Original Article
The Canadian Journal of Gastroenterology
November 2010, Volume 24 Issue 11: 661-670
RP Myers, M Elkashab, M Ma, P Crotty, G Pomier-Layrargues
BACKGROUND: Liver stiffness measurement (LSM) using transient elastography (TE) is a promising tool for the noninvasive assessment of hepatic fibrosis.
OBJECTIVES: To determine the feasibility and performance of TE in a North American cohort of patients with chronic liver disease.
METHODS: LSMs were obtained using TE in 260 patients with chronic hepatitis B or C, or nonalcoholic fatty liver disease from four Canadian hepatology centres. The accuracy of TE compared with liver biopsy for the prediction of significant fibrosis (Metavir fibrosis score of F2 or greater), bridging fibrosis (Metavir fibrosis score of F3 or greater) and cirrhosis (Metavir fibrosis score of F4 ) was assessed using area under ROC curves (AUROCs), and compared with the aspartate aminotransferase-to-platelet ratio index. The influence of alanine aminotransferase (ALT) levels and other factors on liver stiffness was determined using linear regression analyses.
RESULTS: Failure of TE occurred in 2.7% of patients, while liver biopsies were inadequate for staging in 0.8%. Among the remaining 251 patients, the AUROCs of TE for Metavir fibrosis scores of F2 and F3 or greater, and F4 were 0.74 (95% CI 0.68 to 0.80), 0.89 (95% CI 0.84 to 0.94), and 0.94 (95% CI 0.90 to 0.97), respectively. LSM was more accurate than the aminotransferase-to-platelet ratio index for bridging fibrosis (AUROC 0.78) and cirrhosis (AUROC 0.88), but not significant fibrosis (AUROC 0.76). At a cut-off of 11.1 kPa, the sensitivity, specificity, and positive and negative predictive values for cirrhosis (prevalence 11%) were 96%, 81%, 39% and 99%, respectively. For significant fibrosis (prevalence 53%), a cut-off of 7.7 kPa was 68% sensitive and 69% specific, and had a positive predictive value of 70% and a negative predictive value of 65%. Liver stiffness was independently associated with ALT, body mass index and steatosis. The optimal LSM cut-offs for cirrhosis were 11.1 kPa and 11.5 kPa in patients with ALT levels lower than 100 U/L and 100 U/L or greater, respectively. For fibrosis scores of F2 or greater, these figures were 7.0 kPa and 8.6 kPa, respectively.
CONCLUSIONS: The major role of TE is the exclusion of bridging fibrosis and cirrhosis. However, TE cannot replace biopsy for the diagnosis of significant fibrosis. Because liver stiffness may be influenced by significant ALT elevation, body mass index and/or steatosis, tailored liver stiffness cut-offs may be necessary to account for these factors.
Source
November 10, 2010
Vertex Announces Plans to Enroll Additional Treatment Arm in Ongoing Phase 2 Combination Study of Telaprevir and VX-222 for the Treatment of People with Hepatitis C
Nov. 10, 2010, 8:00 a.m. EST
-New treatment arm to evaluate all oral, triple combination regimen of telaprevir, VX-222, and ribavirin-
CAMBRIDGE, Mass., Nov 10, 2010 (BUSINESS WIRE) -- Vertex Pharmaceuticals Incorporated /quotes/comstock/15*!vrtx/quotes/nls/vrtx (VRTX 34.55, +0.28, +0.82%) today announced plans to enroll an additional treatment arm as part of its ongoing Phase 2 clinical trial evaluating 12-week regimens of Vertex's lead investigational hepatitis C virus (HCV) protease inhibitor, telaprevir, in combination with its lead investigational HCV polymerase inhibitor, VX-222. The planned treatment arm is supported by emerging data from multiple ongoing clinical trials of direct-acting antiviral (DAA) therapies, including the trial of telaprevir/VX-222-based combination therapy, which suggest that adding ribavirin to a DAA treatment regimen may increase antiviral activity. In the additional arm, Vertex plans to evaluate a 12-week combination of three oral therapies -- VX-222, telaprevir and ribavirin -- dosed twice a day within a response-guided regimen.
"We are encouraged by the high viral cure rates and shorter treatment durations reported in Phase 3 studies of telaprevir-based combination therapy, and we remain focused on continuing to develop new potential treatments for hepatitis C," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "Evaluating a 12-week combination of telaprevir, VX-222 and ribavirin will provide us with important information about the potential for this all-oral regimen that could be taken twice a day."
About the Ongoing Phase 2 Trial of Telaprevir and VX-222
Beginning in August 2010, patients enrolled in the randomized, parallel-group, dose-ranging Phase 2 trial started receiving treatment. The primary endpoint of this trial is to assess safety and tolerability of 12-week telaprevir/VX-222-based combination therapy in people with genotype 1 chronic hepatitis C. A secondary endpoint of this study is to assess on-treatment antiviral activity and the proportion of patients in each study arm who achieve a sustained viral response (SVR; defined as undetectable HCV RNA 24 weeks after the end of treatment). If patients meet response-guided criteria during treatment (undetectable HCV RNA at week 2 and week 8 of treatment), they may be eligible to stop all therapy at 12 weeks.
The study includes treatment arms that are evaluating 12-week, response-guided regimens of two- and four-drug telaprevir/VX-222 combination therapy, given twice daily, with and without Pegasys(R) (pegylated-interferon alfa-2a) and Copegus(R) (ribavirin). Trial sites for the two- and four-drug ongoing arms completed enrollment in October 2010. The additional three-drug treatment arm of telaprevir, VX-222 and ribavirin announced today is expected to begin patient enrollment in the first quarter of 2011, pending completion of institutional review board (IRB) approvals and consultation with regulatory agencies. Based on further results from the ongoing treatment arms, Vertex may add an additional arm in this study.
Additional Clinical Trial of VX-222 Combination Therapy
Vertex is also conducting a Phase 2 clinical trial evaluating the safety, tolerability and antiviral activity of VX-222 in combination with pegylated-interferon and ribavirin, which began in August 2010. Enrollment is ongoing and Vertex expects to enroll a total of 50 patients. Patients in this trial will receive one of two doses of VX-222 (400 mg or 750 mg twice daily) in combination with pegylated-interferon alfa-2a and ribavirin for 12 weeks, followed by pegylated-interferon alfa-2a and ribavirin alone for 36 weeks.
About Telaprevir and VX-222
Telaprevir is an investigational, oral inhibitor of HCV protease, an enzyme essential for viral replication, and is being developed by Vertex Pharmaceuticals in collaboration with Tibotec Pharmaceuticals and Mitsubishi Tanabe Pharma. Phase 3 studies of telaprevir in combination with pegylated interferon alfa-2a and ribavirin are complete and Vertex is on track to complete its rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration by the end of 2010.
VX-222 is an investigational, oral, non-nucleoside inhibitor of HCV NS5B polymerase. Vertex added VX-222 to its development pipeline as part of the acquisition of ViroChem Pharma Inc. in March 2009. Vertex retains worldwide commercial rights to VX-222.
About Hepatitis C
Hepatitis C is a liver disease caused by the hepatitis C virus, which is found in the liver and blood of people with the disease.(2) According to a 2010 report from the Institute of Medicine, up to 3.9 million people in the United States have chronic hepatitis C and 75% of those infected are unaware of their infection.(3)Approximately 60 percent of genotype 1 patients who undergo an initial 48-week regimen with pegylated-interferon and ribavirin, the currently approved treatment regimen, do not achieve SVR, (4,5,6)or viral cure.(1)
Hepatitis C is spread through direct contact with the blood of infected people.(2) Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.(2) Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.(2) If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.(7,8,9,10,11) In the United States, hepatitis C is the leading cause of liver transplantations and is reported to contribute to 4,600 to 12,000 deaths annually.(8) The majority of people with hepatitis C were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.(11) By 2029, total annual medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.(11)
Additional resources for media, including a hepatitis C backgrounder and glossary of common terms, are available at: http://investors.vrtx.com/press.cfm
About Vertex
Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with other pharmaceutical companies. Vertex's product pipeline is focused on viral diseases, cystic fibrosis, inflammation, autoimmune diseases, epilepsy, cancer and pain.
Vertex co-discovered the HIV protease inhibitor, Lexiva, with GlaxoSmithKline.
Lexiva is a registered trademark of the GlaxoSmithKline group of companies.
PEGASYS(R) and COPEGUS(R) are registered trademarks of Hoffman-La Roche.
References:
(1)Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40. (2) Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed May 25, 2010. (3) Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed May 25, 2010. (4)Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. (5) Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. (6)McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593. (7) Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115). (8)Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521. (9) Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755. (10) Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684. (11) Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. This report was commissioned by Vertex Pharmaceuticals, Inc. (12) Picchio G, et al. Discrepancies between definitions of null response to treatment with peginterferon alfa-2a and ribavirin: Implications for new HCV drug development. [poster 289]. In: Program and Abstracts of the 2010 International Liver Conference by the European Association for the Study of Liver Disease. . Athens, Greece: April 2010. (13)United States Food and Drug Administration. Chronic hepatitis C virus infection: developing direct-acting antiviral agents for treatment. http://www.federalregister.gov/articles/2010/09/14/2010-22806/draft-guidance-for-industry-on-chronic-hepatitis-c-virus-infection-developing-directacting-antiviral. Updated September 14, 2010. Accessed September 14, 2010.
Special Note Regarding Forward-looking Statements
This press release contains forward-looking statements including statements regarding (i) Vertex's plan to enroll an additional treatment arm as part of its ongoing Phase 2 clinical trial evaluating telaprevir in combination with VX-222; (ii) the support provided by emerging data suggesting that adding ribavirin to a direct-acting antiviral treatment regimen may increase antiviral activity; (iii) the plan to evaluate a 12-week combination of the three oral therapies -- VX-222, telaprevir and ribavirin -- dosed twice a day within a response-guided regimen; (iv) the expectation that evaluating a 12-week combination regimen of telaprevir, VX-222, and ribavirin will provide Vertex with important information about the potential for this all oral regimen that could be taken twice daily; (v) the expectation that the additional three-drug treatment arm will begin patient enrollment in the first quarter of 2011, pending completion of IRB approvals and consultation with regulatory agencies; (vi) the possibility that Vertex may add an additional treatment arm to this study; (vii) expectations regarding the additional clinical trial of VX-222 combination therapy; and (viii) Vertex being on track to complete its rolling NDA submission to the U.S. Food and Drug Administration by the end of 2010. While Vertex believes the forward-looking statements contained in this press release are accurate, these statements are subject to risks and uncertainties that could cause actual outcomes to vary materially from the outcomes referenced in the forward-looking statements. These risks and uncertainties include, among other things, the risks that efforts to develop telaprevir and VX-222 separately or in combination may not proceed due to technical, scientific, commercial, financial or other reasons, that clinical trials may not proceed as planned, that additional clinical trials of telaprevir and VX-222 will not reflect the results obtained to date, that an adverse event profile for telaprevir or VX-222 could be revealed in further nonclinical or clinical studies that could put further development of telaprevir or VX-222 in jeopardy or adversely impact their therapeutic value, and other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the Company's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
(VRTX-GEN)
SOURCE: Vertex Pharmaceuticals Incorporated
Vertex Pharmaceuticals Incorporated
Media:
Amy Pasqua, 617-444-6992
or
Dawn Kalmar, 617-444-6992
or
Zachry Barber, 617-444-6992
or
Investors:
Michael Partridge, 617-444-6108
or
Lora Pike, 617-444-6755
or
Matthew Osborne, 617-444-6057
Source
-New treatment arm to evaluate all oral, triple combination regimen of telaprevir, VX-222, and ribavirin-
CAMBRIDGE, Mass., Nov 10, 2010 (BUSINESS WIRE) -- Vertex Pharmaceuticals Incorporated /quotes/comstock/15*!vrtx/quotes/nls/vrtx (VRTX 34.55, +0.28, +0.82%) today announced plans to enroll an additional treatment arm as part of its ongoing Phase 2 clinical trial evaluating 12-week regimens of Vertex's lead investigational hepatitis C virus (HCV) protease inhibitor, telaprevir, in combination with its lead investigational HCV polymerase inhibitor, VX-222. The planned treatment arm is supported by emerging data from multiple ongoing clinical trials of direct-acting antiviral (DAA) therapies, including the trial of telaprevir/VX-222-based combination therapy, which suggest that adding ribavirin to a DAA treatment regimen may increase antiviral activity. In the additional arm, Vertex plans to evaluate a 12-week combination of three oral therapies -- VX-222, telaprevir and ribavirin -- dosed twice a day within a response-guided regimen.
"We are encouraged by the high viral cure rates and shorter treatment durations reported in Phase 3 studies of telaprevir-based combination therapy, and we remain focused on continuing to develop new potential treatments for hepatitis C," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "Evaluating a 12-week combination of telaprevir, VX-222 and ribavirin will provide us with important information about the potential for this all-oral regimen that could be taken twice a day."
About the Ongoing Phase 2 Trial of Telaprevir and VX-222
Beginning in August 2010, patients enrolled in the randomized, parallel-group, dose-ranging Phase 2 trial started receiving treatment. The primary endpoint of this trial is to assess safety and tolerability of 12-week telaprevir/VX-222-based combination therapy in people with genotype 1 chronic hepatitis C. A secondary endpoint of this study is to assess on-treatment antiviral activity and the proportion of patients in each study arm who achieve a sustained viral response (SVR; defined as undetectable HCV RNA 24 weeks after the end of treatment). If patients meet response-guided criteria during treatment (undetectable HCV RNA at week 2 and week 8 of treatment), they may be eligible to stop all therapy at 12 weeks.
The study includes treatment arms that are evaluating 12-week, response-guided regimens of two- and four-drug telaprevir/VX-222 combination therapy, given twice daily, with and without Pegasys(R) (pegylated-interferon alfa-2a) and Copegus(R) (ribavirin). Trial sites for the two- and four-drug ongoing arms completed enrollment in October 2010. The additional three-drug treatment arm of telaprevir, VX-222 and ribavirin announced today is expected to begin patient enrollment in the first quarter of 2011, pending completion of institutional review board (IRB) approvals and consultation with regulatory agencies. Based on further results from the ongoing treatment arms, Vertex may add an additional arm in this study.
Additional Clinical Trial of VX-222 Combination Therapy
Vertex is also conducting a Phase 2 clinical trial evaluating the safety, tolerability and antiviral activity of VX-222 in combination with pegylated-interferon and ribavirin, which began in August 2010. Enrollment is ongoing and Vertex expects to enroll a total of 50 patients. Patients in this trial will receive one of two doses of VX-222 (400 mg or 750 mg twice daily) in combination with pegylated-interferon alfa-2a and ribavirin for 12 weeks, followed by pegylated-interferon alfa-2a and ribavirin alone for 36 weeks.
About Telaprevir and VX-222
Telaprevir is an investigational, oral inhibitor of HCV protease, an enzyme essential for viral replication, and is being developed by Vertex Pharmaceuticals in collaboration with Tibotec Pharmaceuticals and Mitsubishi Tanabe Pharma. Phase 3 studies of telaprevir in combination with pegylated interferon alfa-2a and ribavirin are complete and Vertex is on track to complete its rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration by the end of 2010.
VX-222 is an investigational, oral, non-nucleoside inhibitor of HCV NS5B polymerase. Vertex added VX-222 to its development pipeline as part of the acquisition of ViroChem Pharma Inc. in March 2009. Vertex retains worldwide commercial rights to VX-222.
About Hepatitis C
Hepatitis C is a liver disease caused by the hepatitis C virus, which is found in the liver and blood of people with the disease.(2) According to a 2010 report from the Institute of Medicine, up to 3.9 million people in the United States have chronic hepatitis C and 75% of those infected are unaware of their infection.(3)Approximately 60 percent of genotype 1 patients who undergo an initial 48-week regimen with pegylated-interferon and ribavirin, the currently approved treatment regimen, do not achieve SVR, (4,5,6)or viral cure.(1)
Hepatitis C is spread through direct contact with the blood of infected people.(2) Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.(2) Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.(2) If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.(7,8,9,10,11) In the United States, hepatitis C is the leading cause of liver transplantations and is reported to contribute to 4,600 to 12,000 deaths annually.(8) The majority of people with hepatitis C were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.(11) By 2029, total annual medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.(11)
Additional resources for media, including a hepatitis C backgrounder and glossary of common terms, are available at: http://investors.vrtx.com/press.cfm
About Vertex
Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with other pharmaceutical companies. Vertex's product pipeline is focused on viral diseases, cystic fibrosis, inflammation, autoimmune diseases, epilepsy, cancer and pain.
Vertex co-discovered the HIV protease inhibitor, Lexiva, with GlaxoSmithKline.
Lexiva is a registered trademark of the GlaxoSmithKline group of companies.
PEGASYS(R) and COPEGUS(R) are registered trademarks of Hoffman-La Roche.
References:
(1)Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40. (2) Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed May 25, 2010. (3) Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed May 25, 2010. (4)Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. (5) Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. (6)McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593. (7) Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115). (8)Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521. (9) Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755. (10) Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684. (11) Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. This report was commissioned by Vertex Pharmaceuticals, Inc. (12) Picchio G, et al. Discrepancies between definitions of null response to treatment with peginterferon alfa-2a and ribavirin: Implications for new HCV drug development. [poster 289]. In: Program and Abstracts of the 2010 International Liver Conference by the European Association for the Study of Liver Disease. . Athens, Greece: April 2010. (13)United States Food and Drug Administration. Chronic hepatitis C virus infection: developing direct-acting antiviral agents for treatment. http://www.federalregister.gov/articles/2010/09/14/2010-22806/draft-guidance-for-industry-on-chronic-hepatitis-c-virus-infection-developing-directacting-antiviral. Updated September 14, 2010. Accessed September 14, 2010.
