Public release date: 12-Aug-2010
Contact: Shari Leventhal
sleventhal@asn-online.org
202-416-0658
American Society of Nephrology
Careful monitoring of kidney health may be warranted in this population
Poor kidney function is common among injection drug users, particularly those with HIV, according to a study appearing in an upcoming issue of the Clinical Journal of the American Society Nephrology (CJASN). The results suggest that clinicians should monitor the kidney function of HIV-infected injection drug users and consider them candidates for medical treatments to protect their kidneys when appropriate.
HIV-infected individuals are more likely to have kidney disease compared with the general population. This may be due to a direct effect of HIV infection as well as indirect effects related to known risk factors for kidney disease that are commonly present among HIV-infected populations—for example, the presence of other illnesses, toxic effects of antiretroviral medications, low socioeconomic status, and African American race. Research also indicates that injection drug users exhibit increased risk of becoming infected with HIV. While little information is available about the burden of kidney disease in injection drug users, this population's drug use, higher prevalence of viral hepatitis, and poor access to medical care may increase the risk of kidney disease.
To investigate the issue, Shruti H Mehta, PhD (Johns Hopkins Bloomberg School of Public Health) and her colleagues analyzed the presence of proteinuria, or excess excretion of protein in the urine, in HIV-positive and HIV-negative injection drug users. Individuals with proteinuria often develop kidney disease; therefore, screening for proteinuria may help physicians prevent or slow damage to the kidneys.
Researchers analyzed information from 902 injection drug users who were predominantly African American, 273 of whom were infected with HIV. 24.8% had proteinuria and prevalence was 2.9 times higher among HIV-infected (45%) compared with uninfected individuals (16%). HIV infection, unemployment, increased age, diabetes, hepatitis C infection, and high blood pressure were linked to a higher prevalence of proteinuria.
Because proteinuria can lead to kidney failure and increases one's risk of developing cardiovascular disease, clinicians should aggressively screen HIV-infected injection drug users for proteinuria and consider them candidates for medical treatments that protect the heart and kidneys.
###
Study co-authors include Elizabeth Yanik (University of North Carolina-Chapel Hill School of Public Health); Gregory Lucas, MD, PhD (Johns Hopkins School of Medicine); David Vlahov, PhD (New York Academy of Medicine); and Gregory Kirk, MD, PhD (Johns Hopkins Bloomberg School of Public Health and Johns Hopkins School of Medicine).
Disclosures: The authors reported no financial disclosures.
The article, entitled "HIV and Proteinuria in an Injection Drug User Population," will appear online at http://cjasn.asnjournals.org/ on August 12, 2010, doi 10.2215/CJN.01030210.
The content of this article does not reflect the views or opinions of The American Society of Nephrology (ASN). Responsibility for the information and views expressed therein lies entirely with the author(s). ASN does not offer medical advice. All content in ASN publications is for informational purposes only, and is not intended to cover all possible uses, directions, precautions, drug interactions, or adverse effects. This content should not be used during a medical emergency or for the diagnosis or treatment of any medical condition. Please consult your doctor or other qualified health care provider if you have any questions about a medical condition, or before taking any drug, changing your diet or commencing or discontinuing any course of treatment. Do not ignore or delay obtaining professional medical advice because of information accessed through ASN. Call 911 or your doctor for all medical emergencies.
Founded in 1966, the American Society of Nephrology (ASN) is the world's largest professional society devoted to the study of kidney disease. Comprised of 11,000 physicians and scientists, ASN continues to promote expert patient care, to advance medical research, and to educate the renal community. ASN also informs policymakers about issues of importance to kidney doctors and their patients. ASN funds research, and through its world-renowned meetings and first-class publications, disseminates information and educational tools that empower physicians.
Source
August 12, 2010
New Potential Asthma Treatment Discovered By Researchers
Posted by trump44 on Aug 12th, 2010
Researchers believe they may have discovered evidence that a current protein used to treat cancer and other diseases may also be an effective asthma treatment. Interferon is a protein currently used to treat cancer, MS and hepatitis C. Researchers believe the protein will work by blocking the creation of the cells that cause allergic reactions, which is the basic cause of chronic asthma. These cells are created after the body has come in contact with certain animal hair and pollens.
Researchers believe this could be an exciting breakthrough as interferon is already approved and available for use so the usual delays in bringing a medication to market will not be an issue in this case. Another reason researchers are excited about their discovery is that the only asthma treatment available are medications that provide temporary relief and it is possible that interferon could be more of a long term asthma treatment.
Asthma sufferers currently number around 20 million in the United States, many of which are children.
Researchers believe the evidence they have discovered should warrant a clinical trial to see if interferon could become a new asthma treatment therapy.
Julie Peters
Worlds Breaking News
Source
Aplastic anemia associated with interferon alpha 2a in a patient with chronic hepatitis C virus infection: a case report
Introduction
Hepatitis-associated aplastic anemia is a common syndrome in patients with bone marrow failure. However, hepatitis-associated aplastic anemia is an immune-mediated disease that does not appear to be caused by any of the known hepatitis viruses including hepatitis C virus.
In addition, to the best of our knowledge there are no reported cases of patients with chronic hepatitis C virus infection developing aplastic anemia associated with pegylated interferon alpha 2a treatment.Case presentation. We report the case of a 46-year-old Greek man who developed severe aplastic anemia during treatment with pegylated interferon alpha 2a for chronic hepatitis C virus infection. He presented with generalized purpura and bruising, as well as pallor of the skin and mucous membranes.
His blood tests showed pancytopenia. He underwent allogeneic bone marrow transplantation after completing two courses of immunosuppressive therapy with antithymocyte globulin and cyclosporin A.
Conclusions:
The combination of a specific environmental precipitant represented by the hepatitis C virus infection, an altered metabolic detoxification pathway due to treatment with pegylated interferon alpha 2a and a facilitating genetic background such as polymorphism in metabolic detoxification pathways and specific human leukocyte antigen genes possibly conspired synergistically in the development of aplastic anemia in this patient.
Our case clearly shows that the causative role of pegylated interferon alpha 2a in the development of aplastic anemia must not be ignored.
Author: Savvas Ioannou Gregorios Hatzis Ioanna Vlahadami Michael Voulgarelis
Credits/Source: Journal of Medical Case Reports 2010, 4:268
Published on: 2010-08-12
Source
Hepatitis-associated aplastic anemia is a common syndrome in patients with bone marrow failure. However, hepatitis-associated aplastic anemia is an immune-mediated disease that does not appear to be caused by any of the known hepatitis viruses including hepatitis C virus.
In addition, to the best of our knowledge there are no reported cases of patients with chronic hepatitis C virus infection developing aplastic anemia associated with pegylated interferon alpha 2a treatment.Case presentation. We report the case of a 46-year-old Greek man who developed severe aplastic anemia during treatment with pegylated interferon alpha 2a for chronic hepatitis C virus infection. He presented with generalized purpura and bruising, as well as pallor of the skin and mucous membranes.
His blood tests showed pancytopenia. He underwent allogeneic bone marrow transplantation after completing two courses of immunosuppressive therapy with antithymocyte globulin and cyclosporin A.
Conclusions:
The combination of a specific environmental precipitant represented by the hepatitis C virus infection, an altered metabolic detoxification pathway due to treatment with pegylated interferon alpha 2a and a facilitating genetic background such as polymorphism in metabolic detoxification pathways and specific human leukocyte antigen genes possibly conspired synergistically in the development of aplastic anemia in this patient.
Our case clearly shows that the causative role of pegylated interferon alpha 2a in the development of aplastic anemia must not be ignored.
Author: Savvas Ioannou Gregorios Hatzis Ioanna Vlahadami Michael Voulgarelis
Credits/Source: Journal of Medical Case Reports 2010, 4:268
Published on: 2010-08-12
Source
Which Roads Lead to NASH?
Posted on July 17, 2010 by Kristine Novak, PhD, Science Editor
The progressive liver disease nonalcoholic steatohepatitis (NASH) is mediated by an innate immune response in the liver that causes tissue damage and fibrosis. The innate immune system protects against invading pathogens, but it’s not clear how it becomes activated in livers of patients with NASH. In the July issue of Gastroenterology, Kouichi Miura et al. describe an immune signaling pathway that controls the development of NASH in livers of mice.
Miura et al. induced steatohepatitis in mice by feeding them a choline-deficient amino-acid–defined diet (CDAA). In patients with NASH, Kupffer cells (liver macrophages) produce inflammatory and fibrogenic factors that activate hepatic stellate cells (HSCs) to produce inflammatory cytokines such as interleukin (IL)-1b. What activates these Kupffer cells? Kupffer cells and other cells of the innate immune system express Toll-like receptors (TLRs), which recognize microbial structures and activate production of inflammatory cytokines. So, Miura et al. induced NASH in mice that that did not express a TLR that had been previously associated with liver injury–TLR9, which recognizes bacterial DNA.
Livers of TLR9-null mice developed less steatosis, fibrosis, and inflammation than wild-type mice fed the CDAA diet, and Kupffer cells of the TLR9-null mice did not produce IL-1b. They found that Kupffer cell production of IL-1b promoted NASH by increasing lipid accumulation in hepatocytes and death of these liver cells; it also activated the fibrogenic response of HSCs. Mice that lacked the receptor for IL-1b (IL-1R) or had disruptions in other components of the IL-1R signaling pathway did not develop NASH. The IL-1 signaling pathway therefore mediates disease pathogenesis in these mice.
Previous studies have shown that lipopolysaccharide (LPS), a gut bacteria-derived endotoxin that activates another TLR, TLR4, also induces Kupffer cell activity and can cause NASH. Further studies are needed to learn whether TLR4 and TLR9 have synergistic effects in NASH progression. In patients, Kupffer cells, as well as other liver cells, might encounter bacteria-derived components such as LPS and DNA, simultaneously or sequentially, to activated TLR4 and TLR9 on Kupffer cells and initiate the pathogenic process.
Other liver cell types besides Kupffer cells are also probably involved in the pathogenesis of NASH, and it is not clear what ligands actually activate TLRs in patients with NASH. Bacterial DNA was detected in blood taken from mice on the CDAA diet, so DNA derived from gut bacteria might activate TLR9. TLR9 can also recognize DNA released from necrotic hepatocytes to activate liver inflammation and injury—another potential pathway to NASH.
Miura K, Kodama Y, Inokuchi S, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1β in mice. Gastroenterology 2010;139: 323–334.
Read the article online at Gastroenterology. This article has accompanying CME.
Read the accompanying editorial: Gao B. Innate immunity and steatohepatitis: A critical role of another toll (TLR-9). Gastroenterology 2010;139: 27–30.
Source
The progressive liver disease nonalcoholic steatohepatitis (NASH) is mediated by an innate immune response in the liver that causes tissue damage and fibrosis. The innate immune system protects against invading pathogens, but it’s not clear how it becomes activated in livers of patients with NASH. In the July issue of Gastroenterology, Kouichi Miura et al. describe an immune signaling pathway that controls the development of NASH in livers of mice.
Miura et al. induced steatohepatitis in mice by feeding them a choline-deficient amino-acid–defined diet (CDAA). In patients with NASH, Kupffer cells (liver macrophages) produce inflammatory and fibrogenic factors that activate hepatic stellate cells (HSCs) to produce inflammatory cytokines such as interleukin (IL)-1b. What activates these Kupffer cells? Kupffer cells and other cells of the innate immune system express Toll-like receptors (TLRs), which recognize microbial structures and activate production of inflammatory cytokines. So, Miura et al. induced NASH in mice that that did not express a TLR that had been previously associated with liver injury–TLR9, which recognizes bacterial DNA.
The development of NASH through TLR9 and TLR4 on Kupffer cells.
Livers of TLR9-null mice developed less steatosis, fibrosis, and inflammation than wild-type mice fed the CDAA diet, and Kupffer cells of the TLR9-null mice did not produce IL-1b. They found that Kupffer cell production of IL-1b promoted NASH by increasing lipid accumulation in hepatocytes and death of these liver cells; it also activated the fibrogenic response of HSCs. Mice that lacked the receptor for IL-1b (IL-1R) or had disruptions in other components of the IL-1R signaling pathway did not develop NASH. The IL-1 signaling pathway therefore mediates disease pathogenesis in these mice.
Previous studies have shown that lipopolysaccharide (LPS), a gut bacteria-derived endotoxin that activates another TLR, TLR4, also induces Kupffer cell activity and can cause NASH. Further studies are needed to learn whether TLR4 and TLR9 have synergistic effects in NASH progression. In patients, Kupffer cells, as well as other liver cells, might encounter bacteria-derived components such as LPS and DNA, simultaneously or sequentially, to activated TLR4 and TLR9 on Kupffer cells and initiate the pathogenic process.
Other liver cell types besides Kupffer cells are also probably involved in the pathogenesis of NASH, and it is not clear what ligands actually activate TLRs in patients with NASH. Bacterial DNA was detected in blood taken from mice on the CDAA diet, so DNA derived from gut bacteria might activate TLR9. TLR9 can also recognize DNA released from necrotic hepatocytes to activate liver inflammation and injury—another potential pathway to NASH.
Miura K, Kodama Y, Inokuchi S, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1β in mice. Gastroenterology 2010;139: 323–334.
Read the article online at Gastroenterology. This article has accompanying CME.
Read the accompanying editorial: Gao B. Innate immunity and steatohepatitis: A critical role of another toll (TLR-9). Gastroenterology 2010;139: 27–30.
Source
Predictors of Early Treatment Discontinuation Among Patients with Genotype 1 Hepatitis C and Implications for Viral Eradication.
Clin Gastroenterol Hepatol. 2010 Aug 5. [Epub ahead of print]
Beste LA, Ioannou GN, Larson M, Chapko M, Dominitz JA.
Health Services Research and Development Center of Excellence, VA Puget Sound Healthcare System, Seattle WA; Northwest Hepatitis C Resource Center, VA Puget Sound Healthcare System, Seattle WA; Division of General Internal Medicine, VA Puget Sound Healthcare System.
Abstract
BACKGROUND & AIMS: A significant proportion of patients with hepatitis C virus (HCV) infection discontinue antiviral treatment prematurely. Risk factors for discontinuation before 48 weeks among patients with genotype 1 HCV vary over the course of therapy. We investigated the rates and risk factors for treatment discontinuation within 12 weeks, 12-24 weeks, and 24-48 weeks after therapy began. METHODS: We retrospectively evaluated data from all Veterans Affairs (VA) patients with genotype 1 HCV who initiated pegylated interferon and ribavirin therapy from 2002 to 2007 (n=11,019). We accounted for appropriate discontinuation because of lack of viral response. RESULTS: Overall, 53% of patients completed at least 38.4 weeks of therapy (80% of the projected 48 weeks), 16.5% discontinued early because of viral nonresponse, and 30.9% discontinued despite viral response or in the absence of virologic data. Cirrhosis, diabetes, pre-treatment substance use disorder, lower baseline concentration of hemoglobin, and lack of hematopoietic growth factor use independently predicted discontinuation within the first 12 weeks (P<.05 for all). Among patients with documented early virologic responses, higher baseline levels of creatinine, depression, and lack of growth factor use predicted discontinuation from 12 to 24 weeks. No factors independently predicted discontinuation from 24 to 48 weeks among patients that responded to treatment at 24 weeks. CONCLUSION: Early discontinuation of antiviral therapy is common. Use of growth factors was the strongest independent predictor of treatment retention before 24 weeks and should be evaluated prospectively. Early interventions are also warranted for other risk factors for early discontinuation, such as pre-existing substance use, depression, comorbid cirrhosis, or diabetes. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID: 20692371 [PubMed - as supplied by publisher]
Source
Beste LA, Ioannou GN, Larson M, Chapko M, Dominitz JA.
Health Services Research and Development Center of Excellence, VA Puget Sound Healthcare System, Seattle WA; Northwest Hepatitis C Resource Center, VA Puget Sound Healthcare System, Seattle WA; Division of General Internal Medicine, VA Puget Sound Healthcare System.
Abstract
BACKGROUND & AIMS: A significant proportion of patients with hepatitis C virus (HCV) infection discontinue antiviral treatment prematurely. Risk factors for discontinuation before 48 weeks among patients with genotype 1 HCV vary over the course of therapy. We investigated the rates and risk factors for treatment discontinuation within 12 weeks, 12-24 weeks, and 24-48 weeks after therapy began. METHODS: We retrospectively evaluated data from all Veterans Affairs (VA) patients with genotype 1 HCV who initiated pegylated interferon and ribavirin therapy from 2002 to 2007 (n=11,019). We accounted for appropriate discontinuation because of lack of viral response. RESULTS: Overall, 53% of patients completed at least 38.4 weeks of therapy (80% of the projected 48 weeks), 16.5% discontinued early because of viral nonresponse, and 30.9% discontinued despite viral response or in the absence of virologic data. Cirrhosis, diabetes, pre-treatment substance use disorder, lower baseline concentration of hemoglobin, and lack of hematopoietic growth factor use independently predicted discontinuation within the first 12 weeks (P<.05 for all). Among patients with documented early virologic responses, higher baseline levels of creatinine, depression, and lack of growth factor use predicted discontinuation from 12 to 24 weeks. No factors independently predicted discontinuation from 24 to 48 weeks among patients that responded to treatment at 24 weeks. CONCLUSION: Early discontinuation of antiviral therapy is common. Use of growth factors was the strongest independent predictor of treatment retention before 24 weeks and should be evaluated prospectively. Early interventions are also warranted for other risk factors for early discontinuation, such as pre-existing substance use, depression, comorbid cirrhosis, or diabetes. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID: 20692371 [PubMed - as supplied by publisher]
Source
Crucell and Harvard to Test Experimental AIDS Vaccine in Uninfected Adults
August 11, 2010
The pharmaceutical company Crucell, in collaboration with Harvard University, "plans to test its experimental AIDS vaccine in the U.S. and in Africa, advancing the quest for a protective shot against" HIV, Bloomberg reports. The trial will test the vaccine in uninfected adults "to assess its safety and ability to prompt an immune response ... the company said in a statement." Bloomberg continues, "The vaccine combines shots ... in a so-called prime-boost approach that's designed to both kill infected cells and prevent HIV from entering those that are uninfected" (Bennett, 8/11).
