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.
Tuesday, June 28, 2011
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.
Thursday, June 23, 2011
Join "Viral Matters" HCV drug development discussion group on LinkedIn....
Enjoy Viral Matters on LinkedIn by clicking here
Wednesday, June 22, 2011
Medivir/Tibotec's NS5B Inhibitor TMC649128 starts Phase 1b trial....
TMC649128, a nucleoside inhibitor jointly developed between Sweden's Medivir and Tibotec heads for the clinic in this early stage Phase 1b trial
Huddinge, Sweden - Medivir AB (OMX: MVIR), the emerging research-based specialty pharmaceutical company focused on infectious diseases, today announces the start of a phase Ib clinical trial with TMC649128 intended for the treatment of chronic hepatitis C virus (HCV) infection.
TMC649128 is a nucleoside NS5B polymerase inhibitor developed in collaboration with Tibotec Pharmaceuticals. TMC649128 has demonstrated an attractive pre-clinical profile and displays in vitro activity across multiple HCV genotypes and a high genetic barrier to resistance. A clinical phase Ia double-blind, randomized, placebo-controlled single-ascending dose trial to assess the safety, tolerability and pharmacokinetics in healthy volunteers has now successfully been completed.
The TMC649128 phase Ib study that now is underway is a double-blind, randomized and placebo-controlled trial in genotype 1 HCV-infected patients to evaluate the safety, tolerability, pharmacokinetics and antiviral activity of multiple ascending doses of TMC649128 given as monotherapy and in combination with pegylated interferon and ribavirin.
It is anticipated that TMC649128 will be used in combination with other HCV direct acting antiviral agents, given its high genetic barrier to resistance and antiviral activity across multiple HCV genotypes.
“We are delighted to see TMC649128, our first HCV nucleoside inhibitor, advance into clinical phase Ib studies in HCV patients”, stated Bertil Samuelsson, CSO of Medivir. "The start of this phase Ib trial underscores our commitment to develop new and innovative treatments for hepatitis C infected patients. We view nucleoside inhibitors, such as TMC649128, and protease inhibitors, such as TMC435, as cornerstone components of future direct acting antiviral combinations for HCV therapy.”
For more information about Medivir, please contact;
Medivir (www.medivir.se)
Rein Piir, CFO & VP Investor Relations
Mobile: +46 708 537 292
M:CommunicationsEurope: Mary-Jane Elliott / Amber Bielecka / Katja Toon Medivir@mcomgroup.com
+44(0)20 7920 2330
USA: Roland Tomforde +1 212 232 2356
About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.
About Medivir’s Commitment to HCV
Medivir and Tibotec are also jointly developing the once daily protease inhibitor TMC435 for treatment of hepatitis C virus infections (HCV).
About Medivir
Medivir is an emerging research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development. Medivir has a strong R&D portfolio and has recently launched its first product Xerese™/Xerclear®.
Medivir’s key pipeline asset, TMC435, a protease inhibitor, is in global phase 3 clinical development for Hepatitis C and is partnered with Tibotec Pharmaceuticals.
Xerese™/Xerclear® is an innovative treatment for cold sores, which has been approved in both the US and Europe. It is partnered with GlaxoSmithKline to be sold OTC in Europe and Russia and with Meda AB in North America. Medivir has retained the Rx rights for Xerclear® in Sweden and Finland.
For more information about Medivir, please visit the Company’s website: www.medivir.se.
Huddinge, Sweden - Medivir AB (OMX: MVIR), the emerging research-based specialty pharmaceutical company focused on infectious diseases, today announces the start of a phase Ib clinical trial with TMC649128 intended for the treatment of chronic hepatitis C virus (HCV) infection.
TMC649128 is a nucleoside NS5B polymerase inhibitor developed in collaboration with Tibotec Pharmaceuticals. TMC649128 has demonstrated an attractive pre-clinical profile and displays in vitro activity across multiple HCV genotypes and a high genetic barrier to resistance. A clinical phase Ia double-blind, randomized, placebo-controlled single-ascending dose trial to assess the safety, tolerability and pharmacokinetics in healthy volunteers has now successfully been completed.
The TMC649128 phase Ib study that now is underway is a double-blind, randomized and placebo-controlled trial in genotype 1 HCV-infected patients to evaluate the safety, tolerability, pharmacokinetics and antiviral activity of multiple ascending doses of TMC649128 given as monotherapy and in combination with pegylated interferon and ribavirin.
It is anticipated that TMC649128 will be used in combination with other HCV direct acting antiviral agents, given its high genetic barrier to resistance and antiviral activity across multiple HCV genotypes.
“We are delighted to see TMC649128, our first HCV nucleoside inhibitor, advance into clinical phase Ib studies in HCV patients”, stated Bertil Samuelsson, CSO of Medivir. "The start of this phase Ib trial underscores our commitment to develop new and innovative treatments for hepatitis C infected patients. We view nucleoside inhibitors, such as TMC649128, and protease inhibitors, such as TMC435, as cornerstone components of future direct acting antiviral combinations for HCV therapy.”
For more information about Medivir, please contact;
Medivir (www.medivir.se)
Rein Piir, CFO & VP Investor Relations
Mobile: +46 708 537 292
M:CommunicationsEurope: Mary-Jane Elliott / Amber Bielecka / Katja Toon Medivir@mcomgroup.com
+44(0)20 7920 2330
USA: Roland Tomforde +1 212 232 2356
About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.
About Medivir’s Commitment to HCV
Medivir and Tibotec are also jointly developing the once daily protease inhibitor TMC435 for treatment of hepatitis C virus infections (HCV).
About Medivir
Medivir is an emerging research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development. Medivir has a strong R&D portfolio and has recently launched its first product Xerese™/Xerclear®.
Medivir’s key pipeline asset, TMC435, a protease inhibitor, is in global phase 3 clinical development for Hepatitis C and is partnered with Tibotec Pharmaceuticals.
Xerese™/Xerclear® is an innovative treatment for cold sores, which has been approved in both the US and Europe. It is partnered with GlaxoSmithKline to be sold OTC in Europe and Russia and with Meda AB in North America. Medivir has retained the Rx rights for Xerclear® in Sweden and Finland.
For more information about Medivir, please visit the Company’s website: www.medivir.se.
NPR's "Talk of the Nation" interviews Dr. John Ward, Director, Division of Viral Hepatitis, Centers for Disease Control and Prevention.
You can link to the transcript, streaming audio or podcast formats here.
