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An off-the-shelf cholesterol-lowering drug blocks hepatitis C from gaining entry into the cell.
Noted by Jules @ NATAP: As we move close to very high cure rates, 90% or more, this discussion becomes increasingly relevant. Should any patient defer HCV therapy if cure rates are 90-100%, even though in HCV mono-infection a patient may not progress over 30 years to serious liver disease? We know even though a specific patient may not develop serious liver disease over such a long span of time or even a lifetime, HCV infection can cause other cormorbid diseases including cancers outside the liver, it affects other bodily organs, in other words the presence of HCV-infection is not innocuous even if liver disease does not progress. And if a patient' chance for cure is 90-100% with a 3-drug all oral therapy taken for 12-24 weeks, should everyone be treated, is this cost-effective, should re-imbursers encourage treatment??? These are discussions that will become increasingly likely to be held. There have been in addition recent presentations of these studies finding successful treatment reduces risk for death, liver cancer, & morbidity....
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Hepatitis C affects nearly 4.5 million Americans, and each year nearly 17,000 people are newly infected. Chronic hepatitis C infection is a leading cause of liver cancer and transplants, and is associated with nearly 12,000 deaths each year. The US currently faces a large population of people in growing need of care and treatment.
Being diagnosed with hepatitis C carries with it many emotional and social challenges. It is especially complicated by the lack of comprehensive medical, mental health and community support services. People with hepatitis C report spending countless hours trying to find reliable support and information.
The launch of 877-HELP-4-HEP has been timed to respond to the growing need for hepatitis C care information and referrals as vastly improved treatments become available.
In 2012, the rollout of a new point-of-contact antibody test will occur, and the Centers for Disease Control will release new Guidelines to screen for the virus. More than one-half of people with hepatitis C do not know they are infected. In 2011, two new drugs came to market that have nearly doubled the cure rate, offering hope to many to live free of the virus. Additionally, President Obama increased federal spending on viral hepatitis by $10 million, and the Department of Health & Human Services announced its Action Plan for the Prevention, Care and Treatment of Viral Hepatitis, both of which elevate the national discourse on hepatitis C infection and treatment. These significant policy developments have occurred, in part, as a result of Project Inform’s advocacy.
These recent changes in hep C care provide ample opportunity for supporting and linking people into care. Unique to 877-HELP-4-HEP are specially trained peer counselors using a structured approach to help callers navigate through screening, diagnosis, medical evaluation and treatment. Follow-up contact by the counselors keeps callers engaged at each step of their journey and helps them follow through with their health decisions.
877-HELP-4-HEP also uses an up-to-date national database of 25,000 referral resources and a secure shared caller database for counseling continuity. 877-HELP-4-HEP is designed to maintain contact with callers to improve health outcomes as well as document and measure the impact of our services.
877-HELP-4-HEP (877-435-7443) operates Monday through Friday 9am to 7pm EST. To learn more, visit www.help4hep.org or email firstname.lastname@example.org.
James M. Prentis, M.B.B.S., M.R.C.P., of the Freeman Hospital in Newcastle upon Tyne, U.K., and colleagues utilized preoperative submaximal CPET data for prediction of 90-day post-liver transplant survival. A total of 182 patients underwent CPET preoperatively, and 165 completed it successfully (defined as the ability to determine the AT). Ninety-day post-transplant survival, critical care length of stay, and overall length of hospital stay were evaluated during the post-transplant follow-up.
The researchers found that 33 percent of the patients underwent liver transplantation, and the mortality rate was 10 percent. The mean AT values were significantly higher for survivors compared with those who did not survive. On multivariate analysis, AT was the only significant predictor of mortality. In the receiver operating curve analysis, the sensitivity and specificity of AT was 90.7 and 83.3 percent, respectively, and the area under the receiver operating characteristic curve was 0.92. The optimal AT level for survival was established as greater than 9.0 mL/minute/kg. Substitution of ideal weight for actual body weight of a patient with refractory ascites improved the predictive value.
"Our results demonstrate that patients with good cardiopulmonary reserve (according to an exercise test before liver transplantation) have a higher survival rate and use less critical care resources postoperatively," the authors write.
