Showing posts with label hepatology. Show all posts
Showing posts with label hepatology. Show all posts
Thursday, July 12, 2012
Levels of Hepatitis C Virus Higher Among African-Americans and Males
Posted on 7/10/12 on www.amren.com. A collaborative study between the National Institutes of Health Clinical Center and UCSF to be published in the July issue of "Hepatology" showed that among IVDUs males and African Americans were more likely to have HCV and/or HIV than any other demographic. This has implications for treatment in that African Americans are less likely to respond to current therapy than any other demographic.
Levels of Hepatitis C Virus Higher Among African-Americans and Males
Medical Xpress, July 10, 2012
Epidemiologists have determined that levels of hepatitis C virus (HCV) found among injection drug users (IDUs) were higher in individuals who are male or African American even after differences in other factors were considered. The study, which was funded by the National Cancer Institute and performed with collaborators from the National Institutes of Health Clinical Center and the University of California—San Francisco, was the first to simultaneously examine the association of demographic, viral and human genetic factors on HCV RNA levels. Results of the study published in the July issue of Hepatology, a journal of the American Association for the Study of Liver Diseases (AASLD), also showed higher levels of HCV among IDUs who were co-infected with human immunodeficiency virus (HIV).
A 2010 report from the Centers for Disease Control and Prevention (CDC) estimates that up to 3.9 million Americans have chronic HCV—a leading cause of liver cancer, end-stage liver disease and liver transplantation. According to the CDC 17,000 new cases and 2,800 acute cases of HCV were reported in 2010. Previous epidemiologic studies suggest one-third of those 18 to 30 year-old IDUs and up to 90% of older IDUs are infected with HCV.
“With such a high incidence and prevalence of hepatitis C virus infection among IDUs, it is important to understand the characteristics of the infection in this group,” explains lead author Dr. Thomas O’Brien of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute in Rockville, MD. “The HCV RNA level is an important predictor of response to treatment in patients with chronic hepatitis C. Our study is the first to examine simultaneously the viral, demographic, and genetic factors that impact HCV levels in ethnically diverse IDUs.”
Participants were originally recruited for the Urban Health Study—a multi-ethnic group of IDUs in San Francisco. Researchers used interview data and biological samples from participants to analyze demographic, viral and host characteristics of cancer-causing viruses. A total of 1701 participants had detectable HCV RNA and were included in the present study. The median age at enrollment was 46 years and median age of first illicit drug injection was 18 years. Close to 75% of participants were men and 56% were African American, 34% European (non-Hispanic) and 7% Latino (non-African American).
Adjusted analysis revealed that age, gender, racial ancestry, HIV-1 infection, and IL28B rs12979860 genotype were all independently associated with the HCV RNA level. “We know that the level of HCV is an important predictor of treatment response and that these levels seem to be influenced by a number of demographic, clinical, viral and human genetic factors,” concludes Dr. O’Brien.
Thursday, March 1, 2012
Hypoferremia Predicts Treatment Response to IFN-α...
Posted 3-1-12 on DoctorsLounge.com. According to a study published online in Hepatology, measurements of hepcidin, a regulator of iron homeostasis, may be a surrogate marker of immediate efficacy of pegylated interferon-α in patients with chronic HCV.
Hypoferremia Predicts Treatment Response to IFN-α
Last Updated: March 01, 2012.
Induction of hepcidin, subsequent drop in serum iron may be marker of treatment efficacy in hep C
For patients with hepatitis C virus, hepcidin, a regulator of iron homeostasis, is induced following a single dose of pegylated interferon-α, and may be a surrogate marker of immediate efficacy of interferon-α, according to a study published online Feb. 15 in Hepatology.
THURSDAY, March 1 (HealthDay News) -- For patients with hepatitis C virus (HCV), hepcidin, a regulator of iron homeostasis, is induced following a single dose of pegylated interferon-α (PEG-IFNα), and may be a surrogate marker of immediate efficacy of IFN-α, according to a study published online Feb. 15 in Hepatology.
John D. Ryan, M.D., of the Mater Misericordiae University Hospital in Dublin, and associates analyzed blood samples of HCV patients to assess the clinical importance of the changes in iron homeostasis during the first 24 hours of treatment with PEG-IFNα.
The researchers found that a single dose of PEG-IFNα triggered a significant increase in serum hepcidin that peaked at 12 hours. This coincided with a 50 percent drop in serum iron and transferrin saturation over 24 hours. Significantly lower levels of serum iron and transferring saturation were seen at 12 and 24 hours in patients with a ≥2 log decrease in HCV viral load over the first 24 hours. Serum iron levels at 24 hours were an independent predictor of immediate HCV viral decline. Direct induction of hepcidin by IFN-α was seen in cell culture, and was controlled by the STAT3 transcription factor.
"Hepcidin induction occurs following the initiation of PEG-IFNα treatment for HCV, and is mediated via STAT3 signaling," the authors write. "The subsequent hypoferremia was greatest in those with the most significant decline in viral load, identifying systemic iron withdrawal as a marker of immediate IFN-α efficacy in HCV patients."
Monday, January 30, 2012
Cell Permeable Peptide Identified that Inhibits Hepititis C Replication...
Posted today on Health News Digest.com and published in the Jan 30 issue of 'Hepatology'. UCLA researchers identify heat shock proteins (HSPs) that are important for viral infection and that the natural compound Quercetin inhibits synthesis of these proteins In Vitro.
Cell Permeable Peptide Identified that Inhibits Hepititis C Replication...
By Staff Editor
Jan 30, 2012 - 3:23:54 PM
Discovery Could Lead to a New Treatment for a Disease that Impacts up to 160 Million People Worldwide
(HealthNewsDigest.com) - Researchers from UCLA’s Jonsson Comprehensive Cancer Center have identified a cell-permeable peptide that inhibits a hepatitis C virus protein and blocks viral replication, which can lead to liver cancer and cirrhosis.
This finding by Dr. Samuel French, an assistant professor of pathology and senior author of the study, builds on previous work by the French laboratory that identified two cellular proteins that are important factors in hepatitis C virus infection.
French and his team initially set out to identify the cellular factors involved in hepatitis C replication and, using mass spectrometry, found that heat shock proteins (HSPs) 40 and 70 were important for viral infection. HSP70 was previously known to be involved, but HSP40 was linked for the first time to hepatitis C infection, French said. They further showed that the natural compound Quercetin, which inhibits the synthesis of these proteins, significantly inhibits viral infection in tissue culture.
In this study, published Jan. 30, 2012 in the peer-reviewed journal Hepatology, French and his team demonstrated that the viral non-structural protein 5A (NS5A) directly binds to HSP70 and mapped the site of the NS5A/HSP70 complex on NS5A. While HSP70 was previously shown to bind NS5A in cells, a direct NS5A/HSP70 interaction and complex formation was established in this study. In an effort to stop this interaction, they tested peptides that might inhibit HSP70.