Interesting interview, both available in transcript, streaming and podcast form. Dr. Ward's statement that "not every person living with hepatitis C needs to be treated for hepatitis C, and it really has to be based on the progression of their disease and the timing of that therapy" in the context of the adverse events and costs of the new DAAs is sure be a topic of conversation both within the drug development industry and the HCV provider/patient community.
You can link to the transcript, streaming audio or podcast formats here.
Interesting interview, both available in transcript, streaming and podcast form. Dr. Ward's statement that "not every person living with hepatitis C needs to be treated for hepatitis C, and it really has to be based on the progression of their disease and the timing of that therapy" in the context of the adverse events and costs of the new DAAs is sure be a topic of conversation both within the drug development industry and the HCV provider/patient community.
Sunday, June 19, 2011
NATAP presents "New Advances in Hep C Therapy: The World Is Changing" conference in NYC, Saturday June 25, 2011
S a t u r d a y, June 25th, 2011, 10am-2:30pm
NYU Medical Center: Schwartz Lecture Hall F
550 First Avenue, N.Y. NY 10016 (Between 31st and 32nd st)
New Advances in Hep C Therapy:
The World is Changing!
Speakers: Ira Jacobson MD: Vincent Astor distinguished Professor of Medicine
Cheif, Division of Gastroenterology & Hepatolog Medical Director Center for the study of Hepatitis C.
Andrew Talal MD: Associate Professor of Medicine & Associate Medical Director of the Center for the Study of Hepatitis C.
Nurse Mary Olson: Director, Hepatitis Clinical Trails: From Weill Cornell Medical College in NYC
• How to talk to your Care Provider
• Care Management & side effects
• New HCV Drugs
• HCV/HIV Coinfection treatment issues
• When to begin therapy?
• Future new HCV drugs in development
• Taking new HCV therapy properly
• What is “Response-Guided Therapy”?
• Drug Resistance
F r e e
F o r u m !
Seating is limited.
To reserve your seat:
Call: 1 (888)-266-2827
Fax: (212) 219- 8473
or Email- register@natap.org
Free Breakfast & Raffle!
Nursing contact hours available (must attend entire session), CASAC, and
certificates of attendance.
Breakfast & Registration Begin promptly at 8:30am
This Nursing education activity was approved by NCNA an accredited
approver by the American Nurses credentialing center’s commission on
accreditation. This educational activity has been awarded 3 . 6 6 contact hours
NYU Medical Center: Schwartz Lecture Hall F
550 First Avenue, N.Y. NY 10016 (Between 31st and 32nd st)
New Advances in Hep C Therapy:
The World is Changing!
Speakers: Ira Jacobson MD: Vincent Astor distinguished Professor of Medicine
Cheif, Division of Gastroenterology & Hepatolog Medical Director Center for the study of Hepatitis C.
Andrew Talal MD: Associate Professor of Medicine & Associate Medical Director of the Center for the Study of Hepatitis C.
Nurse Mary Olson: Director, Hepatitis Clinical Trails: From Weill Cornell Medical College in NYC
• How to talk to your Care Provider
• Care Management & side effects
• New HCV Drugs
• HCV/HIV Coinfection treatment issues
• When to begin therapy?
• Future new HCV drugs in development
• Taking new HCV therapy properly
• What is “Response-Guided Therapy”?
• Drug Resistance
F r e e
F o r u m !
Seating is limited.
To reserve your seat:
Call: 1 (888)-266-2827
Fax: (212) 219- 8473
or Email- register@natap.org
Free Breakfast & Raffle!
Nursing contact hours available (must attend entire session), CASAC, and
certificates of attendance.
Breakfast & Registration Begin promptly at 8:30am
This Nursing education activity was approved by NCNA an accredited
approver by the American Nurses credentialing center’s commission on
accreditation. This educational activity has been awarded 3 . 6 6 contact hours
Axium Healthcare Pharmacy Adds New Hepatitis C Drugs to their HEPVisionsSM Therapy Management Program...
One important component to HCV treatment not discussed here on Viral Matters is the Specialty Care Pharmacy. A good SP can take the headache of treatment out of the provider's hands by providing case managers, adherence programs and handle time-consuming prior authorizations. The competition to get provider's business, however, is one of the most brutally competitive environments I've seen out in the field. Axium's press release below is the first I've seen that actually has hired a PR firm to get the word out about their particular program to Hepatitis C providers. This is one area of HCV care where the supply greatly outweighs the demand, so it will be interesting to keep score on what differentiating factors the SPs will employ to earn the business of providers and ultimately, who will survive in the long run.
(openPR) - Axium Healthcare Pharmacy, one of the nation’s largest independent specialty pharmacy providers, announced today the addition of VictrelisTM and IncivekTM to its HEPVisionsSM Therapy Management Program
The announcement comes on the heels of the FDA’s approval of Merck’s VictrelisTM and Vertex’s IncivekTM. Both drugs are approved for use in combination with peg interferon and ribavirin, creating a triple therapy regimen.
Clinical trials have shown that using one of the two new drugs along with peg interferon and ribavirin drugs is more effective at producing a sustained virological response (SVR).
“Axium is pleased to add VictrelisTM and IncivekTM to the HEPVisionsSM program,” said Mark Montgomery, President and CEO of Axium Healthcare Pharmacy. “The new triple therapy regimen is complex and expensive. Careful patient education, monitoring, and adherence are keys to successful treatment.”
Through Axium’s HEPVisionsSM program, Axium’s clinical team provides comprehensive compliance support, patient education, side effect management, clinical interventions and communication with the patientand physician to coordinate the treatment plan. In addition, Axium offers 24-hour Pharmacist/Nurse support, prior authorization assistance, refill management calls, coordination of patient assistance programs, and ongoing delivery coordination.
Marketing Contact: Eireen Luna Bajaria
Phone: 1-888-315-3395
Email: Eireen.Bajaria@axiumhealthcare.com
(openPR) - Axium Healthcare Pharmacy, one of the nation’s largest independent specialty pharmacy providers, announced today the addition of VictrelisTM and IncivekTM to its HEPVisionsSM Therapy Management Program
The announcement comes on the heels of the FDA’s approval of Merck’s VictrelisTM and Vertex’s IncivekTM. Both drugs are approved for use in combination with peg interferon and ribavirin, creating a triple therapy regimen.
Clinical trials have shown that using one of the two new drugs along with peg interferon and ribavirin drugs is more effective at producing a sustained virological response (SVR).
“Axium is pleased to add VictrelisTM and IncivekTM to the HEPVisionsSM program,” said Mark Montgomery, President and CEO of Axium Healthcare Pharmacy. “The new triple therapy regimen is complex and expensive. Careful patient education, monitoring, and adherence are keys to successful treatment.”