Source
Aug. 11, 2010, 2:00 a.m. EDT
Crucell and Harvard (BIDMC) Join Forces with IAVI to Advance AdVac(R)-based AIDS Vaccine
LEIDEN, NETHERLANDS, Aug 11, 2010 (MARKETWIRE via COMTEX) -- Dutch biopharmaceutical company Crucell N.V. (NYSE Euronext, NASDAQ: CRXL) (SWISS: CRX) today announces its intention to participate in an international Phase I clinical trial in the United States and Africa of a combination of two AdVac(R)-based AIDS vaccine candidates, Ad26.ENVA.01 and Ad35-ENV, in healthy adults who are not infected with HIV. The clinical trial, which will be led by the International AIDS Vaccine Initiative (IAVI), represents a collaboration between IAVI, Crucell, the Ragon Institute, and Beth Israel Deaconess Medical Center (BIDMC), a major teaching hospital of Harvard Medical School.
The Ad26.ENVA.01 vaccine candidate used in this study is manufactured by Crucell, while the Ad35-ENV vaccine is developed by IAVI. Both vaccines candidates are based on Crucell's proprietary AdVac(R) technology. The planned Phase 1 trial of the vaccine combination, which follows a Phase I trial of the Ad35-ENV vaccine by IAVI and a Phase I trial of Ad26.ENVA.01 by the Harvard-Crucell consortium, supported by the National Institute of Allergy and Infectious Diseases (NIAID), represents a key step towards proof of concept studies to evaluate the efficacy of the vaccine combination in humans.
The Phase I trial is designed to test two AIDS vaccine candidates in a prime-boost combination in HIV-uninfected healthy adult volunteers. The objectives are to evaluate the safety of the candidate vaccines Ad26.ENVA.01 and Ad35-ENV and their ability to provoke an immune response when administered in a prime-boost regimen.
"We are very happy that IAVI has decided to support the NIAID- sponsored Crucell-Harvard AIDS vaccine program, making it possible to advance this vaccine candidate further towards proof of concept Phase IIb efficacy trials in humans," said Jaap Goudsmit, Chief Scientific Officer at Crucell. "A different prime-boost AIDS vaccine approach has been shown in the RV144 trial (Thai Trial) to protect against HIV in humans, for the first time in the history of AIDS vaccine development. Our program to develop this combination vaccine represents one of the most advanced AIDS vaccine programs in the world and is based on the best science available today. We have the obligation as vaccine producers to do everything in our power to bring an effective AIDS vaccine to all people in need."
About Crucell
Crucell N.V. /quotes/comstock/15*!crxl/quotes/nls/crxl (CRXL 20.22, -0.06, -0.30%) (SWISS: CRX) is a global biopharmaceutical company focused on research development, production and marketing of vaccines, proteins and antibodies that prevent and/or treat infectious diseases. In 2009 alone, Crucell distributed more than 115 million vaccine doses in more than 100 countries around the world, with the fast majority of doses (97%) going to developing countries. Crucell is one of the major suppliers of vaccines to UNICEF and the developing world. Crucell was the first manufacturer to launch a fully-liquid pentavalent vaccine. Called Quinvaxem(R), this innovative combination vaccine protects against five important childhood diseases. Over 130 million doses have been sold since its launch in 2006 in more than 50 GAVI countries. With this innovation, Crucell has become a major partner in protecting children in developing countries. Other products in Crucell's core portfolio include a vaccine against hepatitis B and a virosome-adjuvanted vaccine against influenza. Crucell also markets travel vaccines, such as an oral anti-typhoid vaccine, an oral cholera vaccine and the only aluminum-free hepatitis A vaccine on the market. The Company has a broad development pipeline, with several product candidates based on its unique PER.C6(R) production technology. The Company licenses its PER.C6(R) technology and other technologies to the biopharmaceutical industry. Important partners and licensees include Johnson & Johnson, DSM Biologics, sanofi-aventis, Novartis, Wyeth, GSK, CSL and Merck & Co. Crucell is headquartered in Leiden, the Netherlands, with offices in China, Indonesia, Italy, Korea, Malaysia, Spain, Sweden, Switzerland, UK, the USA and Vietnam. The Company employs over 1200 people. For more information, please visit http://www.crucell.com/.
About Crucell's AdVac(R) technology
AdVac(R) technology is a vaccine technology developed by Crucell. It is considered to play an important role in the fight against emerging and re-emerging infectious diseases, and in biodefense. The technology supports the practice of inserting genetic material from the disease-causing virus or parasite into a 'vehicle' called a vector, which then delivers the immunogenic material directly to the immune system. Most vectors are based on an adenovirus, such as the virus that causes the common cold. The AdVac(R) technology is specifically designed to manage the problem of pre-existing immunity in humans against the most commonly used recombinant vaccine vector, adenovirus serotype 5 (Ad5), without compromising large-scale production capabilities or the immunogenic properties of Ad5. AdVac(R) technology is based on adenoviruses that occur less frequently in the human population, such as Ad26 and Ad35. In contrast to, for instance, Ad35 antibodies, antibodies to Ad5 are widespread among people of all ages and are known to lower the immune response to Ad5- based vaccines, thereby impairing the efficacy of these vaccines. All vaccine candidates based on AdVac(R) are produced using Crucell's PER.C6(R) production technology.
About the Crucell-Harvard (BIDMC) AIDS/HIV Vaccine (Phase I)
In April 2008, Crucell announced the start of a Phase I clinical study of the novel recombinant HIV vaccine. The vaccine is based on Crucell's AdVac(R) and PER.C6(R) technologies, using adenovirus serotype 26 (rAd26) as vector, and is jointly developed by Crucell and the BIDMC, funded by a grant from the US National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. The rAd26 vector is designed to avoid pre- existing neutralizing antibodies to the more commonly used adenovirus serotype 5 (Ad5). Phase I clinical studies are being conducted at the Brigham and Women's Hospital in Boston, USA and are focused on assessing the safety and immunogenicity of the vaccine in several trials including single and multi-dose regimens. In October 2009, preliminary results of the Phase I study were presented at La Conference AIDS Vaccine 2009 in Paris, France. The presentation was given by Dr Dan H. Barouch, MD, PhD, Associate Professor of Medicine, Division of Vaccine Research, Department of Medicine, BIDMC, Boston, USA. The preliminary results of this study show that a 3-dose regimen of this HIV candidate vaccine is safe and immunogenic.
About the International AIDS Vaccine Initiative (IAVI)
IAVI's core mission is to support in every way the development of preventive AIDS vaccines that are not only safe and effective, but also accessible to all people. To that end, IAVI invests the bulk of its resources in the research and clinical assessment of candidate vaccines against strains of HIV that are prevalent in the developing world, where some 95% of new HIV infections occur. For more information, visit http://www.iavi.org/.
About Beth Israel Deaconess Medical Center (BIDMC)
BIDMC is a patient care, teaching and research affiliate of Harvard Medical School, and consistently ranks in the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana- Farber/Harvard Cancer Care Center. For more information, visit http://www.bidmc.org/.
Forward-looking statements
This press release contains forward-looking statements that involve inherent risks and uncertainties. We have identified certain important factors that may cause actual results to differ materially from those contained in such forward-looking statements. For information relating to these factors please refer to our Form 20-F, as filed with the US Securities and Exchange Commission on April 7, 2010, in the section entitled 'Risk Factors'. The Company prepares its financial statements under International Financial Reporting Standards (IFRS).
For further information please contact Crucell:
Oya Yavuz
Vice President Corporate Communications & Investor Relations
Tel. +31 (0)71 519 7064
ir@crucell.com
http://www.crucell.com/
Source
The pharmaceutical company Crucell, in collaboration with Harvard University, "plans to test its experimental AIDS vaccine in the U.S. and in Africa, advancing the quest for a protective shot against" HIV, Bloomberg reports. The trial will test the vaccine in uninfected adults "to assess its safety and ability to prompt an immune response ... the company said in a statement." Bloomberg continues, "The vaccine combines shots ... in a so-called prime-boost approach that's designed to both kill infected cells and prevent HIV from entering those that are uninfected" (Bennett, 8/11).
Source
Aug. 11, 2010, 2:00 a.m. EDT
Crucell and Harvard (BIDMC) Join Forces with IAVI to Advance AdVac(R)-based AIDS Vaccine
LEIDEN, NETHERLANDS, Aug 11, 2010 (MARKETWIRE via COMTEX) -- Dutch biopharmaceutical company Crucell N.V. (NYSE Euronext, NASDAQ: CRXL) (SWISS: CRX) today announces its intention to participate in an international Phase I clinical trial in the United States and Africa of a combination of two AdVac(R)-based AIDS vaccine candidates, Ad26.ENVA.01 and Ad35-ENV, in healthy adults who are not infected with HIV. The clinical trial, which will be led by the International AIDS Vaccine Initiative (IAVI), represents a collaboration between IAVI, Crucell, the Ragon Institute, and Beth Israel Deaconess Medical Center (BIDMC), a major teaching hospital of Harvard Medical School.
The Ad26.ENVA.01 vaccine candidate used in this study is manufactured by Crucell, while the Ad35-ENV vaccine is developed by IAVI. Both vaccines candidates are based on Crucell's proprietary AdVac(R) technology. The planned Phase 1 trial of the vaccine combination, which follows a Phase I trial of the Ad35-ENV vaccine by IAVI and a Phase I trial of Ad26.ENVA.01 by the Harvard-Crucell consortium, supported by the National Institute of Allergy and Infectious Diseases (NIAID), represents a key step towards proof of concept studies to evaluate the efficacy of the vaccine combination in humans.
The Phase I trial is designed to test two AIDS vaccine candidates in a prime-boost combination in HIV-uninfected healthy adult volunteers. The objectives are to evaluate the safety of the candidate vaccines Ad26.ENVA.01 and Ad35-ENV and their ability to provoke an immune response when administered in a prime-boost regimen.
"We are very happy that IAVI has decided to support the NIAID- sponsored Crucell-Harvard AIDS vaccine program, making it possible to advance this vaccine candidate further towards proof of concept Phase IIb efficacy trials in humans," said Jaap Goudsmit, Chief Scientific Officer at Crucell. "A different prime-boost AIDS vaccine approach has been shown in the RV144 trial (Thai Trial) to protect against HIV in humans, for the first time in the history of AIDS vaccine development. Our program to develop this combination vaccine represents one of the most advanced AIDS vaccine programs in the world and is based on the best science available today. We have the obligation as vaccine producers to do everything in our power to bring an effective AIDS vaccine to all people in need."
About Crucell
Crucell N.V. /quotes/comstock/15*!crxl/quotes/nls/crxl (CRXL 20.22, -0.06, -0.30%) (SWISS: CRX) is a global biopharmaceutical company focused on research development, production and marketing of vaccines, proteins and antibodies that prevent and/or treat infectious diseases. In 2009 alone, Crucell distributed more than 115 million vaccine doses in more than 100 countries around the world, with the fast majority of doses (97%) going to developing countries. Crucell is one of the major suppliers of vaccines to UNICEF and the developing world. Crucell was the first manufacturer to launch a fully-liquid pentavalent vaccine. Called Quinvaxem(R), this innovative combination vaccine protects against five important childhood diseases. Over 130 million doses have been sold since its launch in 2006 in more than 50 GAVI countries. With this innovation, Crucell has become a major partner in protecting children in developing countries. Other products in Crucell's core portfolio include a vaccine against hepatitis B and a virosome-adjuvanted vaccine against influenza. Crucell also markets travel vaccines, such as an oral anti-typhoid vaccine, an oral cholera vaccine and the only aluminum-free hepatitis A vaccine on the market. The Company has a broad development pipeline, with several product candidates based on its unique PER.C6(R) production technology. The Company licenses its PER.C6(R) technology and other technologies to the biopharmaceutical industry. Important partners and licensees include Johnson & Johnson, DSM Biologics, sanofi-aventis, Novartis, Wyeth, GSK, CSL and Merck & Co. Crucell is headquartered in Leiden, the Netherlands, with offices in China, Indonesia, Italy, Korea, Malaysia, Spain, Sweden, Switzerland, UK, the USA and Vietnam. The Company employs over 1200 people. For more information, please visit http://www.crucell.com/.
About Crucell's AdVac(R) technology
AdVac(R) technology is a vaccine technology developed by Crucell. It is considered to play an important role in the fight against emerging and re-emerging infectious diseases, and in biodefense. The technology supports the practice of inserting genetic material from the disease-causing virus or parasite into a 'vehicle' called a vector, which then delivers the immunogenic material directly to the immune system. Most vectors are based on an adenovirus, such as the virus that causes the common cold. The AdVac(R) technology is specifically designed to manage the problem of pre-existing immunity in humans against the most commonly used recombinant vaccine vector, adenovirus serotype 5 (Ad5), without compromising large-scale production capabilities or the immunogenic properties of Ad5. AdVac(R) technology is based on adenoviruses that occur less frequently in the human population, such as Ad26 and Ad35. In contrast to, for instance, Ad35 antibodies, antibodies to Ad5 are widespread among people of all ages and are known to lower the immune response to Ad5- based vaccines, thereby impairing the efficacy of these vaccines. All vaccine candidates based on AdVac(R) are produced using Crucell's PER.C6(R) production technology.
About the Crucell-Harvard (BIDMC) AIDS/HIV Vaccine (Phase I)
In April 2008, Crucell announced the start of a Phase I clinical study of the novel recombinant HIV vaccine. The vaccine is based on Crucell's AdVac(R) and PER.C6(R) technologies, using adenovirus serotype 26 (rAd26) as vector, and is jointly developed by Crucell and the BIDMC, funded by a grant from the US National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. The rAd26 vector is designed to avoid pre- existing neutralizing antibodies to the more commonly used adenovirus serotype 5 (Ad5). Phase I clinical studies are being conducted at the Brigham and Women's Hospital in Boston, USA and are focused on assessing the safety and immunogenicity of the vaccine in several trials including single and multi-dose regimens. In October 2009, preliminary results of the Phase I study were presented at La Conference AIDS Vaccine 2009 in Paris, France. The presentation was given by Dr Dan H. Barouch, MD, PhD, Associate Professor of Medicine, Division of Vaccine Research, Department of Medicine, BIDMC, Boston, USA. The preliminary results of this study show that a 3-dose regimen of this HIV candidate vaccine is safe and immunogenic.
About the International AIDS Vaccine Initiative (IAVI)
IAVI's core mission is to support in every way the development of preventive AIDS vaccines that are not only safe and effective, but also accessible to all people. To that end, IAVI invests the bulk of its resources in the research and clinical assessment of candidate vaccines against strains of HIV that are prevalent in the developing world, where some 95% of new HIV infections occur. For more information, visit http://www.iavi.org/.
About Beth Israel Deaconess Medical Center (BIDMC)
BIDMC is a patient care, teaching and research affiliate of Harvard Medical School, and consistently ranks in the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana- Farber/Harvard Cancer Care Center. For more information, visit http://www.bidmc.org/.
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Source
Ribavirin Dosage in Patients with HCV Genotypes 2 and 3 Who Completed Short Therapy with Peg-interferon α-2b and Ribavirin
A. Mangia; O. Dalgard; N. Minerva; H. Verbaan; D. Bacca; H. Ring-Larsen; M. Copetti; V. Carretta; V. Piazzolla; R. Cozzolongo; L. Mottola; A. Andriulli
Posted: 08/11/2010; Alimentary Pharmacology & Therapeutics. 2010;31(12):1346-1353.
© 2010 Blackwell Publishing
Abstract and Introduction
Abstract
Background The optimal dose of ribavirin to be used in combination with Peg-IFN in patients with HCV genotypes 2 and 3 undergoing short treatment has not been established.
Aim To explore the relationship between starting ribavirin doses, expressed as mg/kg body weight and both rapid viral response at treatment week 4 (RVR) and sustained virological response (SVR) in patients treated for 12–14 weeks with peg-interferon α-2b and ribavirin.
Methods A post hoc analysis of data collected from two multicenter clinical trials was performed. Multiple regression analyses were employed to identify independent baseline and on-treatment predictors of RVR and SVR. For each dose of ribavirin, the empirical estimated probability of response was computed and the continuous exposure index was dichotomized by using a recursive partitioning and amalgamation method.
Results A nonlinear relationship was ascertained between ribavirin dose and RVR, but not SVR. A dose of 15.2 mg/kg was selected as the best splitting value for discriminating RVR vs. non-RVR. Regression analysis identified low baseline viraemia, genotype 2 and high ribavirin dose as independent prognostic factors for RVR. The likelihood of an SVR was not correlated with baseline ribavirin dose, but was independently predicted by adherence to the full dose throughout treatment and normal platelet counts.
Conclusions Starting high ribavirin doses appears capable of increasing the rate of RVR in patients with HCV genotypes 2 and 3 undergoing short treatment. Maintenance of the full planned dose throughout treatment is essential for achieving optimal SVR rates.
