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Dear Patient Association Member
We are delighted to announce that we will be holding a second “Medicine and Me: Hepatitis C” half-day conference in conjunction with the Royal Society of Medicine in May 2011 as part of our tenth anniversary celebrations.
‘Medicine and Me’ conferences, initiated and developed by the Royal Society of Medicine, are specifically designed to bring together healthcare professionals and patients, their families, carers and advocates to discuss current management and research issues of a particular condition so that each can learn from the other.
‘Medicine and Me: Hepatitis C’ aims to provide an interactive forum in which the patient’s voice is given top priority. The meeting provides an opportunity for healthcare professionals to hear first hand from patients and their families about their experiences and concerns and for patients to hear about the latest treatment and research by questioning the experts in an informal environment.
Using a mix of both patients and professionals to give their views, some of the themes we are currently considering include:
· The complexity of the hepatitis C virus, what we do know and what we don’t
· Changes to support and care of patients (eg home delivered care, support meetings at their hospital)
· Preparing for and managing treatment
· Managing life with HCV
· Post treatment challenges
· New treatments on the horizon
We want to ensure that your voice is heard, so whether you are a patient or a professional, we would love to have your suggestions on topics you would like covered, or speakers you’d be interested to hear and we will do our best to incorporate your ideas.
If you would like to share your ideas and take advantage of this unique opportunity to contribute to, or take part in, a debate around the latest issues concerning hepatitis C, please email administration@hepctrust.org.uk
or call Karine on 0207 089 6220. Please note we need your contributions by Friday 24th September.
With best wishes
The Hepatitis C Trust
Monday, September 27, 2010
ZymoGenetics Acquisition Highlights Competitive Hepatitis C Treatment Race
ZymoGenetics Acquisition Highlights Competitive Hepatitis C Treatment Race
http://www.onemedplace.com
Bristol-Myers Squibb Company (BMS) announced Tuesday that it had signed an agreement to acquire biopharmaceutical company ZymoGenetics for $9.75 per share in cash, or approximately $885 million. Under the terms of the agreement, BMS will gain control of ZymoGenetics? product development pipeline, which includes potential treatments for surgical bleeding, metastatic skin cancer, and atopic dermatitis.
However, perhaps the biggest prize BMS will acquire in the deal is pegylated-interferon lambda, a novel interferon drug candidate for the treatment of hepatitis C, an infectious disease that affects the liver. Approximately 3.2 million people in the U.S. are chronically infected with hepatitis C, according to the U.S. Centers for Disease Control, and ZymoGenetics? drug candidate has the potential to improve upon the current standard of care, interferon combined with ribavirin. While this drug combination works for many patients, it has to be taken for months and has many potential side effects.
According to a report by market research firm Global Data, the global hepatitis C market was worth $4 billion in 2009 and is projected to grow at a compound annual growth rate of 9.8% to reach $8.5 billion by 2016. ZymoGenetics is competing with Vertex Pharmaceuticals, Merck, Anadys Pharmaceuticals, Idenix Pharmaceuticals, and a number of other companies to be the first to market a hepatitis C drug that outperforms the current standard of care.
Along with ZymoGenetics, Vertex has been drawing a lot of attention; the Cambridge, Mass.-based company released positive late-stage clinical data on Tuesday. In a study of 662 treatment-resistant hepatitis C patients, 65 percent of patients who took Vertex?s telaprevir were cured, compared to 17 percent of patients who were treated with the current standard of care. The news wasn?t as good for Idenix, which halted trials of two of its experimental hepatitis C drugs over safety concerns after liver abnormalities were discovered in three healthy study participants. Other news from the hepatitis C space: PSI-7977, developed by Pharmasset, recently received fast track designation from the FDA. The drug is currently in Phase 2b clinical trials. With such a significant need for effective hepatitis C treatments, and with so many competitors in the field, the race to commercialization continues to be an interesting one.
http://www.onemedplace.com
Bristol-Myers Squibb Company (BMS) announced Tuesday that it had signed an agreement to acquire biopharmaceutical company ZymoGenetics for $9.75 per share in cash, or approximately $885 million. Under the terms of the agreement, BMS will gain control of ZymoGenetics? product development pipeline, which includes potential treatments for surgical bleeding, metastatic skin cancer, and atopic dermatitis.
However, perhaps the biggest prize BMS will acquire in the deal is pegylated-interferon lambda, a novel interferon drug candidate for the treatment of hepatitis C, an infectious disease that affects the liver. Approximately 3.2 million people in the U.S. are chronically infected with hepatitis C, according to the U.S. Centers for Disease Control, and ZymoGenetics? drug candidate has the potential to improve upon the current standard of care, interferon combined with ribavirin. While this drug combination works for many patients, it has to be taken for months and has many potential side effects.
According to a report by market research firm Global Data, the global hepatitis C market was worth $4 billion in 2009 and is projected to grow at a compound annual growth rate of 9.8% to reach $8.5 billion by 2016. ZymoGenetics is competing with Vertex Pharmaceuticals, Merck, Anadys Pharmaceuticals, Idenix Pharmaceuticals, and a number of other companies to be the first to market a hepatitis C drug that outperforms the current standard of care.
Along with ZymoGenetics, Vertex has been drawing a lot of attention; the Cambridge, Mass.-based company released positive late-stage clinical data on Tuesday. In a study of 662 treatment-resistant hepatitis C patients, 65 percent of patients who took Vertex?s telaprevir were cured, compared to 17 percent of patients who were treated with the current standard of care. The news wasn?t as good for Idenix, which halted trials of two of its experimental hepatitis C drugs over safety concerns after liver abnormalities were discovered in three healthy study participants. Other news from the hepatitis C space: PSI-7977, developed by Pharmasset, recently received fast track designation from the FDA. The drug is currently in Phase 2b clinical trials. With such a significant need for effective hepatitis C treatments, and with so many competitors in the field, the race to commercialization continues to be an interesting one.