Through Axium’s HEPVisionsSM program, Axium’s clinical team provides comprehensive compliance support, patient education, side effect management, clinical interventions and communication with the patientand physician to coordinate the treatment plan. In addition, Axium offers 24-hour Pharmacist/Nurse support, prior authorization assistance, refill management calls, coordination of patient assistance programs, and ongoing delivery coordination.
Marketing Contact: Eireen Luna Bajaria
Phone: 1-888-315-3395
Email: Eireen.Bajaria@axiumhealthcare.com
Wednesday, June 15, 2011
Vertex licenses early-stage polymerase inhibitors...
Interesting licensing deal between Vertex and Alios BioPharma for two preclinical HCV polymerase inhibitors. With so many promising HCV compounds in the later stages of development and only so many of the lucrative insured baby boomer Tx naive population to go around, you have to wonder about this deal... Unless Vertex is laying down the foundation for an HCV resistance arms race similar to what we've experienced in the HIV therapeutic category. Could Vertex ultimately cash in on a problem they helped create with Telaprevir resistance? i
Vertex licenses Hep C candidates in milestone-heavy deal
Vertex Pharmaceuticals Inc. of Cambridge and Alios BioPharma Inc. of South San Francisco, Calif., have announced a deal under which Vertex will license two Alios compounds designed to be inhibitors of the hepatitis C virus polymerase enzyme.
With the deal, Vertex said it has multiple opportunities to develop new, all-oral combination regimens for chronic hepatitis C. Vertex expects the nucleotide drug candidates, ALS-2200 and ALS-2158, wto enter clinical development later this year.
In return for Vertex gaining worldwide rights to the hepatitis C drug candidates, Alios gets a $60 million upfront payment and research and development costs of ALS-2200 and ALS-2158 covered by Vertex. The Cambridge pharmaceutical firm could pay up to $715 million in R&D milestone payments if both drugs are approved, and up to $750 million more if both drug candidates then meet sales milestones.
The announcement came just weeks after Vertex won approval from the U.S. Food and Drug Administration for its hepatitis C drug, Incivek.
“The recent approval of Incivek was a milestone in hepatitis C care, and today’s announcement underscores our long-term commitment to further improving the treatment of this disease with new combinations of medicines,” said Peter Mueller, Ph.D., chief scientific officer and executive vice resident of global research and development at Vertex in a press release. “Alios has discovered anti-HCV nucleotides that have the potential to be leading agents in hepatitis C. Based on impressive in vitro data, we look forward to evaluating ALS-2200 and ALS-2158 together and in combination with our approved and investigational hepatitis C medicines with the goal of creating a highly potent all-oral regimen in the years ahead.”
Approval of Incivek also spurred Vertex to sign a lease for a new headquarters in Boston’s waterfront innovation district.
Vertex licenses Hep C candidates in milestone-heavy deal
Vertex Pharmaceuticals Inc. of Cambridge and Alios BioPharma Inc. of South San Francisco, Calif., have announced a deal under which Vertex will license two Alios compounds designed to be inhibitors of the hepatitis C virus polymerase enzyme.
With the deal, Vertex said it has multiple opportunities to develop new, all-oral combination regimens for chronic hepatitis C. Vertex expects the nucleotide drug candidates, ALS-2200 and ALS-2158, wto enter clinical development later this year.
In return for Vertex gaining worldwide rights to the hepatitis C drug candidates, Alios gets a $60 million upfront payment and research and development costs of ALS-2200 and ALS-2158 covered by Vertex. The Cambridge pharmaceutical firm could pay up to $715 million in R&D milestone payments if both drugs are approved, and up to $750 million more if both drug candidates then meet sales milestones.
The announcement came just weeks after Vertex won approval from the U.S. Food and Drug Administration for its hepatitis C drug, Incivek.
“The recent approval of Incivek was a milestone in hepatitis C care, and today’s announcement underscores our long-term commitment to further improving the treatment of this disease with new combinations of medicines,” said Peter Mueller, Ph.D., chief scientific officer and executive vice resident of global research and development at Vertex in a press release. “Alios has discovered anti-HCV nucleotides that have the potential to be leading agents in hepatitis C. Based on impressive in vitro data, we look forward to evaluating ALS-2200 and ALS-2158 together and in combination with our approved and investigational hepatitis C medicines with the goal of creating a highly potent all-oral regimen in the years ahead.”
Approval of Incivek also spurred Vertex to sign a lease for a new headquarters in Boston’s waterfront innovation district.
Friday, June 10, 2011
Diana Sylvestre article on the possibilities of HCV resistance in underserved populations with the new DAA agents....
A sobering article on the very real possibility of HCV resistance developing in underserved population in the June 9, 2011 issue of NATURE by O.A.S.I.S. Executive Director, Diana Sylvestre. On a personal note, I had the great honor of calling on her while I worked at Vertex. Truly one of the most remarkably compassionate human beings I have ever met. Don't let that fool you, because I also had the experience of being with her when she stared down a former patient wielding a golf club. This is one tough lady.
Published online 08 June 2011
The hepatitis C virus is endemic among injection drug users, who could harbour treatment-resistant viruses. We need to adapt to this reality, says Diana Sylvestre
Diana Sylvestre informs her patient that the hepatitis C virus has re-emerged six months after treatment.
The first antiviral agents that act directly on the hepatitis C virus (HCV) are about to hit the market. Healthcare workers have been awaiting the release of these new medications for some time, in the hope that treatment response rates would improve, even in populations of patients who are challenging to treat. But underneath the glow of anticipation lies a concern about poorly characterized risks, including the emergence of drug-resistant viral strains. The real-world impact of this risk is unclear as most of those who contract the virus do so through injection drug use and are disregarded from clinical trails.
The new protease inhibitors can elicit resistance even in patients who follow dosing regimens. But when corners are cut, risk rises. Shortening treatment, as new regimens promise to do, might reduce the burden of side effects. But the day-to-day misery will be worse with triple regimens than with the standard dual treatment, and it is important to appreciate the human tendency to reduce or skip doses of medications that make us feel ill.
Injection drug users are more complex patients: many have an unstable housing situation, unreliable transport or subject to prescription refill delays owing to insurance company bungling, which they are poorly equipped to deal with. They might be arrested and jailed during treatment. So, even though studies have shown that injection drug users have similar medication compliance rates to non-drug users4, 5, 6, external circumstances may prevent the medication fidelity that is expected and needed.