Introduction
The benefit of short (12 or 14 weeks) therapy with Peg-Interferon (Peg-IFN) in combination with ribavirin for patients with chronic HCV genotype 2 or genotype 3 infection has been documented in recent clinical investigations.[1–6] Patients who will benefit the most by short therapy are lean, noncirrhotic individuals capable of clearing the virus at treatment week 4.[7] This experimental evidence has been incorporated in some, but not all, treatment guidelines issued by scientific societies[8–10] and hence, uncertainties still remain about implementing short therapy in everyday clinical practice. Indeed, a clear-cut benefit of short therapy in comparison with the standard 24-week treatment did not emerge in some other clinical trials.[11, 12]
A controversial issue in genotypes 2 and 3 therapy that might explain part of previous inconsistencies across trials is the optimal dose of ribavirin to be used in combination with Peg-IFN: whenever ribavirin was given at higher dosage (800–1400 mg daily, according to body weight) than the one currently recommended (800 mg daily), the benefit of short therapy appeared evident;[1–4] on the contrary, when the administered dosage was the fixed 800 mg daily dosage,[11, 12] the benefit waned off.
The predominant mechanism(s) of ribavirin action against HCV is (are) yet to be established. Although ribavirin monotherapy imposes a transient HCV decline early on therapy, the drug has no apparent long-term effect on serum HCV RNA levels;[13, 14] however, in combination with interferon, it dramatically improves the success of therapy. In naïve patients undergoing treatment with conventional interferon and ribavirin, higher ribavirin concentrations were associated with a higher likelihood of response.[15] Plasma ribavirin concentrations have been shown to correlate with the starting dose of the drug,[15] and therefore selecting appropriate starting dose and maintaining it throughout treatment impact positively on therapeutic outcome. In genotype 1 patients, the probability of achieving a sustained virological response (SVR) increased as a function of the ribavirin dose (mg/kg of body weight), with a 40–50% increase for a 12–16 mg/kg dose.[16] Data are less clear for genotypes 2 and 3 infection, as a single study failed to prove a correlation between probability of SVR after 24 weeks of treatment and the ribavirin dose.[16] Although debate is ongoing as to which ribavirin dosage should be administered in combination with Peg-IFN, it is clear that ribavirin activity is dose/exposure-dependent[15, 16] and selecting and maintaining the optimal dose of the drug might be crucial for a successful therapy. This concept might apply particularly when considering short treatment duration. The objective of this analysis was to explore the relationship between starting ribavirin and both rapid viral response at treatment week 4 (RVR) and SVR in patients with genotypes 2 and 3 undergoing short (12 or 14 weeks) therapy with ribavirin and Peg-IFN α-2b.
Patients and Methods
Study Subjects
Data used in this analysis were collected from two multicentre clinical trials, run in Italy and Scandinavia, in naïve patients with genotypes 2 and 3. The complete inclusion and exclusion criteria, study design and primary results are available elsewhere.[5, 7] The primary efficacy objective of these trials was to compare SVR following Peg-IFN α-2b (Peg-Intron; Schering-Plough, Kenilworth, NJ, USA) plus ribavirin administered for short (12 or 14 weeks respectively) or standard (24 weeks) duration. All patients received Peg-IFN α-2b 1.5 μg/kg subcutaneously weekly together with ribavirin administered orally. In the study by Mangia et al.,[7] 718 patients were treated with Peg-IFN α-2b plus ribavirin 1000 or 1200 mg/day on the basis of body weight higher or lower than 75 kg; 496 patients with week 4 viral clearance (labelled as rapid virological responders, RVR) were allocated to 12-week treatment duration, whereas those without RVR were given therapy for 24 weeks. Italian patients with missing serum creatinine values at baseline were not included in the present analysis. In the 428 patients enrolled in the trial by Dalgard et al.,[5] ribavirin dose varied according to body weight as follows: 800 mg for body weight <65 kg, 1000 mg for body weight ranging from 65 to 85 kg, 1200 for body weight ranging from 85 to 105 kg and 1400 for body weight >105 kg. For the sake of homogeneity with the design of the Italian study, of the original 428 Scandinavian patients, only 148 individuals with RVR who were treated for 14 weeks and 130 non-RVR patients whose treatment lasted 24 weeks were considered eligible for the present investigation; the remaining 150 patients with RVR who were treated for the standard 24 weeks were excluded. Among Scandinavian patients considered eligible, only 10 had body weight >105 kg and required 1400 mg; therefore, the combined database allowed us to evaluate a large series of patients, including a comparable number of genotypes 2 and 3, who received similar dosages of ribavirin.
Per protocol, the ribavirin dose had to be reduced by 200 mg daily in patients who experienced a decrease in haemoglobin level of more than 2 g/dL during treatment, and by 400 mg daily if haemoglobin levels decreased to less than 10 g/dL. Ribavirin was discontinued if haemoglobin levels decreased to less than 8.5 g/dL. The use of erythropoietin was not allowed. Anaemia was defined as haemoglobin concentration <10 g/dL documented on at least one occasion during the studies. For patients who were intolerant to Peg-IFN α-2b, dose reductions in decrements of 12% of the assigned dose were allowed.
Analytical Methods
Definitions: The HCV RNA level was measured using the COBAS AMPLICOR HCV Test [(Roche Molecular Systems, Branchburg, NJ, USA), version 2.0; limit of detection 50 IU/mL]. Rapid virological response (RVR) was defined as undetectable serum HCV RNA at treatment week 4. End-of-treatment response (ETR) was defined as undetectable HCV RNA at weeks 12, 14 or 24 according to the different therapeutic regimens and SVR was defined as undetectable HCV RNA at the end of a 24-week follow-up period.
Statistical Analysis
As the primary objective of the present study was to explore the impact of ribavirin dose on both RVR and SVR, only patients who could tolerate anti-viral drugs for the planned length of therapy were retained in the analysis. Patients who had reduction in ribavirin and/or Peg-IFN at some point during treatment but completed the planned treatment duration were retained. Consequently, of the total 905 eligible patients enrolled in the two previous trials, only 673 patients (405 from the Italian cohort and 268 from the Scandinavian cohort) were retained. Of the 232 excluded patients, 120 had no serum creatinine available for glomerular filtration (GFR) rate calculation and 112 (10 among patients treated for 12–14 weeks and 102 among those treated for 24 weeks) had a premature treatment discontinuation for major side effects or were lost to follow-up.
Baseline patient characteristics were reported as frequencies and groups were compared with Pearson chi-square. Multiple logistic regression analyses were employed to identify independent baseline and on-treatment predictors of RVR and SVR, with age, gender, body mass index, genotype, baseline viraemia, platelet count, aspartate aminotransferase-to-platelet ratio index (APRI) score[17, 18] and starting ribavirin dose as dependent variables. An exploratory analysis was made to assess the nature of the relationship between dose of ribavirin adjusted for GFR and response probability: for each dose, the empirical estimated probability of response was computed. Moreover, the continuous exposure index was dichotomized using the best splitting value by using a Recursive Partitioning and Amalgamation (RECPAM) method.[19] All analyses were performed using SAS release 9.1 (SAS Institute, Cary, NC, USA). Two-tailed P-values <0.05 were considered significant.
Results
Characteristics of Patients
Baseline features of patients derived from the two studies are outlined in Table 1. There were differences in demographics, serum biochemistry and virological features of patients from the two cohorts: in the Scandinavian cohort, patients were as a mean 10 years younger, had a prevalent genotype 3 infection and lower frequency of advanced liver damage, as indicated by the lower proportion of individuals with low platelet counts and APRI score >2. Conversely, a higher proportion of Italian patients received a high (≥15 mg/kg) dose of ribavirin, a finding that might be related to differences in the schedule of ribavirin administration between the two studies: a more stringent weight-related dosing in the Scandinavian trial, and a looser relation to body weight in the Italian study.
Sustained virological response rates and predictability of SVR by RVR in accordance with the different duration of treatment are reported in Table 2.
Impact of Ribavirin Dosing on Rapid Virological Response
No patient had to reduce the ribavirin dose by treatment week 4, so that the relationship between starting ribavirin dose and the probability of RVR could be detailed. As shown in Figure 1, the dose of ribavirin, expressed in mg/kg of body weight, may be a determining factor of RVR in genotype 2 and 3 patients: the probability of RVR increased with increasing ribavirin dose. However, the relationship was a nonlinear one and the probability increased from approximately 54% to 80% for a ribavirin dose increase from 13 to 15.2 mg/kg. The dose of 15.2 mg/kg was determined as the best splitting value for discriminating RVR vs. non-RVR: among the 147 patients receiving a dose of ribavirin higher than 15 mg/kg, an 80% probability of achieving an RVR was observed, while for the 528 patients who received a lower dose, the RVR rate was 67%. At the univariate analysis of predictors of RVR, body mass index, genotype, viral load and ribavirin dose were significantly associated with RVR (Table 3). Multiple logistic regression analysis identified low baseline viraemia (<400 000 IU/mL) (OR = 2.5; 95% CI 1.6–3.8), genotype 2 (OR = 1.7; 95% CI 1.2–2.5) and high ribavirin dose (15 mg/kg) (OR = 1.6; 95% CI 1.1–2.6) as independent prognostic factors.
Figure 1. Probability of rapid virological response (RVR) in patients with hepatitis C virus genotypes 2 and 3 as a function of the ribavirin dose per kilogram of body weight after 12–14 weeks treatment. Observed values are presented as circles. The dashed lines are the 95% point-wise confidence intervals.
Predictors of RVR at the univariate analysis are shown separately for HCV genotypes 2 and 3 in Table 4. At multivariate analysis, young age and low viraemia were independent predictors of RVR in genotype 2 patients, OR = 2.06, 95% CI 1.16–3.64 and OR = 2.01 (1.18–3.40) respectively. For genotype 3 patients, independent predictors of RVR were low viraemia (OR = 2.84, 95% CI 1.60–5.01), high ribavirin dose (OR = 2.13, 95% CI 1.07–4.26) and young age (OR = 2.91, 95% CI 1.77–4.80).
Impact of Ribavirin Dosing on Sustained Virological Response
As per protocol, anti-viral therapy lasted 12–14 weeks in 473 patients with RVR and 364 of them (77.0%) attained an SVR. The likelihood of an SVR was not correlated with baseline ribavirin dose, expressed in mg/kg of body weight, but rather with the inability to adhere to the prescribed dose of the drug. Low viral load (P = 0.033), normal platelet count (P = 0.0001) and maintenance of full dose of ribavirin throughout treatment were associated with SVR (P = 0.0001). Decreasing ribavirin dose relative to target during treatment was a predictor of relapse: of patients who achieved an SVR, only 7% had to reduce the dose of ribavirin after the initial 4 weeks of therapy with a consequent 25% of total amount of ribavirin reduction, whereas 19% of those who failed to clear the virus did so. At multivariate analysis, independent predictors of SVR in patients with RVR were no ribavirin dose reduction (OR = 3.1; 95% CI 1.6–5.9) and normal platelet counts (OR = 2.75; 95% CI 1.6–4.7).
Two hundred patients without RVR were treated per protocol for the standard 24 weeks of therapy and 134 of them achieved an SVR (67%). At univariate analysis, female gender (P = 0.09) and high baseline ribavirin dose (P = 0.05) emerged as the only two predictors of SVR. In particular, of 30 patients without RVR who received ribavirin at dose of ≥15 mg/kg of body weight, 23 (78.7%) individuals attained an SVR, as opposed to 110 of 170 patients in the lower ribavirin dose (64.7%). Dose reduction of ribavirin only occurred in 2% of those without RVR and was not associated with response. At the multivariate analysis, no factor was independently associated with SVR.
Ribavirin-related Side Effects
Sixty four of 673 patients with RVR required modification of the ribavirin dose because of a drop in haemoglobin levels below 10 g/dL. Anaemia was more frequently detected among patients treated with ribavirin dose of ≥15 mg/kg than in those who were treated with lower doses (9.5 vs. 4.4%), but the difference was not significant (P = 0.11). Other ribavirin related side effects as cutaneous rash, cough and dry skin were not differently distributed among patients in the low and high ribavirin dosage: 3% vs. 2.4% (P = 0.35).
Discussion
Current analysis evaluated the impact of ribavirin dosing on the therapeutic outcome in patients with genotypes 2 and 3 infection who received Peg-IFN α-2b in combination with ribavirin for a short treatment duration. Original data were derived from two clinical trials where patients were allocated to short or standard treatment duration depending on whether or not they attained an RVR.[5, 7] We could ascertain a relationship between the dose of ribavirin, expressed as mg/kg of body weight, and the likelihood of achieving an RVR. The relationship held true particularly for patients infected with HCV genotype 3. Furthermore, in RVR patients, the SVR rate was higher among those who were compliant with the initially assigned ribavirin dose throughout treatment.
Weight-based dosing of ribavirin has been extensively utilized in patients with genotype 1, in whom a relationship between ribavirin dose and SVR has been established when the drug was administered in association with either Peg-IFN α-2a or α-2b.[20–25] Based on these data, the ribavirin dose of 15 mg/kg was selected as the best balance between efficacy and a manageable safety profile. Data are less clear for genotypes 2 and 3. When administered in combination with Peg-IFN α-2a for 48 weeks, ribavirin doses of 800 or 1000–1200 mg daily produced equivalent outcomes.[22] Similarly, a comparative trial of fixed-dose (800 mg daily) or weight-based doses of ribavirin (800–1400 mg daily) in combination with Peg-IFN α-2b showed equal SVR rates: 67.7% vs. 65.0%.[23] This study also documented that responses were consistent across all body weight categories in the weight-based group, but lower SVR were attained with increasing weight.[22] However, a randomized study of Peg-IFN α-2a plus ribavirin for 24 weeks at doses of either 400 or 800 mg claimed no decrease in SVR rates in the lower dose group among patients with genotype 3 infection, but SVR rates declined from the 67.5% rate in the 800 mg group to 63.9% in the 400 mg group.[24]
It needs to be reminded that all previous trials administered therapy for at least 24 weeks. In principle, it might be conceivable that for the overall population of genotype 2 and 3 patients, a fixed 800 mg/day dose of ribavirin could be enough to achieve optimal response rates after 24 weeks of therapy. However, as shorter treatment courses may be viable in select genotype 2 and 3 patients, such as those with RVR, it could be speculated that much more promising results could be obtained by weight adjustment of ribavirin dose when considering abbreviated treatment. Indirect evidence supports this claim. In the NORDynamIC trial, patients who achieved SVR had significantly lower body weight than those who did not; as a fixed dose of 800 mg of ribavirin was administered to all patients, it is plausible that SVR patients had been exposed to higher dose of ribavirin than those who did not achieve SVR.[13] A post hoc analysis of the trial showed that the chance of achieving an SVR was associated with higher median serum ribavirin concentrations at week 4.[25]
In a study from Taiwan, an RVR rate of 86% was registered following therapy with Peg-IFN alpha-2a and weight-based ribavirin (1000–1200 mg daily); considering that the mean body weight of patients included in the study was 68 kg, a mean dose of 15–20 mg/kg was administered and could be one factor that might have impacted on the pronounced RVR rate.[4] In opposition, the ACCELERATE trial administered a fixed dose of 800 mg to patients whose mean body weight was 81.5 kg; consequently, they received a low ribavirin dose (9.8 mg daily, as a mean) and attained an RVR at a rate as low as 65.5%.[12] We acknowledge that although suggestive, all mentioned lines of evidence should be interpreted with caution because they were derived from secondary analyses with potential confounding variables.
The present analysis has added new evidence to the ongoing debate on the optimal ribavirin dosage. We found a relationship between body weight and RVR, an observation suggesting that the dose of ribavirin per kilogram may contribute substantially to response to therapy in patients undergoing short therapy. It is important to note that the type of the relationship was nonlinear, but S-shaped, with a low and a high threshold value for dosing of ribavirin. From our analysis, it turned out that a threshold value of ≥15.2 mg/kg was expected to result in a better outcome of therapy when considering short treatment. In previous studies,[16] the concept that ribavirin clearance is linearly dependent on renal function was not incorporated into the analysis, at variance in our patients as suggested by Bruchfeld,[25] the renal effect could be excluded after the adjustment for GFR. As a matter of fact, 80% of patients given ribavirin dose ≥15.2 mg/kg achieve an RVR as compared to 54% of those who were given 13 mg/kg.
Reddy et al. reported that as long as patients achieved RVR, ribavirin dose reduction had minimal impact on SVR after standard treatment duration.[26] Our findings on RVR patients who were treated with only 12–14 weeks of therapy demonstrate lower SVR rates when the initial dosage of ribavirin had to be reduced. Indeed, 46 of 473 patients with RVR required dose modification because of a drop in haemoglobin levels below 10 g/dL, and 54% of them attained an SVR as opposed to a 79% rate in those who could tolerate the starting dose of ribavirin throughout treatment. Although data modelling suggests that RVR increases with ribavirin doses that equate to ≥15 mg/kg, there is also a simultaneous increase in the rate of anaemia. To contrast anaemia development, the use of off-label erythropoietin has been implemented,[27–29] but the drug was not allowed in our patients for cost-saving considerations.
In summary, the results of our study suggest that in patients with HCV genotypes 2 and 3 infection completing short therapy with Peg-IFN α-2b in combination with weight-based doses of ribavirin, a high starting dose of ribavirin appeared one of the factors influencing the rate of RVR. We would recommend administering ribavirin at a dose of ≥15 mg/kg when considering short treatment duration. Larger prospective studies would be required to confirm the role of higher ribavirin doses on SVR, as both the need of maintaining the full planned dose of ribavirin throughout treatment to achieve an optimal SVR rate and the improvement of SVR in patients still viremic at treatment week 4 after an intensified ribavirin dosing suggest that higher ribavirin dosage affects SVR. Finally, the evidence that genotype 3 may derive more benefit from high dosages of ribavirin warrants further confirmation of the present post hoc analysis.
References
1.Dalgard O, Bjoro K, Hellman KB, et al. Treatment with pegylated interferon and ribavirin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study. Hepatology 2004; 41: 1260–3.
2.Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 vs 24 weeks in HCV genotype 2 or 3. New Engl J Med 2005; 352: 2609–17.
3.von Wagner M, Huber M, Berg T, et al. Peginterferon alfa 2a [40 kd] and ribavirin for 16 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; 129: 522–7.