FDA halts Idenix drug studies due to side effects
FDA halts Idenix drug studies due to side effects
businessweek.com
CAMBRIDGE, Mass.
Shares of Idenix Pharmaceuticals were cut nearly in half Tuesday after federal regulators halted development of its two hepatitis drugs due to its potential side effects.
The Food and Drug Administration issued a clinical hold after Idenix reported three cases of liver side effects in patients taking IDX-184 and IDX-320, the company said. Both drugs are experimental treatments for hepatitis C, a type of infection that damages the liver.
Idenix said liver function in all three patients later returned to normal.
Idenix received verbal notice of the FDA's decision Friday. The company had been studying a combination dose of the two drugs in healthy volunteers.
"We remain committed to the future potential of these drug candidates" said Idenix Chairman and Chief Executive Jean-Pierre Sommadossi. "We will work closely with independent experts and our external safety committee to better understand the cause of these serious adverse events."
Shares of Idenix Pharmaceuticals tumbled $2.87 to $3.12 in midday trading.
News Release
Idenix Provides Update on HCV Clinical Development Activities
Conference call today at 8:30 am ET
CAMBRIDGE, Mass., Sept 07, 2010 /PRNewswire via COMTEX/ --
Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced that the company received verbal notice on Friday, September 3, 2010 from the U.S. Food and Drug Administration (FDA) that the IDX184 and IDX320 programs have been placed on clinical hold. A clinical hold is an order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. This decision was made after Idenix notified the FDA of three serious adverse events that occurred during a drug-drug interaction study of the combination of IDX184 and IDX320 in healthy volunteers. These observed serious adverse events were elevated liver function tests detected in three subjects during post exposure safety visits. The liver function tests have returned to nearly normal levels in all thr ee subjects during follow-up. All planned studies of IDX184 and IDX320 to date have been completed and there are currently no healthy volunteers or patients receiving IDX184 or IDX320. Idenix will submit full data to the FDA from recently completed preclinical and clinical studies, including 3-month chronic toxicology studies of IDX184, a 14-day study of IDX184 in combination with pegylated interferon/ribavirin (PegIFN/RBV), a 3-day proof-of-concept study of IDX320 in hepatitis C (HCV) infected patients, and the IDX184 and IDX320 drug-drug interaction study in healthy volunteers in order to assess next steps in the development of both compounds.
"We have not yet received a formal letter from the FDA, nor has the Agency had an opportunity to review the safety and efficacy data from recently completed clinical trials with IDX184 and IDX320. Based upon our discussions with the Agency, we are primarily focused on three cases of elevated liver function tests observed during our drug-drug interaction study of the combination of IDX184 and IDX320 in healthy volunteers," said Jean-Pierre Sommadossi, Ph.D., Idenix Chairman and Chief Executive Officer. "Based upon the safety and antiviral activity we observed in the IDX184 14-day study and the IDX320 3-day proof-of-concept study, both in HCV-infected patients, we remain committed to the future potential of these drug candidates. We will work closely with independent experts and our external safety committee to better understand the cause of these serious adverse events in the combination study of IDX184 and IDX 320 and to provide the FDA with more information in order to expedite their review and resolve this matter as quickly as possible."
Full data presentations of IDX184, IDX320 and IDX375 studies will be presented at the annual meeting of the American Association for the Study of Liver Diseases (AASLD), which will be held at the end of October in Boston.
Phase I: IDX184/IDX320 Combination
Idenix completed a two-week Phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetic drug-drug interaction between IDX320 and IDX184 in healthy volunteers. Two cohorts were evaluated in the study with 10 subjects in each cohort randomized eight to active drug and two to placebo. Subjects in the first cohort received 400 mg once-daily of IDX320 for the first week, subsequently adding 100 mg once-daily of IDX184 for the second week. Subjects in the second cohort received 100 mg once-daily of IDX184 plus placebo for the first week, subsequently adding 400 mg once-daily of IDX320 for the second week. The combination of IDX184 and IDX320 was generally safe and well tolerated during the 14 days of treatment. Liver function abnormalities deemed to be serious adverse events were detected in three subjects during the post exposure safety visits. Liver function tests in thes e subjects have returned to nearly normal during follow-up. Pharmacokinetic drug-drug interactions between IDX184 and IDX320 were not considered to be clinically significant. Neither the plasma exposure of IDX184 and its metabolite, 2'-methylguanosine, nor IDX320 plasma exposure explain these three serious adverse events.
Phase IIa: IDX184, a liver-targeted HCV nucleotide prodrug
This 14-day, Phase IIa clinical trial evaluated 50 to 200 mg doses of IDX184 in combination with PegIFN/RBV in treatment-naive HCV genotype 1-infected patients. At Day 14, mean (+/- standard deviation) viral load reductions were 1.5 (+/- 1.3) logs for placebo (n=16), 2.7 (+/- 1.3) logs for 50 mg IDX184 QD (n=16), 4.0 (+/- 1.7) logs for 50 mg IDX184 BID (n=8), 4.2 (+/- 1.9) logs for 100 mg QD (n=8), 4.1 (+/- 1.2), for 150 mg QD (n=15), 4.1 (+/-1.4) logs for 100 mg BID (n=8) and 3.7 (+/- 1.2) logs for 200 mg QD (n=8). In the cohorts of 100 mg, 150 mg, and 200 mg daily doses in combination with PegIFN/RBV, 50%, 40% and 25%, respectively, of patients achieved undetectable virus levels (<15 IU/mL) by Day 14. Liver injury parameters (ALT and AST) improved with all doses of IDX184. The side effect profile of the three drug combination was consistent with the known side effect profile of PegIFN/RBV alone. The most common adverse events reported were fatigue, myalgia, headache and nausea.