So far, modestly reduced adherence to the interferon-α and ribavirin therapy has not led to viral resistance. Taking only 80% of the prescribed interferon and ribavirin dosages for 80% of the projected duration of treatment is sufficient to achieve optimal response rates. This allows those who treat injection drug users (including me) enough latitude to be successful. We have been able to reduce the burden of HCV in those who are most at risk of transmitting it.
Unfortunately, there is no such information on new treatment regimens. It is unclear at what point reduced adherence may become a problem. The virus rapidly mutates, so the antiviral 'pressure' exerted by the medication needs to be maintained so mutant viruses are constantly destroyed. Such protease-inhibitor-resistant strains can persist for at least three years after the withdrawal of medication1, 2, 3. And the conformational changes that underpin resistance to one protease inhibitor may also confer resistance to other inhibitors of that protease — a phenomenon called class resistance. And worse: if active injection drug users become reservoirs of protease inhibitor resistance, these viral strains could predominate, requiring the kind of therapeutic arms race that we see in other infections such as HIV and Staphylococcus aureus.
Regulators should require that clinical trials consider current or former injection drug users. This is not currently being done. The US Food and Drug Administration (FDA) Guidance for Industry document encourages trial sponsors to initiate trials early in drug development for “special populations” with unmet needs: transplant patients, people co-infected with HIV and HCV, and those with decompensated, or severe, cirrhosis. The document fails to mention injection drug users. It is as though they don't exist. If diabetics or out-of-care asthmatics were at risk, the approach would be different. Instead, the FDA has turned its back on the majority population with HCV and is approving new drugs despite having almost no understanding of their potential to cause long-term harm.
Because HCV affects those on the fringes of society, large-scale treatment studies have not been representative of the face of the disease. Their doctors are not invited to enroll them in trials. Therefore, little is known about which patients are good candidates for treatment, the importance of adherence to the treatment regimen and the outcomes in the real world — this ignorance leaves addicted HCV patients subject to the vagaries of a medical system that might not welcome them. This is unacceptable from both a humanist and a public-health standpoint.
It is time that regulators, pharmaceutical companies and healthcare workers come to terms with the fact that many patients with HCV are injection drug users. These patients must be included in safety, tolerability and efficacy trials; regulatory studies should include clinics where HCV-infected drug users are seen. And study investigators should be more representative of the kinds of doctors that usually care for these patients.
The new therapies raise the possibility of eradicating hepatitis C. But that won't happen unless the key parties in this medical drama develop a more realistic approach to understanding and treating this disease.
Published online 08 June 2011
The hepatitis C virus is endemic among injection drug users, who could harbour treatment-resistant viruses. We need to adapt to this reality, says Diana Sylvestre
Diana Sylvestre informs her patient that the hepatitis C virus has re-emerged six months after treatment.
The first antiviral agents that act directly on the hepatitis C virus (HCV) are about to hit the market. Healthcare workers have been awaiting the release of these new medications for some time, in the hope that treatment response rates would improve, even in populations of patients who are challenging to treat. But underneath the glow of anticipation lies a concern about poorly characterized risks, including the emergence of drug-resistant viral strains. The real-world impact of this risk is unclear as most of those who contract the virus do so through injection drug use and are disregarded from clinical trails.
The new protease inhibitors can elicit resistance even in patients who follow dosing regimens. But when corners are cut, risk rises. Shortening treatment, as new regimens promise to do, might reduce the burden of side effects. But the day-to-day misery will be worse with triple regimens than with the standard dual treatment, and it is important to appreciate the human tendency to reduce or skip doses of medications that make us feel ill.
Injection drug users are more complex patients: many have an unstable housing situation, unreliable transport or subject to prescription refill delays owing to insurance company bungling, which they are poorly equipped to deal with. They might be arrested and jailed during treatment. So, even though studies have shown that injection drug users have similar medication compliance rates to non-drug users4, 5, 6, external circumstances may prevent the medication fidelity that is expected and needed.
So far, modestly reduced adherence to the interferon-α and ribavirin therapy has not led to viral resistance. Taking only 80% of the prescribed interferon and ribavirin dosages for 80% of the projected duration of treatment is sufficient to achieve optimal response rates. This allows those who treat injection drug users (including me) enough latitude to be successful. We have been able to reduce the burden of HCV in those who are most at risk of transmitting it.
Unfortunately, there is no such information on new treatment regimens. It is unclear at what point reduced adherence may become a problem. The virus rapidly mutates, so the antiviral 'pressure' exerted by the medication needs to be maintained so mutant viruses are constantly destroyed. Such protease-inhibitor-resistant strains can persist for at least three years after the withdrawal of medication1, 2, 3. And the conformational changes that underpin resistance to one protease inhibitor may also confer resistance to other inhibitors of that protease — a phenomenon called class resistance. And worse: if active injection drug users become reservoirs of protease inhibitor resistance, these viral strains could predominate, requiring the kind of therapeutic arms race that we see in other infections such as HIV and Staphylococcus aureus.
Regulators should require that clinical trials consider current or former injection drug users. This is not currently being done. The US Food and Drug Administration (FDA) Guidance for Industry document encourages trial sponsors to initiate trials early in drug development for “special populations” with unmet needs: transplant patients, people co-infected with HIV and HCV, and those with decompensated, or severe, cirrhosis. The document fails to mention injection drug users. It is as though they don't exist. If diabetics or out-of-care asthmatics were at risk, the approach would be different. Instead, the FDA has turned its back on the majority population with HCV and is approving new drugs despite having almost no understanding of their potential to cause long-term harm.
Because HCV affects those on the fringes of society, large-scale treatment studies have not been representative of the face of the disease. Their doctors are not invited to enroll them in trials. Therefore, little is known about which patients are good candidates for treatment, the importance of adherence to the treatment regimen and the outcomes in the real world — this ignorance leaves addicted HCV patients subject to the vagaries of a medical system that might not welcome them. This is unacceptable from both a humanist and a public-health standpoint.
It is time that regulators, pharmaceutical companies and healthcare workers come to terms with the fact that many patients with HCV are injection drug users. These patients must be included in safety, tolerability and efficacy trials; regulatory studies should include clinics where HCV-infected drug users are seen. And study investigators should be more representative of the kinds of doctors that usually care for these patients.
The new therapies raise the possibility of eradicating hepatitis C. But that won't happen unless the key parties in this medical drama develop a more realistic approach to understanding and treating this disease.
