Press Releases
Distributed: Dec 13, 2010
Melbourne, Dec 13, 2010 (ABN Newswire) - Benitec Limited (ASX:BLT) (PINK:BNIKF) is pleased to announce that the European Patent Office (EPO) has issued a Communication of Intent to Grant on application 2005 727 680 "Multiple promoter expression cassettes for simultaneous delivery of RNAi agents". The claims cover the use of an RNA interference construct (with multiple promoters) to inhibit the level of Hepatitis C virus in cells, tissues and organs. Additional related applications remain pending to extend the scope of protection, including constructs having single promoters.
Benitec has licensed the rights to use this patent for Hepatitis C exclusively to Tacere Therapeutics, Inc., who are working with Pfizer to further develop and commercialise Tacere's Hepatitis C Virus (HCV) compounds.
Tacere Therapeutics' Chief Executive Officer Sara Hall Renison stated "We are very pleased with the news from the EPO. Benitec has been a strong ally in developing this and other patent families, and Tacere and Pfizer look forward to continuing clinical development of this first-in-class drug".
Benitec's Chief Executive Officer Dr Peter French said, "The intention of the EPO to grant this patent is an important addition to our already broad and robust patent portfolio in RNAi, and complements the patents already granted for this work in the United States, Australia and New Zealand."
About Benitec Limited
Benitec Limited (ASX:BLT) (PINK:BNIKF) is an Australian biotechnology company focused on licensing its extensive intellectual property portfolio and developing therapeutics to treat serious diseases using its proprietary ddRNAi technology. For additional information, please visit http://www.benitec.com/.
Contact
Peter French
Chief Executive Officer
Benitec Limited
Tel: +61-412-457-595
http://www.benitec.com/
Source
December 12, 2010
Pfizer Withdraws Thelin; Blood Pressure Drug Linked to Fatal Liver Damage
By AP Dec 10th 2010 10:33AM
Categories: News
Pfizer Inc. said Friday it is pulling its blood pressure drug Thelin off the market and stopping all clinical trials because the drug can cause fatal liver damage.
Thelin is sold in the European Union, Canada, and Australia as an oral treatment for severe pulmonary arterial hypertension, or high blood pressure in the pulmonary artery. Pfizer said two patients who were taking Thelin died during a clinical trial, and a review of data from clinical studies and post-marketing reports showed a new link to liver injury.
Liver damage was a known side effect of Thelin and similar drugs, the company said, but the review uncovered a link to liver damage that was not tied to identifiable risk factors. It said the problem was unlikely to be detected by routine monitoring, and in some cases, the problems did not go away after patients stopped taking Thelin.
Pfizer said the withdrawal was voluntary and added that it has withdrawn its filing for marketing approval in the U.S.
Since there are other treatment options, Pfizer said the benefits of Thelin don't outweigh the risks. It is stopping all studies of the drug, which Pfizer acquired in 2008 when it bought Encysive Pharmaceuticals Inc. Encysive had been trying to win marketing approval for Thelin since 2005, but the Food and Drug Administration said it was not effective enough. Other agencies only approved the drug for hypertension that was so debilitating that patients' physical activity was severely limited.
The New York company said worldwide sales of Thelin, or sitaxsentan, totaled $44.4 million in the first nine months of 2010.
Source
Categories: News
Pfizer Inc. said Friday it is pulling its blood pressure drug Thelin off the market and stopping all clinical trials because the drug can cause fatal liver damage.
Thelin is sold in the European Union, Canada, and Australia as an oral treatment for severe pulmonary arterial hypertension, or high blood pressure in the pulmonary artery. Pfizer said two patients who were taking Thelin died during a clinical trial, and a review of data from clinical studies and post-marketing reports showed a new link to liver injury.
Liver damage was a known side effect of Thelin and similar drugs, the company said, but the review uncovered a link to liver damage that was not tied to identifiable risk factors. It said the problem was unlikely to be detected by routine monitoring, and in some cases, the problems did not go away after patients stopped taking Thelin.
Pfizer said the withdrawal was voluntary and added that it has withdrawn its filing for marketing approval in the U.S.
Since there are other treatment options, Pfizer said the benefits of Thelin don't outweigh the risks. It is stopping all studies of the drug, which Pfizer acquired in 2008 when it bought Encysive Pharmaceuticals Inc. Encysive had been trying to win marketing approval for Thelin since 2005, but the Food and Drug Administration said it was not effective enough. Other agencies only approved the drug for hypertension that was so debilitating that patients' physical activity was severely limited.
The New York company said worldwide sales of Thelin, or sitaxsentan, totaled $44.4 million in the first nine months of 2010.
Source
December 11, 2010
A Targeted Approach to Hepatitis C Treatment
Peter Mueller PhD, CSO and EVP of Global R&D; Vertex Pharmaceuticals, Cambridge, Mass.
Drug Discovery & Development - December 01, 2010
Hepatitis C is a serious liver disease caused by the hepatitis C virus (HCV) that affects approximately 170 million people worldwide.1 Up to 3.9 million Americans may be infected with HCV and 75 percent are unaware of their infection.2,3 Hepatitis C can be cured with drug therapy. However, for people infected with the most common form of HCV in the United States (genotype 1), less than half achieve a sustained viral response (SVR), or viral cure, with current therapies.4-6
Without effective treatment, chronic hepatitis C can cause liver failure, liver cancer, and death.1 The need for more effective therapy for people with genotype 1 hepatitis C has led to research into direct-acting antivirals (DAAs) that target viral replication proteins such as the HCV protease and HCV polymerase.
Vertex Pharmaceuticals used a structure-based drug design approach to identify telaprevir, a novel small molecule DAA.7 Telaprevir inhibits a protease essential for viral replication, HCV NS3-4A. The complex formed between telaprevir and HCV NS3-4A is covalent yet reversible, with a slow-on, slow-off process.7 This potent, selective inhibitor significantly reduced HCV RNA levels (an indicator of reduced viral replication) in both cell culture systems and early-phase clinical trials.7,8
To date, more than 2,500 people with genotype 1 hepatitis C have received telaprevir-based therapy as part of Phase 2 and Phase 3 clinical trials. Telaprevir was given in combination with pegylated-interferon and ribavirin for the first 12 weeks of treatment followed by pegylated-interferon and ribavirin alone for either 12 or 36 weeks of additional therapy. Telaprevir has been studied in three Phase 3 trials: ADVANCE, ILLUMINATE, and REALIZE. ADVANCE and ILLUMINATE included patients who had never received treatment for hepatitis C (treatment-naïve), whereas REALIZE included patients who had not achieved SVR, or viral cure, after a prior course of interferon-based treatment (treatment-experienced).9-11 REALIZE was the only Phase 3 study of an investigational DAA designed to evaluate all major subgroups of people whose prior treatment was unsuccessful, including those who had a null response (less than a 2-log10 drop in HCV RNA by week 12 of a prior course of treatment) as defined by the U.S. Food and Drug Administration (FDA).6,11,12
The telaprevir Phase 2 study results were published in the New England Journal of Medicine, and Phase 3 results from ADVANCE and ILLUMINATE were presented at the annual meeting of the American Association for the Study of Liver Diseases in October 2010.9,10,13-15
Vertex submitted a new drug application to the FDA in November of 2010 and plans to request priority (6-month) review of the application.
References
1. World Health Organization. Hepatitis C. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index.html. Updated 2002. Accessed August 18, 2010.
2. Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed August 18, 2010.
3. Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed August 18, 2010. This report was commissioned by Vertex Pharmaceuticals.
4. Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis in the United States. J Viral Hepat. 2000;7:196-202.
5. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New Eng J Med. 2002;347(13):975-982.
6. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management and treatment of hepatitis C: An update. Hepatology. 2009;49(4): 1335-1374.
7. Perni RB, Almquist SJ, Byrn RA, et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother. 2006;50(3):899-909.
8. Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006;131(4):997–1002.
9. Jacobson IM, McHutchison JG, Dusheiko GM et al. Telaprevir in combination with Peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: Final results of phase 3 ADVANCE study. Hepatology. 2010;52(Suppl 4): 427A. Abstract 211.
10. Vertex Pharmaceuticals Press Release: Vertex Pharmaceuticals to Start Phase 3 'REALIZE' Trial with Telaprevir in Treatment-Failure HCV Patients, August 19, 2008. Available at: http://investors.vrtx.com/releasedetail.cfm?ReleaseID=328603. Accessed on August 25, 2010.
11. Sherman KE, Flamm SL, Afdhal NH, et al. Telaprevir in combination with peginterferon alfa3a and ribavirin for 34 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: Final results of the Phase 3 ILLUMINATE study. Hepatology. 2010;52(Suppl 4):401A. Abstract LB-2.
12 United States Food and Drug Administration. Chronic hepatitis C virus infection: developing direct-acting antiviral agents for treatment. http://www.federalregister.gov/articles/2010/09/14/2010-22806/draft-guidance-for-industry-on-chronic-hepatitis-c-virus-infection-developing-directacting-antiviral. Updated September 14, 2010. Accessed September 14, 2010.
13. McHutchison JG, Everson GT, Gordon SC, et al. and the PROVE1 Study Team. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. New Eng J Med. 2009;360(18):1827-1838.
14. Hezode C, Forestier N, Dusheiko G, et al. and the PROVE2 Study Team. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. New Eng J Med. 2009;360(18):1839-1850.
15. McHutchison JG, Manns MP, Muir AJ, et al. and the PROVE3 Study Team. Telaprevir for previously treated chronic HCV infection. New Eng J Med. 2010;362(14):1292-1303.
Source
Drug Discovery & Development - December 01, 2010
Hepatitis C is a serious liver disease caused by the hepatitis C virus (HCV) that affects approximately 170 million people worldwide.1 Up to 3.9 million Americans may be infected with HCV and 75 percent are unaware of their infection.2,3 Hepatitis C can be cured with drug therapy. However, for people infected with the most common form of HCV in the United States (genotype 1), less than half achieve a sustained viral response (SVR), or viral cure, with current therapies.4-6
Without effective treatment, chronic hepatitis C can cause liver failure, liver cancer, and death.1 The need for more effective therapy for people with genotype 1 hepatitis C has led to research into direct-acting antivirals (DAAs) that target viral replication proteins such as the HCV protease and HCV polymerase.
Vertex Pharmaceuticals used a structure-based drug design approach to identify telaprevir, a novel small molecule DAA.7 Telaprevir inhibits a protease essential for viral replication, HCV NS3-4A. The complex formed between telaprevir and HCV NS3-4A is covalent yet reversible, with a slow-on, slow-off process.7 This potent, selective inhibitor significantly reduced HCV RNA levels (an indicator of reduced viral replication) in both cell culture systems and early-phase clinical trials.7,8
To date, more than 2,500 people with genotype 1 hepatitis C have received telaprevir-based therapy as part of Phase 2 and Phase 3 clinical trials. Telaprevir was given in combination with pegylated-interferon and ribavirin for the first 12 weeks of treatment followed by pegylated-interferon and ribavirin alone for either 12 or 36 weeks of additional therapy. Telaprevir has been studied in three Phase 3 trials: ADVANCE, ILLUMINATE, and REALIZE. ADVANCE and ILLUMINATE included patients who had never received treatment for hepatitis C (treatment-naïve), whereas REALIZE included patients who had not achieved SVR, or viral cure, after a prior course of interferon-based treatment (treatment-experienced).9-11 REALIZE was the only Phase 3 study of an investigational DAA designed to evaluate all major subgroups of people whose prior treatment was unsuccessful, including those who had a null response (less than a 2-log10 drop in HCV RNA by week 12 of a prior course of treatment) as defined by the U.S. Food and Drug Administration (FDA).6,11,12
The telaprevir Phase 2 study results were published in the New England Journal of Medicine, and Phase 3 results from ADVANCE and ILLUMINATE were presented at the annual meeting of the American Association for the Study of Liver Diseases in October 2010.9,10,13-15
Vertex submitted a new drug application to the FDA in November of 2010 and plans to request priority (6-month) review of the application.
References
1. World Health Organization. Hepatitis C. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index.html. Updated 2002. Accessed August 18, 2010.
2. Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed August 18, 2010.
3. Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed August 18, 2010. This report was commissioned by Vertex Pharmaceuticals.
4. Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis in the United States. J Viral Hepat. 2000;7:196-202.
5. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New Eng J Med. 2002;347(13):975-982.
6. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management and treatment of hepatitis C: An update. Hepatology. 2009;49(4): 1335-1374.
7. Perni RB, Almquist SJ, Byrn RA, et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother. 2006;50(3):899-909.
8. Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006;131(4):997–1002.
9. Jacobson IM, McHutchison JG, Dusheiko GM et al. Telaprevir in combination with Peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: Final results of phase 3 ADVANCE study. Hepatology. 2010;52(Suppl 4): 427A. Abstract 211.
10. Vertex Pharmaceuticals Press Release: Vertex Pharmaceuticals to Start Phase 3 'REALIZE' Trial with Telaprevir in Treatment-Failure HCV Patients, August 19, 2008. Available at: http://investors.vrtx.com/releasedetail.cfm?ReleaseID=328603. Accessed on August 25, 2010.
11. Sherman KE, Flamm SL, Afdhal NH, et al. Telaprevir in combination with peginterferon alfa3a and ribavirin for 34 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: Final results of the Phase 3 ILLUMINATE study. Hepatology. 2010;52(Suppl 4):401A. Abstract LB-2.
12 United States Food and Drug Administration. Chronic hepatitis C virus infection: developing direct-acting antiviral agents for treatment. http://www.federalregister.gov/articles/2010/09/14/2010-22806/draft-guidance-for-industry-on-chronic-hepatitis-c-virus-infection-developing-directacting-antiviral. Updated September 14, 2010. Accessed September 14, 2010.
13. McHutchison JG, Everson GT, Gordon SC, et al. and the PROVE1 Study Team. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. New Eng J Med. 2009;360(18):1827-1838.
14. Hezode C, Forestier N, Dusheiko G, et al. and the PROVE2 Study Team. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. New Eng J Med. 2009;360(18):1839-1850.
15. McHutchison JG, Manns MP, Muir AJ, et al. and the PROVE3 Study Team. Telaprevir for previously treated chronic HCV infection. New Eng J Med. 2010;362(14):1292-1303.
Source
SeraCare Introduces New HCV Seroconversion Panels
SeraCare Life Sciences, a leading expert in human biologicals and the manufacturer of ACCURUN® controls, introduces two new, highly characterized HCV seroconversion panels designed to help diagnostic manufacturers and clinical laboratories effectively evaluate their HCV test systems.
Milford, MA (PRWEB) December 11, 2010
The safety of the blood supply and the accurate diagnosis of Hepatitis C infection depend on the sensitivity and overall quality of tests for markers of HCV. Test developers, regulators and clinical laboratories require highly characterized panels and control materials to challenge sensitivity accuracy and reproducibility of their assays.
SeraCare Life Sciences, a leading expert in human biologicals and the manufacturer of ACCURUN® controls, introduces two new, highly characterized HCV seroconversion panels designed to help diagnostic manufacturers and clinical laboratories effectively evaluate their HCV test systems. The specimens in each panel are collected from a single individual during the evolution of the immune response to HCV. Accurate detection of early HCV infection is especially important for tests used to screen the blood supply, as HCV is not initially symptomatic upon infection.
The two new seroconversion panels, designated PHV922 and PHV923, each consist of a set of undiluted plasma samples collected from a single individual during seroconversion, the period of time during development of infection and early immune response. PHV922 and PHV923 were collected from deferred plasma donors in different regions of the U.S. over 17 and 23 days respectively, in 2008. PHV922 is HCV genotype 3a; PHV923 is HCV genotype 1a. Both series demonstrate the early evolution of the human immune response to HCV, and contain naturally occurring samples to challenge the sensitivity of tests for HCV antibody.
Data for the SeraCare HCV Seroconversion Panels are available at http://www.seracarepanels.com/. The enhanced online data sheets graphically portray the evolution of the HCV markers, and display test results from multiple test methods for each marker. For additional information call +1 508-244-6400 or visit the webpage at http://www.seracarecatalog.com/, or email info(at)seracare(dot)com.
About SeraCare Life Sciences, Inc.:
SeraCare serves the global life sciences industry by providing vital products and services to facilitate the discovery, development and production of human diagnostics and therapeutics. The Company’s innovative portfolio includes diagnostic controls, plasma-derived reagents and molecular biomarkers, biobanking and contract research services. SeraCare’s quality systems, scientific expertise and state-of-the-art facilities support its customers in meeting the stringent requirements of the highly regulated life sciences industry.
Source
Milford, MA (PRWEB) December 11, 2010
The safety of the blood supply and the accurate diagnosis of Hepatitis C infection depend on the sensitivity and overall quality of tests for markers of HCV. Test developers, regulators and clinical laboratories require highly characterized panels and control materials to challenge sensitivity accuracy and reproducibility of their assays.