4.Yu ML, Dai CY, Huang JF, et al. A randomised study on PegInterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut 2007; 56: 553–9.
5.Dalgard O, Bjøro K, Ring-Larsen H, et al. A randomized controlled trial of pegylated interferon alfa and ribavirin for 14 vs 24 weeks in patients with HCV genotype 2 or 3 and rapid virological response. Hepatology 2008; 47: 35–42.
6.Andriulli A, Mangia A, Iacobellis A, Ippolito A, Leandro G, Zeuzem S. Meta-analysis: the outcome of anti-viral therapy in HCV genotype 2 and genotype 3 infected patients with chronic hepatitis. Aliment Pharmacol Ther 2008; 15: 397–404.
7.Mangia A, Minerva N, Bacca D, et al. Determinants of relapse after a short [12 weeks] course of antiviral therapy and re-treatment efficacy of a prolonged course in patients with chronic HCV genotype 2 or 3 infection. Hepatology 2009; 49: 358–63.
8.de Bruijne J, Buster EH, Gelderblom HC, et al. For the Netherlands Association of Gastroenterologists and Hepatologists. Treatment of chronic hepatitis C virus infection – Dutch national guidelines. Neth J Med 2008; 66: 311–22.
9.Zeuzem S, Berg T, Moeller B, et al. Expert opinion on the treatment of patients with chronic hepatitis C. J Viral Hepat 2009; 16: 75–90.
10.Ghany MG, Strader DB, Thomas DL, Seef LB. Diagnosis, management, and treatment of hepatitis C: un update. Hepatology 2009; 49: 1335–74.
11.Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and RBV for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357: 124–34.
12.Lagging M, Langeland N, Pedersen C, et al. Randomized comparison of 12 or 24 weeks of paginterferon alpha 2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection. Hepatology 2008; 47: 1837–45.
13.Dusheiko G, Main J, Thomas H, et al. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J Hepatol 1996; 25: 591–8.
14.Pawlotsky JM, Dahari H, Neuwmann AU, et al. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology 2004; 126: 703–14.
15.Jen JF, Glue P, Gupta S, Zambas D, Hajian G. Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit 2000; 22: 555–65.
16.Snoeck E, Wade JR, Duff F, Lamb M, Jorga K. Predicting sustained virological response and anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a [40 KD] plus ribavirin. Br J Clin Pharmacol 2006; 62: 699–709.
17.Wai CT, Greenson JK, Fontana RJ, et al. A simple non invasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003; 38: 518–26.
18.Smith JO, Sterling RK. Systematic review: non-invasive methods of fibrosis analysis in chronic hepatitis C. Alimentar Pharmacol Ther 2009; 30: 557–76.
19.Cook EF, Goldman L. Empiric comparison of multivariate analytic techniques: advantages and disadvantages of recursive partitioning analysis. J Chr Dis 1984; 37: 721–31.
20.Manns M, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa 2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001; 358: 958–65.
21.Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346–55.
22.Fried MW, Schiffman ML, Reddy KR, et al. Peginterferon alfa2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.
23.Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007; 46: 971–81.
24.Ferenci P, Laferl H, Schrzer TM, et al. A randomized prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alfa-2a in hepatitis C virus genotypes 2 and 3. Gastroenterology 2008; 47: 1816–23.
25.Christensen PB, Alain AA, Buhl MR, et al. Ribavirin concentration at week four is an independent predictor for sustained virological response after treatment of hepatitis C genotype 2/3 (NORDynamic trial). J Hepatol 2008; 48: S6.
26.Reddy KR, Shiffman M, Morgan T, et al. Impact of ribavirin dose reduction in HCV genotype 1 patients completing interferon alfa 2-a and ribavirin treatment. Clin Gastroenterol Hepatol 2007; 5: 124–9.
27.McHutchison JG, Manns MP, Brown RS, Reddy R, Shiffman M, Wong J. Strategies for managing anaemia in hepatitis C patients undergoing antiviral therapy. Am J Gastroenterol 2007; 102: 880–9.
28.Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomised controlled study. Gastroenterology 2004; 126: 1302–11.
29.Morreale A, Plowman B, DeLattre M, Boggie D, Schaefer M. Clinical and economic comparison of epoetin alfa and darbepoetin alfa. Curr Med Res Opin 2004; 20: 381–95.
Source
Posted: 08/11/2010; Alimentary Pharmacology & Therapeutics. 2010;31(12):1346-1353.
© 2010 Blackwell Publishing
Abstract and Introduction
Abstract
Background The optimal dose of ribavirin to be used in combination with Peg-IFN in patients with HCV genotypes 2 and 3 undergoing short treatment has not been established.
Aim To explore the relationship between starting ribavirin doses, expressed as mg/kg body weight and both rapid viral response at treatment week 4 (RVR) and sustained virological response (SVR) in patients treated for 12–14 weeks with peg-interferon α-2b and ribavirin.
Methods A post hoc analysis of data collected from two multicenter clinical trials was performed. Multiple regression analyses were employed to identify independent baseline and on-treatment predictors of RVR and SVR. For each dose of ribavirin, the empirical estimated probability of response was computed and the continuous exposure index was dichotomized by using a recursive partitioning and amalgamation method.
Results A nonlinear relationship was ascertained between ribavirin dose and RVR, but not SVR. A dose of 15.2 mg/kg was selected as the best splitting value for discriminating RVR vs. non-RVR. Regression analysis identified low baseline viraemia, genotype 2 and high ribavirin dose as independent prognostic factors for RVR. The likelihood of an SVR was not correlated with baseline ribavirin dose, but was independently predicted by adherence to the full dose throughout treatment and normal platelet counts.
Conclusions Starting high ribavirin doses appears capable of increasing the rate of RVR in patients with HCV genotypes 2 and 3 undergoing short treatment. Maintenance of the full planned dose throughout treatment is essential for achieving optimal SVR rates.
Introduction
The benefit of short (12 or 14 weeks) therapy with Peg-Interferon (Peg-IFN) in combination with ribavirin for patients with chronic HCV genotype 2 or genotype 3 infection has been documented in recent clinical investigations.[1–6] Patients who will benefit the most by short therapy are lean, noncirrhotic individuals capable of clearing the virus at treatment week 4.[7] This experimental evidence has been incorporated in some, but not all, treatment guidelines issued by scientific societies[8–10] and hence, uncertainties still remain about implementing short therapy in everyday clinical practice. Indeed, a clear-cut benefit of short therapy in comparison with the standard 24-week treatment did not emerge in some other clinical trials.[11, 12]
A controversial issue in genotypes 2 and 3 therapy that might explain part of previous inconsistencies across trials is the optimal dose of ribavirin to be used in combination with Peg-IFN: whenever ribavirin was given at higher dosage (800–1400 mg daily, according to body weight) than the one currently recommended (800 mg daily), the benefit of short therapy appeared evident;[1–4] on the contrary, when the administered dosage was the fixed 800 mg daily dosage,[11, 12] the benefit waned off.
The predominant mechanism(s) of ribavirin action against HCV is (are) yet to be established. Although ribavirin monotherapy imposes a transient HCV decline early on therapy, the drug has no apparent long-term effect on serum HCV RNA levels;[13, 14] however, in combination with interferon, it dramatically improves the success of therapy. In naïve patients undergoing treatment with conventional interferon and ribavirin, higher ribavirin concentrations were associated with a higher likelihood of response.[15] Plasma ribavirin concentrations have been shown to correlate with the starting dose of the drug,[15] and therefore selecting appropriate starting dose and maintaining it throughout treatment impact positively on therapeutic outcome. In genotype 1 patients, the probability of achieving a sustained virological response (SVR) increased as a function of the ribavirin dose (mg/kg of body weight), with a 40–50% increase for a 12–16 mg/kg dose.[16] Data are less clear for genotypes 2 and 3 infection, as a single study failed to prove a correlation between probability of SVR after 24 weeks of treatment and the ribavirin dose.[16] Although debate is ongoing as to which ribavirin dosage should be administered in combination with Peg-IFN, it is clear that ribavirin activity is dose/exposure-dependent[15, 16] and selecting and maintaining the optimal dose of the drug might be crucial for a successful therapy. This concept might apply particularly when considering short treatment duration. The objective of this analysis was to explore the relationship between starting ribavirin and both rapid viral response at treatment week 4 (RVR) and SVR in patients with genotypes 2 and 3 undergoing short (12 or 14 weeks) therapy with ribavirin and Peg-IFN α-2b.
Patients and Methods
Study Subjects
Data used in this analysis were collected from two multicentre clinical trials, run in Italy and Scandinavia, in naïve patients with genotypes 2 and 3. The complete inclusion and exclusion criteria, study design and primary results are available elsewhere.[5, 7] The primary efficacy objective of these trials was to compare SVR following Peg-IFN α-2b (Peg-Intron; Schering-Plough, Kenilworth, NJ, USA) plus ribavirin administered for short (12 or 14 weeks respectively) or standard (24 weeks) duration. All patients received Peg-IFN α-2b 1.5 μg/kg subcutaneously weekly together with ribavirin administered orally. In the study by Mangia et al.,[7] 718 patients were treated with Peg-IFN α-2b plus ribavirin 1000 or 1200 mg/day on the basis of body weight higher or lower than 75 kg; 496 patients with week 4 viral clearance (labelled as rapid virological responders, RVR) were allocated to 12-week treatment duration, whereas those without RVR were given therapy for 24 weeks. Italian patients with missing serum creatinine values at baseline were not included in the present analysis. In the 428 patients enrolled in the trial by Dalgard et al.,[5] ribavirin dose varied according to body weight as follows: 800 mg for body weight <65 kg, 1000 mg for body weight ranging from 65 to 85 kg, 1200 for body weight ranging from 85 to 105 kg and 1400 for body weight >105 kg. For the sake of homogeneity with the design of the Italian study, of the original 428 Scandinavian patients, only 148 individuals with RVR who were treated for 14 weeks and 130 non-RVR patients whose treatment lasted 24 weeks were considered eligible for the present investigation; the remaining 150 patients with RVR who were treated for the standard 24 weeks were excluded. Among Scandinavian patients considered eligible, only 10 had body weight >105 kg and required 1400 mg; therefore, the combined database allowed us to evaluate a large series of patients, including a comparable number of genotypes 2 and 3, who received similar dosages of ribavirin.
Per protocol, the ribavirin dose had to be reduced by 200 mg daily in patients who experienced a decrease in haemoglobin level of more than 2 g/dL during treatment, and by 400 mg daily if haemoglobin levels decreased to less than 10 g/dL. Ribavirin was discontinued if haemoglobin levels decreased to less than 8.5 g/dL. The use of erythropoietin was not allowed. Anaemia was defined as haemoglobin concentration <10 g/dL documented on at least one occasion during the studies. For patients who were intolerant to Peg-IFN α-2b, dose reductions in decrements of 12% of the assigned dose were allowed.
Analytical Methods
Definitions: The HCV RNA level was measured using the COBAS AMPLICOR HCV Test [(Roche Molecular Systems, Branchburg, NJ, USA), version 2.0; limit of detection 50 IU/mL]. Rapid virological response (RVR) was defined as undetectable serum HCV RNA at treatment week 4. End-of-treatment response (ETR) was defined as undetectable HCV RNA at weeks 12, 14 or 24 according to the different therapeutic regimens and SVR was defined as undetectable HCV RNA at the end of a 24-week follow-up period.
Statistical Analysis
As the primary objective of the present study was to explore the impact of ribavirin dose on both RVR and SVR, only patients who could tolerate anti-viral drugs for the planned length of therapy were retained in the analysis. Patients who had reduction in ribavirin and/or Peg-IFN at some point during treatment but completed the planned treatment duration were retained. Consequently, of the total 905 eligible patients enrolled in the two previous trials, only 673 patients (405 from the Italian cohort and 268 from the Scandinavian cohort) were retained. Of the 232 excluded patients, 120 had no serum creatinine available for glomerular filtration (GFR) rate calculation and 112 (10 among patients treated for 12–14 weeks and 102 among those treated for 24 weeks) had a premature treatment discontinuation for major side effects or were lost to follow-up.
Baseline patient characteristics were reported as frequencies and groups were compared with Pearson chi-square. Multiple logistic regression analyses were employed to identify independent baseline and on-treatment predictors of RVR and SVR, with age, gender, body mass index, genotype, baseline viraemia, platelet count, aspartate aminotransferase-to-platelet ratio index (APRI) score[17, 18] and starting ribavirin dose as dependent variables. An exploratory analysis was made to assess the nature of the relationship between dose of ribavirin adjusted for GFR and response probability: for each dose, the empirical estimated probability of response was computed. Moreover, the continuous exposure index was dichotomized using the best splitting value by using a Recursive Partitioning and Amalgamation (RECPAM) method.[19] All analyses were performed using SAS release 9.1 (SAS Institute, Cary, NC, USA). Two-tailed P-values <0.05 were considered significant.
Results
Characteristics of Patients
Baseline features of patients derived from the two studies are outlined in Table 1. There were differences in demographics, serum biochemistry and virological features of patients from the two cohorts: in the Scandinavian cohort, patients were as a mean 10 years younger, had a prevalent genotype 3 infection and lower frequency of advanced liver damage, as indicated by the lower proportion of individuals with low platelet counts and APRI score >2. Conversely, a higher proportion of Italian patients received a high (≥15 mg/kg) dose of ribavirin, a finding that might be related to differences in the schedule of ribavirin administration between the two studies: a more stringent weight-related dosing in the Scandinavian trial, and a looser relation to body weight in the Italian study.
Sustained virological response rates and predictability of SVR by RVR in accordance with the different duration of treatment are reported in Table 2.
Impact of Ribavirin Dosing on Rapid Virological Response
No patient had to reduce the ribavirin dose by treatment week 4, so that the relationship between starting ribavirin dose and the probability of RVR could be detailed. As shown in Figure 1, the dose of ribavirin, expressed in mg/kg of body weight, may be a determining factor of RVR in genotype 2 and 3 patients: the probability of RVR increased with increasing ribavirin dose. However, the relationship was a nonlinear one and the probability increased from approximately 54% to 80% for a ribavirin dose increase from 13 to 15.2 mg/kg. The dose of 15.2 mg/kg was determined as the best splitting value for discriminating RVR vs. non-RVR: among the 147 patients receiving a dose of ribavirin higher than 15 mg/kg, an 80% probability of achieving an RVR was observed, while for the 528 patients who received a lower dose, the RVR rate was 67%. At the univariate analysis of predictors of RVR, body mass index, genotype, viral load and ribavirin dose were significantly associated with RVR (Table 3). Multiple logistic regression analysis identified low baseline viraemia (<400 000 IU/mL) (OR = 2.5; 95% CI 1.6–3.8), genotype 2 (OR = 1.7; 95% CI 1.2–2.5) and high ribavirin dose (15 mg/kg) (OR = 1.6; 95% CI 1.1–2.6) as independent prognostic factors.
Figure 1. Probability of rapid virological response (RVR) in patients with hepatitis C virus genotypes 2 and 3 as a function of the ribavirin dose per kilogram of body weight after 12–14 weeks treatment. Observed values are presented as circles. The dashed lines are the 95% point-wise confidence intervals.
Predictors of RVR at the univariate analysis are shown separately for HCV genotypes 2 and 3 in Table 4. At multivariate analysis, young age and low viraemia were independent predictors of RVR in genotype 2 patients, OR = 2.06, 95% CI 1.16–3.64 and OR = 2.01 (1.18–3.40) respectively. For genotype 3 patients, independent predictors of RVR were low viraemia (OR = 2.84, 95% CI 1.60–5.01), high ribavirin dose (OR = 2.13, 95% CI 1.07–4.26) and young age (OR = 2.91, 95% CI 1.77–4.80).
Impact of Ribavirin Dosing on Sustained Virological Response
As per protocol, anti-viral therapy lasted 12–14 weeks in 473 patients with RVR and 364 of them (77.0%) attained an SVR. The likelihood of an SVR was not correlated with baseline ribavirin dose, expressed in mg/kg of body weight, but rather with the inability to adhere to the prescribed dose of the drug. Low viral load (P = 0.033), normal platelet count (P = 0.0001) and maintenance of full dose of ribavirin throughout treatment were associated with SVR (P = 0.0001). Decreasing ribavirin dose relative to target during treatment was a predictor of relapse: of patients who achieved an SVR, only 7% had to reduce the dose of ribavirin after the initial 4 weeks of therapy with a consequent 25% of total amount of ribavirin reduction, whereas 19% of those who failed to clear the virus did so. At multivariate analysis, independent predictors of SVR in patients with RVR were no ribavirin dose reduction (OR = 3.1; 95% CI 1.6–5.9) and normal platelet counts (OR = 2.75; 95% CI 1.6–4.7).
Two hundred patients without RVR were treated per protocol for the standard 24 weeks of therapy and 134 of them achieved an SVR (67%). At univariate analysis, female gender (P = 0.09) and high baseline ribavirin dose (P = 0.05) emerged as the only two predictors of SVR. In particular, of 30 patients without RVR who received ribavirin at dose of ≥15 mg/kg of body weight, 23 (78.7%) individuals attained an SVR, as opposed to 110 of 170 patients in the lower ribavirin dose (64.7%). Dose reduction of ribavirin only occurred in 2% of those without RVR and was not associated with response. At the multivariate analysis, no factor was independently associated with SVR.
Ribavirin-related Side Effects
Sixty four of 673 patients with RVR required modification of the ribavirin dose because of a drop in haemoglobin levels below 10 g/dL. Anaemia was more frequently detected among patients treated with ribavirin dose of ≥15 mg/kg than in those who were treated with lower doses (9.5 vs. 4.4%), but the difference was not significant (P = 0.11). Other ribavirin related side effects as cutaneous rash, cough and dry skin were not differently distributed among patients in the low and high ribavirin dosage: 3% vs. 2.4% (P = 0.35).