Wednesday, June 8, 2011
Pharmasset Announces the Expansion of the ELECTRON Trial in Chronic Hepatitis C
Pharmasset adding arms to it's genotype 2/3 ELECTRON trial looking at shorter durations of therapy in addition to inteferon-free monotherapy for it's PSI-7977 nucleotide analog. Nucs traditionally have a very high barrier to resistance in comparison to non-nucs, but with a virus capable of making every possibly mutation of itself in the course of a day, is nuc monotherapy without an immune system modulator or another viral life cycle-specific inhibitor enough, even in the relatively easy-to-treat G2 and 3 virus? If it's not, what are the odds of a PSI-7977 resistant quasispecies developing and the corresponding fitness level compared to wild type of those variants? Guess we'll find out soon enough. If anyone can shed further enlightenment, please do.
PRINCETON, N.J., June 8, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today the addition of three treatment cohorts to the ELECTRON trial of PSI-7977, a nucleotide analog polymerase inhibitor, for the treatment of chronic hepatitis C (HCV). The rapid and consistent antiviral effects and high barrier to resistance demonstrated with PSI-7977 to date provide the rationale for additional exploratory regimens in this setting. This amendment will add one arm exploring 12 weeks of PSI-7977 monotherapy (without peginterferon and ribavirin) and two arms of interferon-sparing therapy: one for 8 weeks of PSI-7977 plus peginterferon and ribavirin (Peg-IFN/RBV) in patients with HCV genotype 2 (GT2) or 3 (GT3) and one for 12 weeks of PSI-7977 plus Peg-IFN/RBV in patients with HCV genotype 1 (GT1) prior null responses.
"The combination data reported at EASL demonstrated that SVRs were achievable with two oral DAAs in the absence of peginterferon and ribavirin," stated Bill Symonds, PharmD, Pharmasset's Senior Vice President of Clinical Pharmacology and Translational Medicine, "We continue to explore the potential for removing peginterferon and ribavirin from the HCV treatment regimen. Given the encouraging data we are seeing in ELECTRON, we have decided to expand the study to investigate PSI-7977 monotherapy, as well as shorter treatment regimens based on the promising data we reported at EASL from PROTON."
Pharmasset anticipates reporting results from the first four arms of the trial (n=40) during the second half of 2011. We have submitted a number of abstracts to the 2011 American Association for the Study of Liver Diseases (AASLD) meeting, including data from the ELECTRON and PROTON trials.
About the Trial
The ELECTRON trial is an exploratory study of PSI-7977 for the treatment of chronic HCV infection. Part 1 of the trial is evaluating 12-week regimens of PSI-7977 400mg QD in combination with ribavirin (RBV) only, and in separate arms with abbreviated durations of Peg-IFN for 4, 8, or 12 weeks in treatment-naive patients with HCV GT2 or GT3. The primary endpoint of the trial is the safety and tolerability of PSI-7977 400mg QD and RBV for 12 weeks, administered with or without Peg-IFN. On May 11, 2011, Pharmasset announced the completed enrollment of Part 1 of ELECTRON in patients with HCV GT 2 or GT 3:
* PSI-7977 400mg with RBV for 12 weeks (no peginterferon);
* PSI-7977 400mg with RBV for 12 weeks; Peg-IFN weeks 1-4 only;
* PSI-7977 400mg with RBV for 12 weeks, Peg-IFN weeks 1-8 only;
* PSI-7977 400mg with Peg-IFN and RBV for 12 weeks.
In Part 2 of ELECTRON, Pharmasset will enroll an additional 30 patients into exploratory regimens of monotherapy and abbreviated durations of total therapy. Following on the first four Cohorts of ELECTRON a 5th cohort will be added to explore 7977 400mg monotherapy in treatment-naive patients with HCV GT2 or GT3:
* PSI-7977 400mg monotherapy for 12 weeks.
With the previously reported 100% SVR12 in naive GT2/3 subjects in PROTON, a 6th and 7th cohort will be added to ELECTRON to explore shorter treatment durations in both GT2/3 naive subjects and HCV GT1 subjects who have documented null responses (less than 2 log(10) IU/mL reduction in HCV RNA after 12 weeks of Peg-IFN/RBV):
* PSI-7977 400mg with Peg-IFN/RBV for 8 weeks
* PSI-7977 400mg QD with Peg-IFN/RBV for 12 weeks.
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 the development of oral therapeutics for the treatment of hepatitis C virus (HCV) infection. Our research and development efforts are focused on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates advancing in trials in various populations. Our pyrimidine, PSI-7977, an unpartnered uracil nucleotide analog, is currently under study in three Phase 2b trials in patients with HCV genotypes 1 through 6, including abbreviated duration interferon and interferon-free regimens. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, recently reported safety and efficacy data from 14 days of monotherapy as well as 14 days in combination with the pyrimidine, PSI-7977. An SVR-endpoint study of the purine-pyrimidine combination is anticipated to begin in the third quarter of 2011. Mericitabine (RG7128) continues in two Phase 2b trials and one interferon-free trial being conducted through a strategic collaboration with Roche.
Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Office: +1 (609) 865-0693
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," 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, 2010 and our Quarterly Reports on Form 10-Q 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.
PRINCETON, N.J., June 8, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today the addition of three treatment cohorts to the ELECTRON trial of PSI-7977, a nucleotide analog polymerase inhibitor, for the treatment of chronic hepatitis C (HCV). The rapid and consistent antiviral effects and high barrier to resistance demonstrated with PSI-7977 to date provide the rationale for additional exploratory regimens in this setting. This amendment will add one arm exploring 12 weeks of PSI-7977 monotherapy (without peginterferon and ribavirin) and two arms of interferon-sparing therapy: one for 8 weeks of PSI-7977 plus peginterferon and ribavirin (Peg-IFN/RBV) in patients with HCV genotype 2 (GT2) or 3 (GT3) and one for 12 weeks of PSI-7977 plus Peg-IFN/RBV in patients with HCV genotype 1 (GT1) prior null responses.
"The combination data reported at EASL demonstrated that SVRs were achievable with two oral DAAs in the absence of peginterferon and ribavirin," stated Bill Symonds, PharmD, Pharmasset's Senior Vice President of Clinical Pharmacology and Translational Medicine, "We continue to explore the potential for removing peginterferon and ribavirin from the HCV treatment regimen. Given the encouraging data we are seeing in ELECTRON, we have decided to expand the study to investigate PSI-7977 monotherapy, as well as shorter treatment regimens based on the promising data we reported at EASL from PROTON."