“This is important because we’ve developed a small peptide that binds to that site and blocks the interaction between the proteins that is important for viral replication,” French said. “This is another, potentially highly efficacious way to block replication of hepatitis C.”
An estimated 160 million people worldwide are infected with hepatitis C and the conventional treatments – interferon and ribavirin – can have significant side effects. A new drug targeting cellular proteins rather than viral proteins would be a valuable addition to the treatment arsenal, French said.
“We were surprised that this peptide works this well,” French said. “While its mechanism is different, the activity of this peptide is comparable to other newly developed anti-virals.”
The study, done in tissue culture, shows that the peptide gains entry into the cell easily and blocks the cascade of cellular events that allows the virus to replicate, French said. Blocking the HSP70 protein rather than a viral protein also reduces the chance of patients with the hepatitis C virus developing resistance to the peptide.
“There’s no direct pressure on the virus, so it is less likely to mutate and develop resistance,” French said. “The goal is to achieve a sustained response, essentially a cure, meaning there is no more virus replication. There are a lot of drugs coming out now that are designed to stop hepatitis C replication, but resistance is still an issue. About 10 to 20 percent of patients on the new drugs become resistant. This new peptide may help combat resistance.”
Going forward, French and his team are testing variants of the newly discovered peptide to see if they can develop one with an even higher affinity and can decrease the size of the peptide to improve cellular penetration and liver targeting. The new and improved peptides will be tested in animal models.
This peptide “may be a candidate for hepatitis C therapy,” the study states. “Considering the potency of the peptide in suppressing viral translation levels, treatment with this peptide may significantly improve the efficacy of conventional treatments in patients who become resistant to conventional therapies.”
The study was supported in part by the National Institutes of Health and by the California Center for Antiviral Drug Discovery at the University of California.
UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2011, the Jonsson Cancer Center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 11 of the last 12 years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.
Cell Permeable Peptide Identified that Inhibits Hepititis C Replication...
By Staff Editor
Jan 30, 2012 - 3:23:54 PM
Discovery Could Lead to a New Treatment for a Disease that Impacts up to 160 Million People Worldwide
(HealthNewsDigest.com) - Researchers from UCLA’s Jonsson Comprehensive Cancer Center have identified a cell-permeable peptide that inhibits a hepatitis C virus protein and blocks viral replication, which can lead to liver cancer and cirrhosis.
This finding by Dr. Samuel French, an assistant professor of pathology and senior author of the study, builds on previous work by the French laboratory that identified two cellular proteins that are important factors in hepatitis C virus infection.
French and his team initially set out to identify the cellular factors involved in hepatitis C replication and, using mass spectrometry, found that heat shock proteins (HSPs) 40 and 70 were important for viral infection. HSP70 was previously known to be involved, but HSP40 was linked for the first time to hepatitis C infection, French said. They further showed that the natural compound Quercetin, which inhibits the synthesis of these proteins, significantly inhibits viral infection in tissue culture.
In this study, published Jan. 30, 2012 in the peer-reviewed journal Hepatology, French and his team demonstrated that the viral non-structural protein 5A (NS5A) directly binds to HSP70 and mapped the site of the NS5A/HSP70 complex on NS5A. While HSP70 was previously shown to bind NS5A in cells, a direct NS5A/HSP70 interaction and complex formation was established in this study. In an effort to stop this interaction, they tested peptides that might inhibit HSP70.
“This is important because we’ve developed a small peptide that binds to that site and blocks the interaction between the proteins that is important for viral replication,” French said. “This is another, potentially highly efficacious way to block replication of hepatitis C.”
An estimated 160 million people worldwide are infected with hepatitis C and the conventional treatments – interferon and ribavirin – can have significant side effects. A new drug targeting cellular proteins rather than viral proteins would be a valuable addition to the treatment arsenal, French said.
“We were surprised that this peptide works this well,” French said. “While its mechanism is different, the activity of this peptide is comparable to other newly developed anti-virals.”
The study, done in tissue culture, shows that the peptide gains entry into the cell easily and blocks the cascade of cellular events that allows the virus to replicate, French said. Blocking the HSP70 protein rather than a viral protein also reduces the chance of patients with the hepatitis C virus developing resistance to the peptide.
“There’s no direct pressure on the virus, so it is less likely to mutate and develop resistance,” French said. “The goal is to achieve a sustained response, essentially a cure, meaning there is no more virus replication. There are a lot of drugs coming out now that are designed to stop hepatitis C replication, but resistance is still an issue. About 10 to 20 percent of patients on the new drugs become resistant. This new peptide may help combat resistance.”
Going forward, French and his team are testing variants of the newly discovered peptide to see if they can develop one with an even higher affinity and can decrease the size of the peptide to improve cellular penetration and liver targeting. The new and improved peptides will be tested in animal models.
This peptide “may be a candidate for hepatitis C therapy,” the study states. “Considering the potency of the peptide in suppressing viral translation levels, treatment with this peptide may significantly improve the efficacy of conventional treatments in patients who become resistant to conventional therapies.”
The study was supported in part by the National Institutes of Health and by the California Center for Antiviral Drug Discovery at the University of California.
UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2011, the Jonsson Cancer Center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 11 of the last 12 years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.
Wednesday, December 21, 2011
Clinical Care Options inPractice now offering free online Hepatology textbook...
Clinical Care Options inPractice now offering free online Hepatology textbook....
CCO's inPractice now offering a new Hepatology medical textbook to complement their companion texts in Oncology and HIV. It's free and updated on a regular basis. It's search function allows you to browse for answers at the point of care. It can be found here: http://www.clinicaloptions.com/inPractice.aspx
Some of the texts include:
Virology and Immunology of Hepatitis Viruses
Hepatitis A and E
Hepatitis B Epidemiology, Pathogenesis, Diagnosis, and Natural History
Management of Hepatitis B Infection
Hepatitis B Management in Special Populations
Hepatitis Delta Virus
Hepatitis C Virus Epidemiology, Pathogenesis, Diagnosis, and Natural History
Management of Hepatitis C Infection
Hepatitis C Management in Special Populations
Other Viruses That Affect the Liver
CCO's inPractice now offering a new Hepatology medical textbook to complement their companion texts in Oncology and HIV. It's free and updated on a regular basis. It's search function allows you to browse for answers at the point of care. It can be found here: http://www.clinicaloptions.com/inPractice.aspx
Some of the texts include:
Virology and Immunology of Hepatitis Viruses
Hepatitis A and E
Hepatitis B Epidemiology, Pathogenesis, Diagnosis, and Natural History
Management of Hepatitis B Infection
Hepatitis B Management in Special Populations
Hepatitis Delta Virus
Hepatitis C Virus Epidemiology, Pathogenesis, Diagnosis, and Natural History
Management of Hepatitis C Infection
Hepatitis C Management in Special Populations
Other Viruses That Affect the Liver
Thursday, December 1, 2011
Journal article in Hepatology on green tea flavonoid that may prevent HCV reinfection post-liver transplant...