Discussion
Current analysis evaluated the impact of ribavirin dosing on the therapeutic outcome in patients with genotypes 2 and 3 infection who received Peg-IFN α-2b in combination with ribavirin for a short treatment duration. Original data were derived from two clinical trials where patients were allocated to short or standard treatment duration depending on whether or not they attained an RVR.[5, 7] We could ascertain a relationship between the dose of ribavirin, expressed as mg/kg of body weight, and the likelihood of achieving an RVR. The relationship held true particularly for patients infected with HCV genotype 3. Furthermore, in RVR patients, the SVR rate was higher among those who were compliant with the initially assigned ribavirin dose throughout treatment.
Weight-based dosing of ribavirin has been extensively utilized in patients with genotype 1, in whom a relationship between ribavirin dose and SVR has been established when the drug was administered in association with either Peg-IFN α-2a or α-2b.[20–25] Based on these data, the ribavirin dose of 15 mg/kg was selected as the best balance between efficacy and a manageable safety profile. Data are less clear for genotypes 2 and 3. When administered in combination with Peg-IFN α-2a for 48 weeks, ribavirin doses of 800 or 1000–1200 mg daily produced equivalent outcomes.[22] Similarly, a comparative trial of fixed-dose (800 mg daily) or weight-based doses of ribavirin (800–1400 mg daily) in combination with Peg-IFN α-2b showed equal SVR rates: 67.7% vs. 65.0%.[23] This study also documented that responses were consistent across all body weight categories in the weight-based group, but lower SVR were attained with increasing weight.[22] However, a randomized study of Peg-IFN α-2a plus ribavirin for 24 weeks at doses of either 400 or 800 mg claimed no decrease in SVR rates in the lower dose group among patients with genotype 3 infection, but SVR rates declined from the 67.5% rate in the 800 mg group to 63.9% in the 400 mg group.[24]
It needs to be reminded that all previous trials administered therapy for at least 24 weeks. In principle, it might be conceivable that for the overall population of genotype 2 and 3 patients, a fixed 800 mg/day dose of ribavirin could be enough to achieve optimal response rates after 24 weeks of therapy. However, as shorter treatment courses may be viable in select genotype 2 and 3 patients, such as those with RVR, it could be speculated that much more promising results could be obtained by weight adjustment of ribavirin dose when considering abbreviated treatment. Indirect evidence supports this claim. In the NORDynamIC trial, patients who achieved SVR had significantly lower body weight than those who did not; as a fixed dose of 800 mg of ribavirin was administered to all patients, it is plausible that SVR patients had been exposed to higher dose of ribavirin than those who did not achieve SVR.[13] A post hoc analysis of the trial showed that the chance of achieving an SVR was associated with higher median serum ribavirin concentrations at week 4.[25]
In a study from Taiwan, an RVR rate of 86% was registered following therapy with Peg-IFN alpha-2a and weight-based ribavirin (1000–1200 mg daily); considering that the mean body weight of patients included in the study was 68 kg, a mean dose of 15–20 mg/kg was administered and could be one factor that might have impacted on the pronounced RVR rate.[4] In opposition, the ACCELERATE trial administered a fixed dose of 800 mg to patients whose mean body weight was 81.5 kg; consequently, they received a low ribavirin dose (9.8 mg daily, as a mean) and attained an RVR at a rate as low as 65.5%.[12] We acknowledge that although suggestive, all mentioned lines of evidence should be interpreted with caution because they were derived from secondary analyses with potential confounding variables.
The present analysis has added new evidence to the ongoing debate on the optimal ribavirin dosage. We found a relationship between body weight and RVR, an observation suggesting that the dose of ribavirin per kilogram may contribute substantially to response to therapy in patients undergoing short therapy. It is important to note that the type of the relationship was nonlinear, but S-shaped, with a low and a high threshold value for dosing of ribavirin. From our analysis, it turned out that a threshold value of ≥15.2 mg/kg was expected to result in a better outcome of therapy when considering short treatment. In previous studies,[16] the concept that ribavirin clearance is linearly dependent on renal function was not incorporated into the analysis, at variance in our patients as suggested by Bruchfeld,[25] the renal effect could be excluded after the adjustment for GFR. As a matter of fact, 80% of patients given ribavirin dose ≥15.2 mg/kg achieve an RVR as compared to 54% of those who were given 13 mg/kg.
Reddy et al. reported that as long as patients achieved RVR, ribavirin dose reduction had minimal impact on SVR after standard treatment duration.[26] Our findings on RVR patients who were treated with only 12–14 weeks of therapy demonstrate lower SVR rates when the initial dosage of ribavirin had to be reduced. Indeed, 46 of 473 patients with RVR required dose modification because of a drop in haemoglobin levels below 10 g/dL, and 54% of them attained an SVR as opposed to a 79% rate in those who could tolerate the starting dose of ribavirin throughout treatment. Although data modelling suggests that RVR increases with ribavirin doses that equate to ≥15 mg/kg, there is also a simultaneous increase in the rate of anaemia. To contrast anaemia development, the use of off-label erythropoietin has been implemented,[27–29] but the drug was not allowed in our patients for cost-saving considerations.
In summary, the results of our study suggest that in patients with HCV genotypes 2 and 3 infection completing short therapy with Peg-IFN α-2b in combination with weight-based doses of ribavirin, a high starting dose of ribavirin appeared one of the factors influencing the rate of RVR. We would recommend administering ribavirin at a dose of ≥15 mg/kg when considering short treatment duration. Larger prospective studies would be required to confirm the role of higher ribavirin doses on SVR, as both the need of maintaining the full planned dose of ribavirin throughout treatment to achieve an optimal SVR rate and the improvement of SVR in patients still viremic at treatment week 4 after an intensified ribavirin dosing suggest that higher ribavirin dosage affects SVR. Finally, the evidence that genotype 3 may derive more benefit from high dosages of ribavirin warrants further confirmation of the present post hoc analysis.
References
1.Dalgard O, Bjoro K, Hellman KB, et al. Treatment with pegylated interferon and ribavirin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study. Hepatology 2004; 41: 1260–3.
2.Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 vs 24 weeks in HCV genotype 2 or 3. New Engl J Med 2005; 352: 2609–17.
3.von Wagner M, Huber M, Berg T, et al. Peginterferon alfa 2a [40 kd] and ribavirin for 16 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; 129: 522–7.
4.Yu ML, Dai CY, Huang JF, et al. A randomised study on PegInterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut 2007; 56: 553–9.
5.Dalgard O, Bjøro K, Ring-Larsen H, et al. A randomized controlled trial of pegylated interferon alfa and ribavirin for 14 vs 24 weeks in patients with HCV genotype 2 or 3 and rapid virological response. Hepatology 2008; 47: 35–42.
6.Andriulli A, Mangia A, Iacobellis A, Ippolito A, Leandro G, Zeuzem S. Meta-analysis: the outcome of anti-viral therapy in HCV genotype 2 and genotype 3 infected patients with chronic hepatitis. Aliment Pharmacol Ther 2008; 15: 397–404.
7.Mangia A, Minerva N, Bacca D, et al. Determinants of relapse after a short [12 weeks] course of antiviral therapy and re-treatment efficacy of a prolonged course in patients with chronic HCV genotype 2 or 3 infection. Hepatology 2009; 49: 358–63.
8.de Bruijne J, Buster EH, Gelderblom HC, et al. For the Netherlands Association of Gastroenterologists and Hepatologists. Treatment of chronic hepatitis C virus infection – Dutch national guidelines. Neth J Med 2008; 66: 311–22.
9.Zeuzem S, Berg T, Moeller B, et al. Expert opinion on the treatment of patients with chronic hepatitis C. J Viral Hepat 2009; 16: 75–90.
10.Ghany MG, Strader DB, Thomas DL, Seef LB. Diagnosis, management, and treatment of hepatitis C: un update. Hepatology 2009; 49: 1335–74.
11.Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and RBV for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357: 124–34.
12.Lagging M, Langeland N, Pedersen C, et al. Randomized comparison of 12 or 24 weeks of paginterferon alpha 2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection. Hepatology 2008; 47: 1837–45.
13.Dusheiko G, Main J, Thomas H, et al. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. J Hepatol 1996; 25: 591–8.
14.Pawlotsky JM, Dahari H, Neuwmann AU, et al. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology 2004; 126: 703–14.
15.Jen JF, Glue P, Gupta S, Zambas D, Hajian G. Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit 2000; 22: 555–65.
16.Snoeck E, Wade JR, Duff F, Lamb M, Jorga K. Predicting sustained virological response and anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a [40 KD] plus ribavirin. Br J Clin Pharmacol 2006; 62: 699–709.
17.Wai CT, Greenson JK, Fontana RJ, et al. A simple non invasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003; 38: 518–26.
18.Smith JO, Sterling RK. Systematic review: non-invasive methods of fibrosis analysis in chronic hepatitis C. Alimentar Pharmacol Ther 2009; 30: 557–76.
19.Cook EF, Goldman L. Empiric comparison of multivariate analytic techniques: advantages and disadvantages of recursive partitioning analysis. J Chr Dis 1984; 37: 721–31.
20.Manns M, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa 2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001; 358: 958–65.
21.Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346–55.
22.Fried MW, Schiffman ML, Reddy KR, et al. Peginterferon alfa2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.
23.Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007; 46: 971–81.
24.Ferenci P, Laferl H, Schrzer TM, et al. A randomized prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alfa-2a in hepatitis C virus genotypes 2 and 3. Gastroenterology 2008; 47: 1816–23.
25.Christensen PB, Alain AA, Buhl MR, et al. Ribavirin concentration at week four is an independent predictor for sustained virological response after treatment of hepatitis C genotype 2/3 (NORDynamic trial). J Hepatol 2008; 48: S6.
26.Reddy KR, Shiffman M, Morgan T, et al. Impact of ribavirin dose reduction in HCV genotype 1 patients completing interferon alfa 2-a and ribavirin treatment. Clin Gastroenterol Hepatol 2007; 5: 124–9.
27.McHutchison JG, Manns MP, Brown RS, Reddy R, Shiffman M, Wong J. Strategies for managing anaemia in hepatitis C patients undergoing antiviral therapy. Am J Gastroenterol 2007; 102: 880–9.
28.Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomised controlled study. Gastroenterology 2004; 126: 1302–11.
29.Morreale A, Plowman B, DeLattre M, Boggie D, Schaefer M. Clinical and economic comparison of epoetin alfa and darbepoetin alfa. Curr Med Res Opin 2004; 20: 381–95.
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NICE FINAL APPRAISAL DETERMINATION ISSUED FOR HEPATITIS C AND HIV CO-INFECTED PATIENTS
MSD Posted on:12 Aug 10
12 August 2010, Hoddesdon – The National Institute for Health and Clinical Excellence (NICE) today issued a final appraisal determination (FAD) on the use of peginterferon alfa and ribavirin for the treatment of chronic hepatitis C, which includes MSD’s ViraferonPeg and Rebetol treatment regimen. The updated guidance recommends? combination therapy with peginterferon alfa and ribavirin as a treatment option for patients who are co-infected with HIV or patients with hepatitis C who require re-treatment (as they either did not respond to previous combination treatment, or peginterferon alfa monotherapy, or responded initially to treatment but subsequently relapsed).1
People co-infected with HIV and the hepatitis C virus (HCV) are at greater risk of developing liver disease than those infected with hepatitis C alone. The prevalence of HCV infection in HIV-positive individuals is higher than in the general population but varies among clinics according to risk factors for HIV acquisition. Around a third of people with HIV are estimated to have chronic HCV infection.
An estimated 200,000 to 500,000 people are infected with hepatitis C in England and Wales, with the majority unaware they have the condition. Hepatitis C is an infectious disease of the liver caused by HCV. The virus is acquired primarily through percutaneous exposure to contaminated blood. In approximately 80% of cases the virus will not be cleared and will develop into the chronic form of the disease.2
The final appraisal determination builds on existing guidance issued by NICE in 2004 and 2006 for the treatment of moderate-severe chronic hepatitis C and mild chronic hepatitis C respectively , and reinforces the importance of treating hepatitis C and HIV co-infection.
The previous NICE guidance (TA106 and TA75) recommend combination therapy with ribavirin and either peginterferon alfa-2a or peginterferon alfa-2b for adults with chronic hepatitis C. The previous guidance also recommends that monotherapy with peginterferon alfa-2a or peginterferon alfa-2b should be used only by people who are unable to tolerate ribavirin or for whom ribavirin is contraindicated.1
Treatment with peginterferon alfa and ribavirin aims to clear the virus from the blood.1 Successful treatment is usually indicated by a sustained virological response, which is considered to indicate permanent resolution of infection.1
Dr Harpal Lamba, MSD Medical Affairs, commented “We welcome NICE’s FAD for the use of peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. This guidance will support healthcare professionals to consistently manage patients with hepatitis C when re-treatment is needed or where patients are co-infected with HIV.”
-ends-
About MSD
MSD is a trading name of Schering-Plough Limited and Merck Sharp & Dohme Limited in the UK. For more information on Merck Sharp & Dohme Limited and Schering-Plough Limited, please visit http://www.msd-uk.co.uk/.
Notes to editors:
About ViraferonPeg (peginterferon alfa-2b) and Rebetol (ribavirin)
ViraferonPeg is indicated for the treatment of adult patients with chronic hepatitis C who are positive for hepatitis C virus NRA (HCV-RNA), including patients with compensated cirrhosis and/or co-infected with clinically stable HIV.
The best way to use ViraferonPeg in this indication is in combination with Rebetol. This combination is indicated in naïve patients including patients with clinically stable HIV co-infection and in patients who have failed previous treatment with interferon alpha (pegylated or nonpegylated) and ribavirin combination therapy or interferon alpha monotherapy.
Combination therapy with peginterferon alfa (2a or 2b) and ribavirin is recommended as a treatment option for adults with chronic hepatitis C: who have been treated previously with peginterferon alfa (2a or 2b) and ribavirin in combination, or with peginterferon alfa monotherapy, and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed or who are co-infected with HIV.1
The registered trademark holder for ViraferonPeg® and Rebetol® is Schering-Plough Limited in Switzerland. For more information refer to the Summary of Product Characteristics.
About hepatitis C1
Hepatitis C is an infectious disease of the liver caused by HCV. The virus is acquired primarily through percutaneous exposure to contaminated blood. People infected with HCV are often asymptomatic, but about 20% develop acute hepatitis. In approximately 80% of people who are infected, the virus is not cleared and they go on to develop chronic hepatitis C. Chronic hepatitis C is categorised as mild, moderate or severe depending on the extent of liver damage. The rate of progression from mild to severe disease is slow but variable, taking about 20 to 50 years from the time of infection. About 30% of infected people develop cirrhosis within 20 to 30 years, and some of these develop hepatocellular carcinoma. Some people with end-stage liver disease or hepatocellular carcinoma may require liver transplantation.
About the NICE guidance on peginterferon alfa and ribavirin1
Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C (part review of technology appraisal guidance 75 and 106) – Final appraisal determination
This guidance should be read in conjunction with the following NICE guidance:
• NICE technology appraisal guidance 75 (TA75) ‘interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C’ (which covers moderate to severe hepatitis C)
• NICE technology appraisal guidance 106 (TA106) ‘peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C’.
Guidance [section 1]:
Combination therapy with peginterferon alfa (2a or 2b) and ribavirin is recommended as a treatment option for adults with chronic hepatitis C;
• who have been treated previously with peginterferon alfa (2a or 2b) and ribavirin in combination, or with peginterferon alfa monotherapy, and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed; or
• who are co-infected with HIV.
Shortened courses of combination therapy with peginterferon alfa (2a or 2b) and ribavirin are recommended for the treatment of adults with chronic hepatitis C who:
• have a rapid virological response to treatment at week 4 that is identified by a highly sensitive test; and
• are considered suitable for a shortened course of treatment.
When deciding on the duration of combination therapy, clinicians should take into account the licensed indication of the chosen drug (peginterferon alfa-2a or peginterferon alfa-2b), the genotype of the hepatitis C virus, the viral load at the start of treatment and the response to treatment (as indicated by the viral load).
Overview of previous guidance [section 2.5]:
Previous NICE guidance (TA106 and TA75) recommends combination therapy with ribavirin and either peginterferon alfa-2a or peginterferon alfa-2b for adults with chronic hepatitis C. The previous guidance also recommends that monotherapy with peginterferon alfa-2a or peginterferon alfa-2b should be used only by people who are unable to tolerate ribavirin or for whom ribavirin is contraindicated. The recommended duration of treatment is 24 or 48 weeks depending on a combination of factors, including the HCV genotype, the viral load at the start of treatment and whether a person has a rapid virological response to treatment. For people with mild HCV infection, the person and their clinician should decide whether to treat immediately or adopt an approach of ‘watchful waiting’ (see TA106). The use of peginterferon alfa and ribavirin combination therapy is also considered suitable for people who are co-infected with HCV and HIV, unless it is contraindicated.
http://guidance.nice.org.uk/TA106/Guidance
http://www.nice.org.uk/nicemedia/pdf/TA075guidance.pdf
http://guidance.nice.org.uk/TA/WaveR/20
For more information:
http://www.msd-uk.co.uk/
Editor's Details
Anna Radnavale
http://www.msd-uk.co.uk/
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12 August 2010, Hoddesdon – The National Institute for Health and Clinical Excellence (NICE) today issued a final appraisal determination (FAD) on the use of peginterferon alfa and ribavirin for the treatment of chronic hepatitis C, which includes MSD’s ViraferonPeg and Rebetol treatment regimen. The updated guidance recommends? combination therapy with peginterferon alfa and ribavirin as a treatment option for patients who are co-infected with HIV or patients with hepatitis C who require re-treatment (as they either did not respond to previous combination treatment, or peginterferon alfa monotherapy, or responded initially to treatment but subsequently relapsed).1
People co-infected with HIV and the hepatitis C virus (HCV) are at greater risk of developing liver disease than those infected with hepatitis C alone. The prevalence of HCV infection in HIV-positive individuals is higher than in the general population but varies among clinics according to risk factors for HIV acquisition. Around a third of people with HIV are estimated to have chronic HCV infection.