SeraCare Life Sciences, a leading expert in human biologicals and the manufacturer of ACCURUN® controls, introduces two new, highly characterized HCV seroconversion panels designed to help diagnostic manufacturers and clinical laboratories effectively evaluate their HCV test systems. The specimens in each panel are collected from a single individual during the evolution of the immune response to HCV. Accurate detection of early HCV infection is especially important for tests used to screen the blood supply, as HCV is not initially symptomatic upon infection.
The two new seroconversion panels, designated PHV922 and PHV923, each consist of a set of undiluted plasma samples collected from a single individual during seroconversion, the period of time during development of infection and early immune response. PHV922 and PHV923 were collected from deferred plasma donors in different regions of the U.S. over 17 and 23 days respectively, in 2008. PHV922 is HCV genotype 3a; PHV923 is HCV genotype 1a. Both series demonstrate the early evolution of the human immune response to HCV, and contain naturally occurring samples to challenge the sensitivity of tests for HCV antibody.
Data for the SeraCare HCV Seroconversion Panels are available at http://www.seracarepanels.com/. The enhanced online data sheets graphically portray the evolution of the HCV markers, and display test results from multiple test methods for each marker. For additional information call +1 508-244-6400 or visit the webpage at http://www.seracarecatalog.com/, or email info(at)seracare(dot)com.
About SeraCare Life Sciences, Inc.:
SeraCare serves the global life sciences industry by providing vital products and services to facilitate the discovery, development and production of human diagnostics and therapeutics. The Company’s innovative portfolio includes diagnostic controls, plasma-derived reagents and molecular biomarkers, biobanking and contract research services. SeraCare’s quality systems, scientific expertise and state-of-the-art facilities support its customers in meeting the stringent requirements of the highly regulated life sciences industry.
Source
Hepatitis C: Disease Treatment Insight
Writer Toni Brown
MedPredict Market Research, a global provider of pharmaceutical competitive intelligence and market research, has published a new report entitled “Thought Leader Insight & Analysis: Hepatitis C Virus (HCV),” designed to provide critical strategic insight for pharma and biotech companies with a stake in the market for treatments in this disease area.
“This report summarizes the perspectives of renowned thought leaders who specialize in the treatment of hepatitis C,” according to Elizabeth Mathews, MedPredict’s CEO. “We conducted in-depth interviews with these experts immediately following AASLD to understand the effect that the upcoming approvals of telaprevir and boceprevir will have on the treatment of HCV, as well as to gain insight into how combination therapy will address the unmet needs still remaining after the approval of these protease inhibitors.”
Some of the topics discussed by in this report include:
- Goals of therapy,
- Who should treat HCV,
- Unmet needs and favorite future cocktails; interferon-sparing regimens,
- Warehousing patients in the age of protease inhibitors,
- Potential for resistance development,
- Dosing/compliance,
- IL-28b / CC, CT and TT patients; US, EU and Asian populations,
- Fibrosis score,
- Possible reimbursement/bundling strategies,
- Cost of therapy and duration of treatment, and
- Side effects: rash vs. anemia.
The full report may be purchased by contacting MedPredict.
About MedPredict
MedPredict maintains a proprietary database of over 1,000 global physician thought leaders. Based on primary interviews with these thought leaders, MedPredict publishes periodic therapeutic area reports to keep clients up-to-date on emerging trends and competitive activity. The reports include thought leader reactions to recent publications and presentations, as well as clinical, regulatory and marketing activity.
For more information contact:
Elizabeth Mathews
MedPredict
513.271.1924
Source
`Natural killers' unleashed to search and destroy cancer
Doctors at the University of Miami are treating liver cancer patients by giving immune-system cells more muscle in the lab to recognize and attack their cancer cells.
BY FRED TASKER
ftasker@MiamiHerald.com
They're called ``natural killer cells'' but they're a part of the human immune system that helps save lives. Now doctors from Miami and Japan have developed new ways to pump up the cells to attack cancer even more aggressively.
Encarnacion Miranda, a 58-year-old car salesman from Key Largo, is counting on the cells -- which exist in healthy livers -- to save his life. He's the first patient in a clinical trial at the University of Miami of 25 liver patients seeking Food and Drug Administration approval of the new treatment.
``It's scary,'' Miranda said Thursday, during an announcement of the medical trial. ``But I feel really good.''
Miranda's liver had been dogging him since 1979, when he contracted hepatitis C from a blood transfusion. By October 2009, chronic exhaustion forced him to give up his favorite sport, fishing for yellowtail snapper in the Florida Keys. That's when he learned his hepatitis had become liver cancer.
Doctors gave Miranda a liver transplant. But, knowing that liver cancer recurs in up to 20 percent of cases due to tumor cells left hiding in the body, they went further. Before the transplant, they took blood from the donated liver, extracted the natural killer immune cells from it, then cultured and expanded them in laboratory flasks for four days to increase their power against any remaining cancer cells. They fed them intravenously back into Miranda's new liver.
Doctors say the killer cells, which recognize cancer cells as alien and try to destroy them, also will help fight any remaining hepatitis C. They aren't sure yet whether their findings on natural killer cell expansion might be broadened to work in other organs and combat other cancers.
The procedure was studied for four years at the University of Hiroshima. Dr. Masahiro Ohira performed the procedure on 24 patients; 22 survived cancer-free for more than three years. It cut in half the recurrence of cancer.
``The killer cells act like smart bombs in going after the cancer,'' Ohira said.
Miranda is grateful to the team at the University of Miami Medical School that worked with him at Jackson Memorial Medical Center.
``I was up and walking three days after my [Oct. 19] transplant,'' he said. ``Yesterday I walked six miles.''
Treating Miranda was actually far more complicated than his recovery would indicate. When his three liver tumors were found, they were too big to permit a transplant. So the team from UM used several courses of chemotherapy and radio-frequency ablation -- the use of radio-frequency waves to destroy tumor tissue -- to attack them, finally reducing them enough to make possible the transplant.
When a donor liver became available, the doctors flushed out some of its natural killer cells before transplanting it into Miranda. Ohira put the cells into a laboratory flask and applied an agent known to increase the cells' potency, even though it doesn't increase their number.
``It increases their activity against cancer and hepatitis C by four times,'' he said.
The team included Dr. Andreas Tzakis, director of the Liver Transplant Program, Ohira, now a research associate in the UM Department of Surgery and Drs. Seigo Nishida and David Levi, professors of clinical surgery at UM.
``They're my heroes,'' Miranda said. ``They never gave up.''
Miranda's prognosis?
``We think it's good,'' Tzakis said. ``Of course there are no guarantees.''
Miranda says he has far more energy now.
``Last year I was so exhausted I felt like I was passing away. Today I feel like a new person.''
Miranda's doctors say by next year he and his companion of 14 years, Linda Cozby, can return to catching yellowtail snapper.
Miranda grinned.
``Next year is only three weeks away.''
Source
BY FRED TASKER
ftasker@MiamiHerald.com
They're called ``natural killer cells'' but they're a part of the human immune system that helps save lives. Now doctors from Miami and Japan have developed new ways to pump up the cells to attack cancer even more aggressively.
Encarnacion Miranda, a 58-year-old car salesman from Key Largo, is counting on the cells -- which exist in healthy livers -- to save his life. He's the first patient in a clinical trial at the University of Miami of 25 liver patients seeking Food and Drug Administration approval of the new treatment.
``It's scary,'' Miranda said Thursday, during an announcement of the medical trial. ``But I feel really good.''
Miranda's liver had been dogging him since 1979, when he contracted hepatitis C from a blood transfusion. By October 2009, chronic exhaustion forced him to give up his favorite sport, fishing for yellowtail snapper in the Florida Keys. That's when he learned his hepatitis had become liver cancer.
Doctors gave Miranda a liver transplant. But, knowing that liver cancer recurs in up to 20 percent of cases due to tumor cells left hiding in the body, they went further. Before the transplant, they took blood from the donated liver, extracted the natural killer immune cells from it, then cultured and expanded them in laboratory flasks for four days to increase their power against any remaining cancer cells. They fed them intravenously back into Miranda's new liver.
Doctors say the killer cells, which recognize cancer cells as alien and try to destroy them, also will help fight any remaining hepatitis C. They aren't sure yet whether their findings on natural killer cell expansion might be broadened to work in other organs and combat other cancers.
The procedure was studied for four years at the University of Hiroshima. Dr. Masahiro Ohira performed the procedure on 24 patients; 22 survived cancer-free for more than three years. It cut in half the recurrence of cancer.
``The killer cells act like smart bombs in going after the cancer,'' Ohira said.
Miranda is grateful to the team at the University of Miami Medical School that worked with him at Jackson Memorial Medical Center.
``I was up and walking three days after my [Oct. 19] transplant,'' he said. ``Yesterday I walked six miles.''
Treating Miranda was actually far more complicated than his recovery would indicate. When his three liver tumors were found, they were too big to permit a transplant. So the team from UM used several courses of chemotherapy and radio-frequency ablation -- the use of radio-frequency waves to destroy tumor tissue -- to attack them, finally reducing them enough to make possible the transplant.
When a donor liver became available, the doctors flushed out some of its natural killer cells before transplanting it into Miranda. Ohira put the cells into a laboratory flask and applied an agent known to increase the cells' potency, even though it doesn't increase their number.
``It increases their activity against cancer and hepatitis C by four times,'' he said.
The team included Dr. Andreas Tzakis, director of the Liver Transplant Program, Ohira, now a research associate in the UM Department of Surgery and Drs. Seigo Nishida and David Levi, professors of clinical surgery at UM.
``They're my heroes,'' Miranda said. ``They never gave up.''
Miranda's prognosis?
``We think it's good,'' Tzakis said. ``Of course there are no guarantees.''
Miranda says he has far more energy now.
``Last year I was so exhausted I felt like I was passing away. Today I feel like a new person.''
Miranda's doctors say by next year he and his companion of 14 years, Linda Cozby, can return to catching yellowtail snapper.
Miranda grinned.
``Next year is only three weeks away.''
Source
Fat Index Associated With Liver Damage in Hep C Patients
Last Updated: December 09, 2010
The visceral adiposity index, a score that combines body mass index, waist circumference, triglycerides, and high-density lipoprotein levels, is associated with liver damage and viral load in patients with genotype 1 chronic hepatitis C, according to a study in the November issue of Hepatology.
THURSDAY, Dec. 9 (HealthDay News) -- The visceral adiposity index (VAI), a score that combines body mass index, waist circumference, triglycerides, and high-density lipoprotein levels, is associated with liver damage and viral load in patients with genotype 1 chronic hepatitis C (G1 CHC), according to a study in the November issue of Hepatology.
Salvatore Petta, M.D., of the University of Palermo in Italy, and colleagues performed liver biopsies on 236 patients with G1 CHC and conducted examinations to assess for steatosis, evidence of liver damage (such as necroinflammatory activity and fibrosis), and viral loads. The researchers also conducted metabolic and anthropometric tests and computed each subject's VAI.
The researchers found that VAI scores were independently associated with homeostasis model assessment score, hepatitis C virus (HCV) RNA levels, necroinflammatory activity, and steatosis. Also, in regression analyses, insulin resistance, higher VAI score, and fibrosis all were associated with moderate to severe steatosis, while older age, higher VAI score, and fibrosis were independently associated with steatosis of at least 30 percent, and older age, higher VAI score, and fibrosis were independently related to moderate to severe necroinflammatory activity.
"In conclusion, VAI, a new index of both fat function and distribution, appears to be independently associated with steatosis and necroinflammatory activity in G1 CHC patients and has a direct correlation with HCV viral load. These data suggest a direct role of adipose tissue in liver damage and a possible interference of HCV with adipocyte function. Experimental studies are needed to determine the mechanisms responsible for these associations," the authors write.
Abstract
Full Text (subscription or payment may be required)
Source
The visceral adiposity index, a score that combines body mass index, waist circumference, triglycerides, and high-density lipoprotein levels, is associated with liver damage and viral load in patients with genotype 1 chronic hepatitis C, according to a study in the November issue of Hepatology.
THURSDAY, Dec. 9 (HealthDay News) -- The visceral adiposity index (VAI), a score that combines body mass index, waist circumference, triglycerides, and high-density lipoprotein levels, is associated with liver damage and viral load in patients with genotype 1 chronic hepatitis C (G1 CHC), according to a study in the November issue of Hepatology.
Salvatore Petta, M.D., of the University of Palermo in Italy, and colleagues performed liver biopsies on 236 patients with G1 CHC and conducted examinations to assess for steatosis, evidence of liver damage (such as necroinflammatory activity and fibrosis), and viral loads. The researchers also conducted metabolic and anthropometric tests and computed each subject's VAI.
The researchers found that VAI scores were independently associated with homeostasis model assessment score, hepatitis C virus (HCV) RNA levels, necroinflammatory activity, and steatosis. Also, in regression analyses, insulin resistance, higher VAI score, and fibrosis all were associated with moderate to severe steatosis, while older age, higher VAI score, and fibrosis were independently associated with steatosis of at least 30 percent, and older age, higher VAI score, and fibrosis were independently related to moderate to severe necroinflammatory activity.
"In conclusion, VAI, a new index of both fat function and distribution, appears to be independently associated with steatosis and necroinflammatory activity in G1 CHC patients and has a direct correlation with HCV viral load. These data suggest a direct role of adipose tissue in liver damage and a possible interference of HCV with adipocyte function. Experimental studies are needed to determine the mechanisms responsible for these associations," the authors write.
Abstract
Full Text (subscription or payment may be required)
Source
Lab21 secures new patents in Hepatitis C drug resistance andfluorescent carbon-based nanoparticle technology
Cambridge, UK, December 8th - Lab21 Limited, the Cambridge, UK-based specialist in personalised medicine has secured new patents in Europe and the USA relating to Hepatitis C and its SelahDOTS™ fluorescent nanoparticles, as it continues to expand its intellectual property portfolio.
The hepatitis C patent extends an existing patent, and refers to technology allowing the genotypic identification of drug resistant mutations in the 4 major global genotypes of HCV. With the imminent launch of a series of new small molecule therapies in HCV, this technology will allow accurate monitoring of when drug resistance appears in individual patients, improving patient care.
The SelahDOTS™ nanoparticles technology covers a generic approach to the development of new diagnostic and imaging reagents using carbon-based non-toxic nanoparticles. This platform technology has multiple applications in clinical diagnostics and was originally developed through a licence from Clemson University. The grant of the patent now allows Lab21 to develop a series of new product and service applications in areas such as in vivo imaging, immunodiagnostics and point-of-care biomarker analysis,
The securing of these patents builds on Lab21’s growing intellectual property portfolio as it expands its competitive proprietary position in pharmacogenetic markers, disease markers and its assay technology.
Dr Berwyn Clarke, CSO at Lab21 commented: ‘The HCV patent further strengthens our portfolio in the important HCV diagnostic area while the nanoparticle platform technology has potential to transform the ways in which particulate diagnostics are used, particularly in vivo, where particle-related toxicity has been a significant problem. Additionally we are seeing early development progress in incorporating the SelahDOTS™ technology in our own new molecular and protein based assays.’
Graham Mullis, Lab21 CEO added: ‘The development of an extensive intellectual property portfolio will be an important part of Lab21’s strategy as we continue to grow. Patents such as these will ensure we are able to remain uniquely competitive and ensure we are able to provide our customers with the most advanced products and services in the markets we choose to serve.’
For further information: Lab21 Graham Mullis, CEO Dr Berwyn Clarke, CSDO t: +44 (0)1223 395461 e: graham.mullis@lab-21.com
For media and investor enquiries: College Hill Tony Stephenson/Gemma Howe/Nicole Yost t: +44 (0)20 7866 7864 m: +44 (0)7989 855113 e: lab21@collegehill.com
About Lab21 Lab21 is a global provider of state-of-the-art diagnostic products and services, supporting blood bank screening, medical diagnostics and drug discovery. Its customers include international healthcare providers, pharmaceutical and biotechnology companies. The product division of the Company manufactures immunodiagnostic kits and reagents that are distributed into 110 international countries and is focused on infectious diseases for the blood-banking market. The service division has a growing test portfolio providing companion diagnostics and high technology molecular assays for the growing integration of personalised medicine into healthcare. These services are currently in infectious diseases, oncology and pharmacogenetics areas with emerging interests in cardiovascular and metabolic disease. Lab21's clinical reference laboratory and corporate office is based in Cambridge and has additional UK sites in Newmarket, Bridport, Liverpool and Ipswich. It also has operations in South Carolina, USA. The Company's investors include Merlin Biosciences, Nexus Medical Partners, Medicis Capital, Rowan Dartington and Kreos Capital. Website: http://www.lab21.com/
Source
The hepatitis C patent extends an existing patent, and refers to technology allowing the genotypic identification of drug resistant mutations in the 4 major global genotypes of HCV. With the imminent launch of a series of new small molecule therapies in HCV, this technology will allow accurate monitoring of when drug resistance appears in individual patients, improving patient care.