Some promising news published online in the journal Hepatology discussing in vivo research on the green tea catechin epigallocatechin-3-gallate (EGCG) that could possibly block HCV viral attachment to hepatocytes to prevent hepatitis C reinfection post-transplant.
Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell
Green tea flavonoid may prevent reinfection with hepatitis C virus following liver transplantation
German researchers have determined that epigallocatechin-3-gallate (EGCG)—a flavonoid found in green tea—inhibits the hepatitis C virus (HCV) from entering liver cells. Study findings available in the December issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases, suggest that EGCG may offer an antiviral strategy to prevent HCV reinfection following liver transplantation.
HCV infection can lead to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) or primary liver cancer. HCV is one of the most common causes of chronic liver disease and a primary indication for liver transplantation, affecting up to 170 million individuals worldwide according to estimates from the World Health Organization (WHO). Prior studies report that nearly 2% of the world population is infected with chronic HCV and up to 20% of the population in some countries.
While standard treatment with interferon with ribavirin and newer protease inhibitors may clear infection in some individuals, a substantial number of patients still may not respond to these therapies. For individuals receiving liver transplants due to complications from HCV, reinfection of the healthy donor liver remains a significant concern. Antiviral strategies that target HCV in its early stages are urgently needed to prevent graft reinfection and improve long-term outcomes for patients.
To address this critical issue, Dr. Sandra Ciesek and Dr. Eike Steinmann from the Hannover Medical School in Germany investigated the effect of the EGCG molecule, which is a major component of green tea, in preventing HCV from attaching to liver cells. "Green tea catechins such as EGCG and its derivatives epigallocatechin (EGC), epicatechingallate (ECG), and epicatechin (EC) have been shown to exhibit antiviral and anti-oncogenic properties," explains Dr. Ciesek. "Our study further explores the potential effect these flavonoids have in preventing HCV reinfection following liver transplantation."
Results showed that unlike its derivatives, EGCG inhibits entry of HCV into liver cells. The authors suggest that EGCG may impede HCV cell entry by acting on the host cell as the green tea catechin was not found to alter the density of virus particles. Pretreatment of cells with EGCG before HCV inoculation did not reduce the infection; however application during inoculation inhibited the rapid spread of the HCV. Lastly, researchers showed that EGCG inhibits viral attachment—the initial step in the HCV infection process. "The green tea antioxidant EGCG inhibits HCV cell entry by blocking viral attachment and may offer a new approach to prevent HCV infection, particularly reinfection following liver transplantation." concludes Dr. Ciesek.
###
Full Citation: The Green Tea Polyphenol Epigallocatechin-3-Gallate (EGCG) Inhibits Hepatitis C Virus (HCV) Entry." Sandra Ciesek, Thomas von Hahn, Che C. Colpitts, Luis M Schang,Martina Friesland, Jörg Steinmann, Michael P. Manns, Michael Ott, Heiner Wedemeyer, Philip Meuleman, Thomas Pietschmann and Eike Steinmann. Hepatology; Published Online: November 30, 2011 (DOI: 10.1002/hep.24610); Print Issue Date: December 2011. http://onlinelibrary.wiley.com/doi/10.1002/hep.24610/abstract.
Author Contact: To arrange an interview with Dr. Sandra Ciesek or Dr. Eike Steinmann, please contact Jo Schilling at jo.schilling@twincore.de.
This study is published in Hepatology. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.
About the Journal
Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Hepatology's current impact factor is 10.885.Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350 .
About Wiley-Blackwell
Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.
Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell
Green tea flavonoid may prevent reinfection with hepatitis C virus following liver transplantation
German researchers have determined that epigallocatechin-3-gallate (EGCG)—a flavonoid found in green tea—inhibits the hepatitis C virus (HCV) from entering liver cells. Study findings available in the December issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases, suggest that EGCG may offer an antiviral strategy to prevent HCV reinfection following liver transplantation.
HCV infection can lead to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) or primary liver cancer. HCV is one of the most common causes of chronic liver disease and a primary indication for liver transplantation, affecting up to 170 million individuals worldwide according to estimates from the World Health Organization (WHO). Prior studies report that nearly 2% of the world population is infected with chronic HCV and up to 20% of the population in some countries.
While standard treatment with interferon with ribavirin and newer protease inhibitors may clear infection in some individuals, a substantial number of patients still may not respond to these therapies. For individuals receiving liver transplants due to complications from HCV, reinfection of the healthy donor liver remains a significant concern. Antiviral strategies that target HCV in its early stages are urgently needed to prevent graft reinfection and improve long-term outcomes for patients.
To address this critical issue, Dr. Sandra Ciesek and Dr. Eike Steinmann from the Hannover Medical School in Germany investigated the effect of the EGCG molecule, which is a major component of green tea, in preventing HCV from attaching to liver cells. "Green tea catechins such as EGCG and its derivatives epigallocatechin (EGC), epicatechingallate (ECG), and epicatechin (EC) have been shown to exhibit antiviral and anti-oncogenic properties," explains Dr. Ciesek. "Our study further explores the potential effect these flavonoids have in preventing HCV reinfection following liver transplantation."
Results showed that unlike its derivatives, EGCG inhibits entry of HCV into liver cells. The authors suggest that EGCG may impede HCV cell entry by acting on the host cell as the green tea catechin was not found to alter the density of virus particles. Pretreatment of cells with EGCG before HCV inoculation did not reduce the infection; however application during inoculation inhibited the rapid spread of the HCV. Lastly, researchers showed that EGCG inhibits viral attachment—the initial step in the HCV infection process. "The green tea antioxidant EGCG inhibits HCV cell entry by blocking viral attachment and may offer a new approach to prevent HCV infection, particularly reinfection following liver transplantation." concludes Dr. Ciesek.
###
Full Citation: The Green Tea Polyphenol Epigallocatechin-3-Gallate (EGCG) Inhibits Hepatitis C Virus (HCV) Entry." Sandra Ciesek, Thomas von Hahn, Che C. Colpitts, Luis M Schang,Martina Friesland, Jörg Steinmann, Michael P. Manns, Michael Ott, Heiner Wedemeyer, Philip Meuleman, Thomas Pietschmann and Eike Steinmann. Hepatology; Published Online: November 30, 2011 (DOI: 10.1002/hep.24610); Print Issue Date: December 2011. http://onlinelibrary.wiley.com/doi/10.1002/hep.24610/abstract.
Author Contact: To arrange an interview with Dr. Sandra Ciesek or Dr. Eike Steinmann, please contact Jo Schilling at jo.schilling@twincore.de.
This study is published in Hepatology. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.
About the Journal
Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Hepatology's current impact factor is 10.885.Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350 .
About Wiley-Blackwell
Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.
Tuesday, June 28, 2011
P7 inhibitors face low barrier to resistance in HCV combination therapy...