Special Note Regarding Forward-looking Statements
This press release contains forward-looking statements including statements regarding (i) Vertex's plan to enroll an additional treatment arm as part of its ongoing Phase 2 clinical trial evaluating telaprevir in combination with VX-222; (ii) the support provided by emerging data suggesting that adding ribavirin to a direct-acting antiviral treatment regimen may increase antiviral activity; (iii) the plan to evaluate a 12-week combination of the three oral therapies -- VX-222, telaprevir and ribavirin -- dosed twice a day within a response-guided regimen; (iv) the expectation that evaluating a 12-week combination regimen of telaprevir, VX-222, and ribavirin will provide Vertex with important information about the potential for this all oral regimen that could be taken twice daily; (v) the expectation that the additional three-drug treatment arm will begin patient enrollment in the first quarter of 2011, pending completion of IRB approvals and consultation with regulatory agencies; (vi) the possibility that Vertex may add an additional treatment arm to this study; (vii) expectations regarding the additional clinical trial of VX-222 combination therapy; and (viii) Vertex being on track to complete its rolling NDA submission to the U.S. Food and Drug Administration by the end of 2010. While Vertex believes the forward-looking statements contained in this press release are accurate, these statements are subject to risks and uncertainties that could cause actual outcomes to vary materially from the outcomes referenced in the forward-looking statements. These risks and uncertainties include, among other things, the risks that efforts to develop telaprevir and VX-222 separately or in combination may not proceed due to technical, scientific, commercial, financial or other reasons, that clinical trials may not proceed as planned, that additional clinical trials of telaprevir and VX-222 will not reflect the results obtained to date, that an adverse event profile for telaprevir or VX-222 could be revealed in further nonclinical or clinical studies that could put further development of telaprevir or VX-222 in jeopardy or adversely impact their therapeutic value, and other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the Company's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
(VRTX-GEN)
SOURCE: Vertex Pharmaceuticals Incorporated
Vertex Pharmaceuticals Incorporated
Media:
Amy Pasqua, 617-444-6992
or
Dawn Kalmar, 617-444-6992
or
Zachry Barber, 617-444-6992
or
Investors:
Michael Partridge, 617-444-6108
or
Lora Pike, 617-444-6755
or
Matthew Osborne, 617-444-6057
Source
November 9, 2010
Look out, your medicine is watching you
By Ben Hirschler
NEW YORK
Tue Nov 9, 2010 8:18am EST
NEW YORK (Reuters) - Novartis AG plans to seek regulatory approval within 18 months for a pioneering tablet containing an embedded microchip, bringing the concept of "smart-pill" technology a step closer.
The initial program will use one of the Swiss firm's established drugs taken by transplant patients to avoid organ rejection. But Trevor Mundel, global head of development, believes the concept can be applied to many other pills.
"We are taking forward this transplant drug with a chip and we hope within the next 18 months to have something that we will be able to submit to the regulators, at least in Europe," Mundel told the Reuters Health Summit in New York.
"I see the promise as going much beyond that," he added.
Novartis agreed in January to spend $24 million to secure access to chip-in-a-pill technology developed by privately owned Proteus Biomedical of Redwood City, California, putting it ahead of rivals.
The biotech start-up's ingestible chips are activated by stomach acid and send information to a small patch worn on the patient's skin, which can transmit data to a smartphone or send it over the Internet to a doctor.
Mundel said the initial project was focused on ensuring that patients took drugs at the right time and got the dose they needed -- a key issue for people after kidney and other transplant operations, when treatment frequently needs adjustment.
Longer-term, he hopes to expand the "smart pill" concept to other types of medicine and use the wealth of biometric information the Proteus chip can collect, from heart rate and temperature to body movement, to check that drugs are working properly.
Because the tiny chips are added to existing drugs, Novartis does not expect to have to conduct full-scale clinical trials to prove the new products work. Instead, it aims to do so-called bioequivalence tests to show they are the same as the original.
A bigger issue may be what checks should be put in place to protect patients' personal medical data as it is transmitted from inside their bodies by wireless and Bluetooth.
"The regulators all like the concept and have been very encouraging. But ... they want to understand how we are going to solve the data privacy issues," Mundel said.
A technology that ensures a patient takes his or her medicine and checks that it is working properly should deliver better outcomes and justify a higher price tag.
(Reporting by Ben Hirschler. Editing by Robert MacMillan)
Source
NEW YORK
Tue Nov 9, 2010 8:18am EST
NEW YORK (Reuters) - Novartis AG plans to seek regulatory approval within 18 months for a pioneering tablet containing an embedded microchip, bringing the concept of "smart-pill" technology a step closer.
The initial program will use one of the Swiss firm's established drugs taken by transplant patients to avoid organ rejection. But Trevor Mundel, global head of development, believes the concept can be applied to many other pills.
"We are taking forward this transplant drug with a chip and we hope within the next 18 months to have something that we will be able to submit to the regulators, at least in Europe," Mundel told the Reuters Health Summit in New York.
"I see the promise as going much beyond that," he added.
Novartis agreed in January to spend $24 million to secure access to chip-in-a-pill technology developed by privately owned Proteus Biomedical of Redwood City, California, putting it ahead of rivals.
The biotech start-up's ingestible chips are activated by stomach acid and send information to a small patch worn on the patient's skin, which can transmit data to a smartphone or send it over the Internet to a doctor.
Mundel said the initial project was focused on ensuring that patients took drugs at the right time and got the dose they needed -- a key issue for people after kidney and other transplant operations, when treatment frequently needs adjustment.
Longer-term, he hopes to expand the "smart pill" concept to other types of medicine and use the wealth of biometric information the Proteus chip can collect, from heart rate and temperature to body movement, to check that drugs are working properly.
Because the tiny chips are added to existing drugs, Novartis does not expect to have to conduct full-scale clinical trials to prove the new products work. Instead, it aims to do so-called bioequivalence tests to show they are the same as the original.
A bigger issue may be what checks should be put in place to protect patients' personal medical data as it is transmitted from inside their bodies by wireless and Bluetooth.
"The regulators all like the concept and have been very encouraging. But ... they want to understand how we are going to solve the data privacy issues," Mundel said.
A technology that ensures a patient takes his or her medicine and checks that it is working properly should deliver better outcomes and justify a higher price tag.
(Reporting by Ben Hirschler. Editing by Robert MacMillan)
Source
AASLD: Boceprevir Boosts Response Rate With Interferon and Ribavirin for HCV
Bob Roehr
November 9, 2010 (Boston, Massachusetts) — Boceprevir is a protease inhibitor that targets the hepatitis C virus (HCV). When added to the standard of care (pegylated-interferon alfa-2b and ribavirin), boceprevir improved the sustained viral response (SVR) rate approximately 70% over standard of care alone, according to the final results from the SPRINT-2 trial, reported here at The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting.
The SPRINT-1 findings were published in August, as reported by Medscape Medical News at that time.
Principal investigator Fred Poordad, MD, chief of hepatology at Cedars-Sinai Hospital in Los Angeles, California, presented the SPRINT-2 final results. The researchers evaluated the effect of the triple-drug regimen on patients with HCV genotype 1, and conducted a separate analysis of the treatment effect in black patients. SVR rates have been below 50% in HCV genotype 1 patients, especially in those of African descent, Dr. Poordad noted.
The study had a 3-group design that included a 4-week lead-in of standard of care before adding boceprevir, and response-guided therapy to determine the overall duration of therapy for responders. After the initial lead-in period, the control group received standard of care plus placebo for 44 weeks; the 44-week boceprevir group received boceprevir plus standard of care for 44 weeks; and the response-guided therapy group received boceprevir plus standard of care for 24 weeks, with an additional 20 weeks of standard of care only if HCV RNA was detectable during weeks 8 to 24. Patients with detectable HCV RNA at week 24 were withdrawn from the study.
The pegylated-interferon alfa-2b dose was 1.5 μg/kg subcutaneously once a week; ribavirin dose was weight-based (600 to 1400 mg/day) twice daily, orally; boceprevir dose was 800 mg orally 3 times a day.
The SVR in nonblack patients was 40% in the control group, 67% in the response-guided therapy group, and 68% in the 44-week boceprevir group.
Dr. Poordad said that although "the relapse rate in the control arm was 23%, it was less than 10% for patients receiving boceprevir."
The SVR in the black patient cohort was 23% in the control group, 42% in the response-guided therapy group, and 53% in the 44-week boceprevir group. "Relapse rates were slightly higher than [in nonblacks], roughly the same across all 3 arms, ranging from 12% to 17%," Dr. Poordad said.
"At the end of lead-in [week 4], the viral load measurement predicted quite well who would ultimately respond. Patients who had greater than a 1 log decline at the end of the lead-in phase, if they received boceprevir, ultimately had over an 80% SVR. The control arm had a 52% SVR," he reported.
"Conversely, patients who did not achieve a 1 log decline in the control arm had a 5% SVR; [it was] 29% to 39% in those receiving boceprevir."
Resistance mutations to boceprevir developed in 4% of the more rapid responders. Dr. Poordad said that "patients who had less than a 1 log decline at the end of lead-in ended up with 35% to 47% resistance using population sequencing. This is likely an underestimate of the overall development of resistance associated variants."
Adverse events were higher in the boceprevir groups than in the control group — most notably anemia (20% more likely) and dysgeusia (19% to 25% more likely). Discontinuation because of anemia was less than 2%, but erythropoetin (EPO) use was 19% more in the boceprevir groups than in the control group.
When pressed, Dr. Poordad noted that "this is a problem with all of the protease inhibitors." He said the sponsor provided EPO for use at the discretion of the physician, and acknowledged that most insurance carriers do not cover such use, which could affect clinical practice. He added that "there is an ongoing studying looking at SVR with and without EPO use."
Boceprevir has a low barrier to the emergence of resistance by the virus. The sponsor has adopted the strategy of a 4-week lead-in of standard of care to knock down levels of viremia before boceprevir is added, to minimize the risk of resistance emerging. Boceprevir and telaprevir share resistance points and cannot be rescued by the other, the researcher noted.
Medscape Medical News asked Michael Fried, MD, from the University of North Carolina at Chapel Hill, if it might make sense to re-evaluate patients at this point on whether those with a rapid virological response (HCV RNA <50 IU/mL at week 4) and undetectable HCV RNA level on standard of care really need a third drug.
He hedged a bit in responding: "The problem is that such a small percentage of patients have [rapid virological responses]. With genotype 1 in the United States, it might be 5%. But you have to wait and see what happens with the final results. Then you can adapt with your patient. I don't think it is appropriate to make blanket statements."
Scott L. Friedman, MD, a hepatologist at Mount Sinai School of Medicine in New York City, and immediate past president of AASLD, believes that third-party payers will play a role in determining the staging of therapy through what they are willing to cover. They will ask: "Do you really need to incorporate a very expensive new drug when you have a marker that tells you your standard of care is going to be highly effective?"
SPRINT-2 investigators are predicting that boceprevir will likely to be approved by the US Food and Drug Administration in 2011.
The SPRINT trials were sponsored by Schering-Plough, now part of Merck. Dr. Poordad and Dr. Fried report extensive financial ties with most of the major companies involved in HCV research. Dr. Friedman has disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-4. Presented November 1, 2010.
Source
November 9, 2010 (Boston, Massachusetts) — Boceprevir is a protease inhibitor that targets the hepatitis C virus (HCV). When added to the standard of care (pegylated-interferon alfa-2b and ribavirin), boceprevir improved the sustained viral response (SVR) rate approximately 70% over standard of care alone, according to the final results from the SPRINT-2 trial, reported here at The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting.
The SPRINT-1 findings were published in August, as reported by Medscape Medical News at that time.
Principal investigator Fred Poordad, MD, chief of hepatology at Cedars-Sinai Hospital in Los Angeles, California, presented the SPRINT-2 final results. The researchers evaluated the effect of the triple-drug regimen on patients with HCV genotype 1, and conducted a separate analysis of the treatment effect in black patients. SVR rates have been below 50% in HCV genotype 1 patients, especially in those of African descent, Dr. Poordad noted.
The study had a 3-group design that included a 4-week lead-in of standard of care before adding boceprevir, and response-guided therapy to determine the overall duration of therapy for responders. After the initial lead-in period, the control group received standard of care plus placebo for 44 weeks; the 44-week boceprevir group received boceprevir plus standard of care for 44 weeks; and the response-guided therapy group received boceprevir plus standard of care for 24 weeks, with an additional 20 weeks of standard of care only if HCV RNA was detectable during weeks 8 to 24. Patients with detectable HCV RNA at week 24 were withdrawn from the study.
The pegylated-interferon alfa-2b dose was 1.5 μg/kg subcutaneously once a week; ribavirin dose was weight-based (600 to 1400 mg/day) twice daily, orally; boceprevir dose was 800 mg orally 3 times a day.
The SVR in nonblack patients was 40% in the control group, 67% in the response-guided therapy group, and 68% in the 44-week boceprevir group.
Dr. Poordad said that although "the relapse rate in the control arm was 23%, it was less than 10% for patients receiving boceprevir."
The SVR in the black patient cohort was 23% in the control group, 42% in the response-guided therapy group, and 53% in the 44-week boceprevir group. "Relapse rates were slightly higher than [in nonblacks], roughly the same across all 3 arms, ranging from 12% to 17%," Dr. Poordad said.
"At the end of lead-in [week 4], the viral load measurement predicted quite well who would ultimately respond. Patients who had greater than a 1 log decline at the end of the lead-in phase, if they received boceprevir, ultimately had over an 80% SVR. The control arm had a 52% SVR," he reported.
"Conversely, patients who did not achieve a 1 log decline in the control arm had a 5% SVR; [it was] 29% to 39% in those receiving boceprevir."
Resistance mutations to boceprevir developed in 4% of the more rapid responders. Dr. Poordad said that "patients who had less than a 1 log decline at the end of lead-in ended up with 35% to 47% resistance using population sequencing. This is likely an underestimate of the overall development of resistance associated variants."
Adverse events were higher in the boceprevir groups than in the control group — most notably anemia (20% more likely) and dysgeusia (19% to 25% more likely). Discontinuation because of anemia was less than 2%, but erythropoetin (EPO) use was 19% more in the boceprevir groups than in the control group.
When pressed, Dr. Poordad noted that "this is a problem with all of the protease inhibitors." He said the sponsor provided EPO for use at the discretion of the physician, and acknowledged that most insurance carriers do not cover such use, which could affect clinical practice. He added that "there is an ongoing studying looking at SVR with and without EPO use."
Boceprevir has a low barrier to the emergence of resistance by the virus. The sponsor has adopted the strategy of a 4-week lead-in of standard of care to knock down levels of viremia before boceprevir is added, to minimize the risk of resistance emerging. Boceprevir and telaprevir share resistance points and cannot be rescued by the other, the researcher noted.
Medscape Medical News asked Michael Fried, MD, from the University of North Carolina at Chapel Hill, if it might make sense to re-evaluate patients at this point on whether those with a rapid virological response (HCV RNA <50 IU/mL at week 4) and undetectable HCV RNA level on standard of care really need a third drug.
He hedged a bit in responding: "The problem is that such a small percentage of patients have [rapid virological responses]. With genotype 1 in the United States, it might be 5%. But you have to wait and see what happens with the final results. Then you can adapt with your patient. I don't think it is appropriate to make blanket statements."
Scott L. Friedman, MD, a hepatologist at Mount Sinai School of Medicine in New York City, and immediate past president of AASLD, believes that third-party payers will play a role in determining the staging of therapy through what they are willing to cover. They will ask: "Do you really need to incorporate a very expensive new drug when you have a marker that tells you your standard of care is going to be highly effective?"
SPRINT-2 investigators are predicting that boceprevir will likely to be approved by the US Food and Drug Administration in 2011.
The SPRINT trials were sponsored by Schering-Plough, now part of Merck. Dr. Poordad and Dr. Fried report extensive financial ties with most of the major companies involved in HCV research. Dr. Friedman has disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-4. Presented November 1, 2010.
Source
AASLD: Protease Inhibitor TMC435 Shows Promise Against HCV in Phase 2b Study
Bob Roehr
November 9, 2010 (Boston, Massachusetts) — The second wave of hepatitis C virus (HCV) protease inhibitors includes TMC435, an NS3/4A protease inhibitor being developed by Tibotec/Johnson & Johnson. The compound has a 40-hour half life, which makes it amenable to once-a-day dosing.
Michael Fried, MD, from the University of North Carolina at Chapel Hill, presented an interim 24-week analysis of the ongoing phase 2b Protease Inhibitor TMC435 Trial Assessing the Optimal Dose and Duration as Once Daily Anti-Viral Regimen (PILLAR) here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting.
All 386 patients received a backbone regimen of standard of care, consisting of pegylated-interferon plus ribavirin, for 24 weeks, and were then randomized to add either 75 mg or 150 mg oral TMC435 once daily for 12 or 24 weeks. The fifth group received standard of care for only 48 weeks. Each study group consisted of 75 to 79 patients.
A response-guided treatment algorithm allowed patients in the TMC435 groups to discontinue therapy at week 24 "if they had HCV RNA [levels] less than 25 IU and were also undetectable at treatment weeks 12, 16, and 20. Patients who did not meet these virological criteria were eligible to continue pegylated-interferon and ribavirin for up to 48 weeks," Dr. Fried said. All patients are being followed for 72 weeks.
The primary end point was sustained virologic response. Secondary end points included assessment of antiviral activity, viral breakthrough, safety, tolerability, and IL28B status. Patients were stratified by race and HCV genotype (1a vs 1b).
The study population had a strong female presence (44.8%), was predominately white (93.8%), had a median age of 46.5 years, and had a body mass index of 25.0 kg/m2. The viral load was high; in 85.8%, HCV RNA level was 800,000 IU/mL or higher. Cirrhosis was an exclusionary factor, but fibrosis was present in 13.7% of patients.
Dr. Fried said that all TMC435 groups "had a rapid and steep decline in HCV RNA during the first 4 weeks of treatment that was maintained throughout the 12- or 24-week dosing period."
A more than 5 log decline in viremia was recorded by week 2 in patients in the TMC435 groups, which was maintained throughout the course of treatment. In contrast, the control group showed a much slower slope of decline, needing about 8 weeks to achieve a 4 log decline, and it never achieved the same depth of decline in HCV RNA as the TMC435 groups.