The SelahDOTS™ nanoparticles technology covers a generic approach to the development of new diagnostic and imaging reagents using carbon-based non-toxic nanoparticles. This platform technology has multiple applications in clinical diagnostics and was originally developed through a licence from Clemson University. The grant of the patent now allows Lab21 to develop a series of new product and service applications in areas such as in vivo imaging, immunodiagnostics and point-of-care biomarker analysis,
The securing of these patents builds on Lab21’s growing intellectual property portfolio as it expands its competitive proprietary position in pharmacogenetic markers, disease markers and its assay technology.
Dr Berwyn Clarke, CSO at Lab21 commented: ‘The HCV patent further strengthens our portfolio in the important HCV diagnostic area while the nanoparticle platform technology has potential to transform the ways in which particulate diagnostics are used, particularly in vivo, where particle-related toxicity has been a significant problem. Additionally we are seeing early development progress in incorporating the SelahDOTS™ technology in our own new molecular and protein based assays.’
Graham Mullis, Lab21 CEO added: ‘The development of an extensive intellectual property portfolio will be an important part of Lab21’s strategy as we continue to grow. Patents such as these will ensure we are able to remain uniquely competitive and ensure we are able to provide our customers with the most advanced products and services in the markets we choose to serve.’
For further information: Lab21 Graham Mullis, CEO Dr Berwyn Clarke, CSDO t: +44 (0)1223 395461 e: graham.mullis@lab-21.com
For media and investor enquiries: College Hill Tony Stephenson/Gemma Howe/Nicole Yost t: +44 (0)20 7866 7864 m: +44 (0)7989 855113 e: lab21@collegehill.com
About Lab21 Lab21 is a global provider of state-of-the-art diagnostic products and services, supporting blood bank screening, medical diagnostics and drug discovery. Its customers include international healthcare providers, pharmaceutical and biotechnology companies. The product division of the Company manufactures immunodiagnostic kits and reagents that are distributed into 110 international countries and is focused on infectious diseases for the blood-banking market. The service division has a growing test portfolio providing companion diagnostics and high technology molecular assays for the growing integration of personalised medicine into healthcare. These services are currently in infectious diseases, oncology and pharmacogenetics areas with emerging interests in cardiovascular and metabolic disease. Lab21's clinical reference laboratory and corporate office is based in Cambridge and has additional UK sites in Newmarket, Bridport, Liverpool and Ipswich. It also has operations in South Carolina, USA. The Company's investors include Merlin Biosciences, Nexus Medical Partners, Medicis Capital, Rowan Dartington and Kreos Capital. Website: http://www.lab21.com/
Source
December 7, 2010
Serum microRNA Profiles Serve as Novel Biomarkers for HBV Infection and Diagnosis of HBV-Positive Hepatocarcinoma
Cancer Res. 2010 Nov 23. [Epub ahead of print]
Li LM, Hu ZB, Zhou ZX, Chen X, Liu FY, Zhang JF, Shen HB, Zhang CY, Zen K.
Authors' Affiliations: Institute for Virology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, and Clinical Laboratory, Nanjing Second Hospital, Nanjing, China; and Department of Virology, University of California School of Public Health, Berkeley, California.
Abstract
Diagnosis of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), particularly HCC independent of cirrhosis etiology, presents a great challenge because of a lack of biomarkers. Here we test the hypothesis that expression profiles of microRNAs (miRNAs) in serum can serve as biomarkers for diagnosis of HBV infection and HBV-positive HCC. We recruited 513 subjects (210 controls and 135 HBV-, 48 hepatitis C virus (HCV)-, and 120 HCC-affected individuals) and employed a strategy of initial screening by Solexa sequencing followed by validation with TaqMan probe-based quantitative reverse transcription-PCR assay. First, because of a close link between chronic hepatitis B and HCC, we compared miRNA expression profiles in HBV serum with that in control serum and successfully obtained 13 miRNAs that were differentially expressed in HBV serum. This 13-miRNA-based biomarker accurately discriminated not only HBV cases from controls and HCV cases, but also HBV-positive HCC cases from control and HBV cases. Second, we directly compared miRNA expressions in HCC serum with those in controls and identified 6 miRNAs that were significantly upregulated in HCC samples. Interestingly, 2 of these miRNAs, miR-375 and miR-92a, were also identified by our first approach as HBV specific. When we employed 3 of these miRNAs (miR-25, miR-375, and let-7f) as biomarkers, we could clearly separate HCC cases from controls, and miR-375 alone had an ROC of 0.96 (specificity: 96%; sensitivity: 100%) in HCC prediction. In conclusion, our study demonstrates for the first time that serum miRNA profiles can serve as novel and noninvasive biomarkers for HBV infection and HBV-positive HCC diagnosis. Cancer Res; 70(23); 1-10. ©2010 AACR.
PMID: 21098710 [PubMed - as supplied by publisher]
Source
Li LM, Hu ZB, Zhou ZX, Chen X, Liu FY, Zhang JF, Shen HB, Zhang CY, Zen K.
Authors' Affiliations: Institute for Virology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, and Clinical Laboratory, Nanjing Second Hospital, Nanjing, China; and Department of Virology, University of California School of Public Health, Berkeley, California.
Abstract
Diagnosis of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), particularly HCC independent of cirrhosis etiology, presents a great challenge because of a lack of biomarkers. Here we test the hypothesis that expression profiles of microRNAs (miRNAs) in serum can serve as biomarkers for diagnosis of HBV infection and HBV-positive HCC. We recruited 513 subjects (210 controls and 135 HBV-, 48 hepatitis C virus (HCV)-, and 120 HCC-affected individuals) and employed a strategy of initial screening by Solexa sequencing followed by validation with TaqMan probe-based quantitative reverse transcription-PCR assay. First, because of a close link between chronic hepatitis B and HCC, we compared miRNA expression profiles in HBV serum with that in control serum and successfully obtained 13 miRNAs that were differentially expressed in HBV serum. This 13-miRNA-based biomarker accurately discriminated not only HBV cases from controls and HCV cases, but also HBV-positive HCC cases from control and HBV cases. Second, we directly compared miRNA expressions in HCC serum with those in controls and identified 6 miRNAs that were significantly upregulated in HCC samples. Interestingly, 2 of these miRNAs, miR-375 and miR-92a, were also identified by our first approach as HBV specific. When we employed 3 of these miRNAs (miR-25, miR-375, and let-7f) as biomarkers, we could clearly separate HCC cases from controls, and miR-375 alone had an ROC of 0.96 (specificity: 96%; sensitivity: 100%) in HCC prediction. In conclusion, our study demonstrates for the first time that serum miRNA profiles can serve as novel and noninvasive biomarkers for HBV infection and HBV-positive HCC diagnosis. Cancer Res; 70(23); 1-10. ©2010 AACR.
PMID: 21098710 [PubMed - as supplied by publisher]
Source
Virologic Response Protects Against Death in Liver Transplant Patients With HCV
By: DIANA MAHONEY, Internal Medicine News Digital Network
BOSTON – Achieving sustained virologic response to antiviral therapy was highly protective against liver-related death in liver transplant patients with chronic hepatitis C, according to an analysis of data collected over a 20-year period from 12 liver transplant centers in Italy.
Patients with recurrent HCV who were unable to achieve sustained virologic response (SVR) were at a significantly higher risk of liver-related mortality than were those for whom the virus remained suppressed 6 weeks after treatment, Dr. Maria Rendina reported at the annual meeting of the American Association for the Study of Liver Diseases.
For the study, the investigators retrospectively analyzed data on 464 patients who underwent liver transplantation between 1989 and 2008. All of the patients had viral and histologic confirmation of HCV recurrence and all were treated with recombinant or pegylated interferon plus ribavirin at standard doses for at least 1 year, Dr. Rendina said. Of the study population, 35% achieved SVR, defined as undetectable HCV RNA 6 weeks after the end of treatment, and approximately 30% died during the mean 6.8 years of posttreatment follow-up. "Liver-related mortality was the cause of death in 73% of the patients who did not survive, and all of the liver-related deaths except for one were in the group of patients who did not attain [SVR]," she said.
A comparison of the SVR and non-SVR patient characteristics showed no differences in immunosuppressive strategies between the two groups, according to Dr. Rendina of the University of Bari in Italy. Overall, the SVR patients received livers from younger donors. They also had longer treatment durations, higher cumulative doses of interferon, lower dropout rates, and lower diabetes incidence, she said.
In univariate analysis, older donor age, viral genotypes 1 or 4, diabetes, and lack of SVR to antiviral therapy were significant risk factors for death, Dr. Rendina reported. In a multivariate analysis, after adjustment for donor, viral, and recipient variables including age, gender, genotype, immunosuppression, creatinine, hepatocellular carcinoma, and diabetes, failure to achieve SVR remained "significantly and independently associated with a very high risk of liver-related death," she said, noting that the hazard ratio for liver-related death in the non-SVR group was 3.3.
"Antiviral therapy should be strongly pursued in liver transplant patients with recurrent hepatitis C infection because of the protective role of [SVR]," she said.
The hesitancy to pursue antiviral therapy for HCV recurrence after liver transplantation stems, in large part, from the absence of data regarding the relationship between viral eradication and long-term clinical outcome, said Dr. Rendina. It is further exacerbated by the frequency and severity of adverse events associated with the pegylated interferon/ribavirin standard of care – most notably flulike symptoms, hemolytic anemia, neutropenia, depression, and neurologic symptoms, she said, noting that more than 25% of the patients in the current study stopped treatment because of intolerable side effects.
Despite the drawbacks, antiviral therapy holds the most promise for improving HCV-infected patients’ long-term outcome post transplantation and should be used in clinical practice, Dr. Rendina stated. At the same time, "further randomized trials aimed at exploring various treatment options and the efficacy of new antiviral drugs should be undertaken," she said.
Dr. Rendina disclosed having no financial conflicts of interest with respect to her presentation.
Source
BOSTON – Achieving sustained virologic response to antiviral therapy was highly protective against liver-related death in liver transplant patients with chronic hepatitis C, according to an analysis of data collected over a 20-year period from 12 liver transplant centers in Italy.
Patients with recurrent HCV who were unable to achieve sustained virologic response (SVR) were at a significantly higher risk of liver-related mortality than were those for whom the virus remained suppressed 6 weeks after treatment, Dr. Maria Rendina reported at the annual meeting of the American Association for the Study of Liver Diseases.
For the study, the investigators retrospectively analyzed data on 464 patients who underwent liver transplantation between 1989 and 2008. All of the patients had viral and histologic confirmation of HCV recurrence and all were treated with recombinant or pegylated interferon plus ribavirin at standard doses for at least 1 year, Dr. Rendina said. Of the study population, 35% achieved SVR, defined as undetectable HCV RNA 6 weeks after the end of treatment, and approximately 30% died during the mean 6.8 years of posttreatment follow-up. "Liver-related mortality was the cause of death in 73% of the patients who did not survive, and all of the liver-related deaths except for one were in the group of patients who did not attain [SVR]," she said.
A comparison of the SVR and non-SVR patient characteristics showed no differences in immunosuppressive strategies between the two groups, according to Dr. Rendina of the University of Bari in Italy. Overall, the SVR patients received livers from younger donors. They also had longer treatment durations, higher cumulative doses of interferon, lower dropout rates, and lower diabetes incidence, she said.
In univariate analysis, older donor age, viral genotypes 1 or 4, diabetes, and lack of SVR to antiviral therapy were significant risk factors for death, Dr. Rendina reported. In a multivariate analysis, after adjustment for donor, viral, and recipient variables including age, gender, genotype, immunosuppression, creatinine, hepatocellular carcinoma, and diabetes, failure to achieve SVR remained "significantly and independently associated with a very high risk of liver-related death," she said, noting that the hazard ratio for liver-related death in the non-SVR group was 3.3.
"Antiviral therapy should be strongly pursued in liver transplant patients with recurrent hepatitis C infection because of the protective role of [SVR]," she said.
The hesitancy to pursue antiviral therapy for HCV recurrence after liver transplantation stems, in large part, from the absence of data regarding the relationship between viral eradication and long-term clinical outcome, said Dr. Rendina. It is further exacerbated by the frequency and severity of adverse events associated with the pegylated interferon/ribavirin standard of care – most notably flulike symptoms, hemolytic anemia, neutropenia, depression, and neurologic symptoms, she said, noting that more than 25% of the patients in the current study stopped treatment because of intolerable side effects.
Despite the drawbacks, antiviral therapy holds the most promise for improving HCV-infected patients’ long-term outcome post transplantation and should be used in clinical practice, Dr. Rendina stated. At the same time, "further randomized trials aimed at exploring various treatment options and the efficacy of new antiviral drugs should be undertaken," she said.
Dr. Rendina disclosed having no financial conflicts of interest with respect to her presentation.
Source
December 6, 2010
Pharmacy Student's Drug Model Could Mean Better Outcomes for Hepatitis C Patients
University of Maryland School of Pharmacy researchers have developed a mathematical model for choosing an appropriate dosage of the hepatitis medications for individual patients. The work helps explain why African American patients tend to not respond as well to the drugs as other patients.
For the work, student researcher Runyan Jin, MD, PhD, won the best student research award and a $1,000 prize for her work at the 2010 American College of Clinical Pharmacology (ACCP) scientific meeting. Her project involved analyzing 900 blood samples from 400 patients enrolled in a multi-center trial to determine why hepatitis therapy works for some patients, but not others.
Hepatitis C is a serious liver disease caused by the hepatitis C virus and if not treated can lead to liver cancer and death. African Americans have a higher incidence and death from liver cancer.
The therapy, consisting of the anti-virus drug ribavirin, along with injections of the protective protein interferon, cures hepatitis C in some patients within six months due to a sustained viral response [SVR], suppressing the virus to undetectable levels for an extended period of time.
"Our question was why some patients in the large trial did not get this SVR cure. The response rate of African American patients was about half that of non-African Americans," says Thomas Dowling PharmD, PhD, associate professor in the School of Pharmacy's Clinical Pharmacology Unit. [Jin and Dowling are pictured above.]
Jin, who is Dowling's post-doctorate student and is already a pediatrician, reported that blood from the African American patients contained lower levels of the ribavirin drug than blood from non-African American patients on the same therapy. Especially in early stages of the therapy, the ribavirin was not getting into the blood system as efficiently in African Americans as in Caucasians. The mathematical model showed that the African Americans had a pharmacodynamic difference somehow in the distributional volume, which means the space where the drug moves, says Dowling.
The different response by African Americans to ribavirin is not the first time medical science has seen such a drug response difference between races.
"We are trying to model how to change the dosage not just change dose recommendations now. ýEventually personalized therapy will mean proper doses for each patient's genotype."
Pediatrician Jin hopes that her pharmacy work on anti-virus mediations and how they work in different people, pharmacodynamics, will also be useful in treating children. "This is especially important in children to get the correct dosages for safe and effective treatments." ý
"I was very lucky," says Jin. "When I was a second year [PhD]) student, I was looking for a research project in pharmacodynamics." She applied a mathematical method called Bayesian statistics to simplify the pharmacodynamic relationship between the drug and the 400 patients in the 2006 study, a method taught to her by Michael Fossler, PharmD, PhD, an alum of the School of Pharmacy now with drug maker GlaxoSmithKline.
"Runyan pulled a very nice story together with direct clinical applications. What we are faced with now [in drug development] is studies that are now so very expensive, says Fossler. "Bayesian methodology helps us cut our losses saves some patients from taking drugs that don't work sometimes."
Jin's research poster, "Population Pharmacodynamic Model in Patients with Chronic Hepatitis C Virus Genotype 1," won the 2010 Wayne A. Colburn Memorial Award at the annual ACCP. She has accepted a position at the U.S. Food and Drug Administration. ýIn her new career, she says, "I want to be an expert in this area of quantitative clinical pharmacology."
Posting Date: 12/06/2010
Contact Name: Steve Berberich
Contact Phone: 410-706-0023
Contact Email: sberb001@umaryland.edu
Source
For the work, student researcher Runyan Jin, MD, PhD, won the best student research award and a $1,000 prize for her work at the 2010 American College of Clinical Pharmacology (ACCP) scientific meeting. Her project involved analyzing 900 blood samples from 400 patients enrolled in a multi-center trial to determine why hepatitis therapy works for some patients, but not others.
Hepatitis C is a serious liver disease caused by the hepatitis C virus and if not treated can lead to liver cancer and death. African Americans have a higher incidence and death from liver cancer.
The therapy, consisting of the anti-virus drug ribavirin, along with injections of the protective protein interferon, cures hepatitis C in some patients within six months due to a sustained viral response [SVR], suppressing the virus to undetectable levels for an extended period of time.
"Our question was why some patients in the large trial did not get this SVR cure. The response rate of African American patients was about half that of non-African Americans," says Thomas Dowling PharmD, PhD, associate professor in the School of Pharmacy's Clinical Pharmacology Unit. [Jin and Dowling are pictured above.]