Phase I/II: IDX 320, an HCV protease inhibitor
This randomized, parallel-arm, double-blind, placebo-controlled proof-of-concept trial evaluated the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in treatment-naive HCV genotype 1-infected patients. Thirty patients were randomized equally and received placebo, 50, 100, 200 or 400 mg of IDX320 orally once-a-day for three days. One cohort of eight patients was randomized to receive 200 mg IDX320 BID or placebo. At Day 3, mean (+/- standard deviation) viral load reductions were 0.1 (+/- 0.15) logs for placebo (n=5), 2.6 (+/-0.49) logs for 50 mg IDX320 QD (n=5), 3.1 (+/- 0.29) logs for 100 mg QD (n=6), 3.1 (+/- 0.41) logs for 200 mg QD (n=6) and 3.3 (+/- 0.28) logs for 400 mg QD (n=7). At daily doses of placebo, 50, 100, 200, and 400 mg, 0%, 20%, 67%, 67% and 86%, respectively, of patients achieved greater than or equal to 3 log reduction in HCV RNA at the end of treatment. In the 200 mg IDX 320 BID cohort at Day 3, mean (+/- standard deviation) viral load reductions were 3.8 (+/- 0.52) logs and all patients (100%) achieved greater than or equal to 3 log reduction in HCV RNA. In the 3-day proof-of-concept study, IDX320 was generally safe, well tolerated, and demonstrated potent, dose-related HCV antiviral activity.
Phase I: IDX375, an HCV non-nucleoside polymerase inhibitor
Idenix has an ongoing Phase I clinical trial in healthy volunteers evaluating single doses of the free acid form of IDX375 ranging from 200 to 1200 mg per day. Overall, IDX375 achieved pharmacologically relevant drug exposure and was well tolerated for doses up to 1200 mg for one day in healthy subjects. In the fourth quarter of 2010, Idenix plans to initiate a 3-day proof-of-concept trial in treatment-naive genotype 1 HCV-infected patients.
Conference Call Information
Idenix will hold a conference call today at 8:30 a.m. ET. To access the call please dial (800) 471-3635 U.S./Canada or (706) 758-9475 International and enter passcode 99538089. A replay of the conference call and webcast will be available until September 21, 2010. To access the replay, please dial (800) 642-1687 U.S./Canada or (706) 645-9291 International and enter the passcode 99538089.
About HCV
Hepatitis C virus is a common blood-borne pathogen infecting three to four million people worldwide annually. Currently, an estimated 170 million people are infected worldwide, representing a nearly 5-fold greater prevalence than human immunodeficiency virus.(1)
About Idenix
Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of patients with chronic hepatitis C infection. For further information about Idenix, please refer to www.idenix.com.
Forward-Looking Statements
This press release contains "forward-looking statements" for purposes of the safe harbor provisions of The Private Securities Litigation Reform Act of 1995, including but not limited to the statements regarding the company's future business and financial performance. For this purpose, any statements contained herein that are not statements of historical fact may be deemed forward-looking statements. Without limiting the foregoing, the words "expect," "plans," "anticipates," "will," "expects," "goal," "estimates," "projects," "would," "could," "targets," and similar expressions are also intended to identify forward-looking statements, as are expressed or implied statements with respect to the company's clinical development programs or commercialization activities in hepatitis C, or any potential pipeline candidates, including any expressed or implied statements regarding the efficacy and safety of our drug cand idates, the likelihood and success of any future clinical trials involving our drug candidates or successful development of novel combinations of direct-acting antivirals for the treatment of hepatitis C. Actual results may differ materially from those indicated by such forward-looking statements as a result of risks and uncertainties, including but not limited to the following: there can be no guarantees that the company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization; management's expectations could be affected by unexpected regulatory actions or delays, including the current clinical hold on IDX184 and IDX320; uncertainties relating to, or unsuccessful results of, clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the company's ability to obtain additional funding required to conduct its research, deve lopment and commercialization activities; the company's dependence o n its collaborations with Novartis Pharma AG and GlaxoSmithKline; changes in the company's business plan or objectives; the ability of the company to attract and retain qualified personnel; competition in general; and the company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. These and other risks which may impact management's expectations are described in greater detail under the heading "Risk Factors" in each of the company's annual report on Form 10-K for the year ended December 31, 2009 and quarterly report on form 10-Q for the quarter ended June 30, 2010, as filed with the Securities and Exchange Commission (SEC) and in any subsequent p eriodic or current report that the company files with the SEC.
All forward-looking statements reflect the company's estimates only as of the date of this release (unless another date is indicated) and should not be relied upon as reflecting the company's views, expectations or beliefs at any date subsequent to the date of this release. While Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if the company's estimates change.
(1) Lavanchy (2009) Liver International. 29(s1):74-81
Idenix Pharmaceuticals Contact:
Jonae Barnes (617) 224-4485 (investors)
Kelly Barry (617) 995-9033 (media)
businessweek.com
CAMBRIDGE, Mass.
Shares of Idenix Pharmaceuticals were cut nearly in half Tuesday after federal regulators halted development of its two hepatitis drugs due to its potential side effects.
The Food and Drug Administration issued a clinical hold after Idenix reported three cases of liver side effects in patients taking IDX-184 and IDX-320, the company said. Both drugs are experimental treatments for hepatitis C, a type of infection that damages the liver.
Idenix said liver function in all three patients later returned to normal.
Idenix received verbal notice of the FDA's decision Friday. The company had been studying a combination dose of the two drugs in healthy volunteers.
"We remain committed to the future potential of these drug candidates" said Idenix Chairman and Chief Executive Jean-Pierre Sommadossi. "We will work closely with independent experts and our external safety committee to better understand the cause of these serious adverse events."
Shares of Idenix Pharmaceuticals tumbled $2.87 to $3.12 in midday trading.
