia was more frequent in the telaprevir groups, "we have learned to manage anemia in this group of patients," Dr. Thursz said. "Most patients can tolerate more anemia than the pharmaceutical companies can."
Telaprevir is being developed by Vertex Pharmaceuticals. The US Food and Drug Administration has granted the drug priority review, which is expected on May 23.
Dr. Zeuzem reports relationships with Abbott, Achillion, Anadys, BMS, Gilead, iTherX, Merck, Novartis, Pfizer, Pharmasset, Roche, Santaris, Tibotec, and Vertex. Dr. Thursz has disclosed no relevant financial relationships.
European Association for the Study of the Liver (EASL) 46th Annual Meeting: Opening session. Presented March 30, 2011.
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HCV Advocate Newlsetter: April 2011
In This Months Issue;
Why We Should Test: Editorial
Alan Franciscus, Editor-in-Chief
HCV Snapshots
Lucinda K. Porter, RN
Liver Transplantation: HCV Recurrence and Treatment
Liz Highleyman
HealthWise: Humor, Health, and Hepatitis C
Lucinda K. Porter, RN
Around The World
Japanese drugmakers face radiation challengeDaiichi Sankyo and Eisai Pharmaceuticals, two major Japanese drugmakers with operations in New Jersey, are coping with a new post-earthquake business challenge: Trying to ensure that their medicines and manufacturing materials are protected from the effects of radiation.
Roche Joins in Spanish Research Cooperation for Personalized Treatment of Hepatitis B and C
By Benzinga Staff
April 06, 2011 8:03 AM
Roche Diagnostics (RHHBY) is cooperating with the Spanish Vall d'Hebron Institute of Research, the Networking Biomedical Research Centre in Liver and Digestive Diseases, and the software producer Advanced Biological Laboratories Therapy Edge Spain in a study designed to resolve the current limitations that prevent the individualization of anti-HBV and anti-HCV (hepatitis B and C) treatments.
The project will utilize Roche's 454 Sequencing Systems and bioinformatics analysis, together with other genetic and molecular analytical techniques. Ultimately, the research project aims to identify personalized treatment for each individual while minimizing the healthcare costs and side effects experienced by subjects.
The ETF market can be confusing and hard to beat, but ETF Professor's trading ideas help you make profit consistently
(c) 2011 Benzinga.com. All rights reserved. This material may not be published in its entirety or redistributed without the approval of Benzinga.
Read more:
http://www.benzinga.com/news/11/04/982102/roche-joins-in-spanish-research-cooperation-for-personalized-treatment-of-hepatiti##ixzz1IkG7hOtN
WWE's hepatitis controversy, Messi's sensational shots in global sports video charts
A documentary linking WWE's latest Hall of Famer to the transmission of Hepatitis C and a clip of Lionel Messi's incredible pre-match practice shot are among the world's most viewed sports videos for the week ending April 5.
"Don't Bleed On Me" makes a connection between the dead-end wrestling career of promising rookie Devon "Hannibal" Nicholson and the blood-letting antics of 2011 Hall of Fame inductee Abdullah the Butcher.
Once-Daily Nevirapine for HIV Wins FDA Nod
An extended-release version of the reverse transcriptase inhibitor nevirapine (Viramune XR) has received FDA approval for once-daily dosing in patients with HIV-1 infection, manufacturer Boehringer Ingelheim announced.
In Case You Missed It
Antiviral Therapy Lowers Insulin Resistance in HCV Genotype 1 Infection
NEW YORK (Reuters Health) Mar 03 - Resolution of chronic hepatitis C virus (HCV) genotype 1 infection after treatment with peginterferon and ribavirin is associated with improvement in insulin sensitivity among patients with evidence of insulin resistance before antiviral therapy.
However, factors other than medications may be at work, researchers report in the February issue of Gastroenterology.
Dr. Hari Conjeevaram of The University of Michigan, Ann Arbor, and colleagues note that the insulin resistance associated with the condition might result from liver disease, metabolic factors or hepatitis C virus itself. Moreover, the effect of antiviral treatment on insulin sensitivity isn't well known.
They also point out that insulin resistance may affect the progression of liver disease, but it's uncertain "whether insulin resistance is the cause or the effect of worsening liver function or fibrosis."
To investigate, the team studied data from a prospective trial of a 48-week course of combination peginterferon and ribavirin therapy in 341 patients infected with HCV genotype 1.
Insulin resistance was estimated by the homeostasis model assessment index (HOMA2-IR) based on fasting glucose and insulin levels. Using these criteria, 40% had a HOMA2-IR beyond 2 and were deemed insulin resistant at baseline.