Jin, who is Dowling's post-doctorate student and is already a pediatrician, reported that blood from the African American patients contained lower levels of the ribavirin drug than blood from non-African American patients on the same therapy. Especially in early stages of the therapy, the ribavirin was not getting into the blood system as efficiently in African Americans as in Caucasians. The mathematical model showed that the African Americans had a pharmacodynamic difference somehow in the distributional volume, which means the space where the drug moves, says Dowling.
The different response by African Americans to ribavirin is not the first time medical science has seen such a drug response difference between races.
"We are trying to model how to change the dosage not just change dose recommendations now. ýEventually personalized therapy will mean proper doses for each patient's genotype."
Pediatrician Jin hopes that her pharmacy work on anti-virus mediations and how they work in different people, pharmacodynamics, will also be useful in treating children. "This is especially important in children to get the correct dosages for safe and effective treatments." ý
"I was very lucky," says Jin. "When I was a second year [PhD]) student, I was looking for a research project in pharmacodynamics." She applied a mathematical method called Bayesian statistics to simplify the pharmacodynamic relationship between the drug and the 400 patients in the 2006 study, a method taught to her by Michael Fossler, PharmD, PhD, an alum of the School of Pharmacy now with drug maker GlaxoSmithKline.
"Runyan pulled a very nice story together with direct clinical applications. What we are faced with now [in drug development] is studies that are now so very expensive, says Fossler. "Bayesian methodology helps us cut our losses saves some patients from taking drugs that don't work sometimes."
Jin's research poster, "Population Pharmacodynamic Model in Patients with Chronic Hepatitis C Virus Genotype 1," won the 2010 Wayne A. Colburn Memorial Award at the annual ACCP. She has accepted a position at the U.S. Food and Drug Administration. ýIn her new career, she says, "I want to be an expert in this area of quantitative clinical pharmacology."
Posting Date: 12/06/2010
Contact Name: Steve Berberich
Contact Phone: 410-706-0023
Contact Email: sberb001@umaryland.edu
Source
New HCV Drugs at AASLD
From NATAP:
from Jules: below are links to key data reports on the many new oral HCV drugs at various stages of development and there are numerous drugs in development from the various new classes which include protease inhibitors, polymerase inhibitors (nucleosides, nucletides, various types of NNRTIs), NS5A inhibitors, and if pegIFN must be used there is peg-lambda IFN. Of course Vertex & Merck presented phase 3 data results at AASLD but also there were many data updates from the other drugs in earlier stages of development. Response-Gulded Therapy (RGT) will be the new mantra in HCV therapy once the 1st oral drugs hit the market and this means patients & clinicians must bring in patients at time-checks early after starting therapy to see if viral load is undetectable or not; these time-point checks to decide if a patient should continue or stop therapy, and I see this concept continuing to be refined over time, we will move towards 16 week or even 12 week total therapy as we improve regimens to include 3 or 4 orals with or without peg/rbv.
In the Vertex large phase 3 ADVANCE Study of the HCV protease inhibitor telaprevir, which included over 1000 genotype 1 treatment-naïve patients presented at AASLD, study patients who received telaprevir plus Pegasys/rbv had a significantly higher SVR (Sustained Viral Response, cure): 75% vs 44% of patients who received just Pegasys/rbv. These numbers included patients who had either 24 or 48 weeks total therapy. Patients, both blacks and whites, who had undetectable viral load at the early time-checkpoints, weeks 4 and 12, about 90% achieved SVR. In the Merck SPRINT-2 phase 3 Study of boceprevir presented at AASLD, over 1000 genotype 1 treatment-naïve patients participated, patients received either boceprevir plus Pegintron/rbv or just Pegintron/rbv, with 67-71% of non-Blacks achieving a SVR (cure) vs 40% for study patients who received Pegintron/rbv, and 42-53% of Blacks achieving cure vs 23% who received only Pegintron/rbv, these results were for patients who had a total duration of therapy of 24 or 48 weeks. An undetectable viral load at the early time-check-points in this study, weeks 8 and 24, also achieved high rates of SVR, cure.
How much affect on outcome (SVR) will IL28B and the genotype 1a vs 1b have once oral therapy are added to peg/RBV remains to be seen, but certainly as you add more than 1 oral to peg/rbv their impact will diminish & eventually be minimal or disappear altogether. BMS presented the early data, the 1st data in null-responders receiving 2 orals only or 2 orals plus peg/rbv, the results from this study were highly anticipated and begin to give us important information on treatment without peg/rbv but also in treating null-responders, as all 10 null-responders had undetectable viral load after 12 weeks with all 4 drugs. After initial monotherapy ABT-450 looked very potent, perhaps a 6-log drug. The nucleoside polymerase R7128 shows good 12 week data underscoring the importance that this drug or class appears not be associated with resistance developing easily & early, and this is important. Pharmasset presented data on 2 nucleotides with potency & also the possibility of not be associated with resistance developing. The BMS NS5A is potent. Some drugs are administered once daily, some three times daily, the side effects profiles differ between the drugs, and success with therapy will require management of side effects, like anemia. The data from both Vertex & Merck show that African-Americans can have response rates as high as whites if they have early RGT results, that is if the viral load is undetectable at the early-time-points the cure or SVR rates are equally high for blacks, latinos and whites.
Continue Reading ...
from Jules: below are links to key data reports on the many new oral HCV drugs at various stages of development and there are numerous drugs in development from the various new classes which include protease inhibitors, polymerase inhibitors (nucleosides, nucletides, various types of NNRTIs), NS5A inhibitors, and if pegIFN must be used there is peg-lambda IFN. Of course Vertex & Merck presented phase 3 data results at AASLD but also there were many data updates from the other drugs in earlier stages of development. Response-Gulded Therapy (RGT) will be the new mantra in HCV therapy once the 1st oral drugs hit the market and this means patients & clinicians must bring in patients at time-checks early after starting therapy to see if viral load is undetectable or not; these time-point checks to decide if a patient should continue or stop therapy, and I see this concept continuing to be refined over time, we will move towards 16 week or even 12 week total therapy as we improve regimens to include 3 or 4 orals with or without peg/rbv.
In the Vertex large phase 3 ADVANCE Study of the HCV protease inhibitor telaprevir, which included over 1000 genotype 1 treatment-naïve patients presented at AASLD, study patients who received telaprevir plus Pegasys/rbv had a significantly higher SVR (Sustained Viral Response, cure): 75% vs 44% of patients who received just Pegasys/rbv. These numbers included patients who had either 24 or 48 weeks total therapy. Patients, both blacks and whites, who had undetectable viral load at the early time-checkpoints, weeks 4 and 12, about 90% achieved SVR. In the Merck SPRINT-2 phase 3 Study of boceprevir presented at AASLD, over 1000 genotype 1 treatment-naïve patients participated, patients received either boceprevir plus Pegintron/rbv or just Pegintron/rbv, with 67-71% of non-Blacks achieving a SVR (cure) vs 40% for study patients who received Pegintron/rbv, and 42-53% of Blacks achieving cure vs 23% who received only Pegintron/rbv, these results were for patients who had a total duration of therapy of 24 or 48 weeks. An undetectable viral load at the early time-check-points in this study, weeks 8 and 24, also achieved high rates of SVR, cure.
How much affect on outcome (SVR) will IL28B and the genotype 1a vs 1b have once oral therapy are added to peg/RBV remains to be seen, but certainly as you add more than 1 oral to peg/rbv their impact will diminish & eventually be minimal or disappear altogether. BMS presented the early data, the 1st data in null-responders receiving 2 orals only or 2 orals plus peg/rbv, the results from this study were highly anticipated and begin to give us important information on treatment without peg/rbv but also in treating null-responders, as all 10 null-responders had undetectable viral load after 12 weeks with all 4 drugs. After initial monotherapy ABT-450 looked very potent, perhaps a 6-log drug. The nucleoside polymerase R7128 shows good 12 week data underscoring the importance that this drug or class appears not be associated with resistance developing easily & early, and this is important. Pharmasset presented data on 2 nucleotides with potency & also the possibility of not be associated with resistance developing. The BMS NS5A is potent. Some drugs are administered once daily, some three times daily, the side effects profiles differ between the drugs, and success with therapy will require management of side effects, like anemia. The data from both Vertex & Merck show that African-Americans can have response rates as high as whites if they have early RGT results, that is if the viral load is undetectable at the early-time-points the cure or SVR rates are equally high for blacks, latinos and whites.
Continue Reading ...
Irreversible inhibition of a protease central to hepatitis C infection; New HCV Protease AVL-192: Study
Download the PDF here
Mon, Nov 29, 2010
A new study has demonstrated that irreversible covalent inhibition can increase selectivity, potency and duration of action, broadens applications for targeted covalent drugs to the protease gene family.
Avila Therapeutics Inc., a biotechnology company developing novel targeted covalent drugs, has demonstrated the first-ever selective irreversible inhibition of a viral protease using a targeted covalent drug.
Avila has used its proprietary Avilomics platform to design covalent irreversible protease inhibitors that are highly selective, potent and with superior duration of action as compared to conventional protease inhibitors.
The research has demonstrated that covalent drugs can be designed and targeted to irreversibly and covalently bond to molecular domains specific to proteases.
"This research elevates covalent drug design to a fundamentally new level. By creating extremely selective protease inhibitors with their platform, Avila is showing the remarkable therapeutic potential of irreversible covalent drugs to address a broad spectrum of drug targets," said Simon Campbell , a renowned scientist.
"This approach can make a difference to patients living with HCV infection, and we expect to make an impact in other important areas such as cancer and inflammatory disease," said said Juswinder Singh, co-author of the paper.
In order to maximize selectivity and minimize off-target effects, the irreversible covalent inhibitors of HCV protease were designed to covalently target a unique structure in the HCV protease not found in human proteases. Key findings include:
A representative irreversible covalent inhibitor designed, by Avila, was shown to inhibit the HCV protease (also known as "NS3") in cells at a concentration of 6 nM.
Specific covalent bond formation between the drug and target protease was demonstrated through use of mass spectrometry and also x-ray crystallography.
The findings were published in the journal Nature Chemical Biology. (ANI)
-------------------------------------------
Avila Presents New Data on its Novel, Orally-Available Targeted Covalent Drug, AVL-192
Covalent Inhibition Achieves Superior Potency Against Drug-Resistant HCV Mutants
BOSTON and WALTHAM, MA - November 2, 2010 - Avila TherapeuticsTM, Inc., a biotechnology company developing novel targeted covalent drugs, presented results today of preclinical studies that demonstrate its orally-available targeted covalent drug candidate, AVL-192, achieves superior potency against drug-resistant mutations of the Hepatitis C Virus (HCV). These new data were presented today at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) international meeting in Boston, Massachusetts.
HCV protease (also known as NS3) is a promising target of intervention for the treatment of hepatitis C infection. However, medicines currently in late stages of clinical development are vulnerable to drug- resistant mutations. AVL-192 is a novel, orally available compound that can rapidly and completely silence the HCV protease through highly selective, irreversible covalent bonding to the target protein. Preclinical data have demonstrated that AVL-192 achieves very high potency and selectivity for NS3 and also potently and effectively inhibits the drug-resistant mutations observed clinically.
Avila's covalent approach to silencing the NS3 protein has resulted in a product candidate with a potential best-in-class profile due to the ability to retain potency against clinically-arising resistance mutations, and potential breadth of activity across HCV genotypes with anticipated once-per-day dosing.
In a poster presentation at the meeting, entitled, "Second Generation of Covalent Irreversible Inhibitors Have Superior Potency Across Genotypes and Drug Resistant Mutants," data were presented from preclinical studies that evaluated the efficacy of AVL-192 in biochemical and cell culture studies. Highlights of the data demonstrate:
· AVL-192 has a time-dependent mode of action that delivers potent and rapid inhibition of WT NS3/4A and retains high potency against drug-resistant mutant NS3/4A proteases;
· AVL-192 is able to inhibit the protease long after the compound is removed, offering the benefit of less frequent dosing;
· AVL-192 as monotherapy can be curative in the replicon clearance assay;
· AVL-192 is highly selective and spares host proteases; and
· AVL-192 has high plasma exposure following oral administration in rats and dogs.
"These new data reinforce our belief that our targeted covalent drug candidate AVL-192 has the potential to be a best-in-class, pan-genotype HCV therapeutic due to its unique mechanism of action," said Juswinder Singh, Ph.D., Avila's Founder and Chief Scientific Officer.
About Avila TherapeuticsTM, Inc.
Avila focuses on design and development of targeted covalent drugs to achieve best-in-class outcomes that cannot be achieved through traditional chemistries. This approach is called "protein silencing". The company's product pipeline has been built using its proprietary AvilomicsTM platform and is currently focused on viral infection, cancer and autoimmune disease. Avila is funded by leading venture capital firms: Abingworth, Advent Venture Partners, Atlas Venture, Novartis Option Fund, and Polaris Venture Partners. For additional information, please visit http://www.avilatx.com/
------------------------------------
Selective irreversible inhibition of a protease by targeting a noncatalytic cysteine
Brief Communication
Nature Chemical Biology, 28 November 2010
Margit Hagel, Deqiang Niu, Thia St Martin, Michael P Sheets, Lixin Qiao, Hugues Bernard, Russell M Karp, Zhendong Zhu, Matthew T Labenski, Prasoon Chaturvedi, Mariana Nacht, William F Westlin, Russell C Petter & Juswinder Singh 1Avila Therapeutics, Inc., Waltham, Massachusetts, USA. 2Millenium: The Takeda Oncology Company, Cambridge, Massachusetts, USA. *e-mail: jsingh@avilatx.com
Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the important therapeutic target HCV protease, which has broad implications for the design of other selective protease inhibitors.
The fundamental challenge in designing protease inhibitors is to achieve potency without sacrificing selectivity. This problem arises frequently because the typical protease inhibitor achieves potency through covalent interactions with the catalytic apparatus, yet such pharmacophores also confer affinity for other proteases in the same mechanistic family1. This is a significant challenge for protease drug design, because over 500 proteases exist in the human genome. Achieving selectivity while targeting the catalytic machinery is thus particularly difficult2.
Covalent irreversible drugs that form persistent, nonlabile covalent bonds yield unique therapeutic benefits including rapid onset of inhibition, greater potency, longer duration of drug action and potent and persistent activity against mutations that would otherwise lead to drug resistance3. There are many examples of drugs that work through irreversible covalent bonding that have proven to be safe and successful therapies for a wide variety of indications4. Despite their prevalence, to date covalent drugs have largely been discovered serendipitously, and general methods to facilitate their deliberate discovery and design have yet to be described.
HCV NS3/4A viral protease (HCVP) activity is essential for viral replication5 and has been recently validated as a clinical target6, 7, 8, 9, 10, 11, 12, 13, 14, 15. Protease inhibitors such as telaprevir exemplify the challenges of covalent targeting of the catalytic binding site; upon binding to HCVP, the α-ketoamide forms a reversible covalent linkage with the catalytic serine that is conserved within proteases6, 10. Indeed, telaprevir inhibits some host serine proteases at concentrations that may be achieved in a therapeutic setting14, 16.
The aim of this study was to achieve potent inhibition of viral proteases through covalent bond formation without compromising selectivity of the inhibitors. Our new design strategy used structural bioinformatics to create a structural alignment between viral proteases and host proteases to identify nucleophilic amino acids in the binding site that were unique to the viral proteases. Our structural alignment revealed that current covalent inhibitors such as telaprevir target a catalytic residue that is common across the protease family and therefore susceptible to selectivity issues. In contrast, we identified a nucleophilic amino acid, cysteine 159 (Cys159), in the substrate-binding site that could be targeted for covalent bonding. Importantly, Cys159 is strictly conserved across all 919 HCV NS3 sequences in a database of all known HCVP sequences, including all HCVP subtypes and genotypes sequenced to date (Supplementary Fig. 1), allowing design of a pan-genotype HCVP inhibitor. Although HCVP shows structural similarity with host proteases, Cys159 is structurally unique to HCVP and therefore was an ideal target for achieving selectivity between HCVP and host proteases.
Structure-based drug design was used to create a peptidomimetic inhibitor (1) (Fig. 1a), designed to form canonical reversible interactions with the S2-S1-S1' pockets of HCVP similar to those observed with other reversible peptidomimetic inhibitors12, 17, 18. Further molecular modeling was used to evaluate structures that positioned a low-reactivity Michael acceptor close enough to Cys159 to form a covalent bond (2) (Fig. 1a). 2 was prepared by installation of an acrylamide using a simple glycine linker. Linking the electrophilic acrylamide via a D-alanine linker provides the more conformationally constrained inhibitor 3 (see Supplementary Methods). Our expectation was that propanamide 4, the reversible congener of 3, would bind weakly to the HCVP, as potent inhibitors reported to date typically possess functionality that forms extensive nonbonding interactions with the S3 and S4 pockets.