Pharmasset anticipates reporting results from the first four arms of the trial (n=40) during the second half of 2011. We have submitted a number of abstracts to the 2011 American Association for the Study of Liver Diseases (AASLD) meeting, including data from the ELECTRON and PROTON trials.
About the Trial
The ELECTRON trial is an exploratory study of PSI-7977 for the treatment of chronic HCV infection. Part 1 of the trial is evaluating 12-week regimens of PSI-7977 400mg QD in combination with ribavirin (RBV) only, and in separate arms with abbreviated durations of Peg-IFN for 4, 8, or 12 weeks in treatment-naive patients with HCV GT2 or GT3. The primary endpoint of the trial is the safety and tolerability of PSI-7977 400mg QD and RBV for 12 weeks, administered with or without Peg-IFN. On May 11, 2011, Pharmasset announced the completed enrollment of Part 1 of ELECTRON in patients with HCV GT 2 or GT 3:
* PSI-7977 400mg with RBV for 12 weeks (no peginterferon);
* PSI-7977 400mg with RBV for 12 weeks; Peg-IFN weeks 1-4 only;
* PSI-7977 400mg with RBV for 12 weeks, Peg-IFN weeks 1-8 only;
* PSI-7977 400mg with Peg-IFN and RBV for 12 weeks.
In Part 2 of ELECTRON, Pharmasset will enroll an additional 30 patients into exploratory regimens of monotherapy and abbreviated durations of total therapy. Following on the first four Cohorts of ELECTRON a 5th cohort will be added to explore 7977 400mg monotherapy in treatment-naive patients with HCV GT2 or GT3:
* PSI-7977 400mg monotherapy for 12 weeks.
With the previously reported 100% SVR12 in naive GT2/3 subjects in PROTON, a 6th and 7th cohort will be added to ELECTRON to explore shorter treatment durations in both GT2/3 naive subjects and HCV GT1 subjects who have documented null responses (less than 2 log(10) IU/mL reduction in HCV RNA after 12 weeks of Peg-IFN/RBV):
* PSI-7977 400mg with Peg-IFN/RBV for 8 weeks
* PSI-7977 400mg QD with Peg-IFN/RBV for 12 weeks.
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 the development of oral therapeutics for the treatment of hepatitis C virus (HCV) infection. Our research and development efforts are focused on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates advancing in trials in various populations. Our pyrimidine, PSI-7977, an unpartnered uracil nucleotide analog, is currently under study in three Phase 2b trials in patients with HCV genotypes 1 through 6, including abbreviated duration interferon and interferon-free regimens. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, recently reported safety and efficacy data from 14 days of monotherapy as well as 14 days in combination with the pyrimidine, PSI-7977. An SVR-endpoint study of the purine-pyrimidine combination is anticipated to begin in the third quarter of 2011. Mericitabine (RG7128) continues in two Phase 2b trials and one interferon-free trial being conducted through a strategic collaboration with Roche.
Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Office: +1 (609) 865-0693
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," 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, 2010 and our Quarterly Reports on Form 10-Q 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.
Tuesday, June 7, 2011
Heavy Coffee Consumption Linked to Better Hep C Treatment Response...
The growing amount of evidence seems to support that a good ol' cup o' joe is good for your liver, even better if you happen to be on antiviral therapy for HCV. A synopsis of a study published in the June issue of 'Gastroenterology' below.
Heavy Coffee Consumption Linked to Better Hep C Treatment Response
By: MARY ANN MOON, Internal Medicine News Digital Network
06/01/11
|
Patients with advanced hepatitis C virus–related liver disease who drank three or more cups of coffee per day were three times more likely to respond to therapy with peginterferon alfa-2a plus ribavirin at four time points than were patients who didn’t drink coffee, Neal David Freedman, Ph.D., and his colleagues reported in the June issue of Gastroenterology.
The reason for this benefit is not yet known, but it appears that coffee drinkers’ improved response was independent of other factors known to influence hepatitis C virus (HCV) virologic response to therapy, such as the patient’s race, serum HCV RNA level, the presence or absence of cirrhosis, and the AST/ALT (aspartate aminotransferase/alanine aminotransferase) ratio, said Dr. Freedman of the National Cancer Institute and his associates.
In this study of patients with advanced liver disease related to hepatitis C, 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so.
In previous studies of hepatic disease, coffee drinking has been associated with lower levels of liver enzymes, a reduced progression of chronic liver disease, and a decreased incidence of hepatocellular carcinoma. But coffee’s effect in chronic HCV infection has not been studied until now.
The investigators examined coffee intake and virologic response to treatment using data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, which involved patients with chronic hepatitis C who had fibrosis or cirrhosis at baseline, showed no sign of hepatic decompensation or hepatocellular carcinoma, and had failed to respond to interferon therapy.
For this study, Dr. Freedman and his colleagues assessed 885 subjects who completed a food frequency questionnaire at the beginning of the study. This included a measure of the portion size and frequency of coffee and tea intake, but did not distinguish between caffeinated and decaffeinated drinks and did not differentiate black tea from green tea.
A total of 85% of the subjects were coffee drinkers, and 15% of subjects drank three or more cups per day, which was defined as heavy coffee consumption.
The data showed that 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so (P = .0015). Heavy coffee drinkers also were less likely to require a dose reduction because of either a low neutrophil count or a low platelet count.
The decline in serum HCV RNA levels during treatment was greater with higher coffee intake. In addition, the absolute levels of HCV RNA were lower in heavy coffee drinkers than in nondrinkers at weeks 12, 20, and 24 of treatment. These benefits were seen even though higher coffee consumption had been associated with higher initial HCV RNA levels at baseline, the researchers noted.
In addition, heavy coffee drinkers were more likely than nondrinkers to show a virologic response early in the course of treatment (73% vs. 46%), to show no detectable serum HCV RNA at week 20 (52% vs. 26%), to show no detectable serum HCV RNA at week 48 (49% vs. 22%), and to have a sustained virologic response (26% vs. 11%).
Adjustment of the data to account for potential confounding factors such as age, sex, race, alcohol use, the presence of cirrhosis, the AST/ALT ratio, the baseline HCV RNA level, and the HCV genotype attenuated the associations with coffee somewhat, but the correlations remained significant at each virologic response end point.
The association between heavy coffee drinking and improved virologic response persisted in a subgroup analysis of only white patients, and it was actually stronger in patients with an unfavorable genotype (positive for the IL28B SNP rs12979860) than in those with a favorable genotype (negative for that SNP).
In contrast to these findings for coffee, there were no associations between tea drinking and treatment response.