New study published in Hepatology looking at the potential of p7 inhibitors in combo with P/R. It appears that a low barrier resistance may limit the utility of these drugs, but further research is underway to determine the fate of these particular agent. I know a physician that uses amantidine with P/R on a regular basis and truly believes that this drug enhances SVR.
P7 protein resistance mutations identified; represent drug targets for hepatitis C virus
Combination therapies inhibiting p7 could prevent spread of HCV in the body
British researchers have identified specific resistance mutations for two classes of p7 inhibitor, which may explain their lack of effectiveness in clinical trials combined with current standard of care. Study results support the role of p7 inhibitor combinations as potential components of future HCV-specific therapies and are available in the July issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.
More than 3% of the world population is infected with HCV, which causes severe liver disease. HCV is the leading cause of liver-related mortality and most common cause for liver transplantation in the U.S. Studies have shown that the current treatment of PEGylated interferon alpha (IFN) and ribavirin (Rib) does not adequately achieve a sustained virological response in many HCV patients. This, coupled with the high cost and poor patient compliance, continues to drive demand for new virus-specific therapies.
"The HCV p7 ion channel plays a critical role in infectious virus production, representing an important new therapeutic target," said lead researcher Dr. Stephen Griffin with the Institute of Molecular Medicine at the University of Leeds in the UK. Previously, Dr. Griffin and colleagues determined that p7 acts as a proton channel within HCV infected cells, and that its function could be blocked by small molecule inhibitors, resulting in a blockade of infectious virus production.
In the present study, the team set out to expand on their prior work by predicting inhibitor binding sites using molecular modeling, which were then validated by the identification of resistance mutations. This allowed the researchers to define the mode of action for two prototype p7 inhibitor classes—adamantanes (amantadine and rimantadine) and alkylated imino-sugars (IS). This confirmed not only specific, but distinct effects for these inhibitors on the p7 protein. As these drugs are known to be safe in humans, they could rapidly be combined with new direct-acting HCV drugs, while paving the way for the development of novel, more potent compounds.
Dr. Griffin explains, "Our study confirms that single amino acid changes can mediate resistance to p7 inhibitor drugs." The study describes that low fitness cost for the observed mutations suggest that a minimal genetic barrier to their selection exists, which explains the perceived lack of p7 inhibitor efficacy in clinical trials combined with IFN/Rib. "Further investigation into the molecular basis of p7 drug resistance will aid in the design of novel, more effective therapies to combat HCV," concluded Dr. Griffin.
###
This study was conducted in collaboration with the laboratories of Professor Mark Harris, Professor Colin Fishwick and Dr. Richard Foster (University of Leeds), as well as Professor Steven Weinman (University of Kansas). Funding was through the UK Medical Research Council, Yorkshire Cancer Research and the University of Leeds Biomedical Health Research Centre.
Additional Media Contact:
Paula Gould
University of Leeds Communications & Press Office
+44 (0)113 343 8059
p.a.gould@leeds.ac.uk
This study is published in Hepatology. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.
Full Citation:
Article: "Resistance Mutations Define Specific Antiviral Effects for Inhibitors of the Hepatitis C Virus (HCV) P7 Ion Channel." Toshana L. Foster, Mark Verow, Ann L. Wozniak, Matthew J. Bentham, Joseph Thompson, Elizabeth Atkins, Steven A. Weinman, Colin Fishwick, Richard Foster, Mark Harris and Stephen Griffin. Hepatology; Published Online: June 24, 2011 (DOI: 10.1002/hep.24371); Print Issue Date: July 2011. http://onlinelibrary.wiley.com/doi/10.1002/hep.24371/abstract.
About the Journal
Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350 .
About Wiley-Blackwell
Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.
P7 protein resistance mutations identified; represent drug targets for hepatitis C virus
Combination therapies inhibiting p7 could prevent spread of HCV in the body
British researchers have identified specific resistance mutations for two classes of p7 inhibitor, which may explain their lack of effectiveness in clinical trials combined with current standard of care. Study results support the role of p7 inhibitor combinations as potential components of future HCV-specific therapies and are available in the July issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.
More than 3% of the world population is infected with HCV, which causes severe liver disease. HCV is the leading cause of liver-related mortality and most common cause for liver transplantation in the U.S. Studies have shown that the current treatment of PEGylated interferon alpha (IFN) and ribavirin (Rib) does not adequately achieve a sustained virological response in many HCV patients. This, coupled with the high cost and poor patient compliance, continues to drive demand for new virus-specific therapies.
"The HCV p7 ion channel plays a critical role in infectious virus production, representing an important new therapeutic target," said lead researcher Dr. Stephen Griffin with the Institute of Molecular Medicine at the University of Leeds in the UK. Previously, Dr. Griffin and colleagues determined that p7 acts as a proton channel within HCV infected cells, and that its function could be blocked by small molecule inhibitors, resulting in a blockade of infectious virus production.
In the present study, the team set out to expand on their prior work by predicting inhibitor binding sites using molecular modeling, which were then validated by the identification of resistance mutations. This allowed the researchers to define the mode of action for two prototype p7 inhibitor classes—adamantanes (amantadine and rimantadine) and alkylated imino-sugars (IS). This confirmed not only specific, but distinct effects for these inhibitors on the p7 protein. As these drugs are known to be safe in humans, they could rapidly be combined with new direct-acting HCV drugs, while paving the way for the development of novel, more potent compounds.
Dr. Griffin explains, "Our study confirms that single amino acid changes can mediate resistance to p7 inhibitor drugs." The study describes that low fitness cost for the observed mutations suggest that a minimal genetic barrier to their selection exists, which explains the perceived lack of p7 inhibitor efficacy in clinical trials combined with IFN/Rib. "Further investigation into the molecular basis of p7 drug resistance will aid in the design of novel, more effective therapies to combat HCV," concluded Dr. Griffin.
###
This study was conducted in collaboration with the laboratories of Professor Mark Harris, Professor Colin Fishwick and Dr. Richard Foster (University of Leeds), as well as Professor Steven Weinman (University of Kansas). Funding was through the UK Medical Research Council, Yorkshire Cancer Research and the University of Leeds Biomedical Health Research Centre.
Additional Media Contact:
Paula Gould
University of Leeds Communications & Press Office
+44 (0)113 343 8059
p.a.gould@leeds.ac.uk
This study is published in Hepatology. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.
Full Citation:
Article: "Resistance Mutations Define Specific Antiviral Effects for Inhibitors of the Hepatitis C Virus (HCV) P7 Ion Channel." Toshana L. Foster, Mark Verow, Ann L. Wozniak, Matthew J. Bentham, Joseph Thompson, Elizabeth Atkins, Steven A. Weinman, Colin Fishwick, Richard Foster, Mark Harris and Stephen Griffin. Hepatology; Published Online: June 24, 2011 (DOI: 10.1002/hep.24371); Print Issue Date: July 2011. http://onlinelibrary.wiley.com/doi/10.1002/hep.24371/abstract.