As predicted, 1 and 4 showed weak inhibition of the wild-type HCVP (half-maximal inhibitory concentration (IC50) of 1 = 2,458 nM, 4 IC50 = 1,147 nM) whereas 2 and 3 were very potent inhibitors (2 IC50 = 4 nM, 3 IC50 = 2 nM) (Supplementary Table 1). To further support the importance of covalency in conferring activity of 3, we tested the activity of 3 against a mutant NS3 protein in which the target cysteine is changed to a serine (C159S). The C159S protease is comparable in enzymatic activity to wild-type protease (Supplementary Fig. 2); however, mutation of the amino acid required for bond formation results in a sharp decrease in potency of the covalent inhibitor (IC50 = 1,782 nM; Supplementary Table 1). In further support of the mechanism, 3 shifted the mass of HCVP by 685 Da, consistent with the formation of a covalent complex between 3 and the protease, but was unable to covalently bond to HCVP with the C159S mutation (Supplementary Fig. 3). We also confirmed with X-ray crystallography that 3 was covalently linked to the side chain of Cys159 (Fig. 1b, Supplementary Fig. 4 and Supplementary Table 2).
The selectivity of 3 was further demonstrated using a panel of host proteases. As expected, 3 showed no notable inhibition of host proteases, whereas telaprevir inhibited multiple host proteases, when each inhibitor was tested at 10 µM (Fig. 2a). Moreover, 3 showed no significant nonspecific reactivity toward glutathione (Supplementary Fig. 5). These data highlight the value of covalent bonding to a noncatalytic residue as a means of achieving HCVP selectivity while minimizing the potential for nonspecific reactivity with other thiols such as glutathione.
Huh-7 wild-type (1b) replicon cells were used to demonstrate that 3 can potently inhibit HCVP activity in cells, leading to decreased replication of viral RNA. Luciferase activity was greatly reduced in cells treated with 3 (half-maximal effective concentration (EC50) = 6 nM) (Fig. 2b and Supplementary Table 1). In contrast, the reversible congener, 4, did not inhibit luciferase activity (EC50 > 3000 nM), demonstrating that covalent bonding greatly enhances potency for this class of compounds. Importantly, 3 does not inhibit proliferation of Huh-7 wild-type replicon cells, nor does it affect growth of other cell lines tested (Supplementary Table 3), strongly suggesting that replicon inhibition is because of specific viral protease inhibition. 3 was inactive in the C159S mutant replicon cells (EC50 > 3,000 nM) and, as expected, the activity of 4 and telaprevir were unchanged by the C159S mutation, as they are not dependent on the cysteine for their mechanism of action (EC50 > 3,000 nM, EC50 = 623nM, respectively) (Fig. 2b and Supplementary Table 1). Of note, the C159S mutant replicon cells showed fitness similar to that of wild-type replicon cells (Supplementary Fig. 6).
Numerous NS3 mutations have been reported that render HCVP resistant to the current protease inhibitors. Thus, activity against drug-resistant clinical mutations is important for effective antiviral therapeutics19. 3 was able to inhibit and bond to HCVP proteins of clinically relevant NS3 variants (Supplementary Table 1 and Supplementary Fig. 7). Furthermore, the selectivity conferred by Cys159 also allows for binding and inhibition of HCVP from multiple genotypes (Supplementary Table 1 and Supplementary Fig. 8), suggesting that this approach will lead to potent and selective pan-genotype HCVP inhibitors.
To demonstrate direct inhibition of HCVP activity using our irreversible covalent drug, we developed an assay using the internal self-cleavage activity of HCVP20 (Supplementary Fig. 9). We confirmed the necessity of HCVP activity in the proteolytic cleavage of NS3/4A by expressing wild-type HCVP or a protease-dead mutant, NS3/4A-S139A (Supplementary Fig. 10). This autoproteolytic cleavage activity was used to directly measure HCVP activity in replicon cells in the presence and absence of the covalent inhibitor. When HCVP activity is inhibited, self-cleavage is abolished, leaving only the full-length holoenzyme. 3 demonstrated inhibition of HCVP internal self-cleavage activity, and the inhibition was sustained for 8-24 h after compound removal. In contrast, HCVP self-cleavage activity had completely returned by 30 min after removal of telaprevir (Supplementary Fig. 11a,b).
A unique advantage of an irreversible covalent molecule is that it allows the investigation of target occupancy in a time- and dose-dependent manner. We designed a biotinylated irreversible covalent probe that bonds to NS3/4A protease (Supplementary Scheme 4), enabling the quantitative analysis of NS3 occupancy with 3, and found that inhibitory activity and NS3-occupancy closely correlate (Fig. 3a,b). Following treatment with 3, there is little or no free NS3 available to bind to the biotinylated probe for at least 8 h after 3 has been removed (Fig. 3b). This indicates that essentially all of the NS3 protein was bound by 3, and newly synthesized protein is being detected at 8-24 h. Return of self-cleavage activity is concomitant with the detection of newly synthesized protease. The biotinylated covalent probe compound is also an indicator of the selectivity of 3, as the two compounds share structural similarities and electrophiles. Only the full-length NS3 protein and NS3/4A cleavage products were detected as having been labeled by the biotinylated probe, indicating that it is specific for NS3/4A under these conditions (Fig. 3c).
A targeted covalent design approach21 has been applied to kinases, several of which are currently in clinical testing with encouraging evidence of efficacy and safety22. This study describes the first successful example of applying targeted covalent inhibition to the protease family. Our data indicate that the electrophile on 3 must be brought into close proximity to a nucleophilic thiol via specific affinity-driven binding to enable covalent bond formation between the small molecule and the targeted HCVP . This strategy enables us to selectively inhibit HCVP and minimize the potential for toxicity through reactivity with off-target proteins. 3 is an excellent prototype HCVP inhibitor but has a number of important limitations as a drug candidate; these properties have been optimized in our current development compounds, AVL-181 and AVL-192, which have excellent pharmacokinetics and bind potently to wild-type HCVP as well as to multiple other genotypes and mutant forms of HCVP, including C159S, but only covalently modify when Cys159 is present23. The successful design of a highly selective targeted covalent inhibitor of HCVP suggests that this approach can be broadly applied to other protease family members and indeed to a wide range of protein families.
Source
Mon, Nov 29, 2010
A new study has demonstrated that irreversible covalent inhibition can increase selectivity, potency and duration of action, broadens applications for targeted covalent drugs to the protease gene family.
Avila Therapeutics Inc., a biotechnology company developing novel targeted covalent drugs, has demonstrated the first-ever selective irreversible inhibition of a viral protease using a targeted covalent drug.
Avila has used its proprietary Avilomics platform to design covalent irreversible protease inhibitors that are highly selective, potent and with superior duration of action as compared to conventional protease inhibitors.
The research has demonstrated that covalent drugs can be designed and targeted to irreversibly and covalently bond to molecular domains specific to proteases.
"This research elevates covalent drug design to a fundamentally new level. By creating extremely selective protease inhibitors with their platform, Avila is showing the remarkable therapeutic potential of irreversible covalent drugs to address a broad spectrum of drug targets," said Simon Campbell , a renowned scientist.
"This approach can make a difference to patients living with HCV infection, and we expect to make an impact in other important areas such as cancer and inflammatory disease," said said Juswinder Singh, co-author of the paper.
In order to maximize selectivity and minimize off-target effects, the irreversible covalent inhibitors of HCV protease were designed to covalently target a unique structure in the HCV protease not found in human proteases. Key findings include:
A representative irreversible covalent inhibitor designed, by Avila, was shown to inhibit the HCV protease (also known as "NS3") in cells at a concentration of 6 nM.
Specific covalent bond formation between the drug and target protease was demonstrated through use of mass spectrometry and also x-ray crystallography.
The findings were published in the journal Nature Chemical Biology. (ANI)
-------------------------------------------
Avila Presents New Data on its Novel, Orally-Available Targeted Covalent Drug, AVL-192
Covalent Inhibition Achieves Superior Potency Against Drug-Resistant HCV Mutants
BOSTON and WALTHAM, MA - November 2, 2010 - Avila TherapeuticsTM, Inc., a biotechnology company developing novel targeted covalent drugs, presented results today of preclinical studies that demonstrate its orally-available targeted covalent drug candidate, AVL-192, achieves superior potency against drug-resistant mutations of the Hepatitis C Virus (HCV). These new data were presented today at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) international meeting in Boston, Massachusetts.
HCV protease (also known as NS3) is a promising target of intervention for the treatment of hepatitis C infection. However, medicines currently in late stages of clinical development are vulnerable to drug- resistant mutations. AVL-192 is a novel, orally available compound that can rapidly and completely silence the HCV protease through highly selective, irreversible covalent bonding to the target protein. Preclinical data have demonstrated that AVL-192 achieves very high potency and selectivity for NS3 and also potently and effectively inhibits the drug-resistant mutations observed clinically.
Avila's covalent approach to silencing the NS3 protein has resulted in a product candidate with a potential best-in-class profile due to the ability to retain potency against clinically-arising resistance mutations, and potential breadth of activity across HCV genotypes with anticipated once-per-day dosing.
In a poster presentation at the meeting, entitled, "Second Generation of Covalent Irreversible Inhibitors Have Superior Potency Across Genotypes and Drug Resistant Mutants," data were presented from preclinical studies that evaluated the efficacy of AVL-192 in biochemical and cell culture studies. Highlights of the data demonstrate:
· AVL-192 has a time-dependent mode of action that delivers potent and rapid inhibition of WT NS3/4A and retains high potency against drug-resistant mutant NS3/4A proteases;
· AVL-192 is able to inhibit the protease long after the compound is removed, offering the benefit of less frequent dosing;
· AVL-192 as monotherapy can be curative in the replicon clearance assay;
· AVL-192 is highly selective and spares host proteases; and
· AVL-192 has high plasma exposure following oral administration in rats and dogs.
"These new data reinforce our belief that our targeted covalent drug candidate AVL-192 has the potential to be a best-in-class, pan-genotype HCV therapeutic due to its unique mechanism of action," said Juswinder Singh, Ph.D., Avila's Founder and Chief Scientific Officer.
About Avila TherapeuticsTM, Inc.
Avila focuses on design and development of targeted covalent drugs to achieve best-in-class outcomes that cannot be achieved through traditional chemistries. This approach is called "protein silencing". The company's product pipeline has been built using its proprietary AvilomicsTM platform and is currently focused on viral infection, cancer and autoimmune disease. Avila is funded by leading venture capital firms: Abingworth, Advent Venture Partners, Atlas Venture, Novartis Option Fund, and Polaris Venture Partners. For additional information, please visit http://www.avilatx.com/
------------------------------------
Selective irreversible inhibition of a protease by targeting a noncatalytic cysteine
Brief Communication
Nature Chemical Biology, 28 November 2010
Margit Hagel, Deqiang Niu, Thia St Martin, Michael P Sheets, Lixin Qiao, Hugues Bernard, Russell M Karp, Zhendong Zhu, Matthew T Labenski, Prasoon Chaturvedi, Mariana Nacht, William F Westlin, Russell C Petter & Juswinder Singh 1Avila Therapeutics, Inc., Waltham, Massachusetts, USA. 2Millenium: The Takeda Oncology Company, Cambridge, Massachusetts, USA. *e-mail: jsingh@avilatx.com
Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the important therapeutic target HCV protease, which has broad implications for the design of other selective protease inhibitors.
The fundamental challenge in designing protease inhibitors is to achieve potency without sacrificing selectivity. This problem arises frequently because the typical protease inhibitor achieves potency through covalent interactions with the catalytic apparatus, yet such pharmacophores also confer affinity for other proteases in the same mechanistic family1. This is a significant challenge for protease drug design, because over 500 proteases exist in the human genome. Achieving selectivity while targeting the catalytic machinery is thus particularly difficult2.
Covalent irreversible drugs that form persistent, nonlabile covalent bonds yield unique therapeutic benefits including rapid onset of inhibition, greater potency, longer duration of drug action and potent and persistent activity against mutations that would otherwise lead to drug resistance3. There are many examples of drugs that work through irreversible covalent bonding that have proven to be safe and successful therapies for a wide variety of indications4. Despite their prevalence, to date covalent drugs have largely been discovered serendipitously, and general methods to facilitate their deliberate discovery and design have yet to be described.
HCV NS3/4A viral protease (HCVP) activity is essential for viral replication5 and has been recently validated as a clinical target6, 7, 8, 9, 10, 11, 12, 13, 14, 15. Protease inhibitors such as telaprevir exemplify the challenges of covalent targeting of the catalytic binding site; upon binding to HCVP, the α-ketoamide forms a reversible covalent linkage with the catalytic serine that is conserved within proteases6, 10. Indeed, telaprevir inhibits some host serine proteases at concentrations that may be achieved in a therapeutic setting14, 16.
The aim of this study was to achieve potent inhibition of viral proteases through covalent bond formation without compromising selectivity of the inhibitors. Our new design strategy used structural bioinformatics to create a structural alignment between viral proteases and host proteases to identify nucleophilic amino acids in the binding site that were unique to the viral proteases. Our structural alignment revealed that current covalent inhibitors such as telaprevir target a catalytic residue that is common across the protease family and therefore susceptible to selectivity issues. In contrast, we identified a nucleophilic amino acid, cysteine 159 (Cys159), in the substrate-binding site that could be targeted for covalent bonding. Importantly, Cys159 is strictly conserved across all 919 HCV NS3 sequences in a database of all known HCVP sequences, including all HCVP subtypes and genotypes sequenced to date (Supplementary Fig. 1), allowing design of a pan-genotype HCVP inhibitor. Although HCVP shows structural similarity with host proteases, Cys159 is structurally unique to HCVP and therefore was an ideal target for achieving selectivity between HCVP and host proteases.
Structure-based drug design was used to create a peptidomimetic inhibitor (1) (Fig. 1a), designed to form canonical reversible interactions with the S2-S1-S1' pockets of HCVP similar to those observed with other reversible peptidomimetic inhibitors12, 17, 18. Further molecular modeling was used to evaluate structures that positioned a low-reactivity Michael acceptor close enough to Cys159 to form a covalent bond (2) (Fig. 1a). 2 was prepared by installation of an acrylamide using a simple glycine linker. Linking the electrophilic acrylamide via a D-alanine linker provides the more conformationally constrained inhibitor 3 (see Supplementary Methods). Our expectation was that propanamide 4, the reversible congener of 3, would bind weakly to the HCVP, as potent inhibitors reported to date typically possess functionality that forms extensive nonbonding interactions with the S3 and S4 pockets.
As predicted, 1 and 4 showed weak inhibition of the wild-type HCVP (half-maximal inhibitory concentration (IC50) of 1 = 2,458 nM, 4 IC50 = 1,147 nM) whereas 2 and 3 were very potent inhibitors (2 IC50 = 4 nM, 3 IC50 = 2 nM) (Supplementary Table 1). To further support the importance of covalency in conferring activity of 3, we tested the activity of 3 against a mutant NS3 protein in which the target cysteine is changed to a serine (C159S). The C159S protease is comparable in enzymatic activity to wild-type protease (Supplementary Fig. 2); however, mutation of the amino acid required for bond formation results in a sharp decrease in potency of the covalent inhibitor (IC50 = 1,782 nM; Supplementary Table 1). In further support of the mechanism, 3 shifted the mass of HCVP by 685 Da, consistent with the formation of a covalent complex between 3 and the protease, but was unable to covalently bond to HCVP with the C159S mutation (Supplementary Fig. 3). We also confirmed with X-ray crystallography that 3 was covalently linked to the side chain of Cys159 (Fig. 1b, Supplementary Fig. 4 and Supplementary Table 2).
The selectivity of 3 was further demonstrated using a panel of host proteases. As expected, 3 showed no notable inhibition of host proteases, whereas telaprevir inhibited multiple host proteases, when each inhibitor was tested at 10 µM (Fig. 2a). Moreover, 3 showed no significant nonspecific reactivity toward glutathione (Supplementary Fig. 5). These data highlight the value of covalent bonding to a noncatalytic residue as a means of achieving HCVP selectivity while minimizing the potential for nonspecific reactivity with other thiols such as glutathione.
Huh-7 wild-type (1b) replicon cells were used to demonstrate that 3 can potently inhibit HCVP activity in cells, leading to decreased replication of viral RNA. Luciferase activity was greatly reduced in cells treated with 3 (half-maximal effective concentration (EC50) = 6 nM) (Fig. 2b and Supplementary Table 1). In contrast, the reversible congener, 4, did not inhibit luciferase activity (EC50 > 3000 nM), demonstrating that covalent bonding greatly enhances potency for this class of compounds. Importantly, 3 does not inhibit proliferation of Huh-7 wild-type replicon cells, nor does it affect growth of other cell lines tested (Supplementary Table 3), strongly suggesting that replicon inhibition is because of specific viral protease inhibition. 3 was inactive in the C159S mutant replicon cells (EC50 > 3,000 nM) and, as expected, the activity of 4 and telaprevir were unchanged by the C159S mutation, as they are not dependent on the cysteine for their mechanism of action (EC50 > 3,000 nM, EC50 = 623nM, respectively) (Fig. 2b and Supplementary Table 1). Of note, the C159S mutant replicon cells showed fitness similar to that of wild-type replicon cells (Supplementary Fig. 6).