The portion of patients with very low or undetectable HCV RNA (<25 IU/mL) at week 4 ranged from 88% to 96% in the TMC435 groups, compared with 16% in the control group. At week 12, undetectable HCV RNA was recorded in 91% of those randomized to 12 weeks of TMC435 treatment, 97% in those randomized to 24 weeks of TMC435, and 69% in those randomized to the control group, respectively. At week 24, the numbers were 94%, 97%, and 82%, respectively, he said.
"According to the response-guided treatment algorithm used in the study, between 79% and 86% of patients in the TMC435 arms were able to discontinue treatment at week 24 by achieving the defined biological response criteria," said Dr. Fried. Patients in the control group have not yet completed their longer course of therapy.
A subset of nearly half of the patients on TMC435, with sustained virologic responses ranging from 88% to 97%, had completed all treatment and were available for week 12 follow-up evaluation.
Viral breakthrough by week 24 occurred in 2.5% to 7.8% of the TMC435 groups, compared with 3.9% of the control group. There was no correlation between dose of the drug and breakthrough, although patients on the longer course of treatment did have lower rates of breakthrough.
A retrospective analysis by IL28B genotype showed that TMC435 did increase response rates across all genotypes, and it narrowed the differences between the 3 genetic variations. It also confirmed that those with the CC allele perform better than those with the CT or TT alleles. The higher dose of TMC435 appears to result in a slightly deeper suppression of viremia than the lower dose, particularly among those with the TT allele. Dr. Fried said.
Treatment breakthroughs "were mostly in the CT and TT [allelic] groups" and were less likely to occur in the higher-dose groups, Dr. Fried reported. Resistance was most often found at points "155, 80, and some unique ones at the 168 residue" of the HCV genotype, he added. This provides some encouragement that regimens containing TMC435 will help ameliorate some of the negative effects of the IL28B genotype."
Rates of discontinuation and adverse events with TMC435 were similar to those seen with standard of care alone. There were increases in bilirubin, particularly with the higher dose of TMC435; however, "most were considered to be grade 1" and generally were within the upper limit of normal. The bilirubin increase peaked around week 2 and then declined slightly over time. He said that "this suggests that the mild, reversible increase in bilirubin is not due to hepatotoxicity."
Planning for phase 3 studies is underway.
One member of the audience called the data "very clean and very encouraging," but he wondered if the increase in bilirubin might be an issue. Dr. Fried reiterated that "it was completely reversible and was not progressive during the course of therapy. It is clearly related to a transporter mechanism, as opposed to hepatotoxicity, so I don't think it is going to be a major issue."
Session cochair Douglas R. LaBrecque, MD, director of Liver Services at University of Iowa Health Care in Iowa City, later told Medscape Medical News that "relatively low levels of bilirubin by themselves are not dangerous. From the limited data, it appears that it went away as soon as therapy was done."
This study was sponsored by Tibotec. Dr. Fried reports ongoing research and consulting contacts with the sponsor and several competing companies. Dr. LaBrecque has disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-5. Presented November 1, 2010.
Source
November 9, 2010 (Boston, Massachusetts) — The second wave of hepatitis C virus (HCV) protease inhibitors includes TMC435, an NS3/4A protease inhibitor being developed by Tibotec/Johnson & Johnson. The compound has a 40-hour half life, which makes it amenable to once-a-day dosing.
Michael Fried, MD, from the University of North Carolina at Chapel Hill, presented an interim 24-week analysis of the ongoing phase 2b Protease Inhibitor TMC435 Trial Assessing the Optimal Dose and Duration as Once Daily Anti-Viral Regimen (PILLAR) here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting.
All 386 patients received a backbone regimen of standard of care, consisting of pegylated-interferon plus ribavirin, for 24 weeks, and were then randomized to add either 75 mg or 150 mg oral TMC435 once daily for 12 or 24 weeks. The fifth group received standard of care for only 48 weeks. Each study group consisted of 75 to 79 patients.
A response-guided treatment algorithm allowed patients in the TMC435 groups to discontinue therapy at week 24 "if they had HCV RNA [levels] less than 25 IU and were also undetectable at treatment weeks 12, 16, and 20. Patients who did not meet these virological criteria were eligible to continue pegylated-interferon and ribavirin for up to 48 weeks," Dr. Fried said. All patients are being followed for 72 weeks.
The primary end point was sustained virologic response. Secondary end points included assessment of antiviral activity, viral breakthrough, safety, tolerability, and IL28B status. Patients were stratified by race and HCV genotype (1a vs 1b).
The study population had a strong female presence (44.8%), was predominately white (93.8%), had a median age of 46.5 years, and had a body mass index of 25.0 kg/m2. The viral load was high; in 85.8%, HCV RNA level was 800,000 IU/mL or higher. Cirrhosis was an exclusionary factor, but fibrosis was present in 13.7% of patients.
Dr. Fried said that all TMC435 groups "had a rapid and steep decline in HCV RNA during the first 4 weeks of treatment that was maintained throughout the 12- or 24-week dosing period."
A more than 5 log decline in viremia was recorded by week 2 in patients in the TMC435 groups, which was maintained throughout the course of treatment. In contrast, the control group showed a much slower slope of decline, needing about 8 weeks to achieve a 4 log decline, and it never achieved the same depth of decline in HCV RNA as the TMC435 groups.
The portion of patients with very low or undetectable HCV RNA (<25 IU/mL) at week 4 ranged from 88% to 96% in the TMC435 groups, compared with 16% in the control group. At week 12, undetectable HCV RNA was recorded in 91% of those randomized to 12 weeks of TMC435 treatment, 97% in those randomized to 24 weeks of TMC435, and 69% in those randomized to the control group, respectively. At week 24, the numbers were 94%, 97%, and 82%, respectively, he said.
"According to the response-guided treatment algorithm used in the study, between 79% and 86% of patients in the TMC435 arms were able to discontinue treatment at week 24 by achieving the defined biological response criteria," said Dr. Fried. Patients in the control group have not yet completed their longer course of therapy.
A subset of nearly half of the patients on TMC435, with sustained virologic responses ranging from 88% to 97%, had completed all treatment and were available for week 12 follow-up evaluation.
Viral breakthrough by week 24 occurred in 2.5% to 7.8% of the TMC435 groups, compared with 3.9% of the control group. There was no correlation between dose of the drug and breakthrough, although patients on the longer course of treatment did have lower rates of breakthrough.
A retrospective analysis by IL28B genotype showed that TMC435 did increase response rates across all genotypes, and it narrowed the differences between the 3 genetic variations. It also confirmed that those with the CC allele perform better than those with the CT or TT alleles. The higher dose of TMC435 appears to result in a slightly deeper suppression of viremia than the lower dose, particularly among those with the TT allele. Dr. Fried said.
Treatment breakthroughs "were mostly in the CT and TT [allelic] groups" and were less likely to occur in the higher-dose groups, Dr. Fried reported. Resistance was most often found at points "155, 80, and some unique ones at the 168 residue" of the HCV genotype, he added. This provides some encouragement that regimens containing TMC435 will help ameliorate some of the negative effects of the IL28B genotype."
Rates of discontinuation and adverse events with TMC435 were similar to those seen with standard of care alone. There were increases in bilirubin, particularly with the higher dose of TMC435; however, "most were considered to be grade 1" and generally were within the upper limit of normal. The bilirubin increase peaked around week 2 and then declined slightly over time. He said that "this suggests that the mild, reversible increase in bilirubin is not due to hepatotoxicity."
Planning for phase 3 studies is underway.
One member of the audience called the data "very clean and very encouraging," but he wondered if the increase in bilirubin might be an issue. Dr. Fried reiterated that "it was completely reversible and was not progressive during the course of therapy. It is clearly related to a transporter mechanism, as opposed to hepatotoxicity, so I don't think it is going to be a major issue."
Session cochair Douglas R. LaBrecque, MD, director of Liver Services at University of Iowa Health Care in Iowa City, later told Medscape Medical News that "relatively low levels of bilirubin by themselves are not dangerous. From the limited data, it appears that it went away as soon as therapy was done."
This study was sponsored by Tibotec. Dr. Fried reports ongoing research and consulting contacts with the sponsor and several competing companies. Dr. LaBrecque has disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-5. Presented November 1, 2010.
Source
November 8, 2010
AASLD: Telbivudine Prevents HBV Perinatal Transmission
Bob Roehr
November 8, 2010 (Boston, Massachusetts) — Limited use of telbivudine in highly viremic pregnant women can reduce perinatal hepatitis B virus (HBV) transmission to infants, according to the results of a study presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting. The study was conducted in Nanjing, China, and presented by Calvin Pan, MD, from Mount Sinai Services at Elmhurst Hospital, Mount Sinai School of Medicine in Flushing, New York, on behalf of his colleagues in Nanjing.
Perinatal transmission of HBV is quite common in Southeast Asia and in Asian communities in other parts of the world, even several generations after migration from that region. Despite immunoprophylaxis, HBV transmission continues to occur at rates of 10% to 30% in children born to mothers who are highly viremic, he said.
Previous studies have shown that lamivudine used in the third trimester of pregnancy can significantly reduce HBV transmission. However, the incidence of teratogenicity with telbivudine in animals has restricted its use in pregnant women.
Dr. Pan said the open-label case–controlled study of telbivudine in highly viremic hepatitis B e antigen positive (HBeAg+) mothers was undertaken to assess its efficacy and safety in pregnant women and their offspring. It was the first such study of the drug. A placebo-controlled randomized trial might have raised ethical concerns, given the data on lamivudine. There also was the practical fact that some women knew of and desired prevention intervention and would not have agreed to randomization to placebo.
To participate in the study, the women had to be HBeAg+, have serum HBV DNA levels above 1.0 × 6 log10 copies/mL, and have been screened between 20 and 32 weeks of gestation. It enrolled 95 women who wished to take telbivudine, and a similar number who did not.
Women in the active group received 600 mg/day telbivudine beginning between weeks 20 and 32 of gestation, and continued on it for at least 4 weeks after delivery. Women with elevated alanine transaminase levels had the option of remaining on therapy, and 20% to 30% chose to do so. Physical and laboratory examinations were conducted at baseline, at delivery, and at weeks 4 and 28 after delivery.
"At baseline, both the control arm and the telbivudine arm had HBV DNA of about 8 logs, but at delivery, the mothers in the treatment arm had a tremendous reduction, of about 2.3 logs. About 30% of those on treatment had undetectable [HBV DNA levels]," or less than 1000 copies/mL, said Dr. Pan.
Prior to delivery, HBV DNA levels were 2.35 log10 copies/mL (1.79 standard deviation [SD]) in the treated group, and 7.83 log10 copies/mL (0.67 SD) in the control group (P < .001). The rates of newborns positive for HBV surface antigen (HBsAg+) at birth were 6.32% and 30.43%, respectively (P < .001).
All infants were vaccinated with 200 IU of hepatitis B immunoglobulin within 24 hours of delivery, and with recombinant HBV vaccine 20 μg at birth and at 1 and 6 months. They were tested for HbsAg and HBV DNA at birth and at 28 weeks of age.
At the week-28 end point, according to an intent-to-treat analysis, 2.11% of infants in the active treatment group and 13.04% in the placebo group were either HBsAg+ or had detectible levels of HBV RNA. HBV DNA was only detected in HBsAg+ infants.
Safety proved not to be an issue. There were no discontinuations because of adverse events, and there were no congenital defects that might be attributed to telbivudine.
Anna S. F. Lok, MD, from the University of Michigan in Ann Arbor, congratulated the authors on an excellent study. She asked if there was a threshold level of HBV DNA below which the mother did not transmit virus to the child. Dr. Pan said that analysis on that has not yet been done.
"It's a wonderful study," said Jay H. Hoofnagle, MD, director of the Liver Disease Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland. "I think that randomization is overstressed as an important way to control things. [In this study], you have very nicely balanced groups."
Dr. Hoofnagle said he has no explanation for why the portion of infants who were HBeAg+ or had detectable HBV RNA declined from birth to week 28.
Dr. Pan believes it probably was "a technical issue. We didn't have a very sensitive [polymerase chain reaction] — we were using a cut-off of 1000 — so those patients might simultaneously be DNA-positive."
The Chinese Department of Health underwrote the study with no industry support. None of the physicians have disclosed any relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 212. Presented November 2, 2010.
Source
Also See: AASLD: Drug Therapy Okay for Pregnant Women With Hep B
November 8, 2010 (Boston, Massachusetts) — Limited use of telbivudine in highly viremic pregnant women can reduce perinatal hepatitis B virus (HBV) transmission to infants, according to the results of a study presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting. The study was conducted in Nanjing, China, and presented by Calvin Pan, MD, from Mount Sinai Services at Elmhurst Hospital, Mount Sinai School of Medicine in Flushing, New York, on behalf of his colleagues in Nanjing.
Perinatal transmission of HBV is quite common in Southeast Asia and in Asian communities in other parts of the world, even several generations after migration from that region. Despite immunoprophylaxis, HBV transmission continues to occur at rates of 10% to 30% in children born to mothers who are highly viremic, he said.
Previous studies have shown that lamivudine used in the third trimester of pregnancy can significantly reduce HBV transmission. However, the incidence of teratogenicity with telbivudine in animals has restricted its use in pregnant women.
Dr. Pan said the open-label case–controlled study of telbivudine in highly viremic hepatitis B e antigen positive (HBeAg+) mothers was undertaken to assess its efficacy and safety in pregnant women and their offspring. It was the first such study of the drug. A placebo-controlled randomized trial might have raised ethical concerns, given the data on lamivudine. There also was the practical fact that some women knew of and desired prevention intervention and would not have agreed to randomization to placebo.
To participate in the study, the women had to be HBeAg+, have serum HBV DNA levels above 1.0 × 6 log10 copies/mL, and have been screened between 20 and 32 weeks of gestation. It enrolled 95 women who wished to take telbivudine, and a similar number who did not.
Women in the active group received 600 mg/day telbivudine beginning between weeks 20 and 32 of gestation, and continued on it for at least 4 weeks after delivery. Women with elevated alanine transaminase levels had the option of remaining on therapy, and 20% to 30% chose to do so. Physical and laboratory examinations were conducted at baseline, at delivery, and at weeks 4 and 28 after delivery.
"At baseline, both the control arm and the telbivudine arm had HBV DNA of about 8 logs, but at delivery, the mothers in the treatment arm had a tremendous reduction, of about 2.3 logs. About 30% of those on treatment had undetectable [HBV DNA levels]," or less than 1000 copies/mL, said Dr. Pan.
Prior to delivery, HBV DNA levels were 2.35 log10 copies/mL (1.79 standard deviation [SD]) in the treated group, and 7.83 log10 copies/mL (0.67 SD) in the control group (P < .001). The rates of newborns positive for HBV surface antigen (HBsAg+) at birth were 6.32% and 30.43%, respectively (P < .001).
All infants were vaccinated with 200 IU of hepatitis B immunoglobulin within 24 hours of delivery, and with recombinant HBV vaccine 20 μg at birth and at 1 and 6 months. They were tested for HbsAg and HBV DNA at birth and at 28 weeks of age.
At the week-28 end point, according to an intent-to-treat analysis, 2.11% of infants in the active treatment group and 13.04% in the placebo group were either HBsAg+ or had detectible levels of HBV RNA. HBV DNA was only detected in HBsAg+ infants.
Safety proved not to be an issue. There were no discontinuations because of adverse events, and there were no congenital defects that might be attributed to telbivudine.
Anna S. F. Lok, MD, from the University of Michigan in Ann Arbor, congratulated the authors on an excellent study. She asked if there was a threshold level of HBV DNA below which the mother did not transmit virus to the child. Dr. Pan said that analysis on that has not yet been done.
"It's a wonderful study," said Jay H. Hoofnagle, MD, director of the Liver Disease Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland. "I think that randomization is overstressed as an important way to control things. [In this study], you have very nicely balanced groups."
Dr. Hoofnagle said he has no explanation for why the portion of infants who were HBeAg+ or had detectable HBV RNA declined from birth to week 28.
Dr. Pan believes it probably was "a technical issue. We didn't have a very sensitive [polymerase chain reaction] — we were using a cut-off of 1000 — so those patients might simultaneously be DNA-positive."
The Chinese Department of Health underwrote the study with no industry support. None of the physicians have disclosed any relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 212. Presented November 2, 2010.
Source
Also See: AASLD: Drug Therapy Okay for Pregnant Women With Hep B
AASLD: Rifaximin is Safe and Beneficial in Addressing Hepatic Encephalopathy
Bob Roehr
November 8, 2010 (Boston, Massachusetts) — In March of this year, the US Food and Drug Administration granted a label indication to the antibiotic rifaximin (Xifaxan 550 mg) for the treatment of hepatic encephalopathy. One consequence is a trickle of studies presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting that confirm the efficacy of the drug.
Rifaximin is a potent broad-spectrum antibiotic that has virtually no systemic absorption and is well suited to control intestinal bacterial overgrowth without systemic exposure. Cirrhotic patients are predisposed to intestinal bacterial overgrowth. Deterioration of the gut barrier function can result in the translocation of bacteria and increased abdominal inflammation, which in turn can result in increased portal venous pressure.
Jiannis Vlachogiannakos, MD, and colleagues from the Evangelismos General Hospital in Athens, Greece, conducted a retrospective matched study of patients with alcohol-related decompensated cirrhosis (Child-Pugh score above 7) and ascites. Patients took rifaximin for a short course (4 weeks) and, if they responded with improved liver hemodynamics on hepatic venous pressure gradient testing, were continued on a daily dose of 1200 mg.
The analysis consisted of 23 patients (20 male, 3 female) who took rifaximin, each of whom were sex and age matched (±5 years) to 2 control patients with decompensated cirrhosis of the same etiology who did not take rifaximin. All patients had abstained from alcohol consumption for at least 6 months prior to entering the registry. They were followed for 5 years, death, or liver transplantation, whichever came first.