About the Journal
Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350 .
About Wiley-Blackwell
Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.
Sunday, June 26, 2011
From NATAP.org: HCV Treaters Shortage Editorial - Distributive justice and the arrival of direct-acting antivirals: Who should be first in line?
Full credit to NATAP.org for this "Hepatology" published synopsis and editorial from Donald Jensen and Andrew Aronsohn on 'distributive justice' with the DAA's. Very compelling from an ethical standpoint, worth the read.
HCV Treaters Shortage Editorial - Distributive justice and the arrival of direct-acting antivirals: Who should be first in line?
"The availability of DAA therapy will forever change the landscape of HCV, in that we will be able to cure patients of disease who we were unable to cure in the past. Unfortunately, this medical breakthrough will be coupled with resource scarcity. Historically, some of the greatest scientific discoveries in medicine have failed to provide a distribution system that appropriately emphasized not only justice and equality but also medical need. We hope to learn from the past by proposing a preconceived plan that would both educate patients and allocate therapy to the neediest patients first, thereby fulfilling the moral framework of distributive justice."
"On average, a health care provider can reasonably initiate therapy on only three patients each week before exceeding their work capacity.....current staffing will be unable to meet the demands of all patients with HCV who are expected to request treatment......We propose a needs-based allocation system....patients who have previously deferred therapy and new patients will be prioritized on the basis of need, with patients with cirrhosis at one end of the spectrum and asymptomatic patients with F0-F2 fibrosis at the other end of the spectrum. This system satisfies the principle of justice while placing appropriate emphasis on medical need."
Hepatology
Volume 53, Issue 6, pages 1789Ð1791, June 2011
Andrew Aronsohn M.D.,à, Donald Jensen M.D.
Center for Liver Disease, Section of Gastroenterology, Hepatology and Nutrition, 5841 South Maryland Avenue, MC 7120, Chicago, IL 60637.
In recent years, each edition of HEPATOLOGY has included a viewpoint article written by a member of the Editorial team. This month Dr Michael Charlton has offered his turn at the microphone to Dr. Donald Jensen and Dr Andrew Aronsohn from the University of Chicago, in order that they can address a pressing issue that will emerge in tandem with the likely approval by the U.S. Food and Drug Administration of boceprevir and/or telaprevir.
More than 120 million people are infected with hepatitis C worldwide.1 Hepatitis C virus (HCV) is a leading cause of liver-related mortality and is the most common indication for liver transplantation in the United States.2 Since the introduction of pegylated interferon and ribavirin nearly 10 years ago, response rates have been relatively stagnant, with less than half of treated patients achieving a sustained virological response.2 Data from the first direct-acting antiviral (DAA) agent, BILN 2061, was initially presented at the American Association for the Study of Liver Diseases annual meeting in 2002, which sparked enthusiasm over improving therapeutic efficacy.3 Nearly a decade later, we find ourselves on the brink of a new era of HCV therapy. Telaprevir and boceprevir will likely receive U.S. Food and Drug Administration approval by mid-2011(they both recd FDA approval a few weeks ago), and based on phase 2 and 3 data, will significantly improve rates of sustained virological response in patients infected with HCV genotype 1 when compared to current standard-of-care therapy.4-7 This improved efficacy has been well-publicized for years, and anticipation of DAA availability has already become part of the HCV treatment algorithm. Greater understanding of the natural history of HCV and identification of risk factors for progression to advanced liver disease has allowed many physicians to recommend deferral of standard-of-care therapy in favor of waiting for DAA availability for patients who are at low risk to progress to significant liver disease in the near future. This was demonstrated in a large VA-based study of 4084 patients evaluated for HCV therapy with interferon and ribavirin.8 Of the eligible patients who declined therapy, 50.3% stated they had deferred treatment in anticipation of more effective medications.8 Treatment-naive patients who have deferred standard-of-care therapy, in addition to patients who have failed previous regimens of HCV treatment, will likely create a surge of requests to initiate therapy in mid-2011.
The influx of patients requesting HCV therapy will present a significant problem. HCV therapy is becoming increasingly complex, and the addition of DAAs will only add to the time needed to effectively educate and appropriately monitor patients while they are receiving treatment. This may be partially offset by response-guided therapy that shortens treatment duration. We recently performed a time analysis study at our institution to gain understanding of time allotment needed for each new DAA-treated patient and to estimate the maximum patient capacity of a health care provider. On average, a health care provider can reasonably initiate therapy on only three patients each week before exceeding their work capacity. Because we anticipate at least 500 requests for evaluation for HCV therapy within the first few weeks of DAA availability, current staffing will be unable to meet the demands of all patients with HCV who are expected to request treatment.
Resource scarcity will be a prominent issue once DAA therapy becomes available. Historically, enthusiasm over a scientific breakthrough has caused the medical community to lose sight of the importance of prediction and resolution of problems of scarcity.9 In 1922, Frederick Banting and Charles Best discovered how to produce and use insulin to treat diabetes mellitus. Word of this life-saving medication traveled quickly, creating a deluge of requests for insulin that could not possibly be fulfilled due to limitations of production capacity.10 Unprepared to handle this dilemma, Dr. Banting created a somewhat arbitrary and subjective plan where Banting himself decided whom to treat first, which resulted in friends and politically well-connected individuals unfairly receiving priority over others.9 Twenty years later, penicillin was discovered, and efforts were made to avoid the injustices seen with insulin allocation. From 1942 to 1944, the Committee on Chemotherapeutic and Other Agents was responsible for rationing penicillin to civilians.11 Although efforts were made to prioritize clinical need over political and social worth, penicillin allocation became subject to intense scrutiny due to a double standard in rationing for civilian and military personnel. Penicillin was carefully allocated to civilians based on severity of disease; however, it was liberally given to military personnel to treat gonorrhea, a less serious illness, because it was highly effective and allowed soldiers to quickly return to their duties.9 In 1960, Belding Scribner developed a shunt that allowed patients with chronic kidney disease to safely undergo dialysis.12 Given the paucity of dialysis machines compared to the number of patients with chronic kidney disease, physicians were once again forced to allocate scarce, life-saving technology. A nine-member committee consisting of two physicians and seven lay persons was formed in 1961 to determine who would receive dialysis services. Because most patients with chronic kidney disease had similar medical needs for dialysis, the committee made decisions in part based on a patient's Òsocial worth.Ó9 Not surprisingly, this criterion was widely criticized and eventually led to approval of legislation in 1972 to allow federal funding for hemodialysis to all Americans with chronic kidney disease.