Numerous NS3 mutations have been reported that render HCVP resistant to the current protease inhibitors. Thus, activity against drug-resistant clinical mutations is important for effective antiviral therapeutics19. 3 was able to inhibit and bond to HCVP proteins of clinically relevant NS3 variants (Supplementary Table 1 and Supplementary Fig. 7). Furthermore, the selectivity conferred by Cys159 also allows for binding and inhibition of HCVP from multiple genotypes (Supplementary Table 1 and Supplementary Fig. 8), suggesting that this approach will lead to potent and selective pan-genotype HCVP inhibitors.
To demonstrate direct inhibition of HCVP activity using our irreversible covalent drug, we developed an assay using the internal self-cleavage activity of HCVP20 (Supplementary Fig. 9). We confirmed the necessity of HCVP activity in the proteolytic cleavage of NS3/4A by expressing wild-type HCVP or a protease-dead mutant, NS3/4A-S139A (Supplementary Fig. 10). This autoproteolytic cleavage activity was used to directly measure HCVP activity in replicon cells in the presence and absence of the covalent inhibitor. When HCVP activity is inhibited, self-cleavage is abolished, leaving only the full-length holoenzyme. 3 demonstrated inhibition of HCVP internal self-cleavage activity, and the inhibition was sustained for 8-24 h after compound removal. In contrast, HCVP self-cleavage activity had completely returned by 30 min after removal of telaprevir (Supplementary Fig. 11a,b).
A unique advantage of an irreversible covalent molecule is that it allows the investigation of target occupancy in a time- and dose-dependent manner. We designed a biotinylated irreversible covalent probe that bonds to NS3/4A protease (Supplementary Scheme 4), enabling the quantitative analysis of NS3 occupancy with 3, and found that inhibitory activity and NS3-occupancy closely correlate (Fig. 3a,b). Following treatment with 3, there is little or no free NS3 available to bind to the biotinylated probe for at least 8 h after 3 has been removed (Fig. 3b). This indicates that essentially all of the NS3 protein was bound by 3, and newly synthesized protein is being detected at 8-24 h. Return of self-cleavage activity is concomitant with the detection of newly synthesized protease. The biotinylated covalent probe compound is also an indicator of the selectivity of 3, as the two compounds share structural similarities and electrophiles. Only the full-length NS3 protein and NS3/4A cleavage products were detected as having been labeled by the biotinylated probe, indicating that it is specific for NS3/4A under these conditions (Fig. 3c).
A targeted covalent design approach21 has been applied to kinases, several of which are currently in clinical testing with encouraging evidence of efficacy and safety22. This study describes the first successful example of applying targeted covalent inhibition to the protease family. Our data indicate that the electrophile on 3 must be brought into close proximity to a nucleophilic thiol via specific affinity-driven binding to enable covalent bond formation between the small molecule and the targeted HCVP . This strategy enables us to selectively inhibit HCVP and minimize the potential for toxicity through reactivity with off-target proteins. 3 is an excellent prototype HCVP inhibitor but has a number of important limitations as a drug candidate; these properties have been optimized in our current development compounds, AVL-181 and AVL-192, which have excellent pharmacokinetics and bind potently to wild-type HCVP as well as to multiple other genotypes and mutant forms of HCVP, including C159S, but only covalently modify when Cys159 is present23. The successful design of a highly selective targeted covalent inhibitor of HCVP suggests that this approach can be broadly applied to other protease family members and indeed to a wide range of protein families.
Source
EHSI: Celulas Genetica Eyes China for Testing New Stem Cell Procedure
Posted on: Mon, 06 Dec 2010 09:15:00 EST
HOUSTON, Dec 06, 2010 (BUSINESS WIRE) --
Emerging Healthcare Solutions, Inc. (PinkSheets: EHSI
PowerRating) announced today that its newly acquired biotechnology division Celulas Genetica seeks to contract a Chinese firm to test a new stem-cell treatment for liver disease.
Last week, Celulas Genetica purchased a license to develop and market the revolutionary Rutherford Procedure, a groundbreaking organ regeneration treatment intended to utilize proton-beam technology to destroy diseased organ tissue for regeneration using adult stem cells. Celulas Genetica licensed the procedure from a Chinese firm, BBFITCL, and views the emerging Asian superpower as the ideal locale to test and develop its potential new treatment for liver disease.
"China has pushed hard for years to become a world leader in the fields of stem cell research and regenerative medicine," said EHSI President and CEO Cindy Morrissey. "The scientific and medical resources needed to test the Rutherford Procedure are both abundant and affordable in China, and Celulas Genetica is currently exploring the possibility of working with a proton therapy facility there to develop this new treatment for liver disease."
Morrissey said she plans to travel to China soon to meet with Chinese stem-cell researchers and potentially help open a Celulas Genetica business office there. Extending its reach into the R&D hotbed of China would build on EHSI's rapidly expanding global footprint--Celulas Genetica is headquartered in Panama, and Morrissey opened EHSI business offices in Poland and Germany last month.
"Liver disease is a truly global affliction," Morrissey said. "It requires a global solution. Working together with scientists and doctors in Panama, China and elsewhere, we believe we can develop the Rutherford Procedure into an effective, minimally invasive treatment for liver disease that will not require transplants."
Last week, EHSI announced its acquisition of a Rotary Cell Culture System, or bioreactor, developed using revolutionary NASA research in the field of microgravity. Cell cultures, including stem cells, grown inside the bioreactor look and function much closer to human cells grown within the body than cell cultures grown in Petri dishes. During the Rutherford Procedure, proton therapy will be used to destroy scar-tissue cells in the liver using high-energy proton beams, a non-invasive treatment proven to minimize damage to healthy tissues and to eliminate the side effects (including nausea) of traditional radiation therapy.
As the scar tissue is systematically destroyed by the proton therapy, a catheter will deliver the patient's own cultured stem cells directly to his or her liver through the bloodstream. As more and more diseased tissue is destroyed, these cultured stem cells could help regenerate the patient's damaged, cirrhotic liver into a healthy, functioning organ once more.
EHSI invests in technology developed to compete in the stem-cell research industry alongside Dendreon Corp. (NASDAQ: DNDN), Gilead Sciences (NASDAQ: GILD), Celgene Corp. (NASDAQ: CELG) and Biogen Idec Inc. (NASDAQ: BIIB).
About Emerging Healthcare Solutions, Inc.
Emerging Healthcare Solutions, Inc. invests in and participates in the profits of emerging breakthrough medical technologies. The Company believes the secret of leveraging future value for its shareholders is the proper timing of its investment in promising new medical technologies. EHSI aims to capture future profits of promising new medical technologies by investing in these technologies at the inflection point of product development. We believe this model will deliver long-term positive results for our investors.
For more information, please visit http://www.emerginghealthcaresolutionsinc.com/.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This news release contains forward-looking information within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including statements that include the words "believes," "expects," "anticipate" or similar expressions. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause the actual results, performance or achievements of the company to differ materially from those expressed or implied by such forward-looking statements. In addition, description of anyone's past success, either financial or strategic, is no guarantee of future success. This news release speaks as of the date first set forth above and the company assumes no responsibility to update the information included herein for events occurring after the date hereof.
SOURCE: Emerging Healthcare Solutions, Inc.
Emerging Healthcare Solutions, Inc.
Cindy Morrissey, 713-821-1486
President and CEO
Source
HOUSTON, Dec 06, 2010 (BUSINESS WIRE) --
Emerging Healthcare Solutions, Inc. (PinkSheets: EHSI
PowerRating) announced today that its newly acquired biotechnology division Celulas Genetica seeks to contract a Chinese firm to test a new stem-cell treatment for liver disease.
Last week, Celulas Genetica purchased a license to develop and market the revolutionary Rutherford Procedure, a groundbreaking organ regeneration treatment intended to utilize proton-beam technology to destroy diseased organ tissue for regeneration using adult stem cells. Celulas Genetica licensed the procedure from a Chinese firm, BBFITCL, and views the emerging Asian superpower as the ideal locale to test and develop its potential new treatment for liver disease.
"China has pushed hard for years to become a world leader in the fields of stem cell research and regenerative medicine," said EHSI President and CEO Cindy Morrissey. "The scientific and medical resources needed to test the Rutherford Procedure are both abundant and affordable in China, and Celulas Genetica is currently exploring the possibility of working with a proton therapy facility there to develop this new treatment for liver disease."
Morrissey said she plans to travel to China soon to meet with Chinese stem-cell researchers and potentially help open a Celulas Genetica business office there. Extending its reach into the R&D hotbed of China would build on EHSI's rapidly expanding global footprint--Celulas Genetica is headquartered in Panama, and Morrissey opened EHSI business offices in Poland and Germany last month.
"Liver disease is a truly global affliction," Morrissey said. "It requires a global solution. Working together with scientists and doctors in Panama, China and elsewhere, we believe we can develop the Rutherford Procedure into an effective, minimally invasive treatment for liver disease that will not require transplants."
Last week, EHSI announced its acquisition of a Rotary Cell Culture System, or bioreactor, developed using revolutionary NASA research in the field of microgravity. Cell cultures, including stem cells, grown inside the bioreactor look and function much closer to human cells grown within the body than cell cultures grown in Petri dishes. During the Rutherford Procedure, proton therapy will be used to destroy scar-tissue cells in the liver using high-energy proton beams, a non-invasive treatment proven to minimize damage to healthy tissues and to eliminate the side effects (including nausea) of traditional radiation therapy.
As the scar tissue is systematically destroyed by the proton therapy, a catheter will deliver the patient's own cultured stem cells directly to his or her liver through the bloodstream. As more and more diseased tissue is destroyed, these cultured stem cells could help regenerate the patient's damaged, cirrhotic liver into a healthy, functioning organ once more.
EHSI invests in technology developed to compete in the stem-cell research industry alongside Dendreon Corp. (NASDAQ: DNDN), Gilead Sciences (NASDAQ: GILD), Celgene Corp. (NASDAQ: CELG) and Biogen Idec Inc. (NASDAQ: BIIB).
About Emerging Healthcare Solutions, Inc.
Emerging Healthcare Solutions, Inc. invests in and participates in the profits of emerging breakthrough medical technologies. The Company believes the secret of leveraging future value for its shareholders is the proper timing of its investment in promising new medical technologies. EHSI aims to capture future profits of promising new medical technologies by investing in these technologies at the inflection point of product development. We believe this model will deliver long-term positive results for our investors.
For more information, please visit http://www.emerginghealthcaresolutionsinc.com/.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This news release contains forward-looking information within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including statements that include the words "believes," "expects," "anticipate" or similar expressions. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause the actual results, performance or achievements of the company to differ materially from those expressed or implied by such forward-looking statements. In addition, description of anyone's past success, either financial or strategic, is no guarantee of future success. This news release speaks as of the date first set forth above and the company assumes no responsibility to update the information included herein for events occurring after the date hereof.
SOURCE: Emerging Healthcare Solutions, Inc.
Emerging Healthcare Solutions, Inc.
Cindy Morrissey, 713-821-1486
President and CEO
Source
Achillion To Present Data From Studies Of ACH-1625 In Hepatitis C At Asian Pacific Liver Conference
NEW HAVEN, Conn., Dec. 6, 2010 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced that data from the Company's ongoing clinical studies of ACH-1625 has been accepted for presentation at the 21st Annual Conference of the Asian Pacific Association for the Study of the Liver (APASL 2011) to be held February 17-21, 2011 in Bangkok, Thailand.
ACH-1625 is an inhibitor of HCV NS3 protease that was discovered and is being developed by Achillion.
The presentation, entitled "Viral Kinetics Modeling of Short-term Monotherapy Data of ACH-1625, an HCV Protease Inhibitor," will be presented by Dr. Atul Agarwal, Senior Director of Computational Chemistry of Achillion. (Abstract A-315-0024-00792.) The presentation describes a mathematical analysis of HCV RNA data collected after oral administration of ACH-1625 in HCV genotype 1 infected subjects. This analysis shows rapid and near complete hepatitis C virus clearance following ACH-1625 administration at all dose levels tested. In addition, mathematical modeling of HCV viral kinetics provided information that allowed for subsequent dose selection for Phase II clinical development of ACH-1625.
"These data support and further demonstrate ACH-1625's robust antiviral activity," said Dr. Agarwal. "With clinical data that demonstrated reductions in viral RNA between 3-4.25 log10, these mathematical data quantitatively show the percentage of total virus cleared after five days of ACH-1625 monotherapy. This data also identifies specific patient population characteristics."
"We are pleased to continue to put forward a large body of scientific and clinical data on ACH-1625," commented Michael D. Kishbauch, Chief Executive Officer of Achillion. "We look forward to completing the current Phase II clinical trial of ACH-1625 to further support its profile as a potential best-in-class protease inhibitor for the treatment of HCV."
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.
In clinical studies, HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.07 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 1log10 from baseline through day 12, the last day of viral load measurement in the study.
About HCV
The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease -hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration, as well as Achillion's expectations regarding timing and duration of other clinical trials. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are: uncertainties relating to results of clinical trials, unexpected regulatory actions or delays, and Achillion's ability to obtain additional funding required to conduct its research, development and commercialization activities. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009.
Source
ACH-1625 is an inhibitor of HCV NS3 protease that was discovered and is being developed by Achillion.
The presentation, entitled "Viral Kinetics Modeling of Short-term Monotherapy Data of ACH-1625, an HCV Protease Inhibitor," will be presented by Dr. Atul Agarwal, Senior Director of Computational Chemistry of Achillion. (Abstract A-315-0024-00792.) The presentation describes a mathematical analysis of HCV RNA data collected after oral administration of ACH-1625 in HCV genotype 1 infected subjects. This analysis shows rapid and near complete hepatitis C virus clearance following ACH-1625 administration at all dose levels tested. In addition, mathematical modeling of HCV viral kinetics provided information that allowed for subsequent dose selection for Phase II clinical development of ACH-1625.
"These data support and further demonstrate ACH-1625's robust antiviral activity," said Dr. Agarwal. "With clinical data that demonstrated reductions in viral RNA between 3-4.25 log10, these mathematical data quantitatively show the percentage of total virus cleared after five days of ACH-1625 monotherapy. This data also identifies specific patient population characteristics."
"We are pleased to continue to put forward a large body of scientific and clinical data on ACH-1625," commented Michael D. Kishbauch, Chief Executive Officer of Achillion. "We look forward to completing the current Phase II clinical trial of ACH-1625 to further support its profile as a potential best-in-class protease inhibitor for the treatment of HCV."
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.
In clinical studies, HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.07 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 1log10 from baseline through day 12, the last day of viral load measurement in the study.
About HCV
The hepatitis C virus is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure to the virus. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, and injectable route of administration.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease -hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration, as well as Achillion's expectations regarding timing and duration of other clinical trials. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are: uncertainties relating to results of clinical trials, unexpected regulatory actions or delays, and Achillion's ability to obtain additional funding required to conduct its research, development and commercialization activities. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009.
Source
Research Fuels Hope for Hard-To-Treat Hepatitis C Patients
Released: 12/6/2010 12:00 PM EST
Source: Saint Louis University Medical Center
Newswise — The outlook for patients with hepatitis C continues to improve as results from a clinical trial led by a Saint Louis University researcher found that the drug boceprevir helped cure hard-to-treat patients. The findings were reported at the 61st annual meeting of the American Association for the Study of Liver Disease’s earlier in November.
Bruce R. Bacon, M.D., professor of internal medicine at Saint Louis University School of Medicine and co-principal investigator of the HCV RESPOND-2 study, studied the protease inhibitor, boceprevir, and found that it significantly increased the number of patients whose blood had undetectable levels of the virus.
“These findings are especially significant for patients who don’t respond to initial treatment,” said Bacon. “When the hepatitis C virus is not eliminated, debilitating fatigue and more serious problems can follow.”
Hepatitis C is caused by a virus that is transmitted by contact with blood. The infection may initially be asymptomatic, but for patients who develop chronic hepatitis C infection, inflammation of the liver may develop, leading to fibrosis and cirrhosis (scarring of the liver), as well as other complications including liver cancer and death.
The prognosis varies for patients with chronic hepatitis C. With the current standard therapy, about half fully recover after an initial course of peginterferon and ribavirin anti-viral therapy that may last from six months to a year.
The remaining patients, known as non-responders, may improve with initial treatment but the virus is not eliminated, or may not respond to treatment at all.
For this group, the only current option is to retreat patients with the same or similar drugs, which increases the likelihood of severe treatment side-effects. In addition, researchers have found that the success of treatment depends on the major strain, or genotype, of hepatitis C that a patient has.
The HCV RESPOND-2 study looked at 403 patients with chronic hepatitis C infections with genotype one, the most difficult strain of the virus to treat, who still had significant levels of the virus after being treated with peginterferon and ribavirin, the standard hepatitis C treatment.