Insulin resistance was associated with higher body weight, higher serum triglycerides, and greater degrees of fibrosis and steatosis on liver biopsy. "All of which," say the investigators, "are well-known risk factors for diabetes and insulin resistance."
In the insulin-resistant group, HOMA2-IR values declined on average by 8% at 24 weeks and by 23% by the end of therapy. These results are in line with those of other investigators. The degree of decline in this group didn't differ significantly by virologic response.
Other findings, the team adds, "suggest that improvements in calculated values for insulin resistance are due at least in part to weight loss and the effects of peginterferon and ribavirin treatment, rather than the degree of decline in HCV RNA levels."
But, importantly, they point out, "only patients who ultimately had a sustained viral response had a significantly lower HOMA2-IR at week 24 when compared with baseline, suggesting that viral eradication may affect insulin response to a greater extent than weight loss and simple viral suppression during interferon treatment."
Overall, the researchers conclude that there appears to be "a direct role for HCV in inducing a decrease in insulin sensitivity." The finding, they add, "provides strong support for recommending therapy in patients with chronic hepatitis C and insulin resistance or diabetes."
SOURCE:
http://bit.ly/ijbub9
Healthy You
University of Cincinnati Academic Health Center
Elevated levels of sodium blunt response to stress, study shows
CINCINNATI—All those salty snacks available at the local tavern might be doing more than increasing your thirst: They could also play a role in suppressing social anxiety.
New research from the University of Cincinnati (UC) shows that elevated levels of sodium blunt the body's natural responses to stress by inhibiting stress hormones that would otherwise be activated in stressful situations. These hormones are located along the hypothalamic-pituitary-adrenal (HPA) axis, which controls reactions to stress.
The research is reported in the April 6, 2011, issue of The Journal of Neuroscience, the official journal of the Society for Neuroscience.
"We're calling this the Watering Hole Effect," says Eric Krause, PhD, a research assistant professor in the basic science division of UC's department of psychiatry and behavioral neuroscience and first author of the study. "When you're thirsty, you have to overcome some amount of fear and anxiety to approach a communal water source. And you want to facilitate those interactions—that way everyone can get to the water source."
Krause and his team dehydrated laboratory rats by giving them sodium chloride, then exposed them to stress. Compared with a control group, the rats that received the sodium chloride secreted fewer stress hormones and also displayed a reduced cardiovascular response to stress.
"Their blood pressure and heart rate did not go up as much in response to stress as the control group's, and they returned to resting levels more quickly," says Krause.
"Also, in a social interaction paradigm with two rats interacting, we found them to be more interactive and less socially anxious."
Further research, through examination of brain and blood samples from the rats, showed that the same hormones that act on kidneys to compensate for dehydration also act on the brain to regulate responsiveness to stressors and social anxiety.
The elevated sodium level, known as hypernatremia, limited stress responses by suppressing the release of the pro-stress hormone angiotensin II. Conversely, it increased the activity of oxytocin, an anti-stress hormone.
Further research, Krause says, will examine these hormones and neurocircuits to investigate their role in social anxiety disorders and autism, a neurological disorder whose characteristics include social impairment.
"Oxytocin deficiency has been implicated in autism in previous studies," says Krause. "We'd like to investigate the possibility that dysregulation in fluid balance during pregnancy could result in autistic disorders."
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Krause's team also included Annette de Kloet, Jonathan Flak, Michael Smeltzer, Matia Solomon, Nathan Evanson, Stephen Woods, Randall Sakai and James Herman.
Fatty liver -- how a serious problem arises
Published: Wednesday, April 6, 2011 - 08:36 in Health & Medicine
Excess fat around the hips and belly may not really be compatible with current beauty ideals, but, to a certain degree, it is a normal, even vital energy store of our body. However, it is a different matter if the organism stores fat in organs such as the liver, pancreas or muscles. This is a clear sign of a metabolic disorder. Up to 80 percent of obese people develop fatty liver disease, which is regarded a typical characteristic of the dangerous metabolic syndrome. Deposition of fat in the liver may lead to chronic liver inflammation and even to liver cancer. In addition, fatty liver is considered to be an independent risk factor for coronary heart disease and atherosclerosis.
The great medical relevance of fatty liver as a severe condition accompanying insulin resistance and type II diabetes caused the research group headed by Dr. Stephan Herzig of the Division of Molecular Metabolic Control to investigate how this syndrome arises. Which molecular switches are turned on or off in a cell when food delivers too much energy-rich fat molecules, or triglycerides?
To this end, the investigators determined the level of particular proteins involved in specific gene activation in the liver tissue of mice. These proteins, which are known as transcriptional co-activators, regulate which proteins are read and transcribed into messenger RNA molecules in a cell. In overweight mice, the researchers observed that a high triglyceride level in the liver was always associated with reduced production of a co-activator called TBL1. This was found both in animals that developed fatty liver for hereditary reasons and in those animals that received calorie-rich food.