In 2011, nearly a century after the discovery of insulin, we continue to struggle with issues of resource scarcity. Equitable distribution of antiretroviral medication to patients with human immunodeficiency virus worldwide and organ allocation for transplantation illustrate that despite major advances in medical technology, our underlying moral dilemmas remain unchanged. History has taught us that failure to preemptively develop a moral framework to deal with problems of scarcity can lead to injustices to patients in need. Distributive justice is a moral principle that emphasizes Òfair, equitable, and appropriate distributionÓ of scarce resources.13 Equality for all patients should be paramount, yet this should be carefully balanced with appropriate emphasis on medical need. With the arrival of DAA therapy, we will be unable to initially treat all patients requesting therapy, and we will once again be forced to allocate a scarce resource. Critical analysis of this problem has yielded two potential solutions for this allocation dilemma: a first-come, first-served approach and a needs-based approach.
A conventional first-come, first-served approach, as the name implies, offers therapy, when appropriate, to patients in the order in which they are seen in the clinic after DAA launch. If (and when) the health care team becomes saturated, a waiting list will form, and patients on that list will be offered therapy when the health care team has more capacity. This approach has some advantages. It is the simplest plan and requires no planning prior to DAA availability. In fact, this approach will likely be a default system used by any center that has not enacted a preconceived DAA allocation system. First-come, first-served strictly adheres to the principle of justice, because all patients have an equal claim to therapy, and specific prioritizations are not made. However, it is inadequate because it ignores the importance of medical need where the workforce available to treat is limited in relation to the need.
We propose a needs-based allocation system. Much like the Model for End-Stage Liver Disease system, priority would be given to the sickest patients first in an effort to optimize outcomes for all patients with HCV. Prior to the launch of DAA therapy, treatment-eligible patients with HCV could be provided with an educational symposium outlining the natural progression of HCV and describing an allocation system, which would stress the importance of expediting treatment for the sickest patients and the safety of waiting for therapy in patients with early stages of disease. Then, patients who have previously deferred therapy and new patients will be prioritized on the basis of need, with patients with cirrhosis at one end of the spectrum and asymptomatic patients with F0-F2 fibrosis at the other end of the spectrum. This system satisfies the principle of justice while placing appropriate emphasis on medical need.
There will be inherent difficulties in this prioritization system. First, many patients with early stage disease have been eagerly awaiting the launch of DAA therapy and may be disappointed to find out that they may have to wait even longer to initiate therapy. Although it is anticipated that educational sessions will help these patients understand the reasoning behind their increased wait time, some patients will still choose not to wait and will seek more expedited treatment elsewhere. In addition, the choice to treat patients with more advanced liver disease first will likely result in poorer initial outcomes and more complications related to therapy. Finally, there may be medical legal implications to treating patients who are outside of approved indications for therapy. However, the benefit of a morally sound allocation system should outweigh these legal risks, and by ensuring that health care providers have adequate time with each patient, adverse outcomes can be greatly diminished.
The availability of DAA therapy will forever change the landscape of HCV, in that we will be able to cure patients of disease who we were unable to cure in the past. Unfortunately, this medical breakthrough will be coupled with resource scarcity. Historically, some of the greatest scientific discoveries in medicine have failed to provide a distribution system that appropriately emphasized not only justice and equality but also medical need. We hope to learn from the past by proposing a preconceived plan that would both educate patients and allocate therapy to the neediest patients first, thereby fulfilling the moral framework of distributive justice.
References
# 1Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5: 558-567.
# 2Strader DB, Wright T, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C. HEPATOLOGY 2004; 39: 1147-1171.
# 3Hinrichsen H. First report on the antiviral efficacy of BILN 2061, a novel oral serine protease inhibitor, in patients with chronic hepatitis C genotype 1 [Abstract]. HEPATOLOGY 2002; 36:Abstract 866.
# 4Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-na•ve patients with hepatitis C virus (HCV) genotype (G) 1: SPRINT-2 final results [Abstract]. HEPATOLOGY 2010; 52( 4 Suppl.): 402A-403A.
# 5Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D, Davis MN, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet; 376: 705-716.
# 6McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827-1838.
# 7Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al. Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-na•ve genotype 1 HCV patients who achieved an extended rapid viral response: Final results of phase 3 ILLUMINATE study [Abstract]. HEPATOLOGY 2010; 52( 4 Suppl.): 401A-402A.
# 8Bini EJ, Brau N, Currie S, Shen H, Anand BS, Hu KQ, Jeffers L, et al. Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection. Am J Gastroenterol 2005;100:1772-1779.
# 9McGough LJ, Reynolds SJ, Quinn TC, Zenilman JM. Which patients first? Setting priorities for antiretroviral therapy where resources are limited. Am J Public Health 2005; 95: 1173-1180.
# 10Shampo MA, Kyle RA. Frederick bantingÐNobel laureate for discovery of insulin. Mayo Clin Proc 2005; 80: 576.
# 11Adams DP. Wartime bureaucracy and penicillin allocation: the Committee on Chemotherapeutic and Other Agents, 1942Ð44. J Hist Med Allied Sci 1989; 44: 196-217.
# 12Blagg CR. The early history of dialysis for chronic renal failure in the United States: a view from Seattle. Am J Kidney Dis 2007; 49: 482-496.
# 13Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 5th ed. New York, NY: Oxford University Press; 2001.
HCV Treaters Shortage Editorial - Distributive justice and the arrival of direct-acting antivirals: Who should be first in line?
"The availability of DAA therapy will forever change the landscape of HCV, in that we will be able to cure patients of disease who we were unable to cure in the past. Unfortunately, this medical breakthrough will be coupled with resource scarcity. Historically, some of the greatest scientific discoveries in medicine have failed to provide a distribution system that appropriately emphasized not only justice and equality but also medical need. We hope to learn from the past by proposing a preconceived plan that would both educate patients and allocate therapy to the neediest patients first, thereby fulfilling the moral framework of distributive justice."
"On average, a health care provider can reasonably initiate therapy on only three patients each week before exceeding their work capacity.....current staffing will be unable to meet the demands of all patients with HCV who are expected to request treatment......We propose a needs-based allocation system....patients who have previously deferred therapy and new patients will be prioritized on the basis of need, with patients with cirrhosis at one end of the spectrum and asymptomatic patients with F0-F2 fibrosis at the other end of the spectrum. This system satisfies the principle of justice while placing appropriate emphasis on medical need."
Hepatology
Volume 53, Issue 6, pages 1789Ð1791, June 2011
Andrew Aronsohn M.D.,à, Donald Jensen M.D.
Center for Liver Disease, Section of Gastroenterology, Hepatology and Nutrition, 5841 South Maryland Avenue, MC 7120, Chicago, IL 60637.
In recent years, each edition of HEPATOLOGY has included a viewpoint article written by a member of the Editorial team. This month Dr Michael Charlton has offered his turn at the microphone to Dr. Donald Jensen and Dr Andrew Aronsohn from the University of Chicago, in order that they can address a pressing issue that will emerge in tandem with the likely approval by the U.S. Food and Drug Administration of boceprevir and/or telaprevir.