"These results are very exciting," Bacon said. “In this study, boceprevir helped cure significantly more patients in 24 weeks of therapy than did treatment with peginterferon and ribavirin alone."
A second study, HCV SPRINT-2, examined patients with hepatitis C with genotype one who had not yet been treated with the standard treatment. They, too, responded well to the drug.
Bacon calls the progress made in treating hepatitis C remarkable.
“We’ve gone from the discovery of the virus in 1989 to where we are now, 22 years later, when we have the ability to cure a large majority of those with hepatitis C,” Bacon said. “It’s a true success story.”
“Drugs like boceprevir are going to revolutionize care of those with hepatitis C.”
The clinical trial was funded by Merck, which expects to begin seeking FDA approval this year.
Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.
Source
Source: Saint Louis University Medical Center
Newswise — The outlook for patients with hepatitis C continues to improve as results from a clinical trial led by a Saint Louis University researcher found that the drug boceprevir helped cure hard-to-treat patients. The findings were reported at the 61st annual meeting of the American Association for the Study of Liver Disease’s earlier in November.
Bruce R. Bacon, M.D., professor of internal medicine at Saint Louis University School of Medicine and co-principal investigator of the HCV RESPOND-2 study, studied the protease inhibitor, boceprevir, and found that it significantly increased the number of patients whose blood had undetectable levels of the virus.
“These findings are especially significant for patients who don’t respond to initial treatment,” said Bacon. “When the hepatitis C virus is not eliminated, debilitating fatigue and more serious problems can follow.”
Hepatitis C is caused by a virus that is transmitted by contact with blood. The infection may initially be asymptomatic, but for patients who develop chronic hepatitis C infection, inflammation of the liver may develop, leading to fibrosis and cirrhosis (scarring of the liver), as well as other complications including liver cancer and death.
The prognosis varies for patients with chronic hepatitis C. With the current standard therapy, about half fully recover after an initial course of peginterferon and ribavirin anti-viral therapy that may last from six months to a year.
The remaining patients, known as non-responders, may improve with initial treatment but the virus is not eliminated, or may not respond to treatment at all.
For this group, the only current option is to retreat patients with the same or similar drugs, which increases the likelihood of severe treatment side-effects. In addition, researchers have found that the success of treatment depends on the major strain, or genotype, of hepatitis C that a patient has.
The HCV RESPOND-2 study looked at 403 patients with chronic hepatitis C infections with genotype one, the most difficult strain of the virus to treat, who still had significant levels of the virus after being treated with peginterferon and ribavirin, the standard hepatitis C treatment.
"These results are very exciting," Bacon said. “In this study, boceprevir helped cure significantly more patients in 24 weeks of therapy than did treatment with peginterferon and ribavirin alone."
A second study, HCV SPRINT-2, examined patients with hepatitis C with genotype one who had not yet been treated with the standard treatment. They, too, responded well to the drug.
Bacon calls the progress made in treating hepatitis C remarkable.
“We’ve gone from the discovery of the virus in 1989 to where we are now, 22 years later, when we have the ability to cure a large majority of those with hepatitis C,” Bacon said. “It’s a true success story.”
“Drugs like boceprevir are going to revolutionize care of those with hepatitis C.”
The clinical trial was funded by Merck, which expects to begin seeking FDA approval this year.
Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.
Source
December 4, 2010
Reliability of transient elastography for the detection of fibrosis in Non-Alcoholic Fatty Liver Disease and chronic viral hepatitis
Journal Of Hepatology
Volume 54, Issue 1, Pages 64-71
Silvia Gaia, Silvia Carenzi, Angela L. Barilli, Elisabetta Bugianesi, Antonina Smedile, Franco Brunello, Alfredo Marzano, Mario Rizzetto
Received 7 January 2010; received in revised form 3 May 2010; accepted 2 June 2010.
Background & Aims
Transient elastography (TE) is validated in chronic hepatitis C (CHC) to evaluate hepatic fibrosis; however, limited data are available in chronic hepatitis B (CHB) and Non-Alcoholic Fatty Liver Disease (NAFLD). This prospective study is aimed to assess the accuracy and the efficacy of TE for the detection of fibrosis in patients with chronic liver disease of different etiology and to evaluate the effect of steatosis on the liver stiffness measurement (LSM).
Methods
TE was performed in 219 consecutive patients with chronic liver disease (35% CHC, 32% CHB, and 33% NAFLD) within 6months of the liver biopsy.
Results
LSM was related to the fibrosis stage in each group (CHC: p=0.596, p<0.001; CHB: p=0.418, p<0.001; NAFLD: p=0.573, p<0.001), but the correlation was less strong in CHB and NAFLD than in CHC patients. In CHB patients with histological cirrhosis (F4), the median stiffness value was almost two times lower than in patients with severe fibrosis (F3). In NAFLD patients with advanced fibrosis (F3) and severe steatosis (>33%), the LSM values were lower than expected and were similar to those of patients with initial fibrosis (F1) and fat <33%. TE underestimated the stage of fibrosis in 75% of patients with F3 and steatosis >33%. At multiple logistic regression analysis, in CHC and CHB patients, LSM was the only predictive variable of severe fibrosis/cirrhosis (OR=1.42, p=0.003 and OR=1.354, p=0.003, respectively), while in NAFLD subjects BMI and AST (OR=1.433, p=0.002 and OR=1.053, p=0.020, respectively) but not LSM were independently related with advanced fibrosis and cirrhosis.
Conclusions
This study confirms that TE can be considered a valid support to detect fibrosis in chronic liver disease related to HCV but it should be interpreted cautiously in CHB and NAFLD patients, where host or disease-related factors may modify its accuracy.
Keywords: Transient elastography, Fibroscan, Liver fibrosis, Viral hepatitis, NAFLD
San Giovanni Battista Hospital, Gastroenterology, C. Bramante 88 10128, Italy
Corresponding author. Tel.: +39 3383153995.
PII: S0168-8278(10)00712-9
doi:10.1016/j.jhep.2010.06.022
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved
Source
Volume 54, Issue 1, Pages 64-71
Silvia Gaia, Silvia Carenzi, Angela L. Barilli, Elisabetta Bugianesi, Antonina Smedile, Franco Brunello, Alfredo Marzano, Mario Rizzetto
Received 7 January 2010; received in revised form 3 May 2010; accepted 2 June 2010.
Background & Aims
Transient elastography (TE) is validated in chronic hepatitis C (CHC) to evaluate hepatic fibrosis; however, limited data are available in chronic hepatitis B (CHB) and Non-Alcoholic Fatty Liver Disease (NAFLD). This prospective study is aimed to assess the accuracy and the efficacy of TE for the detection of fibrosis in patients with chronic liver disease of different etiology and to evaluate the effect of steatosis on the liver stiffness measurement (LSM).
Methods
TE was performed in 219 consecutive patients with chronic liver disease (35% CHC, 32% CHB, and 33% NAFLD) within 6months of the liver biopsy.
Results
LSM was related to the fibrosis stage in each group (CHC: p=0.596, p<0.001; CHB: p=0.418, p<0.001; NAFLD: p=0.573, p<0.001), but the correlation was less strong in CHB and NAFLD than in CHC patients. In CHB patients with histological cirrhosis (F4), the median stiffness value was almost two times lower than in patients with severe fibrosis (F3). In NAFLD patients with advanced fibrosis (F3) and severe steatosis (>33%), the LSM values were lower than expected and were similar to those of patients with initial fibrosis (F1) and fat <33%. TE underestimated the stage of fibrosis in 75% of patients with F3 and steatosis >33%. At multiple logistic regression analysis, in CHC and CHB patients, LSM was the only predictive variable of severe fibrosis/cirrhosis (OR=1.42, p=0.003 and OR=1.354, p=0.003, respectively), while in NAFLD subjects BMI and AST (OR=1.433, p=0.002 and OR=1.053, p=0.020, respectively) but not LSM were independently related with advanced fibrosis and cirrhosis.
Conclusions
This study confirms that TE can be considered a valid support to detect fibrosis in chronic liver disease related to HCV but it should be interpreted cautiously in CHB and NAFLD patients, where host or disease-related factors may modify its accuracy.
Keywords: Transient elastography, Fibroscan, Liver fibrosis, Viral hepatitis, NAFLD
San Giovanni Battista Hospital, Gastroenterology, C. Bramante 88 10128, Italy
Corresponding author. Tel.: +39 3383153995.
PII: S0168-8278(10)00712-9
doi:10.1016/j.jhep.2010.06.022
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved
Source
Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-α-2a and ribavirin in HIV/HCV co-infected patients
Journal of Hepatology
Volume 54, Issue 1, Pages 41-47
Marie-Louise C. Vachon 1† , Stephanie H. Factor 2† , Andrea D. Branch 1† , Maria-Isabel Fiel 3† , Maribel Rodriguez-Torres 4† , Norbert Bräu 56† , Richard K. Sterling 7† , Jihad Slim 8† , Andrew H. Talal 9† , Douglas T. Dieterich 1† , Mark S. Sulkowski 10†
Received 19 February 2010; received in revised form 11 June 2010; accepted 16 June 2010.
Background & Aims
Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology.
Methods
This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48weeks. Serum HCV RNA was measured 24weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR>2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined.
Results
Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR<2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2–4, and 7% (3/41) of those with HOMA-IR>4 (p=0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05–0.64, p=0.009, and AOR 0.36; 95% CI 0.14–0.93, p=0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p=0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes.
Conclusions
In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response.
Keywords: Insulin resistance, Hepatitis C virus, Chronic, HIV, Re-treatment, Antiviral therapy, Pegylated interferon alfa-2a, Ribavirin
1 Division of Liver Diseases, Mount Sinai School of Medicine, NY, USA
2 Division of Infectious Diseases, Mount Sinai School of Medicine, NY, USA
3 Department of Pathology, Mount Sinai School of Medicine, NY, USA
4 Fundacion de Investigacion de Diego, San Juan, PR, USA
5 Divisions of Infectious Diseases and Liver Diseases, Mount Sinai School of Medicine, NY, USA
6 Veterans Affairs Medical Center, Bronx, NY, USA
7 Division of Liver Diseases, Virginia Commonwealth University Health Systems, Richmond, VA, USA
8 Division of Infectious Diseases, St-Michael’s Medical Center, NY, USA
9 Division of Gastroenterology and Hepatology and Center for the Study of Hepatitis C, Weill Cornell Medical College, NY, USA
10 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MA, USA
Corresponding author. Address: Mount Sinai School of Medicine, One, Gustave L. Levy Place, Box 1123, NY 10029, USA. Tel.: +1 212 659 8877; fax: +1 212 659 8377.
† On behalf of Hepatitis Resource Network (HRN)-004.
PII: S0168-8278(10)00715-4
doi:10.1016/j.jhep.2010.06.025
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Source
Volume 54, Issue 1, Pages 41-47
Marie-Louise C. Vachon 1† , Stephanie H. Factor 2† , Andrea D. Branch 1† , Maria-Isabel Fiel 3† , Maribel Rodriguez-Torres 4† , Norbert Bräu 56† , Richard K. Sterling 7† , Jihad Slim 8† , Andrew H. Talal 9† , Douglas T. Dieterich 1† , Mark S. Sulkowski 10†
Received 19 February 2010; received in revised form 11 June 2010; accepted 16 June 2010.
Background & Aims
Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology.
Methods
This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48weeks. Serum HCV RNA was measured 24weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR>2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined.
Results
Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR<2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2–4, and 7% (3/41) of those with HOMA-IR>4 (p=0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05–0.64, p=0.009, and AOR 0.36; 95% CI 0.14–0.93, p=0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p=0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes.
Conclusions
In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response.
Keywords: Insulin resistance, Hepatitis C virus, Chronic, HIV, Re-treatment, Antiviral therapy, Pegylated interferon alfa-2a, Ribavirin
1 Division of Liver Diseases, Mount Sinai School of Medicine, NY, USA
2 Division of Infectious Diseases, Mount Sinai School of Medicine, NY, USA
3 Department of Pathology, Mount Sinai School of Medicine, NY, USA
4 Fundacion de Investigacion de Diego, San Juan, PR, USA
5 Divisions of Infectious Diseases and Liver Diseases, Mount Sinai School of Medicine, NY, USA
6 Veterans Affairs Medical Center, Bronx, NY, USA
7 Division of Liver Diseases, Virginia Commonwealth University Health Systems, Richmond, VA, USA
8 Division of Infectious Diseases, St-Michael’s Medical Center, NY, USA
9 Division of Gastroenterology and Hepatology and Center for the Study of Hepatitis C, Weill Cornell Medical College, NY, USA
10 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MA, USA
Corresponding author. Address: Mount Sinai School of Medicine, One, Gustave L. Levy Place, Box 1123, NY 10029, USA. Tel.: +1 212 659 8877; fax: +1 212 659 8377.
† On behalf of Hepatitis Resource Network (HRN)-004.
PII: S0168-8278(10)00715-4
doi:10.1016/j.jhep.2010.06.025
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Source
Elastography for the diagnosis of severity of fibrosis in chronic liver disease: A meta-analysis of diagnostic accuracy
Articles in Press
E.A. Tsochatzis 1, K.S. Gurusamy 2, S. Ntaoula 1, E. Cholongitas 1, B.R. Davidson 2, A.K. Burroughs 1
Received 11 March 2010; received in revised form 16 July 2010; accepted 20 July 2010. published online 30 November 2010.
Uncorrected Proof
Background & Aims
Transient elastography is a non-invasive method of assessing hepatic fibrosis developed as an alternative to liver biopsy. We assessed the performance of elastography for diagnosis of fibrosis using meta-analysis.
Methods
MEDLINE, EMBASE, SCI, Cochrane Library, conference abstracts books, and article references were searched. We included studies using biopsy as a reference standard, with the data necessary to calculate the true and false positive, true and false negative diagnostic results of elastography for a fibrosis stage, and with a 3-month maximum interval between tests. Quality of studies was rated with the QUADAS tool.
Results
We identified 40 eligible studies. Summary sensitivity and specificity was 0.79 (95% CI 0.74–0.82) and 0.78 (95% CI 0.72–0.83) for F2 stage and 0.83 (95% CI 0.79–0.86) and 0.89 (95% CI 0.87–0.91) for cirrhosis. After an elastography result at/over the threshold value for F2 or cirrhosis (“positive” result), the corresponding post-test probability for their presence (if pre-test probability was 50%) was 78%, and 88% respectively, while if values were below these thresholds (“negative” result) the post-test probability was 21% and 16%, respectively. No optimal stiffness cut-offs for individual fibrosis stages were validated in independent cohorts and cut-offs had a wide range and overlap within and between stages.
Conclusion
Elastography theoretically has good sensitivity and specificity for cirrhosis (and less for lesser degrees of fibrosis); however, it should be cautiously applied to everyday clinical practice because there is no validation of the stiffness cut-offs for the various stages. Such validation is required before elastography is considered sufficiently accurate for non-invasive staging of fibrosis.
1 The Royal Free Sheila Sherlock Liver Centre and Division of Surgery, Royal Free Hospital, London NW3 2QG, UK
2 University Department of Surgery, Royal Free Hospital, London NW3 2QG, UK
Corresponding author. Address: The Royal Free Sheila Sherlock Liver Centre and Division of Surgery, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK. Tel.: +44 2074726229; fax: +44 2074726226.
PII: S0168-8278(10)00825-1
doi:10.1016/j.jhep.2010.07.033
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Source
E.A. Tsochatzis 1, K.S. Gurusamy 2, S. Ntaoula 1, E. Cholongitas 1, B.R. Davidson 2, A.K. Burroughs 1
Received 11 March 2010; received in revised form 16 July 2010; accepted 20 July 2010. published online 30 November 2010.
Uncorrected Proof
Background & Aims
Transient elastography is a non-invasive method of assessing hepatic fibrosis developed as an alternative to liver biopsy. We assessed the performance of elastography for diagnosis of fibrosis using meta-analysis.
Methods
MEDLINE, EMBASE, SCI, Cochrane Library, conference abstracts books, and article references were searched. We included studies using biopsy as a reference standard, with the data necessary to calculate the true and false positive, true and false negative diagnostic results of elastography for a fibrosis stage, and with a 3-month maximum interval between tests. Quality of studies was rated with the QUADAS tool.
Results
We identified 40 eligible studies. Summary sensitivity and specificity was 0.79 (95% CI 0.74–0.82) and 0.78 (95% CI 0.72–0.83) for F2 stage and 0.83 (95% CI 0.79–0.86) and 0.89 (95% CI 0.87–0.91) for cirrhosis. After an elastography result at/over the threshold value for F2 or cirrhosis (“positive” result), the corresponding post-test probability for their presence (if pre-test probability was 50%) was 78%, and 88% respectively, while if values were below these thresholds (“negative” result) the post-test probability was 21% and 16%, respectively. No optimal stiffness cut-offs for individual fibrosis stages were validated in independent cohorts and cut-offs had a wide range and overlap within and between stages.