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Laparoscopy for liver malignancy oncologically safe: study
In Case You Missed It
SVR Achieved With Two Direct-acting Antivirals in Absence of Interferon in Small Study
t-acting antiviral agents (DAAs)—asunaprevir and daclatasvir—suppressed hepatitis C virus (HCV) genotype 1 infection in a majority of patients who had previously not responded to treatment, according to results from a small Phase II study published in the Jan. 19 issue of The New England Journal of Medicine (Lok AS et al. 2012;366:216-224).
Success rates were 100% in patients who received the drugs in combination with peginterferon alfa-2a (Peg-IFN) and ribavirin (RBV).
And, most notably, even in patients who received daclatasvir and asunaprevir without Peg-IFN and RBV, sustained virologic response (SVR) was achieved in 36% of patients, making this the first published study to show that SVR can be achieved with an IFN-free treatment in previous null responders.
“The response in some patients to the combination of daclatasvir and asunaprevir alone showed proof-of-concept that a sustained virologic response can be achieved without peginterferon and ribavirin therapy,” concluded the research team, led by Anna S. Lok, MD, professor of internal medicine in the Division of Gastroenterology, University of Michigan Medical School, Ann Arbor.
In an editorial accompanying the study, Raymond T. Chung, MD, director of hepatology and medical director of the liver transplant program at Massachusetts General Hospital, Boston, called the study a “watershed moment in the annals of HCV therapy.
“It shows that sustained virologic response can be achieved without interferon. Implicit in this finding is the concept that two potent agents with complementary resistance profiles, given for a sufficient duration, can impose a stranglehold on viral replication and result in clearance of the virus.”
In this Phase II study, 10 patients received the experimental drugs in combination with Peg-IFN and RBV for 24 weeks. All 10 patients had undetectable viral loads at the end of treatment and at 12 weeks after stopping treatment. Nine patients continued to exhibit SVR at 48 weeks after treatment, whereas one patient had HCV RNA of less than 25 IU/mL at post-treatment week 48 and undetectable HCV RNA 13 days later.
In a separate arm of the study, 11 patients received asunaprevir and daclatasvir alone, without the addition of Peg-IFN and RBV.
Of these, four patients (36%) achieved an SVR at 12 and 24 weeks after treatment. Six patients (55%) had viral breakthrough during treatment, with resistance mutations to both antiviral agents. Breakthroughs occurred as early as treatment week 3 and as late as treatment week 12.
Although only one-third of the patients given the two-drug combination without Peg-IFN and RBV achieved an SVR, investigators and other hepatologists say the finding is “very promising.”
“For years, the concept of IFN-free therapy was hotly debated. Now, we’re very quickly moving toward IFN-free therapy. It’s potentially just around the corner,” said Donald M. Jensen, MD, professor of medicine and director of the Center for Liver Diseases, University of Chicago Medical Center.
“For patients who can wait, they might just have to wait a few more years until IFN-free therapy is on the market,” he said.
Daclatasvir is a first-in-class, highly selective HCV NS5A replication complex inhibitor that has shown picomolar potency in vitro. Asunaprevir is a highly active HCV NS3 protease inhibitor. Both drugs produce robust declines in HCV RNA levels in patients with HCV genotype 1 infection and, taken in combination, there is no clinically meaningful pharmacokinetic interaction.
Hepatologists say that treatment of HCV infection is entering a new era, highlighted by combinations of second-generation DAAs. As more DAAs are developed with non-overlapping resistance profiles, they may reduce dependence on treatment with IFN.
“These data are very encouraging because peginterferon-alfa and ribavirin are associated with many side effects and many patients with hepatitis C choose not to receive treatment for fear that they cannot tolerate those drugs,” said Dr. Lok, in a statement.
The participants in Dr. Lok’s study had previously failed to respond to Peg-IFN and RBV treatment, meaning they represent a difficult-to-treat population with poor expected outcomes. Previous null responders typically do not respond to retreatment with Peg-IFN and RBV and also tend to have a poor response to triple-combination therapy with Peg-IFN and RBV plus a protease inhibitor.
This combination of new DAAs, if supported by larger studies, could help the large number of patients who have not responded to previous treatment.
“Because of this high unmet medical need, there is a necessity for new combination regimens that can increase response rates in that population,” said Dr. Lok.