More than 120 million people are infected with hepatitis C worldwide.1 Hepatitis C virus (HCV) is a leading cause of liver-related mortality and is the most common indication for liver transplantation in the United States.2 Since the introduction of pegylated interferon and ribavirin nearly 10 years ago, response rates have been relatively stagnant, with less than half of treated patients achieving a sustained virological response.2 Data from the first direct-acting antiviral (DAA) agent, BILN 2061, was initially presented at the American Association for the Study of Liver Diseases annual meeting in 2002, which sparked enthusiasm over improving therapeutic efficacy.3 Nearly a decade later, we find ourselves on the brink of a new era of HCV therapy. Telaprevir and boceprevir will likely receive U.S. Food and Drug Administration approval by mid-2011(they both recd FDA approval a few weeks ago), and based on phase 2 and 3 data, will significantly improve rates of sustained virological response in patients infected with HCV genotype 1 when compared to current standard-of-care therapy.4-7 This improved efficacy has been well-publicized for years, and anticipation of DAA availability has already become part of the HCV treatment algorithm. Greater understanding of the natural history of HCV and identification of risk factors for progression to advanced liver disease has allowed many physicians to recommend deferral of standard-of-care therapy in favor of waiting for DAA availability for patients who are at low risk to progress to significant liver disease in the near future. This was demonstrated in a large VA-based study of 4084 patients evaluated for HCV therapy with interferon and ribavirin.8 Of the eligible patients who declined therapy, 50.3% stated they had deferred treatment in anticipation of more effective medications.8 Treatment-naive patients who have deferred standard-of-care therapy, in addition to patients who have failed previous regimens of HCV treatment, will likely create a surge of requests to initiate therapy in mid-2011.
The influx of patients requesting HCV therapy will present a significant problem. HCV therapy is becoming increasingly complex, and the addition of DAAs will only add to the time needed to effectively educate and appropriately monitor patients while they are receiving treatment. This may be partially offset by response-guided therapy that shortens treatment duration. We recently performed a time analysis study at our institution to gain understanding of time allotment needed for each new DAA-treated patient and to estimate the maximum patient capacity of a health care provider. On average, a health care provider can reasonably initiate therapy on only three patients each week before exceeding their work capacity. Because we anticipate at least 500 requests for evaluation for HCV therapy within the first few weeks of DAA availability, current staffing will be unable to meet the demands of all patients with HCV who are expected to request treatment.
Resource scarcity will be a prominent issue once DAA therapy becomes available. Historically, enthusiasm over a scientific breakthrough has caused the medical community to lose sight of the importance of prediction and resolution of problems of scarcity.9 In 1922, Frederick Banting and Charles Best discovered how to produce and use insulin to treat diabetes mellitus. Word of this life-saving medication traveled quickly, creating a deluge of requests for insulin that could not possibly be fulfilled due to limitations of production capacity.10 Unprepared to handle this dilemma, Dr. Banting created a somewhat arbitrary and subjective plan where Banting himself decided whom to treat first, which resulted in friends and politically well-connected individuals unfairly receiving priority over others.9 Twenty years later, penicillin was discovered, and efforts were made to avoid the injustices seen with insulin allocation. From 1942 to 1944, the Committee on Chemotherapeutic and Other Agents was responsible for rationing penicillin to civilians.11 Although efforts were made to prioritize clinical need over political and social worth, penicillin allocation became subject to intense scrutiny due to a double standard in rationing for civilian and military personnel. Penicillin was carefully allocated to civilians based on severity of disease; however, it was liberally given to military personnel to treat gonorrhea, a less serious illness, because it was highly effective and allowed soldiers to quickly return to their duties.9 In 1960, Belding Scribner developed a shunt that allowed patients with chronic kidney disease to safely undergo dialysis.12 Given the paucity of dialysis machines compared to the number of patients with chronic kidney disease, physicians were once again forced to allocate scarce, life-saving technology. A nine-member committee consisting of two physicians and seven lay persons was formed in 1961 to determine who would receive dialysis services. Because most patients with chronic kidney disease had similar medical needs for dialysis, the committee made decisions in part based on a patient's Òsocial worth.Ó9 Not surprisingly, this criterion was widely criticized and eventually led to approval of legislation in 1972 to allow federal funding for hemodialysis to all Americans with chronic kidney disease.
In 2011, nearly a century after the discovery of insulin, we continue to struggle with issues of resource scarcity. Equitable distribution of antiretroviral medication to patients with human immunodeficiency virus worldwide and organ allocation for transplantation illustrate that despite major advances in medical technology, our underlying moral dilemmas remain unchanged. History has taught us that failure to preemptively develop a moral framework to deal with problems of scarcity can lead to injustices to patients in need. Distributive justice is a moral principle that emphasizes Òfair, equitable, and appropriate distributionÓ of scarce resources.13 Equality for all patients should be paramount, yet this should be carefully balanced with appropriate emphasis on medical need. With the arrival of DAA therapy, we will be unable to initially treat all patients requesting therapy, and we will once again be forced to allocate a scarce resource. Critical analysis of this problem has yielded two potential solutions for this allocation dilemma: a first-come, first-served approach and a needs-based approach.
A conventional first-come, first-served approach, as the name implies, offers therapy, when appropriate, to patients in the order in which they are seen in the clinic after DAA launch. If (and when) the health care team becomes saturated, a waiting list will form, and patients on that list will be offered therapy when the health care team has more capacity. This approach has some advantages. It is the simplest plan and requires no planning prior to DAA availability. In fact, this approach will likely be a default system used by any center that has not enacted a preconceived DAA allocation system. First-come, first-served strictly adheres to the principle of justice, because all patients have an equal claim to therapy, and specific prioritizations are not made. However, it is inadequate because it ignores the importance of medical need where the workforce available to treat is limited in relation to the need.
We propose a needs-based allocation system. Much like the Model for End-Stage Liver Disease system, priority would be given to the sickest patients first in an effort to optimize outcomes for all patients with HCV. Prior to the launch of DAA therapy, treatment-eligible patients with HCV could be provided with an educational symposium outlining the natural progression of HCV and describing an allocation system, which would stress the importance of expediting treatment for the sickest patients and the safety of waiting for therapy in patients with early stages of disease. Then, patients who have previously deferred therapy and new patients will be prioritized on the basis of need, with patients with cirrhosis at one end of the spectrum and asymptomatic patients with F0-F2 fibrosis at the other end of the spectrum. This system satisfies the principle of justice while placing appropriate emphasis on medical need.
There will be inherent difficulties in this prioritization system. First, many patients with early stage disease have been eagerly awaiting the launch of DAA therapy and may be disappointed to find out that they may have to wait even longer to initiate therapy. Although it is anticipated that educational sessions will help these patients understand the reasoning behind their increased wait time, some patients will still choose not to wait and will seek more expedited treatment elsewhere. In addition, the choice to treat patients with more advanced liver disease first will likely result in poorer initial outcomes and more complications related to therapy. Finally, there may be medical legal implications to treating patients who are outside of approved indications for therapy. However, the benefit of a morally sound allocation system should outweigh these legal risks, and by ensuring that health care providers have adequate time with each patient, adverse outcomes can be greatly diminished.