Dr. Vlachogiannakos said the active group "had a significantly lower risk of developing variceal bleeding (35% vs 59.5%; P = .011), hepatic encephalopathy (31.5% vs 47%; P = .034), spontaneous bacterial peritonitis (5.5% vs 46%; P = .027), and hepatorenal syndrome (4.5% vs 51%; P = .037) than controls."
Patients who did not take rifaximin died in disproportionate numbers (24/46 vs 7/23). He said that "the probability of 5-year survival was 61% in the rifaximin group and 13.5% in the control group (p = .012).
Michael D. Leise, MD, and colleagues from the Mayo Clinic in Rochester, Minnesota, examined medical records from the Mayo Clinic and identified 280 patients with hepatic encephalitis who were given rifaximin on a long-term open-label basis. They compared it with an algorithm of disease state and survival generated from data recorded in the Organ Procurement and Transplant Network.
They found that patients receiving rifaximin generally had better rates of survival, although the difference did not reach statistical significance except in the highest-risk patient group. The authors conclude that in addition to suggesting benefit, it provides assurance on the long-term safety of rifaximin.
Finally, a study from Virginia Commonwealth University in Richmond offered insights into improvement in brain function with rifaximin. Hepatic encephalopathy is associated with driving impairment.
Jasmohan Bajaj, MD, and colleagues used performance on a 15-minute driving-simulator test to evaluate driving and navigation skills (speeding tickets, collisions, and illegal turns) at baseline and 8 weeks after 42 hepatic encephalopathy patients were randomized in a 1:1 manner to receive rifaximin or placebo.
Comparing results from the 2 time points, he found that "76% of patients in the rifaximin group reduced their driving error, compared with only 33% in the placebo group, which is statistically significant." On the speeding ticket criteria, 81% and 33% of the respective groups reduced their errors. But there was no difference between them in terms of collisions, a fact that he attributed to the greater awareness of and learning from a simulated collision.
When asked what physicians might do if they believe a patient is suffering from hepatic-encephalopathy-related cognitive impairment, Dr. Bajaj said the findings are preliminary. More important, "if you have any questions about your patient's driving ability, you are not qualified as a doctor to make that decision. You should send those patients to your department of motor vehicles."
All of the studies were conducted as part of academic research. The researchers have disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstracts 19, 24, and 22. Presented October 31, 2010.
Source
Also See: AASLD: Antibiotic Reverses Cognition Loss in MHE
November 8, 2010 (Boston, Massachusetts) — In March of this year, the US Food and Drug Administration granted a label indication to the antibiotic rifaximin (Xifaxan 550 mg) for the treatment of hepatic encephalopathy. One consequence is a trickle of studies presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting that confirm the efficacy of the drug.
Rifaximin is a potent broad-spectrum antibiotic that has virtually no systemic absorption and is well suited to control intestinal bacterial overgrowth without systemic exposure. Cirrhotic patients are predisposed to intestinal bacterial overgrowth. Deterioration of the gut barrier function can result in the translocation of bacteria and increased abdominal inflammation, which in turn can result in increased portal venous pressure.
Jiannis Vlachogiannakos, MD, and colleagues from the Evangelismos General Hospital in Athens, Greece, conducted a retrospective matched study of patients with alcohol-related decompensated cirrhosis (Child-Pugh score above 7) and ascites. Patients took rifaximin for a short course (4 weeks) and, if they responded with improved liver hemodynamics on hepatic venous pressure gradient testing, were continued on a daily dose of 1200 mg.
The analysis consisted of 23 patients (20 male, 3 female) who took rifaximin, each of whom were sex and age matched (±5 years) to 2 control patients with decompensated cirrhosis of the same etiology who did not take rifaximin. All patients had abstained from alcohol consumption for at least 6 months prior to entering the registry. They were followed for 5 years, death, or liver transplantation, whichever came first.
Dr. Vlachogiannakos said the active group "had a significantly lower risk of developing variceal bleeding (35% vs 59.5%; P = .011), hepatic encephalopathy (31.5% vs 47%; P = .034), spontaneous bacterial peritonitis (5.5% vs 46%; P = .027), and hepatorenal syndrome (4.5% vs 51%; P = .037) than controls."
Patients who did not take rifaximin died in disproportionate numbers (24/46 vs 7/23). He said that "the probability of 5-year survival was 61% in the rifaximin group and 13.5% in the control group (p = .012).
Michael D. Leise, MD, and colleagues from the Mayo Clinic in Rochester, Minnesota, examined medical records from the Mayo Clinic and identified 280 patients with hepatic encephalitis who were given rifaximin on a long-term open-label basis. They compared it with an algorithm of disease state and survival generated from data recorded in the Organ Procurement and Transplant Network.
They found that patients receiving rifaximin generally had better rates of survival, although the difference did not reach statistical significance except in the highest-risk patient group. The authors conclude that in addition to suggesting benefit, it provides assurance on the long-term safety of rifaximin.
Finally, a study from Virginia Commonwealth University in Richmond offered insights into improvement in brain function with rifaximin. Hepatic encephalopathy is associated with driving impairment.
Jasmohan Bajaj, MD, and colleagues used performance on a 15-minute driving-simulator test to evaluate driving and navigation skills (speeding tickets, collisions, and illegal turns) at baseline and 8 weeks after 42 hepatic encephalopathy patients were randomized in a 1:1 manner to receive rifaximin or placebo.
Comparing results from the 2 time points, he found that "76% of patients in the rifaximin group reduced their driving error, compared with only 33% in the placebo group, which is statistically significant." On the speeding ticket criteria, 81% and 33% of the respective groups reduced their errors. But there was no difference between them in terms of collisions, a fact that he attributed to the greater awareness of and learning from a simulated collision.
When asked what physicians might do if they believe a patient is suffering from hepatic-encephalopathy-related cognitive impairment, Dr. Bajaj said the findings are preliminary. More important, "if you have any questions about your patient's driving ability, you are not qualified as a doctor to make that decision. You should send those patients to your department of motor vehicles."
All of the studies were conducted as part of academic research. The researchers have disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstracts 19, 24, and 22. Presented October 31, 2010.
Source
Also See: AASLD: Antibiotic Reverses Cognition Loss in MHE
AASLD: Therapeutic HCV Vaccine Opens Door to Potential Treatment Option
Bob Roehr
November 8, 2010 (Boston, Massachusetts) — Proof of concept for the therapeutic vaccine GI-5005 (GlobeImmune) against hepatitis C virus (HCV) infection, used in combination with standard of care (pegylated-interferon alfa-2b plus ribavirin), was presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting. Results were presented by Paul J. Pockros, MD, from the Scripps Clinic in San Diego, California.
One novel approach to treating hepatitis C is to stimulate the immune system to better attack and clear the infection, Dr. Pockros explained. This approach contrasts with most interventions currently in development that use small molecules to directly attack the virus.
The vaccine strategy incorporates HCV nonstructural protein 3 (NS3) and core antigens into recombinant Saccharomyces cerevisiae, a family of budding yeast, and expresses those proteins on the surface of the yeast cell. Dr. Pockros said the mechanism of action is not completely clear, but it is thought that subcutaneous injection of the yeast "stimulates a danger signal, which in turn brings antigen-presenting cells like dendritic cells to the surface."
"Those quickly phagocytose the inactivated yeast. The proteins are broken down, and NS3 and core proteins are expressed on the surface of the dendritic cell. This then stimulates helper and killer T cells," which identify and attack hepatocytes infected with hepatitis C.
"If you give this to patients who are chronically infected, it mimics patients who are acutely infected with HCV — they clear the virus," Dr. Pockros explained. Typically, chronically infected patients do not mount a T cell response against the core, envelop, or nonstructural proteins of HCV, whereas patients who clear the virus "mount a modest response against the envelop proteins and a robust response against nonstructural proteins NS3 and NS5," he added.
The phase 2 study was conducted in 133 patients infected with HCV genotype 1 who were randomized in a 1:1 manner to the vaccine or standard of care. Those assigned to active treatment received 40YU GI-5005 monotherapy (1 YU = 107 yeast particles) 5 times a week, then twice monthly during a 12-week lead-in period before adding standard of care (pegylated-interferon alfa-2b plus ribavirin) and reducing the vaccine dosing to once a month. Treatment-naïve patients followed this regimen for 48 weeks, and nonresponders followed it for 72 weeks. The principle end point was end-of-treatment response/sustained viral response (SVR).
Dr. Pockros said that "there was a slight benefit [from the vaccine] in the treatment-naïve and nonresponders; this was numerical only and was not statistically significant. However, when you added the 2 groups together, it became statistically significant" (P = .037).
Stratifying by IL28B gene status in the standard of care group, 2 of 5 patients with the more difficult to treat T/T allele cleared the virus at some point, but 1 subsequently had viral breakthrough while on therapy, and the second relapsed, "so none of the patients had an SVR."
However, "of the T/T patients who received the vaccine, all 5 cleared the virus. Two had to be taken off therapy because of the side effects of [pegylated-interferon alfa-2b plus ribavirin], but the remaining 3 had a sustained virologic response," according to Dr. Pockros.
He said there was only a modest response among those who were previous virologic nonresponders.
There was a statistically significant difference in those whose alanine transaminase (ALT) levels normalized. "Some of these responses were durable, although this did not quite reach significance" in this study, which was underpowered for subset analysis. Biopsy of 32 patients strongly suggests that the normalization of ALTs seen in some patients "is associated with the reduction in necroinflammation."
Perhaps the most interesting response among those who received the vaccine was the T cell, measured by ELISPOT assay. "It mimicked what you saw with a virologic response," Dr. Pockros said. "Four of 5 T/T allele patients had a T cell response; 1 did not actually get treated. But none of the patients who received standard of care had a T cell response." During the discussion, Dr. Pockros said the vaccine is likely to be genotype specific.
Adverse events mirrored those seen with standard of care, with the addition of some modest reactions at the site of injection for the therapeutic vaccine. The product has currently been administered to more than 250 study subjects.
Session cochair Douglas R. LaBrecque, MD, director of liver services at University of Iowa Health Care in Iowa City, told Medscape Medical News that the data "are so preliminary and in such small numbers that all you can say is it wasn't a total failure."
But he does see a benefit to the approach "if it would allow you to eliminate some of the medications [in a regimen], be it the interferon or small molecules, which have their own side effects."
The private biopharmaceutical company GlobeImmune sponsored the trial. Dr. Pockros reports ongoing research ties with the company. Dr. LaBrecque has disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-6. Presented November 1, 2010.
Source
November 8, 2010 (Boston, Massachusetts) — Proof of concept for the therapeutic vaccine GI-5005 (GlobeImmune) against hepatitis C virus (HCV) infection, used in combination with standard of care (pegylated-interferon alfa-2b plus ribavirin), was presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting. Results were presented by Paul J. Pockros, MD, from the Scripps Clinic in San Diego, California.
One novel approach to treating hepatitis C is to stimulate the immune system to better attack and clear the infection, Dr. Pockros explained. This approach contrasts with most interventions currently in development that use small molecules to directly attack the virus.
The vaccine strategy incorporates HCV nonstructural protein 3 (NS3) and core antigens into recombinant Saccharomyces cerevisiae, a family of budding yeast, and expresses those proteins on the surface of the yeast cell. Dr. Pockros said the mechanism of action is not completely clear, but it is thought that subcutaneous injection of the yeast "stimulates a danger signal, which in turn brings antigen-presenting cells like dendritic cells to the surface."
"Those quickly phagocytose the inactivated yeast. The proteins are broken down, and NS3 and core proteins are expressed on the surface of the dendritic cell. This then stimulates helper and killer T cells," which identify and attack hepatocytes infected with hepatitis C.
"If you give this to patients who are chronically infected, it mimics patients who are acutely infected with HCV — they clear the virus," Dr. Pockros explained. Typically, chronically infected patients do not mount a T cell response against the core, envelop, or nonstructural proteins of HCV, whereas patients who clear the virus "mount a modest response against the envelop proteins and a robust response against nonstructural proteins NS3 and NS5," he added.
The phase 2 study was conducted in 133 patients infected with HCV genotype 1 who were randomized in a 1:1 manner to the vaccine or standard of care. Those assigned to active treatment received 40YU GI-5005 monotherapy (1 YU = 107 yeast particles) 5 times a week, then twice monthly during a 12-week lead-in period before adding standard of care (pegylated-interferon alfa-2b plus ribavirin) and reducing the vaccine dosing to once a month. Treatment-naïve patients followed this regimen for 48 weeks, and nonresponders followed it for 72 weeks. The principle end point was end-of-treatment response/sustained viral response (SVR).
Dr. Pockros said that "there was a slight benefit [from the vaccine] in the treatment-naïve and nonresponders; this was numerical only and was not statistically significant. However, when you added the 2 groups together, it became statistically significant" (P = .037).
Stratifying by IL28B gene status in the standard of care group, 2 of 5 patients with the more difficult to treat T/T allele cleared the virus at some point, but 1 subsequently had viral breakthrough while on therapy, and the second relapsed, "so none of the patients had an SVR."
However, "of the T/T patients who received the vaccine, all 5 cleared the virus. Two had to be taken off therapy because of the side effects of [pegylated-interferon alfa-2b plus ribavirin], but the remaining 3 had a sustained virologic response," according to Dr. Pockros.
He said there was only a modest response among those who were previous virologic nonresponders.
There was a statistically significant difference in those whose alanine transaminase (ALT) levels normalized. "Some of these responses were durable, although this did not quite reach significance" in this study, which was underpowered for subset analysis. Biopsy of 32 patients strongly suggests that the normalization of ALTs seen in some patients "is associated with the reduction in necroinflammation."
Perhaps the most interesting response among those who received the vaccine was the T cell, measured by ELISPOT assay. "It mimicked what you saw with a virologic response," Dr. Pockros said. "Four of 5 T/T allele patients had a T cell response; 1 did not actually get treated. But none of the patients who received standard of care had a T cell response." During the discussion, Dr. Pockros said the vaccine is likely to be genotype specific.
Adverse events mirrored those seen with standard of care, with the addition of some modest reactions at the site of injection for the therapeutic vaccine. The product has currently been administered to more than 250 study subjects.
Session cochair Douglas R. LaBrecque, MD, director of liver services at University of Iowa Health Care in Iowa City, told Medscape Medical News that the data "are so preliminary and in such small numbers that all you can say is it wasn't a total failure."
But he does see a benefit to the approach "if it would allow you to eliminate some of the medications [in a regimen], be it the interferon or small molecules, which have their own side effects."
The private biopharmaceutical company GlobeImmune sponsored the trial. Dr. Pockros reports ongoing research ties with the company. Dr. LaBrecque has disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-6. Presented November 1, 2010.
Source
AASLD: Abnormal Liver Histology in HIV-Positive Patients Is Cause for Concern
Bob Roehr
November 8, 2010 (Boston, Massachusetts) — HIV infection itself appears to negatively affect liver histology, according to research presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting.
Abnormal liver enzymes are common in patients infected with HIV, even in the absence of viral hepatitis or known precipitating factors, such as diabetes or alcohol, but there are few data on the histology that explain why this is so, said Richard K. Sterling, MD, from Virginia Commonwealth University in Richmond, although he added that there has been a suggestion that it might be steatohepatitis.
Dr. Sterling and colleagues undertook a prospective pilot study of liver histology in HIV-positive patients with abnormal liver function tests (>1.25 upper limit of normal in aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase [ALP]), but without viral hepatitis, diabetes, or high levels of alcohol consumption (defined as >30 g/day for males and >20 g/day for females). Of the 25 referred patients, to date, 10 have met the entry criteria for this ongoing study.
Dr. Sterling told Medscape Medical News that he wanted to include ALP "because studies in fatty liver patients have shown that some present only with an isolated ALP. By excluding them, I might be excluding something that's out there."
All patients were receiving highly active antiretroviral therapy (HAART) and most had HIV RNA below the level of detection (<48 copies/mL). It is not known how long the patients have been infected or how long they have been on an antiretroviral regimen, factors that might influence disease state. The sample was too small to stratify by HAART regimens, Dr. Sterling noted.
Of the study population, 70% were male and 60% were white. Average age was 46 years, mean weight was 90 kg, mean body mass index (BMI) was 30 kg/m2, mean waist-to-hip ratio was 0.9 5, mean body fat was 33%, mean abdominal fat was 3652 g, and abdomen-to-gynoid-fat ratio was 1.36.
Patients underwent a 2-hour oral glucose tolerance test, had fasting lipids measured, and underwent dual-energy x-ray absorptiometry for fat distribution at the time of liver biopsy. Insulin resistance (IR) was assessed by homeostatic model assessment (HOMA). All histology was blinded and read by the same person.
"The bottom line is that about 60% had steatosis; 20% had grade 1, 30% had grade 2, and 10% had grade 3 steatosis. Cytologic ballooning was seen in 40%, the nonalcoholic steatohepatitis activity score was 2.7, and 40% had steatohepatitis," Dr. Sterling reported.
He added that the lack of difference in body fat, IR, HAART use, and BMI in the patient population did not surprised him. "If you look at the 4 patients who did not have steatosis but did have abnormal liver enzymes, even though their liver enzymes were lower, they still had hepatic inflammation and a fibrosis score of 1."
"There is something going on there. If it is not fat, what is it? I think it may be oxidative stress and other systemic issues related to HIV or HIV treatment. That is what we are trying to explore," he said.
"This has been a population that has been ignored because everyone is so happy that their HIV is under control," said Dr. Sterling. "Perhaps it will be important to identify patients with steatosis because they have an increased cardiovascular risk — which is the number 3 cause of death [in HIV-positive patients], behind HIV [infection itself] and liver [disease]. There may be a relationship between HIV, steatosis, and cardiovascular disease. It is not something that should be ignored."
Clinical implications might include changing HAART regimen to reduce exposure to drugs associated with IR or steatosis. "If they have steatosis, you might start to screen for cardiovascular disease when otherwise you wouldn't," advised Dr. Sterling. "But we don't know for sure, because no one has looked; you have to identify the problem first."