TBL1 was originally discovered in connection with a rare hereditary hearing disorder. In the liver, but not in other tissues, an oversupply of fat reduces the production of TBL1. As a result, fat burning in the liver is reduced so that more fat molecules are deposited in liver cells. "This, in turn, may lead to a further reduction of TBL1," says Stephan Herzig.
Not only in mice is TBL1 linked to the liver fat (lipid) metabolism. The group found the same pattern in human liver tissue samples: the higher their triglyceride levels, the lower their TBL1 levels.
Stephan Herzig expects a practical use of these results. "We might be able in the future to use TBL1 levels for identifying those obese persons who have a special risk of developing fatty liver. We could then give specific dietary recommendations to counteract this."
The research was funded by grants from the National Institutes of Health and the American Heart Association. The authors declare no competing financial interests.
http://www.eurekalert.org/pub_releases/2011-04/uoca-elo040511.php
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Marijuana Allergies: Reactions May Be More Common Than Thought
SAN FRANCISCO – Marijuana hypersensitivity might be more common than previously thought, according to the results of a case series.
Though there are only a few case reports in the literature, "Marijuana allergy, I think, is fairly common," said lead investigator Dr. Gordon Sussman, acting division director of clinical allergy and immunology at the University of Toronto. Even so, "It’s something physicians don’t really generally ask about. People should consider it in the diagnosis of rhinitis [and other allergic symptoms], and even in people that have asthma and anaphylaxis."
Dr. Gordon Sussman says allergic reactions to marijuana shouldn't be a surprise because it is a weed, and weeds are generally known to be allergenic.
The 17 patients who were included in the series reported that marijuana gave them runny noses or other problems; all ended up having positive marijuana skin prick test results, he reported. One patient in the series had an anaphylactic reaction after drinking marijuana tea.
That was the first patient in whom Dr. Sussman diagnosed a marijuana allergy. "I asked him in a detailed history what it could have been, and he actually had drunk marijuana tea. We knew at that point he had an IgE-mediated reaction to marijuana," he said.
Curiosity piqued, and Dr. Sussman began asking allergy patients about marijuana use and reactions. A significant percentage reported symptoms from both contact and inhalation.
To confirm the diagnosis, he and his colleagues did skin-prick tests on the 17 patients between 21 and 58 years old, mostly men. They extracted buds or flowers in 5 mL of water for 15 minutes and pricked beneath drops placed on patients’ skin.
After 15 minutes, the 17 patients had wheals of 4-19 mm and surrounding flares. Fifteen presented with inhalation symptoms, including rhinitis and conjunctivitis, periorbital angioedema, wheezing, sinusitis, and throat swelling. Thirteen also reported hives from contact.
The anaphylaxis patient presented with anxiety, chest tightness, wheezing, GI cramping, and vomiting after drinking the tea.
"I don’t think it’s a contaminant; I’m pretty sure it’s an allergen in the marijuana they are reacting to," Dr. Sussman said, adding that such reactions shouldn’t be a surprise because "marijuana is a weed, and weeds are generally known to be allergenic."
Asking about marijuana use and past reactions should be a routine part of allergy work-ups, especially with expanding medical marijuana use. "People could actually be sensitized to marijuana and have a serious reaction. It’s important for people to recognize this," Dr. Sussman said.
The researchers’ next step is to identify the actual allergens responsible for the reactions using a marijuana extract from a U.S. federal laboratory, serum from positive patients, and Western blot assays.
There was no outside funding for the study. Dr. Sussman said he had no disclosures.
New On The Blog;
Can chronic hepatitis C resolve spontaneously?
This article describes two female patients with transfusion-acquired CHC diagnosed by both positive hepatitis C virus (HCV)-Ab and hepatitis C virus–polymerase chain reaction (HCV–PCR) tests.
Both patients cleared the infection spontaneously after more than 5 and 25years of CHC infection, respectively.
Hepatitis C; IL28B-Genotype Testing Now and in the Era of Direct-Acting Antiviral Agents
Peginterferon alpha and ribavirin treatment for 48 weeks leads to a sustained virological response (SVR) in 40%–50% of subjects infected with hepatitis C virus (HCV) genotype 1 or 4 (G1/4) while treatment for 24 weeks produces SVR in 70%–80% of patients infected with HCV genotype 2 or 3. The variability in response to treatment, especially between patients of different racial groups, suggested that human genetic variability might explain differences in treatment response and led to investigations of the role of host genetics in achieving an SVR.