News Release
Idenix Provides Update on HCV Clinical Development Activities
Conference call today at 8:30 am ET
CAMBRIDGE, Mass., Sept 07, 2010 /PRNewswire via COMTEX/ --
Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced that the company received verbal notice on Friday, September 3, 2010 from the U.S. Food and Drug Administration (FDA) that the IDX184 and IDX320 programs have been placed on clinical hold. A clinical hold is an order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. This decision was made after Idenix notified the FDA of three serious adverse events that occurred during a drug-drug interaction study of the combination of IDX184 and IDX320 in healthy volunteers. These observed serious adverse events were elevated liver function tests detected in three subjects during post exposure safety visits. The liver function tests have returned to nearly normal levels in all thr ee subjects during follow-up. All planned studies of IDX184 and IDX320 to date have been completed and there are currently no healthy volunteers or patients receiving IDX184 or IDX320. Idenix will submit full data to the FDA from recently completed preclinical and clinical studies, including 3-month chronic toxicology studies of IDX184, a 14-day study of IDX184 in combination with pegylated interferon/ribavirin (PegIFN/RBV), a 3-day proof-of-concept study of IDX320 in hepatitis C (HCV) infected patients, and the IDX184 and IDX320 drug-drug interaction study in healthy volunteers in order to assess next steps in the development of both compounds.
"We have not yet received a formal letter from the FDA, nor has the Agency had an opportunity to review the safety and efficacy data from recently completed clinical trials with IDX184 and IDX320. Based upon our discussions with the Agency, we are primarily focused on three cases of elevated liver function tests observed during our drug-drug interaction study of the combination of IDX184 and IDX320 in healthy volunteers," said Jean-Pierre Sommadossi, Ph.D., Idenix Chairman and Chief Executive Officer. "Based upon the safety and antiviral activity we observed in the IDX184 14-day study and the IDX320 3-day proof-of-concept study, both in HCV-infected patients, we remain committed to the future potential of these drug candidates. We will work closely with independent experts and our external safety committee to better understand the cause of these serious adverse events in the combination study of IDX184 and IDX 320 and to provide the FDA with more information in order to expedite their review and resolve this matter as quickly as possible."
Full data presentations of IDX184, IDX320 and IDX375 studies will be presented at the annual meeting of the American Association for the Study of Liver Diseases (AASLD), which will be held at the end of October in Boston.
Phase I: IDX184/IDX320 Combination
Idenix completed a two-week Phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetic drug-drug interaction between IDX320 and IDX184 in healthy volunteers. Two cohorts were evaluated in the study with 10 subjects in each cohort randomized eight to active drug and two to placebo. Subjects in the first cohort received 400 mg once-daily of IDX320 for the first week, subsequently adding 100 mg once-daily of IDX184 for the second week. Subjects in the second cohort received 100 mg once-daily of IDX184 plus placebo for the first week, subsequently adding 400 mg once-daily of IDX320 for the second week. The combination of IDX184 and IDX320 was generally safe and well tolerated during the 14 days of treatment. Liver function abnormalities deemed to be serious adverse events were detected in three subjects during the post exposure safety visits. Liver function tests in thes e subjects have returned to nearly normal during follow-up. Pharmacokinetic drug-drug interactions between IDX184 and IDX320 were not considered to be clinically significant. Neither the plasma exposure of IDX184 and its metabolite, 2'-methylguanosine, nor IDX320 plasma exposure explain these three serious adverse events.
Phase IIa: IDX184, a liver-targeted HCV nucleotide prodrug
This 14-day, Phase IIa clinical trial evaluated 50 to 200 mg doses of IDX184 in combination with PegIFN/RBV in treatment-naive HCV genotype 1-infected patients. At Day 14, mean (+/- standard deviation) viral load reductions were 1.5 (+/- 1.3) logs for placebo (n=16), 2.7 (+/- 1.3) logs for 50 mg IDX184 QD (n=16), 4.0 (+/- 1.7) logs for 50 mg IDX184 BID (n=8), 4.2 (+/- 1.9) logs for 100 mg QD (n=8), 4.1 (+/- 1.2), for 150 mg QD (n=15), 4.1 (+/-1.4) logs for 100 mg BID (n=8) and 3.7 (+/- 1.2) logs for 200 mg QD (n=8). In the cohorts of 100 mg, 150 mg, and 200 mg daily doses in combination with PegIFN/RBV, 50%, 40% and 25%, respectively, of patients achieved undetectable virus levels (<15 IU/mL) by Day 14. Liver injury parameters (ALT and AST) improved with all doses of IDX184. The side effect profile of the three drug combination was consistent with the known side effect profile of PegIFN/RBV alone. The most common adverse events reported were fatigue, myalgia, headache and nausea.
Phase I/II: IDX 320, an HCV protease inhibitor
This randomized, parallel-arm, double-blind, placebo-controlled proof-of-concept trial evaluated the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in treatment-naive HCV genotype 1-infected patients. Thirty patients were randomized equally and received placebo, 50, 100, 200 or 400 mg of IDX320 orally once-a-day for three days. One cohort of eight patients was randomized to receive 200 mg IDX320 BID or placebo. At Day 3, mean (+/- standard deviation) viral load reductions were 0.1 (+/- 0.15) logs for placebo (n=5), 2.6 (+/-0.49) logs for 50 mg IDX320 QD (n=5), 3.1 (+/- 0.29) logs for 100 mg QD (n=6), 3.1 (+/- 0.41) logs for 200 mg QD (n=6) and 3.3 (+/- 0.28) logs for 400 mg QD (n=7). At daily doses of placebo, 50, 100, 200, and 400 mg, 0%, 20%, 67%, 67% and 86%, respectively, of patients achieved greater than or equal to 3 log reduction in HCV RNA at the end of treatment. In the 200 mg IDX 320 BID cohort at Day 3, mean (+/- standard deviation) viral load reductions were 3.8 (+/- 0.52) logs and all patients (100%) achieved greater than or equal to 3 log reduction in HCV RNA. In the 3-day proof-of-concept study, IDX320 was generally safe, well tolerated, and demonstrated potent, dose-related HCV antiviral activity.