An estimated 200,000 to 500,000 people are infected with hepatitis C in England and Wales, with the majority unaware they have the condition. Hepatitis C is an infectious disease of the liver caused by HCV. The virus is acquired primarily through percutaneous exposure to contaminated blood. In approximately 80% of cases the virus will not be cleared and will develop into the chronic form of the disease.2
The final appraisal determination builds on existing guidance issued by NICE in 2004 and 2006 for the treatment of moderate-severe chronic hepatitis C and mild chronic hepatitis C respectively , and reinforces the importance of treating hepatitis C and HIV co-infection.
The previous NICE guidance (TA106 and TA75) recommend combination therapy with ribavirin and either peginterferon alfa-2a or peginterferon alfa-2b for adults with chronic hepatitis C. The previous guidance also recommends that monotherapy with peginterferon alfa-2a or peginterferon alfa-2b should be used only by people who are unable to tolerate ribavirin or for whom ribavirin is contraindicated.1
Treatment with peginterferon alfa and ribavirin aims to clear the virus from the blood.1 Successful treatment is usually indicated by a sustained virological response, which is considered to indicate permanent resolution of infection.1
Dr Harpal Lamba, MSD Medical Affairs, commented “We welcome NICE’s FAD for the use of peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. This guidance will support healthcare professionals to consistently manage patients with hepatitis C when re-treatment is needed or where patients are co-infected with HIV.”
-ends-
About MSD
MSD is a trading name of Schering-Plough Limited and Merck Sharp & Dohme Limited in the UK. For more information on Merck Sharp & Dohme Limited and Schering-Plough Limited, please visit http://www.msd-uk.co.uk/.
Notes to editors:
About ViraferonPeg (peginterferon alfa-2b) and Rebetol (ribavirin)
ViraferonPeg is indicated for the treatment of adult patients with chronic hepatitis C who are positive for hepatitis C virus NRA (HCV-RNA), including patients with compensated cirrhosis and/or co-infected with clinically stable HIV.
The best way to use ViraferonPeg in this indication is in combination with Rebetol. This combination is indicated in naïve patients including patients with clinically stable HIV co-infection and in patients who have failed previous treatment with interferon alpha (pegylated or nonpegylated) and ribavirin combination therapy or interferon alpha monotherapy.
Combination therapy with peginterferon alfa (2a or 2b) and ribavirin is recommended as a treatment option for adults with chronic hepatitis C: who have been treated previously with peginterferon alfa (2a or 2b) and ribavirin in combination, or with peginterferon alfa monotherapy, and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed or who are co-infected with HIV.1
The registered trademark holder for ViraferonPeg® and Rebetol® is Schering-Plough Limited in Switzerland. For more information refer to the Summary of Product Characteristics.
About hepatitis C1
Hepatitis C is an infectious disease of the liver caused by HCV. The virus is acquired primarily through percutaneous exposure to contaminated blood. People infected with HCV are often asymptomatic, but about 20% develop acute hepatitis. In approximately 80% of people who are infected, the virus is not cleared and they go on to develop chronic hepatitis C. Chronic hepatitis C is categorised as mild, moderate or severe depending on the extent of liver damage. The rate of progression from mild to severe disease is slow but variable, taking about 20 to 50 years from the time of infection. About 30% of infected people develop cirrhosis within 20 to 30 years, and some of these develop hepatocellular carcinoma. Some people with end-stage liver disease or hepatocellular carcinoma may require liver transplantation.
About the NICE guidance on peginterferon alfa and ribavirin1
Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C (part review of technology appraisal guidance 75 and 106) – Final appraisal determination
This guidance should be read in conjunction with the following NICE guidance:
• NICE technology appraisal guidance 75 (TA75) ‘interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C’ (which covers moderate to severe hepatitis C)
• NICE technology appraisal guidance 106 (TA106) ‘peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C’.
Guidance [section 1]:
Combination therapy with peginterferon alfa (2a or 2b) and ribavirin is recommended as a treatment option for adults with chronic hepatitis C;
• who have been treated previously with peginterferon alfa (2a or 2b) and ribavirin in combination, or with peginterferon alfa monotherapy, and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed; or
• who are co-infected with HIV.
Shortened courses of combination therapy with peginterferon alfa (2a or 2b) and ribavirin are recommended for the treatment of adults with chronic hepatitis C who:
• have a rapid virological response to treatment at week 4 that is identified by a highly sensitive test; and
• are considered suitable for a shortened course of treatment.
When deciding on the duration of combination therapy, clinicians should take into account the licensed indication of the chosen drug (peginterferon alfa-2a or peginterferon alfa-2b), the genotype of the hepatitis C virus, the viral load at the start of treatment and the response to treatment (as indicated by the viral load).
Overview of previous guidance [section 2.5]:
Previous NICE guidance (TA106 and TA75) recommends combination therapy with ribavirin and either peginterferon alfa-2a or peginterferon alfa-2b for adults with chronic hepatitis C. The previous guidance also recommends that monotherapy with peginterferon alfa-2a or peginterferon alfa-2b should be used only by people who are unable to tolerate ribavirin or for whom ribavirin is contraindicated. The recommended duration of treatment is 24 or 48 weeks depending on a combination of factors, including the HCV genotype, the viral load at the start of treatment and whether a person has a rapid virological response to treatment. For people with mild HCV infection, the person and their clinician should decide whether to treat immediately or adopt an approach of ‘watchful waiting’ (see TA106). The use of peginterferon alfa and ribavirin combination therapy is also considered suitable for people who are co-infected with HCV and HIV, unless it is contraindicated.
http://guidance.nice.org.uk/TA106/Guidance
http://www.nice.org.uk/nicemedia/pdf/TA075guidance.pdf
http://guidance.nice.org.uk/TA/WaveR/20
For more information:
http://www.msd-uk.co.uk/
Editor's Details
Anna Radnavale
http://www.msd-uk.co.uk/
Source
PSI-7977 Receives Fast Track Designation from the FDA for the Treatment of Chronic Hepatitis C Infection
PRINCETON, N.J., Aug. 12 /PRNewswire-FirstCall/ -- Pharmasset, Inc. (Nasdaq: VRUS) has received fast track designation from the U.S. Food and Drug Administration (FDA) for PSI-7977 for the treatment of chronic hepatitis C virus (HCV) infection. PSI-7977 is an oral uridine nucleotide analog polymerase inhibitor of HCV. Pharmasset recently completed dosing in a 28 day Phase 2a trial to evaluate PSI-7977 in combination with Pegasys (pegylated interferon) plus Copegus (ribavirin) in treatment-naive patients chronically infected with HCV genotype 1. Pharmasset expects to initiate a 12-week Phase 2b study of PSI-7977 in the fourth quarter of 2010.
Under the FDA Modernization Act of 1997, fast track designation may facilitate the development and expedite the review of a drug candidate that is intended for the treatment of a serious and life-threatening condition and demonstrates the potential to address an unmet medical need for such a condition. PSI-7977 was granted the fast track designation primarily due to the need for HCV treatments with novel mechanisms of action, oral administration, different resistance profiles and improved safety and efficacy over the existing standard of care for both treatment-naive and treatment-experienced patients.
"The FDA's fast track designation for PSI-7977 acknowledges the urgent need for new HCV drugs," stated Dr. Michael Rogers, Pharmasset's Chief Development Officer. "Currently, there are no HCV nucleoside/tide inhibitors approved for the treatment of chronic HCV infection. We continue to work closely with the FDA on the development and regulatory review of PSI-7977, which has demonstrated compelling antiviral activity, a high barrier to resistance and has been generally well-tolerated in clinical trials to date."
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV) and, secondarily, on the development of Racivir(TM) for the treatment of human immunodeficiency virus (HIV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have four clinical-stage product candidates. RG7128, a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys(R) plus Copegus(R) and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys(R) and Copegus(R) to treat chronic HCV. These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage HCV candidates include PSI-7977, an unpartnered uracil nucleotide analog that has recently completed 28 days of dosing in a Phase 2a study, and PSI-938, an unpartnered guanosine nucleotide analog in a Phase 1 study. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development. Racivir, for the treatment of HIV, has completed a Phase 2 clinical study.
Pegasys® and Copegus® are registered trademarks of Roche.
Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
richard.smith@pharmasset.com
Office: +1 (609) 613-4181
Pharmasset, Inc.
303-A College Road East
Princeton, NJ 08540 U.S.A.
Phone: (609) 613-4100
Fax: (609) 613-4150
http://www.pharmasset.com/
Nasdaq: VRUS
Forward-Looking Statements
Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are "forward-looking statements," including, without limitation, statements that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2009 and our Quarterly Reports on Form 10-Q for the periods ended December 31, 2009, March 31, 2010 and June 30, 2010 filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.
SOURCE Pharmasset, Inc.
RELATED LINKS
http://www.pharmasset.com/
Source
Under the FDA Modernization Act of 1997, fast track designation may facilitate the development and expedite the review of a drug candidate that is intended for the treatment of a serious and life-threatening condition and demonstrates the potential to address an unmet medical need for such a condition. PSI-7977 was granted the fast track designation primarily due to the need for HCV treatments with novel mechanisms of action, oral administration, different resistance profiles and improved safety and efficacy over the existing standard of care for both treatment-naive and treatment-experienced patients.
"The FDA's fast track designation for PSI-7977 acknowledges the urgent need for new HCV drugs," stated Dr. Michael Rogers, Pharmasset's Chief Development Officer. "Currently, there are no HCV nucleoside/tide inhibitors approved for the treatment of chronic HCV infection. We continue to work closely with the FDA on the development and regulatory review of PSI-7977, which has demonstrated compelling antiviral activity, a high barrier to resistance and has been generally well-tolerated in clinical trials to date."
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV) and, secondarily, on the development of Racivir(TM) for the treatment of human immunodeficiency virus (HIV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have four clinical-stage product candidates. RG7128, a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys(R) plus Copegus(R) and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys(R) and Copegus(R) to treat chronic HCV. These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage HCV candidates include PSI-7977, an unpartnered uracil nucleotide analog that has recently completed 28 days of dosing in a Phase 2a study, and PSI-938, an unpartnered guanosine nucleotide analog in a Phase 1 study. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development. Racivir, for the treatment of HIV, has completed a Phase 2 clinical study.
Pegasys® and Copegus® are registered trademarks of Roche.
Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
richard.smith@pharmasset.com
Office: +1 (609) 613-4181
Pharmasset, Inc.
303-A College Road East
Princeton, NJ 08540 U.S.A.
Phone: (609) 613-4100
Fax: (609) 613-4150
http://www.pharmasset.com/
Nasdaq: VRUS
Forward-Looking Statements
Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are "forward-looking statements," including, without limitation, statements that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2009 and our Quarterly Reports on Form 10-Q for the periods ended December 31, 2009, March 31, 2010 and June 30, 2010 filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.
SOURCE Pharmasset, Inc.
RELATED LINKS
http://www.pharmasset.com/
Source
August 11, 2010
Appetite Hormone Could Inhibit HCV-Related Fibrosis
August 11, 2010
Ghrelin is mostly known as a naturally occurring hormone that stimulates the appetite. However, new research demonstrates that this hormone might have therapeutic value to those with Hepatitis C.
by Nicole Cutler, L.Ac.
A hormone normally found in the stomach is proving to be of great interest to the Hepatitis C community. Known as an appetite-stimulating hormone, ghrelin is regarded with disdain by dieters and overweight individuals. Interestingly, ghrelin has demonstrated the ability to minimize one of the greatest hazards of the Hepatitis C virus - liver fibrosis.
About Ghrelin
Made in the stomach, ghrelin levels rise when people are hungry and they wane after a meal. People who get injections of this hormone gorge themselves, and those suffering from a rare disease that keeps ghrelin levels unusually high tend to be obese overeaters. Not surprisingly, researchers seeking to help people shed excessive weight have been actively trying to block ghrelin since its recognition in the late '90s. Of course, blocking an essential hormone carries unknown risks to our health. For people with chronic liver disease, researchers from Spain have uncovered a valid reason to treasure ghrelin - and be weary of blocking this curious hormone.
Fibrosis
One of the few organs that can regenerate, the liver has the remarkable ability to recover from minor injuries by healing itself. Unfortunately, this regenerative capacity can't keep up with diseases that cause significant liver damage. For those individuals living with chronic Hepatitis C (or any other kind of chronic liver disease), progressive scarring of liver tissue is a major concern.
Otherwise known as fibrosis, continual liver scarring can lead to cirrhosis - which ultimately renders the liver unable to function. Over 27,000 Americans die from cirrhosis annually, making it the country's third leading cause of death for people between the ages of 25 and 59, and the seventh leading cause of death overall. Needless to say, strategies to prevent fibrosis from worsening to cirrhosis are in high demand. Despite this need, there are currently no approved anti-fibrotic therapies on the market.
Ghrelin Fights Fibrosis
Published in the March 2010 edition of Hepatology, researchers from Spain's Hospital Clinic of Barcelona discovered that ghrelin has the potential of being a novel, anti-fibrotic therapy. According to Dr. Ramón Bataller, part of the team involved in the Barcelona study, "Our aim was to determine if recombinant ghrelin could regulate the formation of fibrous tissue associated with chronic liver damage."
The research team found the following:
· In animal models, ghrelin reduced the amount of fibrogenic cells by 25 percent.
· Participants with chronic Hepatitis C and alcoholic hepatitis had significantly lower ghrelin levels than did healthy individuals.
The researchers concluded that ghrelin inhibits the development of liver fibrosis in both animals and humans.
Insulin Resistance
The link connecting this appetite-stimulating hormone to its protection against liver fibrosis remains unclear. However, research from 2003 may be on the right track. According to an Italian study published in the Journal of Clinical Endocrinology & Metabolism, insulin resistance may be the bridge between ghrelin levels and liver damage. In individuals with NAFLD (non-alcoholic fatty liver disease), insulin resistance is believed to be relatively independent of obesity. After evaluating subjects with NAFLD, the Italian researchers found that insulin resistance plays a primary role in controlling ghrelin levels.
Insulin resistance is a decreased ability to respond to the effects of insulin, a hormone that helps transport glucose into the body's cells for making energy. Since cells need glucose to survive, the body compensates for insulin resistance by producing additional amounts of this hormone. Although not a disease or specific diagnosis, insulin resistance has a ripple effect on the body and is associated with heart disease, polycystic ovarian syndrome, Type 2 diabetes, obesity and NAFLD.
Thanks to Bataller's team, the connection between ghrelin and fibrosis could help prevent liver scarring in people who are most prone. Future studies are likely going to take insulin resistance into consideration while determining the safety and efficacy of ghrelin in people with chronic liver disease. If this hormone continues to prove its value to the liver, efforts to block ghrelin for weight loss purposes will likely lose steam. On the other hand, those with Hepatitis C could benefit by finally having a therapeutic option to prevent the progression of liver scarring.
References:
http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=31823, Body's own hormone may be liver disease's worst foe, Retrieved March 15, 2010, CORDIS Services, 2010.
http://jcem.endojournals.org/cgi/content/abstract/88/12/5674, Low Ghrelin Concentrations in Nonalcoholic Fatty Liver Disease Are Related to Insulin Resistance, G.Marchesini, et al, Retrieved March 19, 2010, Journal of Clinical Endocrinology & Metabolism, August 2003.
http://www.cbsnews.com/stories/2003/03/11/60II/main543614.shtml, The Hunger Hormone, Carol Kopp, Retrieved March 15, 2010, CBS Interactive Inc., 2010.
http://www.eurekalert.org/pub_releases/2010-03/w-gml022510.php, Ghrelin mitigates liver fibrosis in animal models; regulates human fibrosis, Retrieved March 15, 2010, EurekAlert, 2010.
http://www.healthsquare.com/fgpd/fg4ch20.htm, Dealing with Liver Disease, Retrieved March 19, 2010, The HealthCentral Network, Inc., 2010.
http://www.labtestsonline.org/understanding/conditions/insulin_resistance.html, Insulin Resistance, Retrieved March 19, 2010, American Association for Clinical Chemistry, 2010.
http://www.ncbi.nlm.nih.gov/pubmed/20077562, Ghrelin attenuates hepatocellular injury and liver fibrogenesis in rodents and influences fibrosis progression in humans, Moreno M, et al, Retrieved March 15, 2010, Hepatology, March 2010.
http://www.newscientist.com/article/dn13845-stomach-hormone-turns-hungry-people-into-junkies.html, Stomach hormone turns hungry people into junkies, Ewen Callaway, Retrieved March 18, 2010, Reed Business Information Ltd, 2010.
Source
Ghrelin is mostly known as a naturally occurring hormone that stimulates the appetite. However, new research demonstrates that this hormone might have therapeutic value to those with Hepatitis C.
by Nicole Cutler, L.Ac.
A hormone normally found in the stomach is proving to be of great interest to the Hepatitis C community. Known as an appetite-stimulating hormone, ghrelin is regarded with disdain by dieters and overweight individuals. Interestingly, ghrelin has demonstrated the ability to minimize one of the greatest hazards of the Hepatitis C virus - liver fibrosis.
About Ghrelin
Made in the stomach, ghrelin levels rise when people are hungry and they wane after a meal. People who get injections of this hormone gorge themselves, and those suffering from a rare disease that keeps ghrelin levels unusually high tend to be obese overeaters. Not surprisingly, researchers seeking to help people shed excessive weight have been actively trying to block ghrelin since its recognition in the late '90s. Of course, blocking an essential hormone carries unknown risks to our health. For people with chronic liver disease, researchers from Spain have uncovered a valid reason to treasure ghrelin - and be weary of blocking this curious hormone.