Raymond T. Chung, MD, director of hepatology at Massachusetts General Hospital, in Boston, cautioned against reading too much into a study of 10 patients receiving HAART. Nucleoside reverse-transcriptase inhibitors and protease inhibitors can either "cause intrinsic hepatotoxicity that may include steatosis, or promote peripheral lipolysis and hepatic steatosis, even without clear-cut increases in HOMA-IR. In this group of patients who were on both sets of agents, one must think of their contribution," he told Medscape Medical News.
However, work in his lab suggests that HIV "appears to exert oxidative stress in hepatocytes, likely through the engagement of chemokine coreceptors found in low levels on those cells. This oxidative stress can contribute to a milieu that may promote steatosis and even fibrosis." Perhaps this is sufficient to trigger hepatic injury, particularly when coupled with other insults such as a mild increase in IR or moderate alcohol use.
The National Institutes of Health sponsored the research under an R03 grant. Dr. Sterling and Dr. Chung have disclosed no relevant financial relationships relevant to this study.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 674. Presented October 30, 2010.
Source
November 8, 2010 (Boston, Massachusetts) — HIV infection itself appears to negatively affect liver histology, according to research presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting.
Abnormal liver enzymes are common in patients infected with HIV, even in the absence of viral hepatitis or known precipitating factors, such as diabetes or alcohol, but there are few data on the histology that explain why this is so, said Richard K. Sterling, MD, from Virginia Commonwealth University in Richmond, although he added that there has been a suggestion that it might be steatohepatitis.
Dr. Sterling and colleagues undertook a prospective pilot study of liver histology in HIV-positive patients with abnormal liver function tests (>1.25 upper limit of normal in aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase [ALP]), but without viral hepatitis, diabetes, or high levels of alcohol consumption (defined as >30 g/day for males and >20 g/day for females). Of the 25 referred patients, to date, 10 have met the entry criteria for this ongoing study.
Dr. Sterling told Medscape Medical News that he wanted to include ALP "because studies in fatty liver patients have shown that some present only with an isolated ALP. By excluding them, I might be excluding something that's out there."
All patients were receiving highly active antiretroviral therapy (HAART) and most had HIV RNA below the level of detection (<48 copies/mL). It is not known how long the patients have been infected or how long they have been on an antiretroviral regimen, factors that might influence disease state. The sample was too small to stratify by HAART regimens, Dr. Sterling noted.
Of the study population, 70% were male and 60% were white. Average age was 46 years, mean weight was 90 kg, mean body mass index (BMI) was 30 kg/m2, mean waist-to-hip ratio was 0.9 5, mean body fat was 33%, mean abdominal fat was 3652 g, and abdomen-to-gynoid-fat ratio was 1.36.
Patients underwent a 2-hour oral glucose tolerance test, had fasting lipids measured, and underwent dual-energy x-ray absorptiometry for fat distribution at the time of liver biopsy. Insulin resistance (IR) was assessed by homeostatic model assessment (HOMA). All histology was blinded and read by the same person.
"The bottom line is that about 60% had steatosis; 20% had grade 1, 30% had grade 2, and 10% had grade 3 steatosis. Cytologic ballooning was seen in 40%, the nonalcoholic steatohepatitis activity score was 2.7, and 40% had steatohepatitis," Dr. Sterling reported.
He added that the lack of difference in body fat, IR, HAART use, and BMI in the patient population did not surprised him. "If you look at the 4 patients who did not have steatosis but did have abnormal liver enzymes, even though their liver enzymes were lower, they still had hepatic inflammation and a fibrosis score of 1."
"There is something going on there. If it is not fat, what is it? I think it may be oxidative stress and other systemic issues related to HIV or HIV treatment. That is what we are trying to explore," he said.
"This has been a population that has been ignored because everyone is so happy that their HIV is under control," said Dr. Sterling. "Perhaps it will be important to identify patients with steatosis because they have an increased cardiovascular risk — which is the number 3 cause of death [in HIV-positive patients], behind HIV [infection itself] and liver [disease]. There may be a relationship between HIV, steatosis, and cardiovascular disease. It is not something that should be ignored."
Clinical implications might include changing HAART regimen to reduce exposure to drugs associated with IR or steatosis. "If they have steatosis, you might start to screen for cardiovascular disease when otherwise you wouldn't," advised Dr. Sterling. "But we don't know for sure, because no one has looked; you have to identify the problem first."
Raymond T. Chung, MD, director of hepatology at Massachusetts General Hospital, in Boston, cautioned against reading too much into a study of 10 patients receiving HAART. Nucleoside reverse-transcriptase inhibitors and protease inhibitors can either "cause intrinsic hepatotoxicity that may include steatosis, or promote peripheral lipolysis and hepatic steatosis, even without clear-cut increases in HOMA-IR. In this group of patients who were on both sets of agents, one must think of their contribution," he told Medscape Medical News.
However, work in his lab suggests that HIV "appears to exert oxidative stress in hepatocytes, likely through the engagement of chemokine coreceptors found in low levels on those cells. This oxidative stress can contribute to a milieu that may promote steatosis and even fibrosis." Perhaps this is sufficient to trigger hepatic injury, particularly when coupled with other insults such as a mild increase in IR or moderate alcohol use.
The National Institutes of Health sponsored the research under an R03 grant. Dr. Sterling and Dr. Chung have disclosed no relevant financial relationships relevant to this study.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 674. Presented October 30, 2010.
Source
Study offers new clues to effective HIV vaccine
By Julie Steenhuysen
CHICAGO
Fri Nov 5, 2010 12:27pm EDT
CHICAGO (Reuters) - Slight differences in five amino acids in a protein called HLA-B may explain why certain people resist the human immunodeficiency virus, U.S. researchers said on Thursday in a study that lends new clues about how to make a vaccine to prevent AIDS.
"For a long time, we've known that some people progress extremely rapidly when they get infected, and others can stay well for three decades and never need treatment and still look entirely well," said Dr. Bruce Walker of Massachusetts General Hospital and Harvard University, whose study appears in the journal Science.
"We thought we could apply new techniques from the human genome project to understand what the genetic basis was for that," he said.
About one in 300 people infected with HIV can suppress the virus with the immune system, keeping the virus at extremely low levels.
The team searched the genetic makeup of nearly 1,000 people with that ability and compared it with the genetic code of 2,600 others who were infected with HIV.
That helped them identify some 300 different sites in the genetic code that were linked with immune control of HIV, all located on chromosome 6.
They narrowed that down to four single-letter changes in the DNA, known as single nucleotide polymorphisms or SNPs -- pronounced "snips" -- all related to the immune system.
"We did a second study where we looked amino acid by amino acid in that region," Walker said.
They found five amino acids in the HLA-B protein linked with differences in a person's ability to control HIV.
That protein is important for helping the immune system tag and destroy cells infected by a virus, and Walker said those genetic variants could make a big difference in a person's ability to control HIV.
Knowing how some people mount an effective immune response to HIV could be an important step in understanding how to make a vaccine to fight the virus.
It was not a vaccine yet, Walker cautions, but it is promising.
"We've got a clearer indication of why people can survive in the face of HIV, and we've gotten more focused in terms of the research we need to do to get where we've got to go," he said.
No vaccine exists against the human immunodeficiency virus that causes AIDS. Since the AIDS pandemic started in the early 1980s, almost 60 million people have been infected with HIV, many of them in Africa, and it has killed 25 million.
In September 2009, scientists reported their biggest success yet with an experimental vaccine that showed a modest effect and appeared to slow the rate of infection by about 30 percent. In July, U.S. researchers found antibodies that can protect against a wide range of AIDS viruses and said they may be able to use them to design a vaccine.
(Editing by Peter Cooney)
Source
CHICAGO
Fri Nov 5, 2010 12:27pm EDT
CHICAGO (Reuters) - Slight differences in five amino acids in a protein called HLA-B may explain why certain people resist the human immunodeficiency virus, U.S. researchers said on Thursday in a study that lends new clues about how to make a vaccine to prevent AIDS.
"For a long time, we've known that some people progress extremely rapidly when they get infected, and others can stay well for three decades and never need treatment and still look entirely well," said Dr. Bruce Walker of Massachusetts General Hospital and Harvard University, whose study appears in the journal Science.
"We thought we could apply new techniques from the human genome project to understand what the genetic basis was for that," he said.
About one in 300 people infected with HIV can suppress the virus with the immune system, keeping the virus at extremely low levels.
The team searched the genetic makeup of nearly 1,000 people with that ability and compared it with the genetic code of 2,600 others who were infected with HIV.
That helped them identify some 300 different sites in the genetic code that were linked with immune control of HIV, all located on chromosome 6.
They narrowed that down to four single-letter changes in the DNA, known as single nucleotide polymorphisms or SNPs -- pronounced "snips" -- all related to the immune system.
"We did a second study where we looked amino acid by amino acid in that region," Walker said.
They found five amino acids in the HLA-B protein linked with differences in a person's ability to control HIV.
That protein is important for helping the immune system tag and destroy cells infected by a virus, and Walker said those genetic variants could make a big difference in a person's ability to control HIV.
Knowing how some people mount an effective immune response to HIV could be an important step in understanding how to make a vaccine to fight the virus.
It was not a vaccine yet, Walker cautions, but it is promising.
"We've got a clearer indication of why people can survive in the face of HIV, and we've gotten more focused in terms of the research we need to do to get where we've got to go," he said.
No vaccine exists against the human immunodeficiency virus that causes AIDS. Since the AIDS pandemic started in the early 1980s, almost 60 million people have been infected with HIV, many of them in Africa, and it has killed 25 million.
In September 2009, scientists reported their biggest success yet with an experimental vaccine that showed a modest effect and appeared to slow the rate of infection by about 30 percent. In July, U.S. researchers found antibodies that can protect against a wide range of AIDS viruses and said they may be able to use them to design a vaccine.
(Editing by Peter Cooney)
Source
AASLD: Short-Course Telaprevir Equal to Full-Course in Some Patients With HCV
Bob Roehr
November 8, 2010 (Boston, Massachusetts) — Treatment of hepatitis C virus (HCV) infection with the protease inhibitor telaprevir added to a standard of care regimen of pegylated interferon alfa-2a plus ribavirin can be shortened from 48 weeks to 24 weeks in patients with an extended rapid viral response (eRVR), according to data presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting.
ILLUMINATE was a multicenter phase 3 open-label study in genotype 1 treatment-naïve patients that used guided duration of treatment to determine the length of the regimen. Principal investigator Kenneth E. Sherman, MD, from the University of Cincinnati College of Medicine in Ohio, delivered the results.
Patients received 12 weeks of telaprevir (750 mg every 8 hours) added to peginterferon alfa-2a (180 μg/week) and weight-based ribavirin (standard of care). Those who achieved an eRVR (undetectable HCV RNA at weeks 4 and 12) were randomized at week 20 to receive an additional 4 weeks or 28 weeks of telaprevir plus standard of care, for a total of 24 or 48 weeks of treatment. Patients who did not meet the eRVR criteria received a standard 48-week course of therapy.
The primary end point was sustained virologic response (SVR) below 25 copies/mL (TaqMan assay) 24 weeks after completion of the regimen. The margin of noninferiority was predefined as –10.5% on intent-to-treat analysis.
Dr. Sherman said stopping rules included discontinuation of telaprevir in those who had HCV RNA levels above 1000 copies/mL at week 4 and continuation of standard of care.
At week 12, "those who failed to achieve at least a 2 log drop from baseline were discontinued on all study drugs and classified as a nonresponders. Between weeks 24 and 36, any patient with a detectable HCV RNA level discontinued all study drugs."
ILLUMINATE involved 540 patients. Of these, 100 discontinued treatment for a variety of reasons before reaching week 20, when randomization was done.
In all, 322 (65%) achieved eRVR (72% on intent-to-treat analysis) and were randomized to either 24 or 48 weeks of telaprevir treatment. SVR was achieved in 92% and 88%, respectively, Dr. Sherman reported.
"There was a positive 4.5% increase in the shorter therapy period; clearly, that was within the noninferiority range," he added. There was no statistical difference between the 2 groups in terms of relapse.
Turning to factors that traditionally predict a poorer response, Dr. Sherman said patients with hepatic fibrosis and cirrhosis showed "quite a respectable 63%" in SVR. "Among those who achieved eRVR, there was no difference between the groups, and no difference between 24 and 48 weeks of therapy," he reported.
There continues to be differences in responses along the lines of race/ethnicity, "but among those who achieved eRVR, there was no difference in response based on race or ethnicity."
Adverse events were those commonly seen in patients treated with the backbone of interferon and ribavirin. Rash attributed to telaprevir was a principle difference, with 63% of patients experiencing some degree of rash and 7% experiencing severe rash. It resolved upon discontinuation or completion of telaprevir. Discontinuation of all drugs for all causes was 7%; rash and anemia each caused 1% of discontinuations.
"Overall, due to any adverse event, 12% discontinued use of telaprevir; rash events constituted 7% and anemia events 2%," he said. There was a 17% discontinuation of all drugs because of adverse events. The rates were similar to those seen in other phase 2 and 3 trials of telaprevir.
Dr. Sherman concluded that there was "no clinical benefit to extending telaprevir-based therapy beyond 24 weeks in patients with eRVR, [which comprised] two thirds of the study patients. All study patients, regardless of liver fibrosis stage, race, or ethnicity, achieved high SVR rates with response-guided therapy."
In response to a question on resistance from the audience, he said that "breakthrough was observed in 1% to 3% of patients who were in the eRVR groups. The resistance patterns are similar to what has been seen previously in patients who do not ultimately clear" the virus, Dr. Sherman responded.
Conference chair Arun Sanyal, MD, from the Medical College of Virginia in Richmond, called the rates of response "incredible when you think about the time when we only had a 5% response rate to interferon." It represents another big step forward in our ability to treat HCV infection, he asserted.
Vertex/Johnson & Johnson sponsored the ILLUMINATE study. Dr. Sherman reports research funding and consulting ties to the company. Dr. Sanyal reports research and consulting ties to other companies developing HCV drugs.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-2 Presented November 1, 2010.
Source
November 8, 2010 (Boston, Massachusetts) — Treatment of hepatitis C virus (HCV) infection with the protease inhibitor telaprevir added to a standard of care regimen of pegylated interferon alfa-2a plus ribavirin can be shortened from 48 weeks to 24 weeks in patients with an extended rapid viral response (eRVR), according to data presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting.
ILLUMINATE was a multicenter phase 3 open-label study in genotype 1 treatment-naïve patients that used guided duration of treatment to determine the length of the regimen. Principal investigator Kenneth E. Sherman, MD, from the University of Cincinnati College of Medicine in Ohio, delivered the results.
Patients received 12 weeks of telaprevir (750 mg every 8 hours) added to peginterferon alfa-2a (180 μg/week) and weight-based ribavirin (standard of care). Those who achieved an eRVR (undetectable HCV RNA at weeks 4 and 12) were randomized at week 20 to receive an additional 4 weeks or 28 weeks of telaprevir plus standard of care, for a total of 24 or 48 weeks of treatment. Patients who did not meet the eRVR criteria received a standard 48-week course of therapy.
The primary end point was sustained virologic response (SVR) below 25 copies/mL (TaqMan assay) 24 weeks after completion of the regimen. The margin of noninferiority was predefined as –10.5% on intent-to-treat analysis.
Dr. Sherman said stopping rules included discontinuation of telaprevir in those who had HCV RNA levels above 1000 copies/mL at week 4 and continuation of standard of care.
At week 12, "those who failed to achieve at least a 2 log drop from baseline were discontinued on all study drugs and classified as a nonresponders. Between weeks 24 and 36, any patient with a detectable HCV RNA level discontinued all study drugs."
ILLUMINATE involved 540 patients. Of these, 100 discontinued treatment for a variety of reasons before reaching week 20, when randomization was done.
In all, 322 (65%) achieved eRVR (72% on intent-to-treat analysis) and were randomized to either 24 or 48 weeks of telaprevir treatment. SVR was achieved in 92% and 88%, respectively, Dr. Sherman reported.
"There was a positive 4.5% increase in the shorter therapy period; clearly, that was within the noninferiority range," he added. There was no statistical difference between the 2 groups in terms of relapse.
Turning to factors that traditionally predict a poorer response, Dr. Sherman said patients with hepatic fibrosis and cirrhosis showed "quite a respectable 63%" in SVR. "Among those who achieved eRVR, there was no difference between the groups, and no difference between 24 and 48 weeks of therapy," he reported.
There continues to be differences in responses along the lines of race/ethnicity, "but among those who achieved eRVR, there was no difference in response based on race or ethnicity."
Adverse events were those commonly seen in patients treated with the backbone of interferon and ribavirin. Rash attributed to telaprevir was a principle difference, with 63% of patients experiencing some degree of rash and 7% experiencing severe rash. It resolved upon discontinuation or completion of telaprevir. Discontinuation of all drugs for all causes was 7%; rash and anemia each caused 1% of discontinuations.
"Overall, due to any adverse event, 12% discontinued use of telaprevir; rash events constituted 7% and anemia events 2%," he said. There was a 17% discontinuation of all drugs because of adverse events. The rates were similar to those seen in other phase 2 and 3 trials of telaprevir.
Dr. Sherman concluded that there was "no clinical benefit to extending telaprevir-based therapy beyond 24 weeks in patients with eRVR, [which comprised] two thirds of the study patients. All study patients, regardless of liver fibrosis stage, race, or ethnicity, achieved high SVR rates with response-guided therapy."
In response to a question on resistance from the audience, he said that "breakthrough was observed in 1% to 3% of patients who were in the eRVR groups. The resistance patterns are similar to what has been seen previously in patients who do not ultimately clear" the virus, Dr. Sherman responded.
Conference chair Arun Sanyal, MD, from the Medical College of Virginia in Richmond, called the rates of response "incredible when you think about the time when we only had a 5% response rate to interferon." It represents another big step forward in our ability to treat HCV infection, he asserted.
Vertex/Johnson & Johnson sponsored the ILLUMINATE study. Dr. Sherman reports research funding and consulting ties to the company. Dr. Sanyal reports research and consulting ties to other companies developing HCV drugs.