In the current study, investigators screened 56 patients and ultimately enrolled 21 patients in an exploratory cohort to assess the safety and antiviral activity of the new DAAs. All patients were between the ages of 18 and 70 years, had a chronic HCV genotype 1 infection with an HCV RNA level of 105 IU/mL or higher, showed no evidence of cirrhosis and exhibited no response to previous HCV therapy. Of these patients, 90% had interleukin 28B (IL28B) genotype CT or TT, both of which are associated with poor response to Peg-IFN and RBV, and most patients had HCV genotype 1a infection.
Daclatasvir was administered orally at a dose of 60 mg once daily and asunaprevir at a dose of 600 mg twice daily, with no dose reductions permitted. Ten patients also received Peg-IFN 180 mcg per week, administered subcutaneously, and RBV, administered orally twice daily, with doses determined according to body weight.
Investigators believe that the combination of two DAAs increases the resistance barrier, particularly for patients with HCV genotype 1b infection. In this study, all viral breakthroughs occurred in patients with HCV genotype 1a infection.
This study appears to confirm the results of a recent Japanese study, which showed a high SVR rate among patients with HCV genotype 1b infection in a pilot study of 10 previous non-responders who received combination therapy with asunaprevir and daclatasvir (Chayama K et al. Hepatology 2011 Oct 10; 10.1002/hep.24724 [Epub ahead of print]).
The key benefit of treatment with Peg-IFN and RBV appears to be prevention of viral breakthrough. No patient who received the four-drug combination in the current study experienced a viral breakthrough, whereas six patients in the group that received the DAAs alone had viral breakthroughs. All patients who had a viral breakthrough received and initially responded to Peg-IFN and RBV as rescue therapy. Most ultimately had therapeutic failure.
The high frequency of resistance sends a strong cautionary note about these therapies, said investigators. Future studies of combinations of DAAs without Peg-IFN and RBV in patients with HCV genotype 1a infection should proceed carefully, said the investigators.
But, they added, further research on combinations of DAAs, with or without Peg-IFN and RBV, should be encouraged.
The most common adverse events in this study were diarrhea, fatigue, headache and nausea, which were mild or moderate in all cases. Grade 3 or 4 neutropenia occurred in six patients, all of whom were receiving Peg-IFN and RBV in addition to the two DAAs. No grade 3 or 4 events related to hemoglobin levels or platelet counts were observed.
“This is an exciting study that means care will be better for patients,” said Andrew J. Muir, MD, clinical director of hepatology, Duke University Health System, Durham, N.C., who was not involved with the study.
“For the first time, patients were cured of HCV without interferon-a. Interferon-a has always been the backbone of HCV therapy but has many side effects that make treatment too difficult for many patients.”
Bristol-Myers Squibb, manufacturer of asunaprevir and daclatasvir, funded this study. Dr. Lok has received consulting fees from Abbott Laboratories, Bristol-Myers Squibb and Gilead Sciences, and grant support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck–Schering-Plough and Roche. Dr. Muir has received grant support from Bristol-Myers Squibb, Gilead Sciences, Merck–Schering-Plough, Roche and Vertex Pharmaceuticals. Dr. Jensen has served on advisory committees or review panels for Abbott Laboratories, Boehringer Ingelheim, Genentech/Roche, GlobeImmune, Human Genome Sciences, Merck, Pfizer, Pharmasset, Tibotec and Vertex Pharmaceuticals; he has received consulting fees from Abbott Laboratories, Bristol-Myers Squibb, Genentech/Roche and Vertex Pharmaceuticals; and he has received grant/research support from Boehringer Ingelheim, Genentech/Roche, Tibotec and Vertex Pharmaceuticals.
Among the many challenges to health, infectious diseases stand out for their ability to have a profound impact on the human species. Great pandemics and local epidemics alike have influenced the course of wars, determined the fates of nations and empires, and affected the progress of civilization, making infections compelling actors in the drama of human history.1-11 For 200 years, the Journal has captured the backdrop to this human drama in thousands of articles about infectious diseases and about biomedical research and public health efforts to understand, treat, control, and prevent them.An unanticipated outcome of the explosion of information concerning the microbial world is the recognition that a growing number of chronic diseases that were once attributed to host, environmental, or lifestyle factors or to unknown causes are actually directly or indirectly caused by infectious agents that potentially can be controlled through prevention and treatment.