Fibrosis
One of the few organs that can regenerate, the liver has the remarkable ability to recover from minor injuries by healing itself. Unfortunately, this regenerative capacity can't keep up with diseases that cause significant liver damage. For those individuals living with chronic Hepatitis C (or any other kind of chronic liver disease), progressive scarring of liver tissue is a major concern.
Otherwise known as fibrosis, continual liver scarring can lead to cirrhosis - which ultimately renders the liver unable to function. Over 27,000 Americans die from cirrhosis annually, making it the country's third leading cause of death for people between the ages of 25 and 59, and the seventh leading cause of death overall. Needless to say, strategies to prevent fibrosis from worsening to cirrhosis are in high demand. Despite this need, there are currently no approved anti-fibrotic therapies on the market.
Ghrelin Fights Fibrosis
Published in the March 2010 edition of Hepatology, researchers from Spain's Hospital Clinic of Barcelona discovered that ghrelin has the potential of being a novel, anti-fibrotic therapy. According to Dr. Ramón Bataller, part of the team involved in the Barcelona study, "Our aim was to determine if recombinant ghrelin could regulate the formation of fibrous tissue associated with chronic liver damage."
The research team found the following:
· In animal models, ghrelin reduced the amount of fibrogenic cells by 25 percent.
· Participants with chronic Hepatitis C and alcoholic hepatitis had significantly lower ghrelin levels than did healthy individuals.
The researchers concluded that ghrelin inhibits the development of liver fibrosis in both animals and humans.
Insulin Resistance
The link connecting this appetite-stimulating hormone to its protection against liver fibrosis remains unclear. However, research from 2003 may be on the right track. According to an Italian study published in the Journal of Clinical Endocrinology & Metabolism, insulin resistance may be the bridge between ghrelin levels and liver damage. In individuals with NAFLD (non-alcoholic fatty liver disease), insulin resistance is believed to be relatively independent of obesity. After evaluating subjects with NAFLD, the Italian researchers found that insulin resistance plays a primary role in controlling ghrelin levels.
Insulin resistance is a decreased ability to respond to the effects of insulin, a hormone that helps transport glucose into the body's cells for making energy. Since cells need glucose to survive, the body compensates for insulin resistance by producing additional amounts of this hormone. Although not a disease or specific diagnosis, insulin resistance has a ripple effect on the body and is associated with heart disease, polycystic ovarian syndrome, Type 2 diabetes, obesity and NAFLD.
Thanks to Bataller's team, the connection between ghrelin and fibrosis could help prevent liver scarring in people who are most prone. Future studies are likely going to take insulin resistance into consideration while determining the safety and efficacy of ghrelin in people with chronic liver disease. If this hormone continues to prove its value to the liver, efforts to block ghrelin for weight loss purposes will likely lose steam. On the other hand, those with Hepatitis C could benefit by finally having a therapeutic option to prevent the progression of liver scarring.
References:
http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=31823, Body's own hormone may be liver disease's worst foe, Retrieved March 15, 2010, CORDIS Services, 2010.
http://jcem.endojournals.org/cgi/content/abstract/88/12/5674, Low Ghrelin Concentrations in Nonalcoholic Fatty Liver Disease Are Related to Insulin Resistance, G.Marchesini, et al, Retrieved March 19, 2010, Journal of Clinical Endocrinology & Metabolism, August 2003.
http://www.cbsnews.com/stories/2003/03/11/60II/main543614.shtml, The Hunger Hormone, Carol Kopp, Retrieved March 15, 2010, CBS Interactive Inc., 2010.
http://www.eurekalert.org/pub_releases/2010-03/w-gml022510.php, Ghrelin mitigates liver fibrosis in animal models; regulates human fibrosis, Retrieved March 15, 2010, EurekAlert, 2010.
http://www.healthsquare.com/fgpd/fg4ch20.htm, Dealing with Liver Disease, Retrieved March 19, 2010, The HealthCentral Network, Inc., 2010.
http://www.labtestsonline.org/understanding/conditions/insulin_resistance.html, Insulin Resistance, Retrieved March 19, 2010, American Association for Clinical Chemistry, 2010.
http://www.ncbi.nlm.nih.gov/pubmed/20077562, Ghrelin attenuates hepatocellular injury and liver fibrogenesis in rodents and influences fibrosis progression in humans, Moreno M, et al, Retrieved March 15, 2010, Hepatology, March 2010.
http://www.newscientist.com/article/dn13845-stomach-hormone-turns-hungry-people-into-junkies.html, Stomach hormone turns hungry people into junkies, Ewen Callaway, Retrieved March 18, 2010, Reed Business Information Ltd, 2010.
Source
Infergen Gives Hepatitis C Patients An Extra Chance
ALEXANDRIA, Va. (WUSA) -- Approximately 50 percent of chronic hepatitis C patients do not respond to their initial course of therapy, according to Bruce R. Bacon M.D. of Saint Louis University School of Medicine.
Dr. Bacon is the lead investigator of the registration trial for Infergen, a new treatment for Hepatitis C patients that recieved FDA approval last month.
Dr. Bacon says, "The FDA's recognition of the expanded label allows patients failing therapy a safe and efficacious retreatment strategy."
This is good news for 59 year-old Hubert "Shep" Sheppard. Shep is a physically active man who bikes 60 miles a week and used to jump out of airplanes as a paratrooper. Now he is a private detective.
However, the one challenge that could have cost Shep his vitality, even his life, was Hepatitis C.
Shep says, "I have no idea where I got it. I was totally shocked I had this disease."
He adds, "I probably had it for a while, and had no indications of it."
In Shep's case, the chronic infection was attacking his liver. His first round of treatment wasn't enough to clear it.
Shep says, "There's some difference in African-Americans in that we don't respond well to some treatment."
Dr. Jonathan McCone of Alexandria, Virginia says Hepatitis C can be a silent killer.
Dr. McCone says, "Its basically not a sexually transmitted disease. Its not transmitted by kissing or sneezing in somebody's face, or breathing the same air. It's a blood-to-blood disease."
He adds, "One can end up with advanced liver disease, cirrhosis, liver cancer, and the need for liver transplant."
Fortunately Shep was able to take advantage of Infergen, given daily with ribivirin pills, it delivers a one-two punch to the virus.
The down-side, the regimen that lasts for months also delivers a whallop of side effects from extreme fatigue to weight and hair loss, and anemia.
But Shep says he approached it with a military mind-set.
Shep says, "I just saw it as a personal combat between me and this disease, and I just thought that one of us is going to be carried out in a box and its not going to be me."
Shep tested clean of the virus last year, and is now considered cured.
There is no vaccine for Hepatitis C, like there is for A and B.
Source
Portuguese scientists discover an extraordinary new type of white blood cells
11 August 2010
Ciência Viva - Agência Nacional para a Cultura Científica e Tecnológica
After a transplant – and to assure that the new organ is not rejected - patients are put on life-long therapy to suppress their immune system (IS), which, nevertheless, needs to be left intact enough to be able to defend the body against all kinds of disease. A tricky balance as the many rejected organs attest. But a discovery by Maria Monteiro and Luis Graça, two Portuguese scientists, could change all this, at least for the liver. Their work, just out in the Journal of Immunology (1), describes how they found a new type of white blood cell – baptised NKTreg (reg from regulatory) – that, once activated, migrate into the liver and suppress any immune response in its vicinity. What is most remarkable is that the immune system elsewhere is left intact. And the implications do not end in better liver transplants as, once these cells create an “immune tolerant organ”, we can graft any type of tissue or express any gene that the body might need into it, knowing that it would be safe from the IS. The potential of the discovery is such that a patent by Monteiro and Graça for the production and therapeutic use of NKTreg cells in humans has already been accepted.
Controlling an unwanted immune response, whether to stop organ rejection after a transplant or for the treatment of autoimmune diseases – in which an abnormal IS attacks the own body- can be tricky. At the moment there are two types of approaches: general immunosuppression or deletion of entire “arms” of the IS. Both methods require a difficult equilibrium between stopping the damaging immune response while allowing patients to remain immuno-competent, and both carry potentially serious side effects. Most recent therapies fall in the second approach and work by deleting a particular type of cell or protein (an “arm” of the IS) at the core of the immune response we want to stop. While these methods can be extraordinarily effective – thousand of patients had their lives changed by them – unfortunately, they do not seem to work for long, probably because the IS adapts and brings other cells and proteins to do the job of the lost “arm”. While this is not a problem for pharmaceutical companies that can go on developing new and even more expensive drugs, to patients it means a life of constant uncertainty and many potential problems– will the next new drug be effective, will it stop working, will then be yet another drug ready, what about side effects?
The truth is that these kinds of approaches are a far cry from a 21st century medicine with emphasis in personalised and very specific therapies, and it is crucial that new and better treatments are found.
It is in this context that a family of white blood cells called regulatory T cells has been hailed as “next big thing” - shown to suppress immune responses and part of the body’s mechanisms to stop undesired immune responses, these cells could be key to more specific treatments while are also less prone to be “overridden” by the body control mechanisms. And in fact, human trials for their use in transplantation are already under way although much work needs to be done. But meanwhile another family of white blood cells - called NKT cells - has also came to the attention of scientists when shown to protect mice from several autoimmune diseases, including diabetes and autoimmune encephalomyelitis (EAE) - the animal equivalent of multiple sclerosis
To try to understand better the potential of NKT cells Marta Monteiro, Luis Graça and colleagues at the Instituto de Medicina Molecular, University of Lisbon and the Instituto Gulbenkian de Ciência in Oeiras, Portugal looked at mice protected from EAE using NKT cells (like shown by others). In these mice they analysed the lymph nodes that drain the brain – the logic being that since EAE affects the brain, protective cells should be found in the lymph nodes directly linked to it. To their surprise they discover a total new population of NKT cells that expressed Foxp3 – a marker for regulatory T cell, linked to these cells immunosuppressive capabilities. When these new NKT cells were studied in laboratory they revealed several other similarities – not only they share many other receptors of regulatory T cells but, like them, both Foxp3 and their suppressive abilities are triggered by a protein called TGFbeta – leading Monteiro and Graça to name them NKTreg cells.
But how do these cells act when in the body? To answer this question, and after activating NKT cells to become NKTreg (so Foxp3 positive) and tag them with a fluorescent marker so they could be easily traced, Monteiro and Graça injected the (suppressive) cells back into mice. Remarkably these cells homed straight to the liver – in this they are very different from regulatory T cells that move into all lymphoid organs; spleen, lymph nodes, etc - suggesting that in normal conditions NKTreg cells could perform some immunosuppressive role in this organ.
The implications of this discovery are important and many. In liver transplants although success rate has increased substantially the odds that the organ will survive up to 15 years are still only around 58%, with as many as 10-15% of patients experiencing organ rejection before the end of the first year. Not only that, but current immunosuppression therapies are costly and affect patients’ life expectancy by putting them at higher risk of cancer and mortal infections. NKTreg cells – if proved to function in the same way in humans, and Monteiro has already shown that we at least have them - might be the answer to these problems.
As Luis Graça explains “the liver is already the transplanted organ with higher chances of success due to its unique characteristics, by using these new cells we might be able to achieve almost 100% organ acceptance and this without touching the remaining IS, what is remarkable. Patients might be able to survive with only a minimum dose of other immunsuppressors”.
But there are other major implications to be able to create a “bubble of tolerance” within the body. Many diseases caused by the absence of a molecule or metabolic tissue are being treated with therapies that insert replacements into the body. The problem is that the IS soon or later detects these new “parts” and attacks them. The liver is already a place where the immune system seems to be less vigilant - probably so it is not over-activated all the time by the food and microbial molecules that come through the digestive system – add NKTreg cells to this organ and it can became the perfect place to hide anything from the IS.
And in fact, at the moment, some diabetic patients – that lack insulin to metabolise sugars – already have insulin-producing grafts on their liver, while some gene therapies, for example for the production of clothing factors in haemophilia (a disease where patients can not coagulate their blood) are already being expressed in the organ. NKTreg, if they work in the same way in humans as in mice, can radically improve the chances of success of these and other therapies. The potential of being able to create a contained area of immunosuppression within the body without touching the remaining immune responses elsewhere in the body, is immense. But first we need to see if and how NKTreg cells work in humans and that is what Monteiro and Graça plan to do next.
Piece by:Catarina Amorim
http://www.jimmunol.org/cgi/content/abstract/jimmunol.1000359v1
Source
Ciência Viva - Agência Nacional para a Cultura Científica e Tecnológica
After a transplant – and to assure that the new organ is not rejected - patients are put on life-long therapy to suppress their immune system (IS), which, nevertheless, needs to be left intact enough to be able to defend the body against all kinds of disease. A tricky balance as the many rejected organs attest. But a discovery by Maria Monteiro and Luis Graça, two Portuguese scientists, could change all this, at least for the liver. Their work, just out in the Journal of Immunology (1), describes how they found a new type of white blood cell – baptised NKTreg (reg from regulatory) – that, once activated, migrate into the liver and suppress any immune response in its vicinity. What is most remarkable is that the immune system elsewhere is left intact. And the implications do not end in better liver transplants as, once these cells create an “immune tolerant organ”, we can graft any type of tissue or express any gene that the body might need into it, knowing that it would be safe from the IS. The potential of the discovery is such that a patent by Monteiro and Graça for the production and therapeutic use of NKTreg cells in humans has already been accepted.
Controlling an unwanted immune response, whether to stop organ rejection after a transplant or for the treatment of autoimmune diseases – in which an abnormal IS attacks the own body- can be tricky. At the moment there are two types of approaches: general immunosuppression or deletion of entire “arms” of the IS. Both methods require a difficult equilibrium between stopping the damaging immune response while allowing patients to remain immuno-competent, and both carry potentially serious side effects. Most recent therapies fall in the second approach and work by deleting a particular type of cell or protein (an “arm” of the IS) at the core of the immune response we want to stop. While these methods can be extraordinarily effective – thousand of patients had their lives changed by them – unfortunately, they do not seem to work for long, probably because the IS adapts and brings other cells and proteins to do the job of the lost “arm”. While this is not a problem for pharmaceutical companies that can go on developing new and even more expensive drugs, to patients it means a life of constant uncertainty and many potential problems– will the next new drug be effective, will it stop working, will then be yet another drug ready, what about side effects?
The truth is that these kinds of approaches are a far cry from a 21st century medicine with emphasis in personalised and very specific therapies, and it is crucial that new and better treatments are found.
It is in this context that a family of white blood cells called regulatory T cells has been hailed as “next big thing” - shown to suppress immune responses and part of the body’s mechanisms to stop undesired immune responses, these cells could be key to more specific treatments while are also less prone to be “overridden” by the body control mechanisms. And in fact, human trials for their use in transplantation are already under way although much work needs to be done. But meanwhile another family of white blood cells - called NKT cells - has also came to the attention of scientists when shown to protect mice from several autoimmune diseases, including diabetes and autoimmune encephalomyelitis (EAE) - the animal equivalent of multiple sclerosis
To try to understand better the potential of NKT cells Marta Monteiro, Luis Graça and colleagues at the Instituto de Medicina Molecular, University of Lisbon and the Instituto Gulbenkian de Ciência in Oeiras, Portugal looked at mice protected from EAE using NKT cells (like shown by others). In these mice they analysed the lymph nodes that drain the brain – the logic being that since EAE affects the brain, protective cells should be found in the lymph nodes directly linked to it. To their surprise they discover a total new population of NKT cells that expressed Foxp3 – a marker for regulatory T cell, linked to these cells immunosuppressive capabilities. When these new NKT cells were studied in laboratory they revealed several other similarities – not only they share many other receptors of regulatory T cells but, like them, both Foxp3 and their suppressive abilities are triggered by a protein called TGFbeta – leading Monteiro and Graça to name them NKTreg cells.
But how do these cells act when in the body? To answer this question, and after activating NKT cells to become NKTreg (so Foxp3 positive) and tag them with a fluorescent marker so they could be easily traced, Monteiro and Graça injected the (suppressive) cells back into mice. Remarkably these cells homed straight to the liver – in this they are very different from regulatory T cells that move into all lymphoid organs; spleen, lymph nodes, etc - suggesting that in normal conditions NKTreg cells could perform some immunosuppressive role in this organ.
The implications of this discovery are important and many. In liver transplants although success rate has increased substantially the odds that the organ will survive up to 15 years are still only around 58%, with as many as 10-15% of patients experiencing organ rejection before the end of the first year. Not only that, but current immunosuppression therapies are costly and affect patients’ life expectancy by putting them at higher risk of cancer and mortal infections. NKTreg cells – if proved to function in the same way in humans, and Monteiro has already shown that we at least have them - might be the answer to these problems.
As Luis Graça explains “the liver is already the transplanted organ with higher chances of success due to its unique characteristics, by using these new cells we might be able to achieve almost 100% organ acceptance and this without touching the remaining IS, what is remarkable. Patients might be able to survive with only a minimum dose of other immunsuppressors”.
But there are other major implications to be able to create a “bubble of tolerance” within the body. Many diseases caused by the absence of a molecule or metabolic tissue are being treated with therapies that insert replacements into the body. The problem is that the IS soon or later detects these new “parts” and attacks them. The liver is already a place where the immune system seems to be less vigilant - probably so it is not over-activated all the time by the food and microbial molecules that come through the digestive system – add NKTreg cells to this organ and it can became the perfect place to hide anything from the IS.