The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-2 Presented November 1, 2010.
Source
November 7, 2010
Metabolic factors are associated with serum alanine aminotransferase levels in patients with chronic hepatitis C
J Gastroenterol. 2010 Nov 3. [Epub ahead of print]
Kobayashi Y, Kawaguchi Y, Mizuta T, Kuwashiro T, Oeda S, Oza N, Takahashi H, Iwane S, Eguchi Y, Anzai K, Ozaki I, Fujimoto K.
Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga, Japan.
Abstract
BACKGROUND: Although serum alanine aminotransferase (ALT) activity is an important marker for the management of chronic hepatitis C (CHC), the factors associated with serum ALT levels remain to be fully understood. This study aimed to clarify the association between serum ALT levels and clinical, histological, and virological factors in patients with CHC.
METHODS: We retrospectively analyzed 256 patients with CHC who underwent liver biopsy, and classified them into three groups according to serum ALT levels: normal to minimal (<40 IU/L), mild (40-80 IU/L), and moderate to severe elevation (≥80 IU/L). All demographic and laboratory data were collected at the time of liver biopsy. All biopsies were evaluated for fibrosis, inflammation, and steatosis. Glucose metabolism was assessed by various indices derived from oral glucose tolerance tests, including the homeostasis model assessment for insulin resistance (HOMA-IR). In 180 patients, visceral fat area was measured at the umbilical level by abdominal computed tomography.
RESULTS: Ordered logistic regression analysis showed that higher serum ALT levels were significantly associated with male sex, lower high-density lipoprotein cholesterol (HDL-C), higher HOMA-IR, and higher grades of histological inflammation and steatosis. HOMA-IR, HDL-C, and hepatic steatosis were associated with visceral fat accumulation.
CONCLUSIONS: Metabolic factors, as well as sex and hepatic inflammation, are independent risk factors for serum ALT elevation in hepatititis C virus (HCV)-infected patients. Metabolic factors may offer targets to decrease serum ALT levels.
PMID: 21046172 [PubMed - as supplied by publisher]
Source
Kobayashi Y, Kawaguchi Y, Mizuta T, Kuwashiro T, Oeda S, Oza N, Takahashi H, Iwane S, Eguchi Y, Anzai K, Ozaki I, Fujimoto K.
Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga, Japan.
Abstract
BACKGROUND: Although serum alanine aminotransferase (ALT) activity is an important marker for the management of chronic hepatitis C (CHC), the factors associated with serum ALT levels remain to be fully understood. This study aimed to clarify the association between serum ALT levels and clinical, histological, and virological factors in patients with CHC.
METHODS: We retrospectively analyzed 256 patients with CHC who underwent liver biopsy, and classified them into three groups according to serum ALT levels: normal to minimal (<40 IU/L), mild (40-80 IU/L), and moderate to severe elevation (≥80 IU/L). All demographic and laboratory data were collected at the time of liver biopsy. All biopsies were evaluated for fibrosis, inflammation, and steatosis. Glucose metabolism was assessed by various indices derived from oral glucose tolerance tests, including the homeostasis model assessment for insulin resistance (HOMA-IR). In 180 patients, visceral fat area was measured at the umbilical level by abdominal computed tomography.
RESULTS: Ordered logistic regression analysis showed that higher serum ALT levels were significantly associated with male sex, lower high-density lipoprotein cholesterol (HDL-C), higher HOMA-IR, and higher grades of histological inflammation and steatosis. HOMA-IR, HDL-C, and hepatic steatosis were associated with visceral fat accumulation.
CONCLUSIONS: Metabolic factors, as well as sex and hepatic inflammation, are independent risk factors for serum ALT elevation in hepatititis C virus (HCV)-infected patients. Metabolic factors may offer targets to decrease serum ALT levels.
PMID: 21046172 [PubMed - as supplied by publisher]
Source
Randomized controlled trial of pegylated interferon-alfa 2a and ribavirin in treatment-naive chronic hepatitis C genotype 6
Hepatology. 2010 Nov;52(5):1573-80.
Lam KD, Trinh HN, Do ST, Nguyen TT, Garcia RT, Nguyen T, Phan QQ, Nguyen HA, Nguyen KK, Nguyen LH, Nguyen MH.
Pacific Health Foundation, San Jose, CA, USA.
Abstract
Hepatitis C virus (HCV) genotype is an important criteria in determining duration of therapy and predictor of sustained virologic response (SVR) to pegylated interferon (PEG IFN) and ribavirin (RBV) therapy. Optimal duration of therapy for patients with HCV genotype 6 is not known. We conducted a multicenter, open-label randomized controlled trial of patients with HCV genotype 6 at five gastroenterology clinics in the western U.S. Patients were stratified by viral load and histologic stage and assigned to receive PEG IFN-α2a 180 μg subcutaneously weekly and weight-based oral RBV 800 to 1,200 mg daily for 24 or 48 weeks. Primary outcome measurement was SVR rate by intention-to-treat analysis. From February 2005 to October 2007 a total of 60 patients (age 51 ± 10 years, 47% male, log HCVRNA 6.3 ± 1.1 IU/mL) were enrolled: 27 patients to 24 weeks and 33 patients to 48 weeks of therapy. In the 24-week and 48-week groups, 96% and 97% achieved early virologic response (P = 0.90); 89% versus 94% achieved end of therapy virologic response (P = 0.48). SVR was achieved in 70% versus 79% of patients assigned to 24 weeks versus 48 weeks (P = 0.45). Rapid virologic response (RVR) was a significant predictor of SVR in the 48-week group and trending towards significance in the 24-week group: 82% and 83% of those with RVR achieved SVR versus 33% and 29% for the 24-week and 48-week groups, respectively (P = 0.07 and P = 0.02). CONCLUSION: There was no significant difference in SVR rates in patients with HCV genotype 6 treated with PEG IFN-α2a and RBV for 24 versus 48 weeks.
PMID: 21038410 [PubMed - in process]
Source
Lam KD, Trinh HN, Do ST, Nguyen TT, Garcia RT, Nguyen T, Phan QQ, Nguyen HA, Nguyen KK, Nguyen LH, Nguyen MH.
Pacific Health Foundation, San Jose, CA, USA.
Abstract
Hepatitis C virus (HCV) genotype is an important criteria in determining duration of therapy and predictor of sustained virologic response (SVR) to pegylated interferon (PEG IFN) and ribavirin (RBV) therapy. Optimal duration of therapy for patients with HCV genotype 6 is not known. We conducted a multicenter, open-label randomized controlled trial of patients with HCV genotype 6 at five gastroenterology clinics in the western U.S. Patients were stratified by viral load and histologic stage and assigned to receive PEG IFN-α2a 180 μg subcutaneously weekly and weight-based oral RBV 800 to 1,200 mg daily for 24 or 48 weeks. Primary outcome measurement was SVR rate by intention-to-treat analysis. From February 2005 to October 2007 a total of 60 patients (age 51 ± 10 years, 47% male, log HCVRNA 6.3 ± 1.1 IU/mL) were enrolled: 27 patients to 24 weeks and 33 patients to 48 weeks of therapy. In the 24-week and 48-week groups, 96% and 97% achieved early virologic response (P = 0.90); 89% versus 94% achieved end of therapy virologic response (P = 0.48). SVR was achieved in 70% versus 79% of patients assigned to 24 weeks versus 48 weeks (P = 0.45). Rapid virologic response (RVR) was a significant predictor of SVR in the 48-week group and trending towards significance in the 24-week group: 82% and 83% of those with RVR achieved SVR versus 33% and 29% for the 24-week and 48-week groups, respectively (P = 0.07 and P = 0.02). CONCLUSION: There was no significant difference in SVR rates in patients with HCV genotype 6 treated with PEG IFN-α2a and RBV for 24 versus 48 weeks.
PMID: 21038410 [PubMed - in process]
Source
Telaprevir is Effective Given Every 8 or 12 Hours with Ribavirin and Peginterferon Alfa-2a or 2b to Patients with Chronic Hepatitis C
Gastroenterology. 2010 Oct 26. [Epub ahead of print]
Marcellin P, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, Drenth JP, Serfaty L, De Backer K, Van Heeswijk R, Luo D, Picchio G, Beumont M.
Service d'Hépatologie and Inserm CRB3, Hôpital Beaujon, APHP University of Paris, Clichy, France.
Abstract
BACKGROUND & AIMS: Recent studies demonstrated that 12 weeks of telaprevir, administered every 8 hours (q8h), combined with peginterferon alfa-2a plus ribavirin (peginterferon alfa-2a/ribavirin), significantly increased the rate of hepatitis C virus (HCV) eradication (sustained virologic response [SVR]) in patients infected with HCV genotype-1 compared with approved therapy. We investigated the efficacy, safety, tolerability, and pharmacokinetics of telaprevir given q8h or every 12 hours (q12h), in combination with peginterferon alfa 2a or 2b.
METHODS: Treatment-naïve patients (n=161) infected with HCV genotype-1 were randomly assigned to groups that were given open-label telaprevir (750 mg q8h or 1125 mg q12h), in combination with standard doses of peginterferon alfa-2a (180 μg/week) and ribavirin (1000-1200 mg/day) or peginterferon alfa-2b (1.5 μg/kg/week) and ribavirin (800-1200 mg/day). Patients received triple therapy for 12 weeks, followed by 12 or 36 additional weeks of peginterferon alfa and ribavirin, based on virologic response.
RESULTS: Baseline characteristics were similar for all groups. SVR rates were 81.0%-85.0% among groups; most patients received 24 weeks of therapy (68.0%). There were no significant differences in SVR rates (intent-to-treat analysis) among groups (P≥0.787), between the pooled q8h and q12h groups (P = 0.997), or between the pooled peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin groups (P = 0.906). The safety profile was similar among all groups.
CONCLUSIONS: A high proportion (>80%) of patients achieved a SVR regardless of the telaprevir dosing frequency (q8h or q12h) or type of peginterferon alfa used (alfa-2a or alfa-2b). All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID: 21034744 [PubMed - as supplied by publisher]
Source
Marcellin P, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, Drenth JP, Serfaty L, De Backer K, Van Heeswijk R, Luo D, Picchio G, Beumont M.
Service d'Hépatologie and Inserm CRB3, Hôpital Beaujon, APHP University of Paris, Clichy, France.
Abstract
BACKGROUND & AIMS: Recent studies demonstrated that 12 weeks of telaprevir, administered every 8 hours (q8h), combined with peginterferon alfa-2a plus ribavirin (peginterferon alfa-2a/ribavirin), significantly increased the rate of hepatitis C virus (HCV) eradication (sustained virologic response [SVR]) in patients infected with HCV genotype-1 compared with approved therapy. We investigated the efficacy, safety, tolerability, and pharmacokinetics of telaprevir given q8h or every 12 hours (q12h), in combination with peginterferon alfa 2a or 2b.
METHODS: Treatment-naïve patients (n=161) infected with HCV genotype-1 were randomly assigned to groups that were given open-label telaprevir (750 mg q8h or 1125 mg q12h), in combination with standard doses of peginterferon alfa-2a (180 μg/week) and ribavirin (1000-1200 mg/day) or peginterferon alfa-2b (1.5 μg/kg/week) and ribavirin (800-1200 mg/day). Patients received triple therapy for 12 weeks, followed by 12 or 36 additional weeks of peginterferon alfa and ribavirin, based on virologic response.
RESULTS: Baseline characteristics were similar for all groups. SVR rates were 81.0%-85.0% among groups; most patients received 24 weeks of therapy (68.0%). There were no significant differences in SVR rates (intent-to-treat analysis) among groups (P≥0.787), between the pooled q8h and q12h groups (P = 0.997), or between the pooled peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin groups (P = 0.906). The safety profile was similar among all groups.
CONCLUSIONS: A high proportion (>80%) of patients achieved a SVR regardless of the telaprevir dosing frequency (q8h or q12h) or type of peginterferon alfa used (alfa-2a or alfa-2b). All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID: 21034744 [PubMed - as supplied by publisher]
Source
Sporadic Reappearance of Minute Amounts of HCV RNA after Successful Therapy Stimulates Cellular Immune Responses
Article in Press
Naga Suresh Veerapu, Sukanya Raghuraman, T. Jake Liang, Theo Heller, Barbara Rehermann
Received 26 May 2010; received in revised form 24 September 2010; accepted 22 October 2010. published online 01 November 2010.
Accepted Manuscript
Abstract
Background & Aims
Several studies have reported persistence of hepatitis C virus (HCV) RNA in the circulation after treatment-induced or spontaneous recovery. We investigated whether the HCV RNA represents persistence of HCV infection or re-infection.
Methods
We studied 117 patients that recovered from HCV infection (98 following therapy and 19 spontaneously). A reverse transcriptase (RT)-PCR assay was used to detect the 5’UTR of HCV RNA. T-cell responses were studied by ELISpot analysis of interferon-γ.
Results
Plasma samples from 15% of patients who recovered following treatment and none who recovered spontaneously tested positive for HCV RNA. Lymphocytes from 3 patients that responded to therapy and 1 that recovered spontaneously tested positive. The frequency of HCV RNA detection in plasma correlated inversely with the time after the end of treatment. Post-treatment HCV 5’-UTR sequences matched pre-treatment sequences in 85% of cases. T-cell responses were significantly greater at timepoints with detectable trace amounts of HCV RNA than at timepoints without detectable HCV RNA (P=0.035) and were primarily against nonstructural HCV antigens. The immune hierarchy was preserved over 5 years in patients; post-treatment HCV RNA sequences matched pretreatment sequences, indicating HCV RNA persistence. An altered immune hierarchy with dominant immune responses, shifting from nonstructural to structural antigens, was observed in a single patient. The genotype of the detected post-treatment HCV RNA differed from that of the pretreatment genotype in this patient, indicating re-infection with HCV.
Conclusions
Trace amounts of HCV RNA of pretreatment sequence persisted and re-appeared sporadically in the circulation within 8 years after recovery from hepatitis C but not thereafter, indicating that patients are cured of HCV infection. Reappearance of HCV RNA induced HCV-specific T-cell responses.
All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
Keywords: IFN, liver disease, virology
Source
Naga Suresh Veerapu, Sukanya Raghuraman, T. Jake Liang, Theo Heller, Barbara Rehermann
Received 26 May 2010; received in revised form 24 September 2010; accepted 22 October 2010. published online 01 November 2010.
Accepted Manuscript
Abstract
Background & Aims
Several studies have reported persistence of hepatitis C virus (HCV) RNA in the circulation after treatment-induced or spontaneous recovery. We investigated whether the HCV RNA represents persistence of HCV infection or re-infection.
Methods
We studied 117 patients that recovered from HCV infection (98 following therapy and 19 spontaneously). A reverse transcriptase (RT)-PCR assay was used to detect the 5’UTR of HCV RNA. T-cell responses were studied by ELISpot analysis of interferon-γ.
Results
Plasma samples from 15% of patients who recovered following treatment and none who recovered spontaneously tested positive for HCV RNA. Lymphocytes from 3 patients that responded to therapy and 1 that recovered spontaneously tested positive. The frequency of HCV RNA detection in plasma correlated inversely with the time after the end of treatment. Post-treatment HCV 5’-UTR sequences matched pre-treatment sequences in 85% of cases. T-cell responses were significantly greater at timepoints with detectable trace amounts of HCV RNA than at timepoints without detectable HCV RNA (P=0.035) and were primarily against nonstructural HCV antigens. The immune hierarchy was preserved over 5 years in patients; post-treatment HCV RNA sequences matched pretreatment sequences, indicating HCV RNA persistence. An altered immune hierarchy with dominant immune responses, shifting from nonstructural to structural antigens, was observed in a single patient. The genotype of the detected post-treatment HCV RNA differed from that of the pretreatment genotype in this patient, indicating re-infection with HCV.
Conclusions
Trace amounts of HCV RNA of pretreatment sequence persisted and re-appeared sporadically in the circulation within 8 years after recovery from hepatitis C but not thereafter, indicating that patients are cured of HCV infection. Reappearance of HCV RNA induced HCV-specific T-cell responses.
All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
Keywords: IFN, liver disease, virology
Source
AASLD: Extended Follow-Up of HALT-C Study Shows Some Benefit of Interferon
Bob Roehr
November 7, 2010 (Boston, Massachusetts) — The utility of maintenance pegylated interferon (PegIFN) therapy to prevent hepatocellular carcinoma (HCC) in patients with advanced chronic hepatitis has been a contentious matter for some time.
The pendulum has swung from support for the idea to early evidence of a lack of efficacy. Now, here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting, longer-term data suggest marginal, limited support for its use. Most surprisingly, data opposing its use — and now for its support — have come from the same study, the ongoing Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial.
Anna S. Lok, MD, from the University of Michigan Medical Center in Ann Arbor, presented the latest iteration of data on extended follow-up. "In an earlier report, which included a median follow-up of up to 4.6 years, with a total of 53 HCC cases, we found no difference between the treated and the control groups. The 2 lines basically were identical."
The newer analysis was based on a median of 6.1 years of follow-up. There were "almost double the number of HCC cases, with a total of 88," Dr. Lok reported. The cumulative incidence of HCC at 3, 5, and 7 years for the treated group was 2.3%, 6%, and 8.1%, respectively. Incidence in the control group was 2.5%, 6.2%, and 13.8% at 3, 5, and 7 years, respectively.
"The 2 lines of the Kaplan-Meier Curve completely overlap until the end of year 6, when there is a divergence in the 2 lines, and the P value was not significant," Dr. Lok said.
"However, when we analyzed the data separately, for the fibrosis substratum and the cirrhosis substratum, we saw that the treated group had a significantly lower incidence of HCC compared with the untreated group, with a hazard ratio of 0.45 and a P value of .01."
Subsequent analysis showed that incidence of HCC was significantly lower in patients who had completed at least 2 years of treatment. "They had less advanced liver disease, more normal platelet counts, and normal [aspartate aminotransferase] levels."