Conclusion
Elastography theoretically has good sensitivity and specificity for cirrhosis (and less for lesser degrees of fibrosis); however, it should be cautiously applied to everyday clinical practice because there is no validation of the stiffness cut-offs for the various stages. Such validation is required before elastography is considered sufficiently accurate for non-invasive staging of fibrosis.
1 The Royal Free Sheila Sherlock Liver Centre and Division of Surgery, Royal Free Hospital, London NW3 2QG, UK
2 University Department of Surgery, Royal Free Hospital, London NW3 2QG, UK
Corresponding author. Address: The Royal Free Sheila Sherlock Liver Centre and Division of Surgery, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK. Tel.: +44 2074726229; fax: +44 2074726226.
PII: S0168-8278(10)00825-1
doi:10.1016/j.jhep.2010.07.033
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
Source
Induction Pegylated Interferon Alfa-2a and High Dose Ribavirin Do Not Increase SVR in Heavy Patients With HCV Genotype 1 and High Viral Loads
Gastroenterology
Volume 139, Issue 6 , Pages 1972-1983, December 2010
K. Rajender Reddy, Mitchell L. Shiffman, Maribel Rodriguez–Torres, Hugo Cheinquer, Djamal Abdurakhmanov, Igor Bakulin, Viacheslav Morozov, Giovanni Faria Silva, Natalia Geyvandova, Carol Stanciu, Michael Rabbia, Michael McKenna, James A. Thommes, Stephen A. Harrison, PROGRESS Study Investigators
Received 28 May 2010; accepted 17 August 2010. published online 06 September 2010.
Abstract
Background & Aims
Patients infected with hepatitis C virus (HCV) genotype 1, body weight ≥85 kg, and high baseline viral load respond poorly to standard doses of pegylated interferon (peginterferon) and ribavirin. We evaluated intensified therapy with peginterferon alfa-2a plus ribavirin.
Methods
This double-blind randomized trial included HCV genotype 1-infected outpatients from hepatology clinics with body weight ≥85 kg and HCV RNA titer ≥400,000 IU/mL. Patients were randomized to 180 μg/wk peginterferon alfa-2a for 48 weeks plus 1200 mg/day ribavirin (standard of care) (group A, n = 191) or 1400/1600 mg/day ribavirin (group B, n = 189). Additional groups included 360 μg/wk peginterferon alfa-2a for 12 weeks then 180 μg/wk peginterferon alfa-2a for 36 weeks plus 1200 mg/day ribavirin (group C, n = 382) or 1400/1600 mg/day ribavirin (group D, n = 383). Follow-up lasted 24 weeks after treatment.
Results
Sustained virologic response rates (HCV RNA level <15 IU/mL at end of follow-up) in groups A, B, C, and D were 38%, 43%, 44%, and 41%, respectively. There were no significant differences among the 4 groups or between pooled peginterferon alfa-2a regimens (A + B vs C + D: odds ratio [OR], 1.08; 95% confidence interval [CI], 0.83–1.39; P = .584) or pooled ribavirin regimens (A + C vs B + D: OR, 1.00; 95% CI, 0.79–1.28; P = .974).
Conclusions
In patients infected with HCV genotype 1 who are difficult to treat (high viral load, body weight ≥85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen.
Keywords: Chronic Hepatitis C, Tolerability of High-Dose Pegylated Interferon, Steatosis and Response to HCV Therapy, Tolerability of High-Dose Ribavirin
Source
Volume 139, Issue 6 , Pages 1972-1983, December 2010
K. Rajender Reddy, Mitchell L. Shiffman, Maribel Rodriguez–Torres, Hugo Cheinquer, Djamal Abdurakhmanov, Igor Bakulin, Viacheslav Morozov, Giovanni Faria Silva, Natalia Geyvandova, Carol Stanciu, Michael Rabbia, Michael McKenna, James A. Thommes, Stephen A. Harrison, PROGRESS Study Investigators
Received 28 May 2010; accepted 17 August 2010. published online 06 September 2010.
Abstract
Background & Aims
Patients infected with hepatitis C virus (HCV) genotype 1, body weight ≥85 kg, and high baseline viral load respond poorly to standard doses of pegylated interferon (peginterferon) and ribavirin. We evaluated intensified therapy with peginterferon alfa-2a plus ribavirin.
Methods
This double-blind randomized trial included HCV genotype 1-infected outpatients from hepatology clinics with body weight ≥85 kg and HCV RNA titer ≥400,000 IU/mL. Patients were randomized to 180 μg/wk peginterferon alfa-2a for 48 weeks plus 1200 mg/day ribavirin (standard of care) (group A, n = 191) or 1400/1600 mg/day ribavirin (group B, n = 189). Additional groups included 360 μg/wk peginterferon alfa-2a for 12 weeks then 180 μg/wk peginterferon alfa-2a for 36 weeks plus 1200 mg/day ribavirin (group C, n = 382) or 1400/1600 mg/day ribavirin (group D, n = 383). Follow-up lasted 24 weeks after treatment.
Results
Sustained virologic response rates (HCV RNA level <15 IU/mL at end of follow-up) in groups A, B, C, and D were 38%, 43%, 44%, and 41%, respectively. There were no significant differences among the 4 groups or between pooled peginterferon alfa-2a regimens (A + B vs C + D: odds ratio [OR], 1.08; 95% confidence interval [CI], 0.83–1.39; P = .584) or pooled ribavirin regimens (A + C vs B + D: OR, 1.00; 95% CI, 0.79–1.28; P = .974).
Conclusions
In patients infected with HCV genotype 1 who are difficult to treat (high viral load, body weight ≥85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen.
Keywords: Chronic Hepatitis C, Tolerability of High-Dose Pegylated Interferon, Steatosis and Response to HCV Therapy, Tolerability of High-Dose Ribavirin
Source
Factors associated with sustained virological response in liver transplant recipients with recurrent hepatitis C
Transplant Proc. 2010 Nov;42(9):3647-51.
Pillai AA, Lee VS, Wang E, Rinella ME, Levitsky J.
Abstract
BACKGROUND: Antiviral therapy has achieved sustained virological response (SVR) in less than one third of orthotopic liver transplantation (OLT) patients with recurrent hepatitis C.
AIM: The aim of this study was to identify predictors of SVR in OLT patients treated with pegylated interferon and ribavirin (PEG+RBV) for recurrent hepatitis C virus (HCV).
METHODS: We analyzed data from our transplantation database for 62 subjects treated with PEG+RBV between August 2001 and September 2008. After univariate examination for factors known to be associated with SVR, significant associations (P < .05) were probed using multivariate logistic regression. Kaplan-Meier patient and graft survival analyses were compared between patients with (n = 19; 30.6%) versus without SVR.
RESULTS: On univariate analysis, longer duration of therapy, low pretreatment HCV RNA (<1 million IU/mL), and early virological response (EVR) were associated with SVR. On multivariate analysis, only low pretreatment HCV RNA predicted SVR. Patient survival was significantly higher in the SVR group.
CONCLUSIONS: Covariates associated with SVR among OLT patients with recurrent HCV were similar to the pretransplantation group. Potentially modifiable risk factors, such as obesity, diabetes mellitus, and metabolic syndrome, were not significant predictors of treatment response. Patient survival was associated with SVR, highlighting the impact of successful HCV therapy on long-term post-OLT outcomes.
Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 21094833 [PubMed - in process]
Source
Pillai AA, Lee VS, Wang E, Rinella ME, Levitsky J.
Abstract
BACKGROUND: Antiviral therapy has achieved sustained virological response (SVR) in less than one third of orthotopic liver transplantation (OLT) patients with recurrent hepatitis C.
AIM: The aim of this study was to identify predictors of SVR in OLT patients treated with pegylated interferon and ribavirin (PEG+RBV) for recurrent hepatitis C virus (HCV).
METHODS: We analyzed data from our transplantation database for 62 subjects treated with PEG+RBV between August 2001 and September 2008. After univariate examination for factors known to be associated with SVR, significant associations (P < .05) were probed using multivariate logistic regression. Kaplan-Meier patient and graft survival analyses were compared between patients with (n = 19; 30.6%) versus without SVR.
RESULTS: On univariate analysis, longer duration of therapy, low pretreatment HCV RNA (<1 million IU/mL), and early virological response (EVR) were associated with SVR. On multivariate analysis, only low pretreatment HCV RNA predicted SVR. Patient survival was significantly higher in the SVR group.
CONCLUSIONS: Covariates associated with SVR among OLT patients with recurrent HCV were similar to the pretransplantation group. Potentially modifiable risk factors, such as obesity, diabetes mellitus, and metabolic syndrome, were not significant predictors of treatment response. Patient survival was associated with SVR, highlighting the impact of successful HCV therapy on long-term post-OLT outcomes.
Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 21094833 [PubMed - in process]
Source
Importance of hepatitis vaccination in patients with chronic liver disease
South Med J. 2010 Dec;103(12):1223-31.
Kumar M, Herrera JL.
From the Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, AL.
Abstract
Acute hepatitis A or B infection can be lethal in patients with chronic liver disease. Safe and effective vaccines are currently available to prevent hepatitis A and B. Despite wide availability of vaccines, most patients with chronic liver disease are not immunized, in part due to nonuniform and inconsistent current recommendations for this population. A better understanding of the importance of preventing acute hepatitis A and B in patients with chronic liver disease and a proactive approach to vaccination by primary care physicians can positively influence the outcome of patients with chronic liver disease.
PMID: 21057383 [PubMed - in process]
Source
Kumar M, Herrera JL.
From the Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, AL.
Abstract
Acute hepatitis A or B infection can be lethal in patients with chronic liver disease. Safe and effective vaccines are currently available to prevent hepatitis A and B. Despite wide availability of vaccines, most patients with chronic liver disease are not immunized, in part due to nonuniform and inconsistent current recommendations for this population. A better understanding of the importance of preventing acute hepatitis A and B in patients with chronic liver disease and a proactive approach to vaccination by primary care physicians can positively influence the outcome of patients with chronic liver disease.
PMID: 21057383 [PubMed - in process]
Source
Assessment of liver fibrosis before and after antiviral therapy by different serum marker panels in patients with chronic hepatitis C
Alimentary Pharmacology & Therapeutics
Early View (Articles online in advance of print)
S. M. Martinez 1, G. Fernández-Varo 2, P. González 1, E. Sampson 3, M. Bruguera 1, M. Navasa 1, W. Jiménez 2, J. M. Sánchez-Tapias 1, X. Forns 1
Article first published online: 26 OCT 2010
DOI: 10.1111/j.1365-2036.2010.04500.x
© 2010 Blackwell Publishing Ltd
Author Information
1 Liver Unit, Hospital Clinic, IDIBAPS and Ciberehd, Barcelona, Spain.
2 Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS and Ciberehd, Barcelona, Spain.
3 Siemens Healthcare Diagnostics, Tarrytown, NY, USA.
*Correspondence: Dr X. Forns, Liver Unit, Hospital Clinic, IDIBAPS and Ciberehd, Villarroel 170, Barcelona 08036, Spain. E-mail: xforns@clinic.ub.es
Abstract
Summary
Background Liver biopsy is the reference standard to assess liver fibrosis in chronic hepatitis C.
Aim To validate and compare the diagnostic performance of non-invasive tests for prediction of liver fibrosis severity and assessed changes in extracellular matrix markers after antiviral treatment.
Methods The performances of Forns’ score, AST to platelet ratio index (APRI), FIB-4 index and Enhanced Liver Fibrosis (ELF) score were validated in 340 patients who underwent antiviral therapy. These scores were determined 24 weeks after treatment in 161 patients.
Results Forns’ score, APRI, FIB-4 and ELF score showed comparable diagnostic accuracies for significant fibrosis [area under the receiver operating characteristic curve (AUROC) 0.83, 0.83, 0.85 and 0.81, respectively]. To identify cirrhosis, FIB-4 index showed a significantly better performance over APRI and ELF score (AUROC 0.89 vs. 0.83 and 0.82, respectively). ELF score decreased significantly in patients with sustained virological response (SVR) (P < 0.0001) but remained unchanged in nonresponders. Non-1 hepatitis C virus (HCV) genotype, baseline lower HCV RNA, glucose, hyaluronic acid and higher cholesterol levels were independently associated with SVR.
Conclusions Simple panel markers and ELF score are accurate at identifying significant fibrosis and cirrhosis in chronic hepatitis C. A decrease in ELF score after antiviral treatment reflects the impact of viral clearance in hepatic extracellular matrix and probably in the improvement of liver fibrosis.
Source
Early View (Articles online in advance of print)
S. M. Martinez 1, G. Fernández-Varo 2, P. González 1, E. Sampson 3, M. Bruguera 1, M. Navasa 1, W. Jiménez 2, J. M. Sánchez-Tapias 1, X. Forns 1
Article first published online: 26 OCT 2010
DOI: 10.1111/j.1365-2036.2010.04500.x
© 2010 Blackwell Publishing Ltd
Author Information
1 Liver Unit, Hospital Clinic, IDIBAPS and Ciberehd, Barcelona, Spain.
2 Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS and Ciberehd, Barcelona, Spain.
3 Siemens Healthcare Diagnostics, Tarrytown, NY, USA.
*Correspondence: Dr X. Forns, Liver Unit, Hospital Clinic, IDIBAPS and Ciberehd, Villarroel 170, Barcelona 08036, Spain. E-mail: xforns@clinic.ub.es
Abstract
Summary
Background Liver biopsy is the reference standard to assess liver fibrosis in chronic hepatitis C.
Aim To validate and compare the diagnostic performance of non-invasive tests for prediction of liver fibrosis severity and assessed changes in extracellular matrix markers after antiviral treatment.
Methods The performances of Forns’ score, AST to platelet ratio index (APRI), FIB-4 index and Enhanced Liver Fibrosis (ELF) score were validated in 340 patients who underwent antiviral therapy. These scores were determined 24 weeks after treatment in 161 patients.
Results Forns’ score, APRI, FIB-4 and ELF score showed comparable diagnostic accuracies for significant fibrosis [area under the receiver operating characteristic curve (AUROC) 0.83, 0.83, 0.85 and 0.81, respectively]. To identify cirrhosis, FIB-4 index showed a significantly better performance over APRI and ELF score (AUROC 0.89 vs. 0.83 and 0.82, respectively). ELF score decreased significantly in patients with sustained virological response (SVR) (P < 0.0001) but remained unchanged in nonresponders. Non-1 hepatitis C virus (HCV) genotype, baseline lower HCV RNA, glucose, hyaluronic acid and higher cholesterol levels were independently associated with SVR.
Conclusions Simple panel markers and ELF score are accurate at identifying significant fibrosis and cirrhosis in chronic hepatitis C. A decrease in ELF score after antiviral treatment reflects the impact of viral clearance in hepatic extracellular matrix and probably in the improvement of liver fibrosis.
Source
Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial
Alimentary Pharmacology & Therapeutics
Early View (Articles online in advance of print)
N. D. Freedman 1, T. M. Curto 2, C. Morishima 3, L. B. Seeff 4, Z. D. Goodman 5, E. C. Wright 6, R. Sinha 1, J. E. Everhart 7, the HALT-C Trial Group 1
Article first published online: 2 NOV 2010
DOI: 10.1111/j.1365-2036.2010.04503.x
Published 2010. This article is a US Government work and is in the public domain in the USA.
Author Information
1 Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD, USA.
2 New England Research Institutes, Watertown, MA, USA.
3 Division of Virology, Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
4 Division of Digestive Diseases and Nutrition, and Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
5 Division of Hepatic Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.
6 Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
7 Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
* Correspondence: Dr N. D. Freedman, Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, EPS/320, MSC 7232, Rockville, MD 20852, USA. E-mail: freedmanne@mail.nih.gov
Abstract
Summary
Background Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear.
Aim To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment.
Methods Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes.
Results At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33–1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes.
Conclusions Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).
Source
Early View (Articles online in advance of print)
N. D. Freedman 1, T. M. Curto 2, C. Morishima 3, L. B. Seeff 4, Z. D. Goodman 5, E. C. Wright 6, R. Sinha 1, J. E. Everhart 7, the HALT-C Trial Group 1
Article first published online: 2 NOV 2010
DOI: 10.1111/j.1365-2036.2010.04503.x
Published 2010. This article is a US Government work and is in the public domain in the USA.
Author Information
1 Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD, USA.
2 New England Research Institutes, Watertown, MA, USA.
3 Division of Virology, Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
4 Division of Digestive Diseases and Nutrition, and Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
5 Division of Hepatic Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.
6 Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
7 Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
* Correspondence: Dr N. D. Freedman, Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, EPS/320, MSC 7232, Rockville, MD 20852, USA. E-mail: freedmanne@mail.nih.gov
Abstract
Summary
Background Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear.
Aim To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment.
Methods Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes.
Results At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33–1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes.
Conclusions Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).
Source
Subscribe to:
Posts (Atom)