Phase I: IDX375, an HCV non-nucleoside polymerase inhibitor
Idenix has an ongoing Phase I clinical trial in healthy volunteers evaluating single doses of the free acid form of IDX375 ranging from 200 to 1200 mg per day. Overall, IDX375 achieved pharmacologically relevant drug exposure and was well tolerated for doses up to 1200 mg for one day in healthy subjects. In the fourth quarter of 2010, Idenix plans to initiate a 3-day proof-of-concept trial in treatment-naive genotype 1 HCV-infected patients.
Conference Call Information
Idenix will hold a conference call today at 8:30 a.m. ET. To access the call please dial (800) 471-3635 U.S./Canada or (706) 758-9475 International and enter passcode 99538089. A replay of the conference call and webcast will be available until September 21, 2010. To access the replay, please dial (800) 642-1687 U.S./Canada or (706) 645-9291 International and enter the passcode 99538089.
About HCV
Hepatitis C virus is a common blood-borne pathogen infecting three to four million people worldwide annually. Currently, an estimated 170 million people are infected worldwide, representing a nearly 5-fold greater prevalence than human immunodeficiency virus.(1)
About Idenix
Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of patients with chronic hepatitis C infection. For further information about Idenix, please refer to www.idenix.com.
Forward-Looking Statements
This press release contains "forward-looking statements" for purposes of the safe harbor provisions of The Private Securities Litigation Reform Act of 1995, including but not limited to the statements regarding the company's future business and financial performance. For this purpose, any statements contained herein that are not statements of historical fact may be deemed forward-looking statements. Without limiting the foregoing, the words "expect," "plans," "anticipates," "will," "expects," "goal," "estimates," "projects," "would," "could," "targets," and similar expressions are also intended to identify forward-looking statements, as are expressed or implied statements with respect to the company's clinical development programs or commercialization activities in hepatitis C, or any potential pipeline candidates, including any expressed or implied statements regarding the efficacy and safety of our drug cand idates, the likelihood and success of any future clinical trials involving our drug candidates or successful development of novel combinations of direct-acting antivirals for the treatment of hepatitis C. Actual results may differ materially from those indicated by such forward-looking statements as a result of risks and uncertainties, including but not limited to the following: there can be no guarantees that the company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization; management's expectations could be affected by unexpected regulatory actions or delays, including the current clinical hold on IDX184 and IDX320; uncertainties relating to, or unsuccessful results of, clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the company's ability to obtain additional funding required to conduct its research, deve lopment and commercialization activities; the company's dependence o n its collaborations with Novartis Pharma AG and GlaxoSmithKline; changes in the company's business plan or objectives; the ability of the company to attract and retain qualified personnel; competition in general; and the company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. These and other risks which may impact management's expectations are described in greater detail under the heading "Risk Factors" in each of the company's annual report on Form 10-K for the year ended December 31, 2009 and quarterly report on form 10-Q for the quarter ended June 30, 2010, as filed with the Securities and Exchange Commission (SEC) and in any subsequent p eriodic or current report that the company files with the SEC.
All forward-looking statements reflect the company's estimates only as of the date of this release (unless another date is indicated) and should not be relied upon as reflecting the company's views, expectations or beliefs at any date subsequent to the date of this release. While Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if the company's estimates change.
(1) Lavanchy (2009) Liver International. 29(s1):74-81
Idenix Pharmaceuticals Contact:
Jonae Barnes (617) 224-4485 (investors)
Kelly Barry (617) 995-9033 (media)
Vertex, J&J Hepatitis C Drug Works After Others Fail
Vertex, J&J Hepatitis C Drug Works After Others Fail
By Ellen Gibson and Elizabeth Lopatto - Bloomberg, Sep 7, 2010 5:16 PM ET
Vertex Pharmaceuticals Inc.?s most advanced experimental drug, in development with Johnson & Johnson, worked in patients with hepatitis C who didn?t respond to other treatment, a study found.
Vertex?s medicine, telaprevir, added to standard treatments for the infection, cured 65 percent of patients overall compared with 17 percent on the other regimen alone, according to a company-funded study that Vertex reported today in a statement.
No proven medicines are available for hepatitis C patients who don?t respond to standard care. If approved by the U.S. Food and Drug Administration, Vertex?s drug may garner $4 billion in global annual sales by 2014, said Phil Nadeau, an analyst at Cowen & Co. Vertex, of Cambridge, Massachusetts, said it will seek U.S. approval of telaprevir in the fourth quarter.
“What most physicians have been doing up to now is warehousing those treatment-failed patients,” Nadeau said in a phone interview. “Now they have a real chance of being cured.”
Standard hepatitis C treatment -- a combination of the antiviral medicine ribavirin and a pegylated interferon such as Roche Holding AG?s Pegasys -- cures fewer than half of those who take them, and many patients develop serious side effects. With a second round of treatment using the same combination, the success rate drops as low as 10 percent.
Shares of Vertex rose 24 cents to $35.25 at 4:49 p.m. New York time in extended trading after closing down 2.9 percent on the Nasdaq Stock Market. Trial results were reported after the close of U.S. markets. The shares fell 3.6 percent in past 12 months.
Racing Merck
Telaprevir is racing boceprevir from Whitehouse Station, New Jersey-based Merck & Co. to become the first new hepatitis C treatment approved in a decade. Both are in a family of medicines known as protease inhibitors that work by blocking an enzyme that viruses use to copy themselves.
“Today?s results give people who haven?t achieved success with prior treatments some real hope for having a cure,” Robert Kauffman, the chief medical officer for Vertex, said today in a telephone interview.
About 3.6 million people in the U.S. and 170 million worldwide have hepatitis C, a chronic and potentially fatal infection, according to the World Health Organization, based in Geneva.
The virus, which typically spreads through contact with contaminated blood, damages the liver and can cause the organ to fail. While many people with hepatitis C have no symptoms and go undiagnosed, others experience stomach pain, jaundice, fevers and fatigue.