Coffee contains more than 1,000 compounds, "any one of which could be involved in the virologic response." This study could not differentiate any possible role for caffeine, a major constituent of coffee.
However, "it is unlikely that coffee or its constituents have a direct antiviral effect. If so, HCV RNA levels at baseline would have been expected to be lower with greater coffee consumption," when in fact they were higher. It is more likely that coffee facilitates the response to peginterferon and ribavirin by some mechanism that is not yet understood, perhaps related to its association with cholesterol or with insulin resistance.
"As in all observational studies, we cannot exclude unmeasured or residual confounding as an explanation for our results. Observed associations could also simply be due to chance," Dr. Freedman and his associates said.
For that reason, further studies are needed to replicate these results in other populations, they added.
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, and Hoffman–La Roche. One of Dr. Freedman’s associates reported ties to Hoffmann–La Roche (now Genentech) and Tibotec.
Heavy Coffee Consumption Linked to Better Hep C Treatment Response
By: MARY ANN MOON, Internal Medicine News Digital Network
06/01/11
|
Patients with advanced hepatitis C virus–related liver disease who drank three or more cups of coffee per day were three times more likely to respond to therapy with peginterferon alfa-2a plus ribavirin at four time points than were patients who didn’t drink coffee, Neal David Freedman, Ph.D., and his colleagues reported in the June issue of Gastroenterology.
The reason for this benefit is not yet known, but it appears that coffee drinkers’ improved response was independent of other factors known to influence hepatitis C virus (HCV) virologic response to therapy, such as the patient’s race, serum HCV RNA level, the presence or absence of cirrhosis, and the AST/ALT (aspartate aminotransferase/alanine aminotransferase) ratio, said Dr. Freedman of the National Cancer Institute and his associates.
In this study of patients with advanced liver disease related to hepatitis C, 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so.
In previous studies of hepatic disease, coffee drinking has been associated with lower levels of liver enzymes, a reduced progression of chronic liver disease, and a decreased incidence of hepatocellular carcinoma. But coffee’s effect in chronic HCV infection has not been studied until now.
The investigators examined coffee intake and virologic response to treatment using data from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, which involved patients with chronic hepatitis C who had fibrosis or cirrhosis at baseline, showed no sign of hepatic decompensation or hepatocellular carcinoma, and had failed to respond to interferon therapy.
For this study, Dr. Freedman and his colleagues assessed 885 subjects who completed a food frequency questionnaire at the beginning of the study. This included a measure of the portion size and frequency of coffee and tea intake, but did not distinguish between caffeinated and decaffeinated drinks and did not differentiate black tea from green tea.
A total of 85% of the subjects were coffee drinkers, and 15% of subjects drank three or more cups per day, which was defined as heavy coffee consumption.
The data showed that 61% of the heavy coffee drinkers tolerated the full dose of peginterferon alfa-2a plus ribavirin, while only 50% of the non–coffee drinkers did so (P = .0015). Heavy coffee drinkers also were less likely to require a dose reduction because of either a low neutrophil count or a low platelet count.
The decline in serum HCV RNA levels during treatment was greater with higher coffee intake. In addition, the absolute levels of HCV RNA were lower in heavy coffee drinkers than in nondrinkers at weeks 12, 20, and 24 of treatment. These benefits were seen even though higher coffee consumption had been associated with higher initial HCV RNA levels at baseline, the researchers noted.
In addition, heavy coffee drinkers were more likely than nondrinkers to show a virologic response early in the course of treatment (73% vs. 46%), to show no detectable serum HCV RNA at week 20 (52% vs. 26%), to show no detectable serum HCV RNA at week 48 (49% vs. 22%), and to have a sustained virologic response (26% vs. 11%).
Adjustment of the data to account for potential confounding factors such as age, sex, race, alcohol use, the presence of cirrhosis, the AST/ALT ratio, the baseline HCV RNA level, and the HCV genotype attenuated the associations with coffee somewhat, but the correlations remained significant at each virologic response end point.
The association between heavy coffee drinking and improved virologic response persisted in a subgroup analysis of only white patients, and it was actually stronger in patients with an unfavorable genotype (positive for the IL28B SNP rs12979860) than in those with a favorable genotype (negative for that SNP).
In contrast to these findings for coffee, there were no associations between tea drinking and treatment response.
Coffee contains more than 1,000 compounds, "any one of which could be involved in the virologic response." This study could not differentiate any possible role for caffeine, a major constituent of coffee.
However, "it is unlikely that coffee or its constituents have a direct antiviral effect. If so, HCV RNA levels at baseline would have been expected to be lower with greater coffee consumption," when in fact they were higher. It is more likely that coffee facilitates the response to peginterferon and ribavirin by some mechanism that is not yet understood, perhaps related to its association with cholesterol or with insulin resistance.
"As in all observational studies, we cannot exclude unmeasured or residual confounding as an explanation for our results. Observed associations could also simply be due to chance," Dr. Freedman and his associates said.
For that reason, further studies are needed to replicate these results in other populations, they added.
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, and Hoffman–La Roche. One of Dr. Freedman’s associates reported ties to Hoffmann–La Roche (now Genentech) and Tibotec.
Friday, June 3, 2011
Analysts speculate on PSI-7977 possibly receiving earlier than anticipated FDA approval...
From Forbes.com
Associated Press
Ahead of the Bell: Pharmasset shares rise
Associated Press, 06.03.11, 09:02 AM EDT
NEW YORK -- A Citi Investment Research analyst said Friday that Pharmasset Inc.'s leading hepatitis C drug candidate could be approved sooner than expected, and he nearly tripled his price target on Pharmasset shares.
Shares of the Princeton, N.J., company rose $3.33, or 3.3 percent, to $104.20 in pre-market trading.
Analyst Yaron Werber said the drug candidate, which is designated PSI-7977, could be approved as soon as mid-2014 to treat two relatively rare types of hepatitis C.
Werber previously thought PSI-7977 wouldn't reach the market until late 2015, and he raised his target on Pharmasset ( VRUS - news - people ) to $200 per share from $71 to reflect the chances of an earlier approval, which would boost sales of the drug.
Werber said PSI-7977 could get to the market sooner if it is approved to treat hepatitis C genotypes 2 and 3, which make up a minority of cases. In late May, Pharmasset started a mid-stage clinical trial of PSI-7977 as a treatment for hepatitis C genotypes 1, 2, and 3. Genotype 1 makes up about 70 percent of hepatitis C diagnoses. Werber said he thinks the drug "will have solid data and will be one of the dominant drugs in hepatitis C."