For example, liver cancer and cirrhosis are complications of hepatitis B and C infections, cervical cancer is a complication of human papillomavirus (HPV) infection, and gastric and duodenal ulcers may result from Helicobacter pylori infection.70-72 Vaccines against two of these agents, hepatitis B and HPV, are already in use, exemplifying the concept of cancer-preventing vaccines. H. pylori infection can be cured with antibiotics, and chronic hepatitis B and C infections are being treated by means of antiviral regimens with growing success rates. Certain autoimmune conditions have also been attributed to infections. For example, enteric microbes have been associated with inflammatory arthritides, and Campylobacter jejuni and certain viruses have been associated with the Guillain–Barré syndrome.73
In addition, with new technologies and approaches, scientists are exploring new facets of microbiology, including the role of the human microbiome in maintaining homeostasis in the ecosystems of our bodies and its possible relationship to conditions such as obesity and inflammatory bowel disease.
Regenerative Sciences claims that the procedure, called Regenexx, is an alternative to potentially painful surgery for injuries such as bone fractures and torn tendons. Doctors take stem cells from the bone marrow of a patient, and process them in a solution, so that they strengthen and multiply. They are then injected into the injured joints, helping to rebuild damaged tissue.
The FDA states that stem cell treatments are a type of medication, and so fall under its jurisdiction. It says the safety of the procedure has not been sufficiently tested, and inspections showed that facilities offering the treatment do not meet its standards. It has insisted that Regenerative Sciences stop performing the Regenexx procedure until the case is resolved.
Regenerative Sciences counter that because stem cells are produced by the body, they are not drugs, so the treatment does not need FDA approval. The group claims to have treated more than 1,000 patients and spent over $500,000 on testing. Regenerative Sciences also point out that the California clinic uses a modified version of the technique that does not include a growth enhancer, a crucial part of the FDA's lawsuit.
Dr Christopher Centeno, director of Regenerative Sciences, says that the FDA is pursuing the case because it fears that Regenexx will become a successful alternative to pain medication, and threaten the FDA's control of a lucrative market. 'Unfortunately, in many cases, it's the clients suffering the most that we can't treat now', he told 5280 - the Denver Magazine.
However, Professor George Muschler, an orthopedic surgeon at Case Western Reserve University in Ohio is concerned by the medical risks of Regenexx after reviewing the published case studies. The procedure 'may be degenerating into an undisciplined and unfocused and even groping and wishful fishing expedition', he told ABC7 News.
The FDA's lawsuit was filed in August 2010 but may not reach a federal court until 2013.
We give you the facts without the fiction. Professor Sir Muir Gray, founder of Behind the Headlines, explains more...
|BioLineRx In-Licenses Second Oral Hepatitis C Treatment|
|06 Feb 2012|
BL-8030 is a potent and selective second generation NS3 protease inhibitor. The NS3 protease is essential for the replication of the Hepatitis C virus (HCV) and is an important target for HCV therapies. BL-8030 has been shown to have excellent antiviral activity against various HCV genotypes. Pre-clinical studies have demonstrated an improved resistance profile against common protease inhibitor mutants, resulting in a lower probability that the virus will develop resistance to treatment. In addition, BL-8030 has demonstrated a good toxicity profile in pre-clinical studies, exhibiting specificity only to the viral protease and lack of activity against a relevant panel of human proteases as well as a clean profile versus human liver enzymes, which is expected to lead to less drug-drug interactions.
BL-8030 was invented by Professor Philippe Halfon and his team at Genoscience and co-developed with assistance from scientists at RFS Pharma, LLC. Prof. Halfon, Co-Founder and President of Genoscience, is a specialist in molecular virology and infectious diseases, especially HIV, HPV (Human Papilloma Virus) and Hepatitis. In addition he is the founder of several biotechnology companies focusing on antiviral drug discovery and development including ACTgene, Alphabio and Genoscience. RFS Pharma was founded by Professor Raymond F. Schinazi; he currently serves as the Frances Winship Walters Professor of Pediatrics at Emory University. He is also a founder of
Pharmasset, Idenix, Triangle and ActivBiotics Pharma.