Revenue
In the U.S., there are 270,000 to 300,000 patients with hepatitis C who failed standard treatments, Vertex Chief Financial Officer Ian Smith said in a presentation to investors in Boston on Aug. 12. The company expects most of telaprevir?s revenue to come from this group during the first three years after the drug is cleared for sale, he said.
Today?s study, called Realize, was from the third and final stage of testing generally needed for FDA approval. It involved 662 people who had received prior treatment and weren?t cured, or who relapsed after the course of therapy ended.
The trial included three patient groups. One group received telaprevir for 12 weeks, added to ribavirin and interferon, followed by an added 36 weeks on the two older drugs alone. Among those people, 64 percent were cured, meaning the virus was reduced to undetectable levels in a blood test.
Study Results
A second group received that same 12-week cocktail. This group also got 4 weeks of prior treatment and 32 weeks of follow-up therapy with ribavirin and interferon. For them, the cure rate was 66 percent. (from Jules: see results I emailed yesterday - 31% SVR in null responders, 80+% in relapsers, 57% in prior partial responders)
A third set of patients had 48 weeks of treatment with the older drugs alone, and had a cure rate of 17 percent.
About 4 percent of patients enrolled in the trial discontinued treatment with telaprevir, interferon and ribaviron, compared with 3 percent in the control arm. With telaprevir, 0.6 percent stopped because of anemia, and 0.4 percent discontinued due to rashes.
“The safety profile is comparable to previous studies,” Kauffman said.
Previously reported results from two other late-stage trials of telaprevir showed the drug achieved a 75 percent cure rate in patients who had received no prior therapies and that treatment time can be cut to 24 weeks, from 48, in those patients without affecting the drug?s efficacy.
Johnson & Johnson, of New Brunswick, New Jersey, funded the study reported today. J&J agreed in 2006 to pay as much as $545 million to jointly develop the drug and sell it in Europe, South America, the Middle East, Africa and Australia. Vertex retained rights to North American sales. Mitsubishi Tanabe Pharma Corp. of Osaka, Japan, has rights for parts of Asia.
To contact the reporters on this story: Ellen Gibson in New York at egibson9@bloomberg.net; Elizabeth Lopatto in New York at elopatto@bloomberg.net
By Ellen Gibson and Elizabeth Lopatto - Bloomberg, Sep 7, 2010 5:16 PM ET
Vertex Pharmaceuticals Inc.?s most advanced experimental drug, in development with Johnson & Johnson, worked in patients with hepatitis C who didn?t respond to other treatment, a study found.
Vertex?s medicine, telaprevir, added to standard treatments for the infection, cured 65 percent of patients overall compared with 17 percent on the other regimen alone, according to a company-funded study that Vertex reported today in a statement.
No proven medicines are available for hepatitis C patients who don?t respond to standard care. If approved by the U.S. Food and Drug Administration, Vertex?s drug may garner $4 billion in global annual sales by 2014, said Phil Nadeau, an analyst at Cowen & Co. Vertex, of Cambridge, Massachusetts, said it will seek U.S. approval of telaprevir in the fourth quarter.
“What most physicians have been doing up to now is warehousing those treatment-failed patients,” Nadeau said in a phone interview. “Now they have a real chance of being cured.”
Standard hepatitis C treatment -- a combination of the antiviral medicine ribavirin and a pegylated interferon such as Roche Holding AG?s Pegasys -- cures fewer than half of those who take them, and many patients develop serious side effects. With a second round of treatment using the same combination, the success rate drops as low as 10 percent.
Shares of Vertex rose 24 cents to $35.25 at 4:49 p.m. New York time in extended trading after closing down 2.9 percent on the Nasdaq Stock Market. Trial results were reported after the close of U.S. markets. The shares fell 3.6 percent in past 12 months.
Racing Merck
Telaprevir is racing boceprevir from Whitehouse Station, New Jersey-based Merck & Co. to become the first new hepatitis C treatment approved in a decade. Both are in a family of medicines known as protease inhibitors that work by blocking an enzyme that viruses use to copy themselves.
“Today?s results give people who haven?t achieved success with prior treatments some real hope for having a cure,” Robert Kauffman, the chief medical officer for Vertex, said today in a telephone interview.
About 3.6 million people in the U.S. and 170 million worldwide have hepatitis C, a chronic and potentially fatal infection, according to the World Health Organization, based in Geneva.
The virus, which typically spreads through contact with contaminated blood, damages the liver and can cause the organ to fail. While many people with hepatitis C have no symptoms and go undiagnosed, others experience stomach pain, jaundice, fevers and fatigue.
Revenue
In the U.S., there are 270,000 to 300,000 patients with hepatitis C who failed standard treatments, Vertex Chief Financial Officer Ian Smith said in a presentation to investors in Boston on Aug. 12. The company expects most of telaprevir?s revenue to come from this group during the first three years after the drug is cleared for sale, he said.
Today?s study, called Realize, was from the third and final stage of testing generally needed for FDA approval. It involved 662 people who had received prior treatment and weren?t cured, or who relapsed after the course of therapy ended.
The trial included three patient groups. One group received telaprevir for 12 weeks, added to ribavirin and interferon, followed by an added 36 weeks on the two older drugs alone. Among those people, 64 percent were cured, meaning the virus was reduced to undetectable levels in a blood test.
Study Results
A second group received that same 12-week cocktail. This group also got 4 weeks of prior treatment and 32 weeks of follow-up therapy with ribavirin and interferon. For them, the cure rate was 66 percent. (from Jules: see results I emailed yesterday - 31% SVR in null responders, 80+% in relapsers, 57% in prior partial responders)
A third set of patients had 48 weeks of treatment with the older drugs alone, and had a cure rate of 17 percent.
About 4 percent of patients enrolled in the trial discontinued treatment with telaprevir, interferon and ribaviron, compared with 3 percent in the control arm. With telaprevir, 0.6 percent stopped because of anemia, and 0.4 percent discontinued due to rashes.