Dr. Lok concluded, "Extended follow-up of the HALT-C cohort showed a modest effect of long-term low-dose PegIFN in reducing the incidence of HCC in patients with hepatitis C and cirrhosis, but not in those with advanced fibrosis.
"Given the marginal benefit on HCC, the lack of overall benefit on disease progression, and the side effects of PegIFN, the utility of maintenance PegIFN to prevent HCC in patients with HCV-related cirrhosis who failed to achieve SVR is limited," she acknowledged.
Arun J. Sanyal, MD, American Association for the Study of Liver Diseases president and head of the division of gastroenterology at Virginia Commonwealth University, in Richmond, said, "This, potentially, could be very important."
During the question session, treatment activist Jules Levin said 4 years ago the initial analysis and strong recommendations not to treat "did a lot of damage to patients and to the field. I took issue with the investigators over that" at the time, Mr. Levin said.
Subsequent research and analysis of this trial have shown that they were wrong. "It has done irreparable damage to patients. It is important to take note of this." Mr. Levin said. "Patients and their own clinicians should be able to make their own decision for what benefits them based on a clear understanding of the data."
The National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases is funding the HALT-C trial. The speakers have disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting: Abstract 214. Presented November 2, 2010.
Source
November 7, 2010 (Boston, Massachusetts) — The utility of maintenance pegylated interferon (PegIFN) therapy to prevent hepatocellular carcinoma (HCC) in patients with advanced chronic hepatitis has been a contentious matter for some time.
The pendulum has swung from support for the idea to early evidence of a lack of efficacy. Now, here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting, longer-term data suggest marginal, limited support for its use. Most surprisingly, data opposing its use — and now for its support — have come from the same study, the ongoing Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial.
Anna S. Lok, MD, from the University of Michigan Medical Center in Ann Arbor, presented the latest iteration of data on extended follow-up. "In an earlier report, which included a median follow-up of up to 4.6 years, with a total of 53 HCC cases, we found no difference between the treated and the control groups. The 2 lines basically were identical."
The newer analysis was based on a median of 6.1 years of follow-up. There were "almost double the number of HCC cases, with a total of 88," Dr. Lok reported. The cumulative incidence of HCC at 3, 5, and 7 years for the treated group was 2.3%, 6%, and 8.1%, respectively. Incidence in the control group was 2.5%, 6.2%, and 13.8% at 3, 5, and 7 years, respectively.
"The 2 lines of the Kaplan-Meier Curve completely overlap until the end of year 6, when there is a divergence in the 2 lines, and the P value was not significant," Dr. Lok said.
"However, when we analyzed the data separately, for the fibrosis substratum and the cirrhosis substratum, we saw that the treated group had a significantly lower incidence of HCC compared with the untreated group, with a hazard ratio of 0.45 and a P value of .01."
Subsequent analysis showed that incidence of HCC was significantly lower in patients who had completed at least 2 years of treatment. "They had less advanced liver disease, more normal platelet counts, and normal [aspartate aminotransferase] levels."
Dr. Lok concluded, "Extended follow-up of the HALT-C cohort showed a modest effect of long-term low-dose PegIFN in reducing the incidence of HCC in patients with hepatitis C and cirrhosis, but not in those with advanced fibrosis.
"Given the marginal benefit on HCC, the lack of overall benefit on disease progression, and the side effects of PegIFN, the utility of maintenance PegIFN to prevent HCC in patients with HCV-related cirrhosis who failed to achieve SVR is limited," she acknowledged.
Arun J. Sanyal, MD, American Association for the Study of Liver Diseases president and head of the division of gastroenterology at Virginia Commonwealth University, in Richmond, said, "This, potentially, could be very important."
During the question session, treatment activist Jules Levin said 4 years ago the initial analysis and strong recommendations not to treat "did a lot of damage to patients and to the field. I took issue with the investigators over that" at the time, Mr. Levin said.
Subsequent research and analysis of this trial have shown that they were wrong. "It has done irreparable damage to patients. It is important to take note of this." Mr. Levin said. "Patients and their own clinicians should be able to make their own decision for what benefits them based on a clear understanding of the data."
The National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases is funding the HALT-C trial. The speakers have disclosed no relevant financial relationships.
The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting: Abstract 214. Presented November 2, 2010.
Source
Supersonic Shear Imaging Is a Fast, Reliable Method for Noninvasive Liver Fibrosis Staging: Presented at AASLD
By Cheryl Lathrop
BOSTON -- November 5, 2010 -- Supersonic shear imaging (SSI) appears to be a fast, simple, and reliable method for noninvasive liver fibrosis staging and shows better discrimination than one-dimensional transient elastography for each fibrosis stage, researchers said here at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
Eric Bavu, MD, INSERM, and Langevin Institute, Paris, France, and colleagues reported the findings here on November 1.
The study included 113 patients with hepatitis C virus. Patients underwent both SSI one-dimensional transient elastography. Of these, 108 patients had results that were relevant and that were included in the final analysis.
Hepatic fibrosis was determined retrospectively on the basis of liver biopsy, on clinical history, and on 3 noninvasive biomarkers gathered the day of the imaging, aspartate to platelets ratio index, and Forn's Index.
The researchers assessed a comparison between the performances of SSI and one-dimensional transient elastography using receiver operator characteristic (ROC) curves analysis and one-way analysis of variance (ANOVA) analysis between the assessed elasticity value and the fibrosis stage.
There was a better correlation between fibrosis staging and elasticity measurements with SSI (p ~10-16) than with one-dimensional transient elastography (p ~10-15).
The areas under the ROC curves for stiffness values assessed by SSI were 0.948 for fibrosis staging >=2; 0.962 for staging >=3; and 0.968 for staging =4. In comparison, with one-dimensional transient elastography, the values were 0.846 for >=2, 0.857 for >=3, and 0.940 for =4, respectively.
The comparisons between SSI and one-dimensional transient elastography were particularly significant for mild (F0-F1; P =.005) and moderate (F2; P =.001) fibrosis.
"SSI is a fair method to evaluate patients with chronic liver disease, and determine those to treat and those not to treat," said Dr. Bavu.
[Presentation title: A New Potent Morphological Non-Invasive Predictor of Liver Fibrosis Staging by Supersonic Shear Imaging. Abstract 1327]
Source
BOSTON -- November 5, 2010 -- Supersonic shear imaging (SSI) appears to be a fast, simple, and reliable method for noninvasive liver fibrosis staging and shows better discrimination than one-dimensional transient elastography for each fibrosis stage, researchers said here at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
Eric Bavu, MD, INSERM, and Langevin Institute, Paris, France, and colleagues reported the findings here on November 1.
The study included 113 patients with hepatitis C virus. Patients underwent both SSI one-dimensional transient elastography. Of these, 108 patients had results that were relevant and that were included in the final analysis.
Hepatic fibrosis was determined retrospectively on the basis of liver biopsy, on clinical history, and on 3 noninvasive biomarkers gathered the day of the imaging, aspartate to platelets ratio index, and Forn's Index.
The researchers assessed a comparison between the performances of SSI and one-dimensional transient elastography using receiver operator characteristic (ROC) curves analysis and one-way analysis of variance (ANOVA) analysis between the assessed elasticity value and the fibrosis stage.
There was a better correlation between fibrosis staging and elasticity measurements with SSI (p ~10-16) than with one-dimensional transient elastography (p ~10-15).
The areas under the ROC curves for stiffness values assessed by SSI were 0.948 for fibrosis staging >=2; 0.962 for staging >=3; and 0.968 for staging =4. In comparison, with one-dimensional transient elastography, the values were 0.846 for >=2, 0.857 for >=3, and 0.940 for =4, respectively.
The comparisons between SSI and one-dimensional transient elastography were particularly significant for mild (F0-F1; P =.005) and moderate (F2; P =.001) fibrosis.
"SSI is a fair method to evaluate patients with chronic liver disease, and determine those to treat and those not to treat," said Dr. Bavu.
[Presentation title: A New Potent Morphological Non-Invasive Predictor of Liver Fibrosis Staging by Supersonic Shear Imaging. Abstract 1327]
Source
SAFE IN COMMON Launches Global Injection Safety Website
Online Community Championing Improved Global Injection Safety Standards Coincides with the 10th Anniversary of the Needlestick Safety and Prevention Act
LEWISBERRY, Pa., Nov. 5, 2010 /PRNewswire/ -- SAFE IN COMMON, an online community of healthcare workers, educators, patients, community leaders and individuals, today announced the launch of its website dedicated to raising awareness of global injection safety challenges.
SAFE IN COMMON's launch coincides with the 10th anniversary of the passage of the Needlestick Safety and Prevention Act, which mandates the use of safety engineered medical devices, (SEMDs), within U.S. healthcare facilities to protect healthcare workers and patients from the risk of needlestick injuries. Despite this legislation and its enforcement by OSHA, healthcare workers continue to remain at risk of harm. For example, reports in the U.S. indicate that currently available safety syringes are not providing adequate levels of protection. In fact, reported needlestick injuries in Massachusetts have not fallen since 2002, and safety products are responsible for the majority of those injuries.
While steps have been taken in the U.S. and Europe to mandate the use of SEMDs, the harm caused by unsafe injection practices represents a global humanitarian challenge. According to the World Health Organization (WHO), there are more than 1.3 million needlestick related deaths worldwide each year.
"As a former nurse, I have first hand experience with the physical and emotional dangers of a needlestick injury. However, the problems and risks associated with needlestick injuries are real and affect the lives of millions of people around the world, not just those in the healthcare field," commented Dr. Mary Foley, Associate Director, Center for Nursing Research and Innovation. "Much has been accomplished since the signing of the Needlestick Safety and Prevention Act of 2000, but the safety laws and policies currently in place are poorly enforced and need to be addressed. SAFE IN COMMON is in a unique to position to advocate for this change. Not only will SAFE IN COMMON serve as a community for those impacted by unsafe needlestick practices and injuries, but it will also act as a unified voice to educate and fight for better, more effective solutions."
Led by a team of highly experienced and influential board members, SAFE IN COMMON was created to raise awareness and support the global transition to safe, simple injections. As a social community, SAFE IN COMMON will also seek to provide support and coverage to all international markets focused on the enhancement of safe injection practices.
Outside of healthcare facilities, SAFE IN COMMON will also seek to address specific injection safety challenges relating to patients who administer prescription drugs at home, injecting drug users and other stakeholders associated with harm reduction, and the vaccination / immunization programs of developing and emerging nations. With such markets that operate largely outside of healthcare facilities, unsafe injection practices such as the re-use, sharing or unsafe disposal of non-sterile injection devices may accelerate HIV and hepatitis C epidemics.
The new website, http://www.safeincommon.org/, will feature blogs, a resource library, links to industry information, forums for contributors to express thoughts and experiences, surveys, and other ways to interact and promote injection safety.
Current SAFE IN COMMON board members include:
• Mary Foley: RN, MS, PhD, Past President American Nursing Association and Associate Director, Center for Nursing Research and Innovation, University of California, San Francisco.
• Ron Stoker: Executive Director of the International Sharps Injury Protection Society (ISIPS).
• Gerald Verollet: Former head of the medical device division at the World Health Organization (WHO).
• Jason Tetro: Infection control advocate, blogger and coordinator at two research centers for microbiology at the University of Ottawa.
• Evelyn McKnight: Patient safety advocate, author of "A Never Event" and founder of HONOReform, a national advocacy organization dedicated to protecting patients through safeguarding the medical injection process.
SAFE IN COMMON is also being sponsored by Unilife Corporation (Nasdaq: UNIS), a medical device company focused on the design, development, manufacture and supply of a proprietary range of retractable syringes.
The Community seeks additional alliances with organizations that share in the goal of reducing the global harms of needlestick injuries and other unsafe injection practices. For more information about SAFE IN COMMON, please visit the website at http://www.safeincommon.org/.
About SAFE IN COMMON:
Launched in November 2010, SAFE IN COMMON is a community of healthcare workers, educators, patients, community leaders and individuals who share one desire…a world where every injection is both simple and safe. SAFE IN COMMON features blogs, a resource library, links to industry information, forums for contributors to express thoughts and experiences, surveys, and other ways to interact and promote injection safety. For more information about SAFE IN COMMON, please visit the community's official website at http://www.safeincommon.org/.
Website development by http://www.trajectory4brands.com/.
Media Contact:
Susan Carr
susan.carr@safeincommon.org
SOURCE SAFE IN COMMON
RELATED LINKS
http://www.safeincommon.org/
Source
LEWISBERRY, Pa., Nov. 5, 2010 /PRNewswire/ -- SAFE IN COMMON, an online community of healthcare workers, educators, patients, community leaders and individuals, today announced the launch of its website dedicated to raising awareness of global injection safety challenges.
SAFE IN COMMON's launch coincides with the 10th anniversary of the passage of the Needlestick Safety and Prevention Act, which mandates the use of safety engineered medical devices, (SEMDs), within U.S. healthcare facilities to protect healthcare workers and patients from the risk of needlestick injuries. Despite this legislation and its enforcement by OSHA, healthcare workers continue to remain at risk of harm. For example, reports in the U.S. indicate that currently available safety syringes are not providing adequate levels of protection. In fact, reported needlestick injuries in Massachusetts have not fallen since 2002, and safety products are responsible for the majority of those injuries.
While steps have been taken in the U.S. and Europe to mandate the use of SEMDs, the harm caused by unsafe injection practices represents a global humanitarian challenge. According to the World Health Organization (WHO), there are more than 1.3 million needlestick related deaths worldwide each year.
"As a former nurse, I have first hand experience with the physical and emotional dangers of a needlestick injury. However, the problems and risks associated with needlestick injuries are real and affect the lives of millions of people around the world, not just those in the healthcare field," commented Dr. Mary Foley, Associate Director, Center for Nursing Research and Innovation. "Much has been accomplished since the signing of the Needlestick Safety and Prevention Act of 2000, but the safety laws and policies currently in place are poorly enforced and need to be addressed. SAFE IN COMMON is in a unique to position to advocate for this change. Not only will SAFE IN COMMON serve as a community for those impacted by unsafe needlestick practices and injuries, but it will also act as a unified voice to educate and fight for better, more effective solutions."
Led by a team of highly experienced and influential board members, SAFE IN COMMON was created to raise awareness and support the global transition to safe, simple injections. As a social community, SAFE IN COMMON will also seek to provide support and coverage to all international markets focused on the enhancement of safe injection practices.
Outside of healthcare facilities, SAFE IN COMMON will also seek to address specific injection safety challenges relating to patients who administer prescription drugs at home, injecting drug users and other stakeholders associated with harm reduction, and the vaccination / immunization programs of developing and emerging nations. With such markets that operate largely outside of healthcare facilities, unsafe injection practices such as the re-use, sharing or unsafe disposal of non-sterile injection devices may accelerate HIV and hepatitis C epidemics.
The new website, http://www.safeincommon.org/, will feature blogs, a resource library, links to industry information, forums for contributors to express thoughts and experiences, surveys, and other ways to interact and promote injection safety.
Current SAFE IN COMMON board members include:
• Mary Foley: RN, MS, PhD, Past President American Nursing Association and Associate Director, Center for Nursing Research and Innovation, University of California, San Francisco.
• Ron Stoker: Executive Director of the International Sharps Injury Protection Society (ISIPS).
• Gerald Verollet: Former head of the medical device division at the World Health Organization (WHO).
• Jason Tetro: Infection control advocate, blogger and coordinator at two research centers for microbiology at the University of Ottawa.
• Evelyn McKnight: Patient safety advocate, author of "A Never Event" and founder of HONOReform, a national advocacy organization dedicated to protecting patients through safeguarding the medical injection process.
SAFE IN COMMON is also being sponsored by Unilife Corporation (Nasdaq: UNIS), a medical device company focused on the design, development, manufacture and supply of a proprietary range of retractable syringes.
The Community seeks additional alliances with organizations that share in the goal of reducing the global harms of needlestick injuries and other unsafe injection practices. For more information about SAFE IN COMMON, please visit the website at http://www.safeincommon.org/.
About SAFE IN COMMON:
Launched in November 2010, SAFE IN COMMON is a community of healthcare workers, educators, patients, community leaders and individuals who share one desire…a world where every injection is both simple and safe. SAFE IN COMMON features blogs, a resource library, links to industry information, forums for contributors to express thoughts and experiences, surveys, and other ways to interact and promote injection safety. For more information about SAFE IN COMMON, please visit the community's official website at http://www.safeincommon.org/.
Website development by http://www.trajectory4brands.com/.
Media Contact:
Susan Carr
susan.carr@safeincommon.org
SOURCE SAFE IN COMMON
RELATED LINKS
http://www.safeincommon.org/
Source
Small protein changes may make big difference in natural HIV control
Submitted by editor on November 7, 2010 - 10:33
Tiny variants in a protein that alerts the immune system to the presence of infection may underlie the rare ability of some individuals to control HIV infection without the need for medications. In a report that will appear in Science and is receiving early online release, an international research team led by investigators from the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard and from the Broad Institute of MIT and Harvard describe finding that differences in five amino acids in a protein called HLA-B are associated with whether or not HIV-infected individuals can control viral levels with their immune system only.
We found that, of the three billion nucleotides in the human genome, just a handful make the difference between those who can stay healthy in spite of HIV infection and those who, without treatment, will develop AIDS, says Bruce Walker, MD, director of the Ragon Institute and co-senior author of the Science article. Understanding where this difference occurs allows us to sharpen the focus of our efforts to ultimately harness the immune system to defend against HIV.
Earlier studies had showed that certain genes involved with the HLA system were important for HIV control, adds Paul de Bakker, PhD, of the Broad Institute and Brigham and Womens Hospital, co-senior author. But they couldnt tell us exactly which genes were involved and how they produced this difference. Our findings take us not only to a specific protein, but to a part of that protein that is essential to its function.