The analyst said Pharmasset should present study data in November and should start late-stage studies in early 2012. He thinks the company will be profitable in 2016.
Associated Press
Ahead of the Bell: Pharmasset shares rise
Associated Press, 06.03.11, 09:02 AM EDT
NEW YORK -- A Citi Investment Research analyst said Friday that Pharmasset Inc.'s leading hepatitis C drug candidate could be approved sooner than expected, and he nearly tripled his price target on Pharmasset shares.
Shares of the Princeton, N.J., company rose $3.33, or 3.3 percent, to $104.20 in pre-market trading.
Analyst Yaron Werber said the drug candidate, which is designated PSI-7977, could be approved as soon as mid-2014 to treat two relatively rare types of hepatitis C.
Werber previously thought PSI-7977 wouldn't reach the market until late 2015, and he raised his target on Pharmasset ( VRUS - news - people ) to $200 per share from $71 to reflect the chances of an earlier approval, which would boost sales of the drug.
Werber said PSI-7977 could get to the market sooner if it is approved to treat hepatitis C genotypes 2 and 3, which make up a minority of cases. In late May, Pharmasset started a mid-stage clinical trial of PSI-7977 as a treatment for hepatitis C genotypes 1, 2, and 3. Genotype 1 makes up about 70 percent of hepatitis C diagnoses. Werber said he thinks the drug "will have solid data and will be one of the dominant drugs in hepatitis C."
The analyst said Pharmasset should present study data in November and should start late-stage studies in early 2012. He thinks the company will be profitable in 2016.
Ever wonder who came up with the brand name "Incivek"?
I have an insatiable interest in the business side of drug development paralleled only by my equally insatiable interest in nearly useless drug development trivia. So thank the Gods for self-congratulatory PR statements from brand consulting companies to feed the need. If you ever wondered who came up with the brand name for Telaprevir, look no further.
Addison Whitney Develops Name for Newly Approved Hepatitis C Treatment
Global branding firm names newly approved INCIVEK.
(PRWEB) June 03, 2011
Addison Whitney is pleased to announce the FDA approval of INCIVEK™ (telaprevir) from Vertex Pharmaceuticals Incorporated. INCIVEK is a prescription medication used with peginterferon alfa and ribavirin. The new drug will treat chronic hepatitis C genotype 1 infection in adults with stable liver problems who have not been treated before or who have failed previous treatment.
After developing the name INCIVEK, Addison Whitney streamlined the approval process by conducting safety validation research and providing Vertex with supporting documentation for the FDA review. “This was a true collaboration with our clients at Vertex that required a time sensitive approach to all aspects of the naming process,” said Daniel Plaisance, Vice President.
INCIVEK is expected to become a leading treatment for hepatitis C. FDA panelists said it appeared to raise the cure rate for hepatitis C to about 80 percent, compared with 40 percent with current therapies. The FDA has approved INCIVEK tablets for a broad group of people with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver).
“This is a very exciting time for Addison Whitney Health,” said Senior Vice President Vince Budd. “Not only is it great to see another one of our brands approved for a potential blockbuster product, but it showcases our high success rate of getting names approved by the global health authorities. Our clients have already received a number of approvals for names our company created, screened, tested and supported this year; and I look forward to seeing many more over the coming months.”
About Addison Whitney:
Addison Whitney is a global, full-service brand consulting firm. Founded in 1991, the firm offers branding expertise in the areas of verbal branding, visual branding, brand strategy, and research and analysis. Clients come to Addison Whitney from industries including: consumer, technology, business to business, financial, hospitality and other market segments. Addison Whitney health, a specialized healthcare division of Addison Whitney, serves the branding needs of pharmaceutical, biotechnology, life science, and medical specialties. For more information, visit http://www.addisonwhitney.com.
For more information please contact Sara Abadi at 704-697-4039 or sara.abadi(at)addisonwhitney(dot)com.
Addison Whitney Develops Name for Newly Approved Hepatitis C Treatment
Global branding firm names newly approved INCIVEK.
(PRWEB) June 03, 2011
Addison Whitney is pleased to announce the FDA approval of INCIVEK™ (telaprevir) from Vertex Pharmaceuticals Incorporated. INCIVEK is a prescription medication used with peginterferon alfa and ribavirin. The new drug will treat chronic hepatitis C genotype 1 infection in adults with stable liver problems who have not been treated before or who have failed previous treatment.
After developing the name INCIVEK, Addison Whitney streamlined the approval process by conducting safety validation research and providing Vertex with supporting documentation for the FDA review. “This was a true collaboration with our clients at Vertex that required a time sensitive approach to all aspects of the naming process,” said Daniel Plaisance, Vice President.
INCIVEK is expected to become a leading treatment for hepatitis C. FDA panelists said it appeared to raise the cure rate for hepatitis C to about 80 percent, compared with 40 percent with current therapies. The FDA has approved INCIVEK tablets for a broad group of people with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver).
“This is a very exciting time for Addison Whitney Health,” said Senior Vice President Vince Budd. “Not only is it great to see another one of our brands approved for a potential blockbuster product, but it showcases our high success rate of getting names approved by the global health authorities. Our clients have already received a number of approvals for names our company created, screened, tested and supported this year; and I look forward to seeing many more over the coming months.”
About Addison Whitney:
Addison Whitney is a global, full-service brand consulting firm. Founded in 1991, the firm offers branding expertise in the areas of verbal branding, visual branding, brand strategy, and research and analysis. Clients come to Addison Whitney from industries including: consumer, technology, business to business, financial, hospitality and other market segments. Addison Whitney health, a specialized healthcare division of Addison Whitney, serves the branding needs of pharmaceutical, biotechnology, life science, and medical specialties. For more information, visit http://www.addisonwhitney.com.
For more information please contact Sara Abadi at 704-697-4039 or sara.abadi(at)addisonwhitney(dot)com.
Thursday, June 2, 2011
New trials looking at treating HCV genotypes 1,2,3,4 and 5 with Pharmasett's PSI-7997
New studies that popped up in Clinical Trials.gov looking at Pharmasett's PSI-7977 with and without Peg in Genotypes 1, 2, 3, 4 and 5. Many thanks to the good people over at NATAP.org for the heads' up on these trials.
PSI-7977 With Pegylated Interferon and Ribavirin Hepatitis C Virus (HCV) Genotypes 1,4,5,6 (ATOMIC)
Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3
PSI-7977 With Pegylated Interferon and Ribavirin Hepatitis C Virus (HCV) Genotypes 1,4,5,6 (ATOMIC)
Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3
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