“The safety profile is comparable to previous studies,” Kauffman said.
Previously reported results from two other late-stage trials of telaprevir showed the drug achieved a 75 percent cure rate in patients who had received no prior therapies and that treatment time can be cut to 24 weeks, from 48, in those patients without affecting the drug?s efficacy.
Johnson & Johnson, of New Brunswick, New Jersey, funded the study reported today. J&J agreed in 2006 to pay as much as $545 million to jointly develop the drug and sell it in Europe, South America, the Middle East, Africa and Australia. Vertex retained rights to North American sales. Mitsubishi Tanabe Pharma Corp. of Osaka, Japan, has rights for parts of Asia.
To contact the reporters on this story: Ellen Gibson in New York at egibson9@bloomberg.net; Elizabeth Lopatto in New York at elopatto@bloomberg.net
65% of People Whose Prior Treatment for Hepatitis C Was Unsuccessful Achieved SVR (Viral Cure) with Telaprevir-Based Therapy in Phase 3 REALIZE Study
65% of People Whose Prior Treatment for Hepatitis C Was Unsuccessful Achieved SVR (Viral Cure) with Telaprevir-Based Therapy in Phase 3 REALIZE Study
-17% of people achieved SVR with pegylated-interferon and ribavirin alone in the control arm-
press release
Sept. 7, 2010, 4:01 p.m. EDT
CAMBRIDGE, Mass., Sep 07, 2010 (BUSINESS WIRE) -- ---Safety and tolerability results were consistent with prior Phase 3 studies-
---Completion of rolling New Drug Application submission on track for the fourth quarter 2010-
Vertex Pharmaceuticals Incorporated /quotes/comstock/15*!vrtx/quotes/nls/vrtx (VRTX 35.60, +0.59, +1.69%) today announced that 65% of people overall achieved a sustained viral response (SVR or viral cure) with a telaprevir-based regimen in the pivotal Phase 3 REALIZE study, as compared to 17% of people in the control arm who received pegylated-interferon and ribavirin alone. REALIZE enrolled three groups of patients with genotype 1 hepatitis C who had undergone at least one prior treatment course with pegylated-interferon and ribavirin but did not achieve SVR: (1) those who relapsed, (2) those who achieved a partial response and (3) those who had almost no response, known as a null response. REALIZE is the only Phase 3 hepatitis C study to date of an investigational direct-acting antiviral therapy that was designed to evaluate all major subgroups of people whose prior treatment was unsuccessful, including those who had a null response. The safety and tolerability results were consistent with results from the other two Phase 3 studies of telaprevir. The REALIZE study was conducted by Vertex's collaborator, Tibotec.
"The REALIZE data represent a major milestone in the development of new treatments for hepatitis C, as patients who received telaprevir-based therapy had a viral cure rate almost four times greater than the cure rate in those treated with available medicines," said Stefan Zeuzem, M.D., Professor of Medicine and Chief of the Department of Medicine at the JW Goethe University Hospital, Frankfurt, Germany and Principal Investigator of the trial. "These results may provide hope to people who have not been cured and who are in need of new treatment options, including those with advanced liver disease."
"Along with results from ADVANCE and ILLUMINATE, the REALIZE data provide us with a strong understanding of telaprevir's potential role in helping many people with hepatitis C achieve a cure, regardless of their treatment history," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "With these data, we look forward to completing our rolling New Drug Application submission for telaprevir later this year."
Overview of SVR Results
The primary endpoint of the study was SVR in each of the two telaprevir arms compared to the control arm, as well as across the three subgroups of people included in the study. One of the telaprevir treatment arms was designed to evaluate, for the first time, whether there was any further improvement in viral cure rates when delaying the start of telaprevir by four weeks, during which time patients received four weeks of pegylated-interferon and ribavirin alone, compared to a simultaneous start. The SVR rates between these two arms were similar and there was no clinical benefit to the telaprevir delayed start treatment arm in any of the subgroups of patients. The table below combines the two telaprevir arms compared to the control.
Relapsers Partial Responders Null Overall (ITT)
(n=354) (n=124) Responders (n=662)
(n=184)
----------- --------------------- ---------- -------------
Telaprevir- 86%* 57%* 31%* 65%*
based (n=245/286) (n=55/97) (n=46/147) (n=346/530)
Treatment
Arms+
----------- ---------------------
Pooled Analysis: 78% (n=300/383)**
------------------------------------------
Control 24% 15% 5% 17%
Arm++ (n=16/68) (n=4/27) (n=2/37) (n=22/132)
----------- ----------- --------------------- ---------- -------------
Pooled Analysis: 21% (n = 20/95)**
--------------------------------
*Combined endpoint analysis: The SVR rates observed in
the overall combined telaprevir-based arms were statistically
significant when compared with the control arm (p
+Reflects SVR rates from the combined telaprevir-based
treatment groups. There were two telaprevir-based treatment groups:
1. 12 weeks of telaprevir (750 mg, q8h), pegylated-interferon
(Peg-IFN) & ribavirin (RBV), followed by 36 weeks of Peg-IFN & RBV
alone or
2. 4 weeks of Peg-IFN & RBV alone followed by 12 weeks of
telaprevir (750 mg, q8h), Peg-IFN & RBV, followed by 32 weeks of
Peg-IFN & RBV alone
++12 weeks of placebo, Peg-IFN & RBV, followed by 36
weeks of Peg-IFN and RBV alone
**Supplemental analysis
Null Responder: Defined as a
person who achieved a less than 2 log10 reduction in
HCV RNA at week 12 of a prior course of therapy.
---------------------------------------------------------------------------------------
Relapser: Defined as a
person whose hepatitis C virus was undetectable at the completion
of at least 42 weeks of a prior course of therapy but whose virus
became detectable during the follow-up period.