Prof. Philippe Halfon said, "We were impressed by the drug development expertise of the BioLineRx team and are very pleased to collaborate with them on a second HCV project. There is clearly a huge unmet medical need in finding a safe and effective treatment for HCV, and based on pre-clinical results, we believe that our product, especially when combined with other available Hepatitis C drugs, has the potential to become an important addition to HCV combination therapies and bring remedy to millions suffering from this devastating disease."
“We worked closely with the group at Genoscience to determine the optimum characteristic that led to the discovery of BL-8030 and related protease inhibitors,” said Dr. Steven J. Coats, Senior
Director of Chemistry at RFS Pharma.
“We are privileged and fortunate to partner with two world class groups in the development of viral therapeutics," said Dr. Kinneret Savitsky, CEO of BioLineRx. "Two years ago, we took a strategic decision to enter the dynamic and rapidly growing field of Hepatitis C. Since that time, we have evaluated numerous projects in the field. A year ago, we identified and decided to focus on the in-licensing of the two most promising candidates: BL-8020, which we've recently licensed, and now BL-8030. We will do our utmost to develop these promising drugs as swiftly as possible for the benefit of Hepatitis C infected individuals around the world.”
About Hepatitis C
Hepatitis C is a blood borne infection of the liver caused by the Hepatitis C virus (HCV) which becomes chronic in about 85% of cases. According to the World Health Organization (WHO), up to 170 million people worldwide are chronically infected with HCV. In addition, HCV infection is the leading cause of liver transplantation and is a risk factor for liver cancer. The Hepatitis C market is growing rapidly and is forecasted to reach $16 billion in 2015 in the seven major markets (US, France, Germany, Italy, Spain, UK and Japan).
BioLineRx Ltd. is a publicly-traded biopharmaceutical development company. It is dedicated to building a portfolio of products for unmet medical needs or with advantages over currently available therapies. BioLineRx’s current portfolio consists of five clinical stage candidates: BL-1020 for schizophrenia has commenced a Phase II/III study; BL-1040, for prevention of pathological cardiac remodeling following a myocardial infarction, is currently undergoing a pivotal CE-Mark registration trial and has been out-licensed to Ikaria Inc. for a total deal value of $282.5 million, in addition to sales royalties; BL-5010 for non-surgical removal of skin lesions has completed a Phase I/II study; BL-1021 for neuropathic pain is in Phase I development and BL-7040 for treating Inflammatory Bowel Disease (IBD) has completed Phase I. In addition, BioLineRx has 13 products in various pre-clinical development stages for a variety of indications, including central nervous system diseases, oncology, infectious diseases, cardiovascular and autoimmune diseases.
BioLineRx’s business model is based on acquiring molecules mainly from biotechnological incubators and academic institutions. The Company performs feasibility assessment studies and development through pre-clinical and clinical stages, with partial funding from the Israeli Government’s Office of the Chief Scientist (OCS). The final stage includes partnering with medium and large pharmaceutical companies for advanced clinical development (Phase III) and commercialization.
For more information on BioLineRx, please visit www.biolinerx.com.
Genoscience, a biopharmaceutical company located in Marseille, France, is focused on the development of new drugs for the treatment of viral diseases as HCV. Genoscience’s innovative technology platform, which combines internal expertise in resistance with unique molecular modeling through its proprietary software (GenMol™), allows for the development of highly targeted molecules, taking into account the phenomenon of resistance. For further information about Genoscience, please refer to http://www.genosciencepharma.com.
About RFS Pharma, LLC
RFS Pharma, LLC was founded in September 2004 and is located in a 26,500 sq. ft. state-of-the-art research facility in Tucker, Georgia. RFS Pharma is a privately owned biotech company committed to the discovery and development of antiviral agents and other human therapeutics. The company capitalizes on its expertise in nucleoside chemistry to develop drugs to combat infections caused by drug-resistant HIV and hepatitis viruses. RFS Pharma’s lead product candidate is amdoxovir, which is in advanced Phase 2 clinical studies for the treatment of HIV-1 infections. In addition, the company has identified promising, early stage compounds for hepatitis infections, analogs that are effective against noroviruses, and has a proprietary novel nucleoside prodrug technology. For further information about RFS Pharma, please refer to our website, www.rfspharma.com.