It has been known for almost two decades that a small minority – about one in 300 – of individuals infected with HIV are naturally able to suppress viral replication with their immune system, keeping viral load at extremely low levels. To identify genetic differences that may underlie this rare ability, Florencia Pereyra, MD, at the Ragon Institute established the International HIV Controllers Study(http://www.hivcontrollers.org/) in 2006, with a goal of enrolling 1,000 HIV controllers from medical clinics and research institutes around the world. That goal was expanded to 2,000 controllers in 2008, and thus far over 1,500 controllers have been enrolled.
The current investigation began with a genome-wide association study (GWAS) of almost 1,000 controllers and 2,600 individuals with progressive HIV infection, through a collaboration with the AIDS Clinical Trials Group. The GWAS, which tests variations at a million points in the human genome, identified some 300 sites that were statistically associated with immune control of HIV, all in regions of chromosome 6 that code for HLA proteins. Further analysis narrowed the number of gene sites to four but could not indicate whether those differences actually affected viral control or were just located near the causal variants. Fully sequencing that genome region in all participants was not feasible, but a process developed by Sherman Jia – a medical student in the Harvard-MIT Health Sciences and Technology program, working with de Bakker at the Broad – pinpointed specific amino acids; and directly testing those sites associated five amino acids in the HLA-B protein with differences in viral control.
HLA-B is essential to the process by which the immune system recognizes and destroys virus-infected cells. Usually HLA-B grabs onto viral protein segments called peptides that are inside the cell and carries them to the cell membrane where they essentially flag the infected cell for destruction by CD8 killer T cells. The portion of the HLA-B protein that grabs and displays viral peptides is called the binding pocket, and all of the five identified amino acid sites are in the lining of the binding pocket.
Amino acid variation within the HLA-B binding pocket will impact its shape and structure, probably resulting in some peptides being presented effectively and others not, de Bakker says. Our work demonstrates that these variants could make a crucial difference in the individuals ability to control HIV by changing how HLA-B presents peptides from this virus to the immune system.
Walker adds, HIV is slowly revealing its secrets, and this is yet another. Knowing how an effective immune response against HIV is generated is an important step toward replicating that response with a vaccine. We have a long way to go before translating this into a treatment for infected patients and a vaccine to prevent infection, but we are an important step closer.
The investigators note that these findings would not have been possible without the participation of the hundreds of HIV controllers, many of whom traveled to Boston for testing, who have enrolled in the study. The enthusiasm among the patients we have enrolled and the HIV providers who referred them has been amazing, says Pereyra. They tell us that being part of this collaborative study means a lot to them.
###
Original support for the International HIV Controllers study came through a 2006 grant from the Mark and Lisa Schwartz Foundation, and the study was expanded in 2008 through the support of the Bill and Melinda Gates Foundation. Additional supporting agencies include the Harvard Center for AIDS Research and the National Institutes of Health.
Walker is a professor and de Bakker an assistant professor of Medicine at Harvard Medical School. Under the leadership of Pereyra, more than 300 investigators at over 200 institutions around the world contributed to the Science study. Study co-authors include, among others, Steven Deeks, MD, University of California, San Francisco; Amalio Telenti, MD, PhD, University of Lausanne, Switzerland; Mary Carrington, PhD, National Institutes of Health; Vincent Marconi, MD, Emory University; David Haas, MD, Vanderbilt University; John Fangman, MD, AIDS Resource Center of Wisconsin: Martin Markowitz, MD, Aaron Diamond AIDS Research Center; Richard Harrigan, PhD, British Columbia Centre for Excellence in HIV/AIDS; James Braun, DO, Physicians Research Network, New York; Ronald Nahass, MD, I.D. Care Associates, Hillsborough, New Jersey: and Otto O. Yang, MD, University of California. Los Angeles.
The Eli and Edythe L. Broad Institute of MIT and Harvard was founded in 2003 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community. Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org/.
The Ragon Institute of MGH, MIT and Harvard was established in 2009 with a gift from the Philip T. and Susan M. Ragon Foundation, creating a collaborative scientific mission among these institutions to harness the immune system to combat and cure human diseases. The primary initial focus of the institute is to contribute to the development of an effective AIDS vaccine. The Ragon Institute draws scientists and engineers from diverse backgrounds and areas of expertise across the Harvard and MIT communities and throughout the world, in order to apply the full arsenal of scientific knowledge to understanding mechanisms of immune control and immune failure and to apply these advances to directly benefit patients. For further information visit http://www.ragoninstitute.org/
Source
Tiny variants in a protein that alerts the immune system to the presence of infection may underlie the rare ability of some individuals to control HIV infection without the need for medications. In a report that will appear in Science and is receiving early online release, an international research team led by investigators from the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard and from the Broad Institute of MIT and Harvard describe finding that differences in five amino acids in a protein called HLA-B are associated with whether or not HIV-infected individuals can control viral levels with their immune system only.
We found that, of the three billion nucleotides in the human genome, just a handful make the difference between those who can stay healthy in spite of HIV infection and those who, without treatment, will develop AIDS, says Bruce Walker, MD, director of the Ragon Institute and co-senior author of the Science article. Understanding where this difference occurs allows us to sharpen the focus of our efforts to ultimately harness the immune system to defend against HIV.
Earlier studies had showed that certain genes involved with the HLA system were important for HIV control, adds Paul de Bakker, PhD, of the Broad Institute and Brigham and Womens Hospital, co-senior author. But they couldnt tell us exactly which genes were involved and how they produced this difference. Our findings take us not only to a specific protein, but to a part of that protein that is essential to its function.
It has been known for almost two decades that a small minority – about one in 300 – of individuals infected with HIV are naturally able to suppress viral replication with their immune system, keeping viral load at extremely low levels. To identify genetic differences that may underlie this rare ability, Florencia Pereyra, MD, at the Ragon Institute established the International HIV Controllers Study(http://www.hivcontrollers.org/) in 2006, with a goal of enrolling 1,000 HIV controllers from medical clinics and research institutes around the world. That goal was expanded to 2,000 controllers in 2008, and thus far over 1,500 controllers have been enrolled.
The current investigation began with a genome-wide association study (GWAS) of almost 1,000 controllers and 2,600 individuals with progressive HIV infection, through a collaboration with the AIDS Clinical Trials Group. The GWAS, which tests variations at a million points in the human genome, identified some 300 sites that were statistically associated with immune control of HIV, all in regions of chromosome 6 that code for HLA proteins. Further analysis narrowed the number of gene sites to four but could not indicate whether those differences actually affected viral control or were just located near the causal variants. Fully sequencing that genome region in all participants was not feasible, but a process developed by Sherman Jia – a medical student in the Harvard-MIT Health Sciences and Technology program, working with de Bakker at the Broad – pinpointed specific amino acids; and directly testing those sites associated five amino acids in the HLA-B protein with differences in viral control.
HLA-B is essential to the process by which the immune system recognizes and destroys virus-infected cells. Usually HLA-B grabs onto viral protein segments called peptides that are inside the cell and carries them to the cell membrane where they essentially flag the infected cell for destruction by CD8 killer T cells. The portion of the HLA-B protein that grabs and displays viral peptides is called the binding pocket, and all of the five identified amino acid sites are in the lining of the binding pocket.
Amino acid variation within the HLA-B binding pocket will impact its shape and structure, probably resulting in some peptides being presented effectively and others not, de Bakker says. Our work demonstrates that these variants could make a crucial difference in the individuals ability to control HIV by changing how HLA-B presents peptides from this virus to the immune system.
Walker adds, HIV is slowly revealing its secrets, and this is yet another. Knowing how an effective immune response against HIV is generated is an important step toward replicating that response with a vaccine. We have a long way to go before translating this into a treatment for infected patients and a vaccine to prevent infection, but we are an important step closer.
The investigators note that these findings would not have been possible without the participation of the hundreds of HIV controllers, many of whom traveled to Boston for testing, who have enrolled in the study. The enthusiasm among the patients we have enrolled and the HIV providers who referred them has been amazing, says Pereyra. They tell us that being part of this collaborative study means a lot to them.
###
Original support for the International HIV Controllers study came through a 2006 grant from the Mark and Lisa Schwartz Foundation, and the study was expanded in 2008 through the support of the Bill and Melinda Gates Foundation. Additional supporting agencies include the Harvard Center for AIDS Research and the National Institutes of Health.
Walker is a professor and de Bakker an assistant professor of Medicine at Harvard Medical School. Under the leadership of Pereyra, more than 300 investigators at over 200 institutions around the world contributed to the Science study. Study co-authors include, among others, Steven Deeks, MD, University of California, San Francisco; Amalio Telenti, MD, PhD, University of Lausanne, Switzerland; Mary Carrington, PhD, National Institutes of Health; Vincent Marconi, MD, Emory University; David Haas, MD, Vanderbilt University; John Fangman, MD, AIDS Resource Center of Wisconsin: Martin Markowitz, MD, Aaron Diamond AIDS Research Center; Richard Harrigan, PhD, British Columbia Centre for Excellence in HIV/AIDS; James Braun, DO, Physicians Research Network, New York; Ronald Nahass, MD, I.D. Care Associates, Hillsborough, New Jersey: and Otto O. Yang, MD, University of California. Los Angeles.
The Eli and Edythe L. Broad Institute of MIT and Harvard was founded in 2003 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community. Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org/.
The Ragon Institute of MGH, MIT and Harvard was established in 2009 with a gift from the Philip T. and Susan M. Ragon Foundation, creating a collaborative scientific mission among these institutions to harness the immune system to combat and cure human diseases. The primary initial focus of the institute is to contribute to the development of an effective AIDS vaccine. The Ragon Institute draws scientists and engineers from diverse backgrounds and areas of expertise across the Harvard and MIT communities and throughout the world, in order to apply the full arsenal of scientific knowledge to understanding mechanisms of immune control and immune failure and to apply these advances to directly benefit patients. For further information visit http://www.ragoninstitute.org/
Source
Pharmasset Makes Remarkable Recovery on Hepatitis C Franchise
November 07, 2010
With so much attention paid to the relative merits of novel protease inhibitors, telaprevir and boceprevir, at the recent American Association for the Study of Liver Diseases (AASLD) meeting, arguably the biggest beneficiary from the conference was Pharmasset (VRUS).
Shares in the New Jersey biotech have gained 20% since the meeting started and now trade at a record high of $41, valuing the viral specialist with just two phase II hepatitis C candidates at a highly impressive $1.4bn. Key value driver is nucleoside polymerase inhibitor, RG7128, partnered with Roche (RHHBY.PK) and widely regarded as posing a genuine competitive threat to telaprevir and boceprevir. For Pharmasset the recovery over the last 18 months has been quite remarkable since the stock slumped to $7.80 with the failure of its lead pipeline candidate (Pharmasset hepatitis B failure focuses attention on hepatitis C, April 20, 2009).
Looking to the next generations
For the moment all eyes are on Vertex Pharmaceuticals (VRTX) and Johnson & Johnson’s (JNJ) telaprevir and Merck & Co’s (MRK) boceprevir, oral drugs with the potential to transform the way patients are treated for hepatitis C.
The current standard of care is a combination of pegylated alpha interferon and ribavirin, taken for up to 48 weeks. However, the long-treatment duration with weekly injections and modest efficacy - sustained virologic response (SVR) is around 55% - mean only a fraction of hepatitis C patients receive treatment.
The protease inhibitors, with much shorter treatment times of 12-24 weeks, twice-daily oral dosing and greater SVR rates up to 80%, offer obvious advantages and are expected to significantly increase the numbers of patients treated; currently patients are being ‘warehoused’ until these new drugs reach the market in the second half of 2011.
Pivotal data presented at AASLD suggest there is little to choose between the two candidates, with telaprevir appearing to hold an edge, although perhaps not quite to the extent that current consensus forecasts suggest. Telaprevir sales in 2016 of $3.55bn are more than five times higher than boceprevir at $686m (Where now for Vertex and Lilly's regrets after hat trick of telaprevir wins, September 9, 2010).
While protease inhibitors will undoubtedly be a major advance in treating hepatitis C, there are concerns about a higher rate of adverse events, particularly anemia and rashes, with these drugs over standard of care, as well as the potential for viral resistance.
Which is where Pharmasset, with its slightly different approach of nucleoside polymerase inhibitors, comes in.
Propelling data
Pharmasset’s pipeline of hepatitis C candidates are all nucleoside polymerase inhibitors. As well as RG7128, the company has unpartnered assets in PSI-7977, undergoing a phase IIb study, and PSI-938, which reported positive preliminary phase I data last week.
For now though the successful development of RG7128 is key to Pharmasset’s future.
Phase IIb data from the Propel study showed that more than 80% of patients receiving twice-daily oral dosing with the drug for 12 weeks had undetectable levels of the virus, a so-called early virologic response (EVR) rate; standard of care alone gave a 49% EVR. Importantly as well there was no evidence of viral resistance after 12 weeks.
Another phase IIb, called Jump-C, started earlier this year and is testing a 24-week dose with the drug. Meanwhile, a phase III trial is expected to start next year in comparison to standard of care; this is significant in that these are likely to be the last pivotal trials which use current therapy as the comparator and therefore a clearer regulatory pathway to approval.
Valuable franchise
Roche and Pharmasset signed a broad collaboration in 2004 to develop nucleoside polymerase inhibitors, in a deal worth up to $300m in upfront fees and milestones. Pharmasset will receive royalties and with some analysts forecasting sales of RG7128 to reach $2bn by 2016, just three years after launch, these should be significant.
Analysts covering Pharmasset have penciled in royalties of $268m by 2016, which potentially values the drug at $1.49bn, according to EvaluatePharma’s NPV Analyzer, assuming it reaches the market by 2013.
With the market already valuing Pharmasset at a similar level to this best-case scenario, it seems investors are currently placing a major bet that nucleoside polymerase inhibitors could be just as much of a breakthrough in treating hepatitis C as the current crop of protease inhibitors.
Source
With so much attention paid to the relative merits of novel protease inhibitors, telaprevir and boceprevir, at the recent American Association for the Study of Liver Diseases (AASLD) meeting, arguably the biggest beneficiary from the conference was Pharmasset (VRUS).
Shares in the New Jersey biotech have gained 20% since the meeting started and now trade at a record high of $41, valuing the viral specialist with just two phase II hepatitis C candidates at a highly impressive $1.4bn. Key value driver is nucleoside polymerase inhibitor, RG7128, partnered with Roche (RHHBY.PK) and widely regarded as posing a genuine competitive threat to telaprevir and boceprevir. For Pharmasset the recovery over the last 18 months has been quite remarkable since the stock slumped to $7.80 with the failure of its lead pipeline candidate (Pharmasset hepatitis B failure focuses attention on hepatitis C, April 20, 2009).
Looking to the next generations
For the moment all eyes are on Vertex Pharmaceuticals (VRTX) and Johnson & Johnson’s (JNJ) telaprevir and Merck & Co’s (MRK) boceprevir, oral drugs with the potential to transform the way patients are treated for hepatitis C.
The current standard of care is a combination of pegylated alpha interferon and ribavirin, taken for up to 48 weeks. However, the long-treatment duration with weekly injections and modest efficacy - sustained virologic response (SVR) is around 55% - mean only a fraction of hepatitis C patients receive treatment.
The protease inhibitors, with much shorter treatment times of 12-24 weeks, twice-daily oral dosing and greater SVR rates up to 80%, offer obvious advantages and are expected to significantly increase the numbers of patients treated; currently patients are being ‘warehoused’ until these new drugs reach the market in the second half of 2011.
Pivotal data presented at AASLD suggest there is little to choose between the two candidates, with telaprevir appearing to hold an edge, although perhaps not quite to the extent that current consensus forecasts suggest. Telaprevir sales in 2016 of $3.55bn are more than five times higher than boceprevir at $686m (Where now for Vertex and Lilly's regrets after hat trick of telaprevir wins, September 9, 2010).
While protease inhibitors will undoubtedly be a major advance in treating hepatitis C, there are concerns about a higher rate of adverse events, particularly anemia and rashes, with these drugs over standard of care, as well as the potential for viral resistance.
Which is where Pharmasset, with its slightly different approach of nucleoside polymerase inhibitors, comes in.
Propelling data
Pharmasset’s pipeline of hepatitis C candidates are all nucleoside polymerase inhibitors. As well as RG7128, the company has unpartnered assets in PSI-7977, undergoing a phase IIb study, and PSI-938, which reported positive preliminary phase I data last week.
For now though the successful development of RG7128 is key to Pharmasset’s future.
Phase IIb data from the Propel study showed that more than 80% of patients receiving twice-daily oral dosing with the drug for 12 weeks had undetectable levels of the virus, a so-called early virologic response (EVR) rate; standard of care alone gave a 49% EVR. Importantly as well there was no evidence of viral resistance after 12 weeks.
Another phase IIb, called Jump-C, started earlier this year and is testing a 24-week dose with the drug. Meanwhile, a phase III trial is expected to start next year in comparison to standard of care; this is significant in that these are likely to be the last pivotal trials which use current therapy as the comparator and therefore a clearer regulatory pathway to approval.
Valuable franchise
Roche and Pharmasset signed a broad collaboration in 2004 to develop nucleoside polymerase inhibitors, in a deal worth up to $300m in upfront fees and milestones. Pharmasset will receive royalties and with some analysts forecasting sales of RG7128 to reach $2bn by 2016, just three years after launch, these should be significant.
Analysts covering Pharmasset have penciled in royalties of $268m by 2016, which potentially values the drug at $1.49bn, according to EvaluatePharma’s NPV Analyzer, assuming it reaches the market by 2013.
With the market already valuing Pharmasset at a similar level to this best-case scenario, it seems investors are currently placing a major bet that nucleoside polymerase inhibitors could be just as much of a breakthrough in treating hepatitis C as the current crop of protease inhibitors.
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How to Recognize the Symptoms of Liver Disease
Symptoms that indicate liver disease include changes in skin coloration, hyper-pigmentation, jaundice and a yellowing of the eyes. Learn about symptoms of liver disease, such as difficulty clotting blood, from a family practice physician in this free video series on health care and medical conditions.
Expert: Ken Savage
Contact: http://www.wearehdtv.com/
Bio: Ken Savage is a graduate of Kansas City University of Medicine and Biosciences.
Filmmaker: Christopher Rokosz
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