And in fact, at the moment, some diabetic patients – that lack insulin to metabolise sugars – already have insulin-producing grafts on their liver, while some gene therapies, for example for the production of clothing factors in haemophilia (a disease where patients can not coagulate their blood) are already being expressed in the organ. NKTreg, if they work in the same way in humans as in mice, can radically improve the chances of success of these and other therapies. The potential of being able to create a contained area of immunosuppression within the body without touching the remaining immune responses elsewhere in the body, is immense. But first we need to see if and how NKTreg cells work in humans and that is what Monteiro and Graça plan to do next.
Piece by:Catarina Amorim
http://www.jimmunol.org/cgi/content/abstract/jimmunol.1000359v1
Source
Highest Rates Of Hepatitis C Virus Transmission Found In Egypt
Article Date: 11 Aug 2010 - 1:00 PDT
The Arab Republic of Egypt has the highest rates of new hepatitis C virus (HCV) infection in the world, according to a new study published in the prestigious Proceedings of the National Academy of Sciences. The study also estimates more than 500,000 new HCV infections occur in Egypt every year, likely signaling an epidemic in a country of more than 77 million people. This high rate of HCV transmission may be due to the lack of sufficient standard safety precautions in medical and dental facilities, the authors suggest.
"Nearly 7 out of every 1,000 Egyptians acquire HCV infections every year, suggesting intense ongoing transmission. This is the highest level of HCV transmission ever recorded at a national level for a blood borne infectious disease transmitted parenterally, that is, by use of non-sterile medical instruments," said Dr. F. DeWolfe Miller, lead author of this study and professor of epidemiology at the Department of Tropical Medicine and Medical Microbiology and Pharmacology at the University of Hawaii.
Although the high prevalence of hepatitis C in Egypt has been well established for many years, and linked in part to limited safety measures during anti-bilharzia campaigns, published estimates of prevalence from different Egyptian communities failed to provide a nationwide picture of the magnitude of ongoing HCV infection transmission. To estimate the rate of new HCV cases of infection in Egypt, the authors of the study performed epidemiologic modeling of data from a range of studies, including a 2008 national HCV survey with a representative sample and well-documented study design.
"The study opened our eyes to a disease burden similar in scale and challenge to the HIV problem in sub-Saharan Africa: Millions of cases of an infection for which there is no vaccine, no effective treatment, and where case management is so expensive that it is beyond the reach of most patients," said Dr. Laith J. Abu-Raddad, co-author of the study and assistant professor of public health at the Infectious Disease Epidemiology Group at the Weill Cornell Medical College-Qatar.
The study necessitates not only further analysis of HCV transmission in Egypt but also justifies the immediate increase of resources to strengthen public health measures aimed at reducing the transmission of HCV in clinical and non-clinical settings, according to the authors. Failure to address this problem will result in a massive disease burden in the nation in terms of HCV infection complications, including active liver disease, liver failure, or liver cancer.
"There is only one way to deal with the HCV challenge in this country: HCV prevention," warned Dr. Miller. "Effective and stronger HCV prevention programs are urgently needed in Egypt. Failure to act could swamp the public health system over the coming decades with millions of cases of HCV disease complications with an economic and social cost that this nation does not have the means to confront."
Key scientific findings of the study
• Nearly 7 out of each 1,000 Egyptians acquire HCV infection every year for a total of 537,000 new HCV infections every year. This is by far the largest ever recorded rate of occurrence of HCV at a national level of all countries in the world.
• One in every 10 Egyptians is a carrier of the HCV infection, which means that there are at least 4,459,000 persons infected with HCV who are infectious to others. This is the largest reservoir of HCV infection in the world.
• Contrary to the widely-held perception that this rate of occurrence reflects merely the limited safety measures during anti-bilharzia campaigns, HCV incidence likely continues at alarming levels due to limitations in the implementation and enforcement of stringent standard precautions in public and private medical and dental facilities.
F. DeWolfe Miller, PhD (Lead Author)
Department of Tropical Medicine and Medical Microbiology and Pharmacology
University of Hawaii
Honolulu, HI, USA
Laith Abu-Raddad, PhD (Co-Author)
Director of Epidemiology, Biostatistics and Biomathematics Research Core
Assistant Professor in Public Health
Weill Cornell Medical College - Qatar
Doha, Qatar
Source:
Weill Cornell
Source
The Arab Republic of Egypt has the highest rates of new hepatitis C virus (HCV) infection in the world, according to a new study published in the prestigious Proceedings of the National Academy of Sciences. The study also estimates more than 500,000 new HCV infections occur in Egypt every year, likely signaling an epidemic in a country of more than 77 million people. This high rate of HCV transmission may be due to the lack of sufficient standard safety precautions in medical and dental facilities, the authors suggest.
"Nearly 7 out of every 1,000 Egyptians acquire HCV infections every year, suggesting intense ongoing transmission. This is the highest level of HCV transmission ever recorded at a national level for a blood borne infectious disease transmitted parenterally, that is, by use of non-sterile medical instruments," said Dr. F. DeWolfe Miller, lead author of this study and professor of epidemiology at the Department of Tropical Medicine and Medical Microbiology and Pharmacology at the University of Hawaii.
Although the high prevalence of hepatitis C in Egypt has been well established for many years, and linked in part to limited safety measures during anti-bilharzia campaigns, published estimates of prevalence from different Egyptian communities failed to provide a nationwide picture of the magnitude of ongoing HCV infection transmission. To estimate the rate of new HCV cases of infection in Egypt, the authors of the study performed epidemiologic modeling of data from a range of studies, including a 2008 national HCV survey with a representative sample and well-documented study design.
"The study opened our eyes to a disease burden similar in scale and challenge to the HIV problem in sub-Saharan Africa: Millions of cases of an infection for which there is no vaccine, no effective treatment, and where case management is so expensive that it is beyond the reach of most patients," said Dr. Laith J. Abu-Raddad, co-author of the study and assistant professor of public health at the Infectious Disease Epidemiology Group at the Weill Cornell Medical College-Qatar.
The study necessitates not only further analysis of HCV transmission in Egypt but also justifies the immediate increase of resources to strengthen public health measures aimed at reducing the transmission of HCV in clinical and non-clinical settings, according to the authors. Failure to address this problem will result in a massive disease burden in the nation in terms of HCV infection complications, including active liver disease, liver failure, or liver cancer.
"There is only one way to deal with the HCV challenge in this country: HCV prevention," warned Dr. Miller. "Effective and stronger HCV prevention programs are urgently needed in Egypt. Failure to act could swamp the public health system over the coming decades with millions of cases of HCV disease complications with an economic and social cost that this nation does not have the means to confront."
Key scientific findings of the study
• Nearly 7 out of each 1,000 Egyptians acquire HCV infection every year for a total of 537,000 new HCV infections every year. This is by far the largest ever recorded rate of occurrence of HCV at a national level of all countries in the world.
• One in every 10 Egyptians is a carrier of the HCV infection, which means that there are at least 4,459,000 persons infected with HCV who are infectious to others. This is the largest reservoir of HCV infection in the world.
• Contrary to the widely-held perception that this rate of occurrence reflects merely the limited safety measures during anti-bilharzia campaigns, HCV incidence likely continues at alarming levels due to limitations in the implementation and enforcement of stringent standard precautions in public and private medical and dental facilities.
F. DeWolfe Miller, PhD (Lead Author)
Department of Tropical Medicine and Medical Microbiology and Pharmacology
University of Hawaii
Honolulu, HI, USA
Laith Abu-Raddad, PhD (Co-Author)
Director of Epidemiology, Biostatistics and Biomathematics Research Core
Assistant Professor in Public Health
Weill Cornell Medical College - Qatar
Doha, Qatar
Source:
Weill Cornell
Source
Transplant Patients Can Benefit From Loved Ones' Care
August 10, 2010, 16:00 EST
Caregiving by those with emotional connection lessens anxiety, depression after surgery, study found
TUESDAY, Aug. 10 (HealthDay News) -- Transplant patients who have a close emotional connection with family members or other caregivers experience less depression and anxiety after surgery, new research has found.
The study included 74 liver transplant patients and their primary caregivers who were surveyed before surgery and six months after transplantation. Caregivers were asked to rate how close they felt to the patient, and the sample was divided into a group whose caregivers reported the most closeness and a group whose caregivers reported the least.
Symptoms of depression and anxiety decreased among the patients after their liver transplant, but the improvements weren't as significant for those with an emotionally distant caregiver, according to the researchers from the Henry Ford Hospital in Detroit.
"If you live with someone who loves you, the quality of care they provide may be much better, they may be more encouraging, you may want to please them and recuperate faster so you can spend quality time with them," lead author Anne Eshelman, of the Henry Ford Health System Behavioral Health Services, said in a hospital news release.
"Caregivers who are not close may provide the basic requirements, but don't help give someone a reason to live and look to the future," she added.
The study findings also indicated that emotional closeness was critical in male patients, but less so for women (although the researchers pointed out that interpretation of the results was difficult due to the small sample size).
"Men who had an adequate number of support people, but did not have close support, were still depressed and anxious at follow-up, compared to those who had closer support," Eshelman said. "Other literature shows that women have wider support, more friends and family they are connected to than men, and if the primary support person is not that close, they probably rely on the other people such as girlfriends."
The study was scheduled for presentation Aug. 6 at the International Congress of Behavioral Medicine in Washington, D.C.
More information
The American Society of Transplantation has more about health after transplantation.
-- Robert Preidt
SOURCE: Henry Ford Hospital, news release, Aug. 6, 2010
Source
Caregiving by those with emotional connection lessens anxiety, depression after surgery, study found
TUESDAY, Aug. 10 (HealthDay News) -- Transplant patients who have a close emotional connection with family members or other caregivers experience less depression and anxiety after surgery, new research has found.
The study included 74 liver transplant patients and their primary caregivers who were surveyed before surgery and six months after transplantation. Caregivers were asked to rate how close they felt to the patient, and the sample was divided into a group whose caregivers reported the most closeness and a group whose caregivers reported the least.
Symptoms of depression and anxiety decreased among the patients after their liver transplant, but the improvements weren't as significant for those with an emotionally distant caregiver, according to the researchers from the Henry Ford Hospital in Detroit.
"If you live with someone who loves you, the quality of care they provide may be much better, they may be more encouraging, you may want to please them and recuperate faster so you can spend quality time with them," lead author Anne Eshelman, of the Henry Ford Health System Behavioral Health Services, said in a hospital news release.
"Caregivers who are not close may provide the basic requirements, but don't help give someone a reason to live and look to the future," she added.
The study findings also indicated that emotional closeness was critical in male patients, but less so for women (although the researchers pointed out that interpretation of the results was difficult due to the small sample size).
"Men who had an adequate number of support people, but did not have close support, were still depressed and anxious at follow-up, compared to those who had closer support," Eshelman said. "Other literature shows that women have wider support, more friends and family they are connected to than men, and if the primary support person is not that close, they probably rely on the other people such as girlfriends."
The study was scheduled for presentation Aug. 6 at the International Congress of Behavioral Medicine in Washington, D.C.
More information
The American Society of Transplantation has more about health after transplantation.
-- Robert Preidt
SOURCE: Henry Ford Hospital, news release, Aug. 6, 2010
Source
Love the Glove: Glove Use in Hospitals Appears to Cut Risk of Needlestick Injury
August 10, 2010
Wearing gloves reduces the risk of injury by needles and sharp medical devices, or sharps injuries, by about 66 percent, according to a new study by Canadian and U.S. researchers. Double-gloving brought the risk down further, by about 80 percent.
The study involved 636 health care workers from 13 medical centers in the United States or Canada who presented to employee health clinics after a sharps injury. Of the workers, 195 were scrubbed in an operating room or procedure suite when injured, and 441 were non-scrubbed and injured elsewhere. The latter were more likely to be gloved when treating patients who were perceived to have a high risk of HIV, hepatitis B or hepatitis C.
In case-crossover analyses, gloves reduced injury risk (incidence rate ratio [IRR] 0.33 [95 percent CI, 0.22-0.50]. Among scrubbed individuals, "involvement in an orthopedic procedure was associated with double-gloving at injury (adjusted odds ratio, 13.7 [95 percent CI, 4.55-41.3]); this gloving practice was associated with decreased injury risk (IRR, 0.20 [95 percent CI, 0.10-0.42])."
"Gloving actually reduces the likelihood that a needle will go through your skin and inoculate you with blood," said senior study author Dr. David Fisman, an epidemiologist and researcher with the University of Toronto and Toronto's Hospital for Sick Children. In passing through the latex or vinyl membrane, some of the blood from the needle will be removed, reducing the inoculum or potentially infected blood, he explained.
Yet despite this, "There are kind of these weird beliefs about if you glove then you get clumsier and if you get clumsier, then you stick yourself," Fisman said.
The full report, "Use of Gloves and Reduction of Risk of Injury Caused by Needles or Sharp Medical Devices in Healthcare Workers: Results From a Case-Crossover Study," was published in Infection Control & Hospital Epidemiology (2010;31:908-917).
Source
Wearing gloves reduces the risk of injury by needles and sharp medical devices, or sharps injuries, by about 66 percent, according to a new study by Canadian and U.S. researchers. Double-gloving brought the risk down further, by about 80 percent.
The study involved 636 health care workers from 13 medical centers in the United States or Canada who presented to employee health clinics after a sharps injury. Of the workers, 195 were scrubbed in an operating room or procedure suite when injured, and 441 were non-scrubbed and injured elsewhere. The latter were more likely to be gloved when treating patients who were perceived to have a high risk of HIV, hepatitis B or hepatitis C.
In case-crossover analyses, gloves reduced injury risk (incidence rate ratio [IRR] 0.33 [95 percent CI, 0.22-0.50]. Among scrubbed individuals, "involvement in an orthopedic procedure was associated with double-gloving at injury (adjusted odds ratio, 13.7 [95 percent CI, 4.55-41.3]); this gloving practice was associated with decreased injury risk (IRR, 0.20 [95 percent CI, 0.10-0.42])."
"Gloving actually reduces the likelihood that a needle will go through your skin and inoculate you with blood," said senior study author Dr. David Fisman, an epidemiologist and researcher with the University of Toronto and Toronto's Hospital for Sick Children. In passing through the latex or vinyl membrane, some of the blood from the needle will be removed, reducing the inoculum or potentially infected blood, he explained.
Yet despite this, "There are kind of these weird beliefs about if you glove then you get clumsier and if you get clumsier, then you stick yourself," Fisman said.
The full report, "Use of Gloves and Reduction of Risk of Injury Caused by Needles or Sharp Medical Devices in Healthcare Workers: Results From a Case-Crossover Study," was published in Infection Control & Hospital Epidemiology (2010;31:908-917).
Source
For Lilly, it's a big one that got away
J.K. Wall August 11, 2010
Mark this one in Eli Lilly and Co.’s “Oops!” category.
An experimental medicine for hepatitis C that Lilly helped identify and develop is now on the cusp of market approval. According to an article in Xconomy.com, a biotech trade publication, some analysts are predicting as much as $2 billion in annual U.S. sales after the drug's expected market launch in 2011.
But in December 2002, Lilly sold back its rights to the drug, telaprevir, to its inventor, Massachusetts-based Vertex Pharmaceuticals Inc
Any revenue from telaprevir, which would have been split with Vertex, would have been awfully nice right now for Lilly. The Indianapolis-based drugmaker will watch patents expire on its cancer drug Gemzar in November and its antipsyhotic blockbuster Zyprexa a year later.
Cheaper generic copies will steal the lion’s share of those two drugs’ $6 billion in annual sales.
“It’s a decision that Lilly has to regret,” Xconomy.com reporter Ryan McBride wrote about telaprevir, which proved effective for three out of four patients with hepatitis C, a chronic liver disease, during a large Phase 3 clinical trial.
McBride cited a former Vertex executive who said telaprevir’s champions within Lilly were shuffled off the program, and it subsequently fell down Lilly’s priority list.
Vertex later signed co-development deals with New Jersey-based Johnson & Johnson and Japan-based Mitsubishi Tanabe, according to Xconomy.com.
“At Lilly, we regularly review our portfolio and sometimes re-prioritize assets based on resource availability,” Lilly spokesman Mark Taylor said in a statement. “Although we may decide to discontinue internal development of a molecule, we many times try to find ways to allow partner companies to continue the development. We believe this is in the best interest of the patients who may ultimately benefit if a new medicine makes it to the market."
Source
Mark this one in Eli Lilly and Co.’s “Oops!” category.
An experimental medicine for hepatitis C that Lilly helped identify and develop is now on the cusp of market approval. According to an article in Xconomy.com, a biotech trade publication, some analysts are predicting as much as $2 billion in annual U.S. sales after the drug's expected market launch in 2011.
But in December 2002, Lilly sold back its rights to the drug, telaprevir, to its inventor, Massachusetts-based Vertex Pharmaceuticals Inc
Any revenue from telaprevir, which would have been split with Vertex, would have been awfully nice right now for Lilly. The Indianapolis-based drugmaker will watch patents expire on its cancer drug Gemzar in November and its antipsyhotic blockbuster Zyprexa a year later.
Cheaper generic copies will steal the lion’s share of those two drugs’ $6 billion in annual sales.
“It’s a decision that Lilly has to regret,” Xconomy.com reporter Ryan McBride wrote about telaprevir, which proved effective for three out of four patients with hepatitis C, a chronic liver disease, during a large Phase 3 clinical trial.
McBride cited a former Vertex executive who said telaprevir’s champions within Lilly were shuffled off the program, and it subsequently fell down Lilly’s priority list.
Vertex later signed co-development deals with New Jersey-based Johnson & Johnson and Japan-based Mitsubishi Tanabe, according to Xconomy.com.
“At Lilly, we regularly review our portfolio and sometimes re-prioritize assets based on resource availability,” Lilly spokesman Mark Taylor said in a statement. “Although we may decide to discontinue internal development of a molecule, we many times try to find ways to allow partner companies to continue the development. We believe this is in the best interest of the patients who may ultimately benefit if a new medicine makes it to the market."
Source
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