The availability of DAA therapy will forever change the landscape of HCV, in that we will be able to cure patients of disease who we were unable to cure in the past. Unfortunately, this medical breakthrough will be coupled with resource scarcity. Historically, some of the greatest scientific discoveries in medicine have failed to provide a distribution system that appropriately emphasized not only justice and equality but also medical need. We hope to learn from the past by proposing a preconceived plan that would both educate patients and allocate therapy to the neediest patients first, thereby fulfilling the moral framework of distributive justice.
References
# 1Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5: 558-567.
# 2Strader DB, Wright T, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C. HEPATOLOGY 2004; 39: 1147-1171.
# 3Hinrichsen H. First report on the antiviral efficacy of BILN 2061, a novel oral serine protease inhibitor, in patients with chronic hepatitis C genotype 1 [Abstract]. HEPATOLOGY 2002; 36:Abstract 866.
# 4Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir (BOC) combined with peginterferon alfa-2b/ribavirin (P/R) for treatment-na•ve patients with hepatitis C virus (HCV) genotype (G) 1: SPRINT-2 final results [Abstract]. HEPATOLOGY 2010; 52( 4 Suppl.): 402A-403A.
# 5Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D, Davis MN, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet; 376: 705-716.
# 6McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827-1838.
# 7Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, et al. Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-na•ve genotype 1 HCV patients who achieved an extended rapid viral response: Final results of phase 3 ILLUMINATE study [Abstract]. HEPATOLOGY 2010; 52( 4 Suppl.): 401A-402A.
# 8Bini EJ, Brau N, Currie S, Shen H, Anand BS, Hu KQ, Jeffers L, et al. Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection. Am J Gastroenterol 2005;100:1772-1779.
# 9McGough LJ, Reynolds SJ, Quinn TC, Zenilman JM. Which patients first? Setting priorities for antiretroviral therapy where resources are limited. Am J Public Health 2005; 95: 1173-1180.
# 10Shampo MA, Kyle RA. Frederick bantingÐNobel laureate for discovery of insulin. Mayo Clin Proc 2005; 80: 576.
# 11Adams DP. Wartime bureaucracy and penicillin allocation: the Committee on Chemotherapeutic and Other Agents, 1942Ð44. J Hist Med Allied Sci 1989; 44: 196-217.
# 12Blagg CR. The early history of dialysis for chronic renal failure in the United States: a view from Seattle. Am J Kidney Dis 2007; 49: 482-496.
# 13Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 5th ed. New York, NY: Oxford University Press; 2001.
Friday, April 15, 2011
Modeling data shows that Telaprevir increases second-phase HCV decline...
Predictive models make me nervous, especially those with the word "new" in front of them because I always think of the one person who might take this study as gospel and actually treat accordingly. But this data, (published online in the journal Hepatology) using a new predictive model, does offer a plausible hypothesis - that the steep decline in the second phase viral clearance is responsible for the shortened duration of therapy with Telaprevir and, assuming high compliance and no resistance, HCV viral particles could be cleared in as little as seven weeks. Compelling, because we've heard of patients who had truncated durations of therapy with Telaprevir + Peg & Riba and still clear virus. Interesting, but again, only a model.
Telaprevir Increases Second-Phase Hepatitis C Decline
Predictive model indicates virus particles could be cleared in seven weeks assuming high compliance
Analysis of the kinetics of telaprevir treatment for hepatitis C virus shows a rapid second-phase viral decline, which may allow for shorter duration of treatment, according to a study published online March 7 in Hepatology.
FRIDAY, April 8 (HealthDay News) -- Analysis of the kinetics of telaprevir treatment for hepatitis C virus (HCV) shows a rapid second-phase viral decline, which may allow for shorter duration of treatment, according to a study published online March 7 in Hepatology.
Jeremie Guedj, Ph.D., and Alan S. Perelson, Ph.D., from the Los Alamos National Laboratory in New Mexico, examined second-phase HCV viral decline during treatment with telaprevir. Two aspects of telaprevir treatment were investigated: the effect of varying regimens of telaprevir monotherapy in 28 participants, and the comparison of telaprevir monotherapy in eight patients with telaprevir plus interferon therapy in eight patients. Using a new viral kinetic model, and assuming that drug resistance can be avoided, the treatment time needed to eliminate all virus and infected cells was estimated.
The investigators found that the second-phase viral decline was associated with the effectiveness of treatment, and was approximately four times more rapid with telaprevir than interferon-based therapies. In the predictive model, assuming 95 percent of the patients are fully compliant, the last virus particle could be eliminated within seven weeks, and the clearance of remaining infections in the hepatocytes by no more than 10 weeks. This time would be extended if doses were missed.
"Using a new viral kinetic model that allowed for an improved description of the changes in antiviral treatment effectiveness, the second phase of viral decay was found to be very rapid compared with second phases observed in patients treated with interferon alone, with no differences according to the treatment regimen," the authors write.
Telaprevir Increases Second-Phase Hepatitis C Decline
Predictive model indicates virus particles could be cleared in seven weeks assuming high compliance
Analysis of the kinetics of telaprevir treatment for hepatitis C virus shows a rapid second-phase viral decline, which may allow for shorter duration of treatment, according to a study published online March 7 in Hepatology.
FRIDAY, April 8 (HealthDay News) -- Analysis of the kinetics of telaprevir treatment for hepatitis C virus (HCV) shows a rapid second-phase viral decline, which may allow for shorter duration of treatment, according to a study published online March 7 in Hepatology.
Jeremie Guedj, Ph.D., and Alan S. Perelson, Ph.D., from the Los Alamos National Laboratory in New Mexico, examined second-phase HCV viral decline during treatment with telaprevir. Two aspects of telaprevir treatment were investigated: the effect of varying regimens of telaprevir monotherapy in 28 participants, and the comparison of telaprevir monotherapy in eight patients with telaprevir plus interferon therapy in eight patients. Using a new viral kinetic model, and assuming that drug resistance can be avoided, the treatment time needed to eliminate all virus and infected cells was estimated.
The investigators found that the second-phase viral decline was associated with the effectiveness of treatment, and was approximately four times more rapid with telaprevir than interferon-based therapies. In the predictive model, assuming 95 percent of the patients are fully compliant, the last virus particle could be eliminated within seven weeks, and the clearance of remaining infections in the hepatocytes by no more than 10 weeks. This time would be extended if doses were missed.
"Using a new viral kinetic model that allowed for an improved description of the changes in antiviral treatment effectiveness, the second phase of viral decay was found to be very rapid compared with second phases observed in patients treated with interferon alone, with no differences according to the treatment regimen," the authors write.
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