---------------------------------------------------------------------------------------
Partial Responder: Defined
as a person who achieved at least a 2 log10 reduction
at week 12, but whose hepatitis C virus never became undetectable
by week 24 of a prior course of therapy.
---------------------------------------------------------------------------------------
Backgrounders on hepatitis C treatment response and the REALIZE
http://investors.vrtx.com/press.cfm---------------------------------------------------------------------------------------
SVR rates for the telaprevir simultaneous start arm and the delayed start arm were 64% and 66%, respectively, overall, based on an intent-to-treat (ITT) analysis. For the primary analysis, the SVR rates for the telaprevir simultaneous start arm, delayed start arm and control arm, respectively, were 83%, 88% and 24% in relapsers (p<0.0001); 59%, 54% and 15% in partial responders, (p<0.0001); and 29%, 33% and 5% in null responders, (p<0.001).
Safety & Tolerability Results
The safety and tolerability results of the telaprevir-based regimens in the REALIZE study were consistent with results reported from the Phase 3 ADVANCE and ILLUMINATE studies. The most common adverse events, reported in any treatment arm during the telaprevir dosing periods and up to week 16 to account for the telaprevir delayed start arm in order of frequency, were fatigue, pruritis, headache, rash, flu-like symptoms, nausea and anemia, with the majority being mild to moderate. Of these, fatigue, pruritis, rash, flu-like symptoms, nausea and anemia were more common in the telaprevir-based treatment arms compared to control. Adverse events leading to discontinuation of all study drugs during the telaprevir dosing period and up to week 16 occurred in 4% of people in the combined telaprevir arms and 3% in the control arm during the same period. Discontinuation of all drugs due to anemia and rash during the telaprevir dosing period and up to week 16 occurred in 0.6% and 0.4% of patients, respectively, in the combined telaprevir arms, while discontinuation of all three drugs due to rash and anemia did not occur in the control arm during the same period. As in ADVANCE and ILLUMINATE, the use of erythropoiesis-stimulating agents (ESAs) was not allowed in this study.
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. With results from the three Phase 3 studies of telaprevir - ADVANCE, ILLUMINATE and REALIZE - Vertex is on track to complete its rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2010.
Patient Demographics
REALIZE enrolled people with hepatitis C who did not achieve a viral cure after receiving at least one course of prior treatment with pegylated-interferon and ribavirin. Patients in the study were enrolled based on their response to prior treatment: 53% were prior relapsers, 19% were prior partial responders and 28% were prior null responders. In this study, 26% of patients overall had cirrhosis and 89% of patients overall had a high viral load (HCV RNA greater-than or equal to 800,000 IU/mL) when entering the study. Specifically in the null responder population, there were an even greater number of people with cirrhosis (33%) and high viral load (95%). Approximately 50% of patients were genotype 1a and 50% were genotype 1b.
About the Study
REALIZE was a pivotal Phase 3, randomized, double-blind, placebo-controlled study conducted in 662 people at more than 100 international clinical trial sites with the majority in Europe and North America. The study was designed to evaluate the efficacy, safety and tolerability of telaprevir-based regimens in people infected with genotype 1 chronic hepatitis C who did not achieve a viral cure after at least one prior treatment with interferon-based therapy. There were two telaprevir-based arms (simultaneous and delayed start) and one control arm. Patients were randomized 2:2:1 to the two telaprevir arms and the control arm, respectively.
The primary endpoint of the REALIZE study was SVR, defined as the proportion of people who had undetectable HCV RNA (<25IU/mL undetectable by Roche COBAS Taqman HCV test) 24 weeks after the end of all treatment. REALIZE was designed to compare the SVR rates for each of the telaprevir-based regimens with the control arm, separately for the prior response subgroups of relapsers and non-responders (null and partial responders), and then for the two subgroups of non-responders. The secondary endpoint was to evaluate the safety and tolerability of telaprevir in combination with pegylated-interferon and ribavirin.
As in all Phase 3 studies of telaprevir, patients received no more than 12 weeks of telaprevir given in combination with pegylated interferon and ribavirin. In REALIZE, the telaprevir arms included 12 weeks of telaprevir in combination with pegylated-interferon and ribavirin with 36 weeks of pegylated-interferon and ribavirin alone for a total of 48 weeks of treatment.
About the Telaprevir Development Program
To date, more than 2,500 people with hepatitis C have received telaprevir-based therapy as part of Phase 2 studies and the Phase 3 ADVANCE, ILLUMINATE and REALIZE studies. Together, these studies enrolled people with genotype 1 hepatitis C who had not been treated for their disease previously as well as people who had been treated before but did not achieve a viral cure.
Vertex retains commercial rights to telaprevir in North America. Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.
About Hepatitis C
Hepatitis C is a liver disease caused by the hepatitis C virus, which is found in the 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 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 major 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.
References:
(1)Ghany, m.G., Strader, d.B., Thomas, d.L., Seeff, Leondard B. Diagnosis, Management and Treatment of Hepatitis C; An Update. 2009. 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. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Available at http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. 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 T.R, 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, Michael I., Tocco, Rachel, Saini, Sameer, Lok, Anna S.F. Public Health Impact of Antiviral Therapy for Hepatitis C in the United States. Hepatology.2009;50(6):1750-1755. (10) Veldt, B.J., 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. Milliman, Inc. This report was commissioned by Vertex Pharmaceuticals, Inc. May, 2009.
Special Note Regarding Forward-looking Statements
This press release contains forward-looking statements, including statements regarding (i) the Company being on track to complete the NDA for telaprevir in the fourth quarter of 2010 and (ii) the REALIZE data providing the Company with a strong understanding of telaprevir's potential role in helping many people with hepatitis C achieve a cure, regardless of their treatment history. While the Company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the Company could experience unforeseen delays in submitting the NDA for telaprevir and/or obtaining approval to market telaprevir; that there may be varying interpretations of the data from the telaprevir clinical trials; that future outcomes from clinical trials of telaprevir may not be favorable; and that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir-based combination therapy and the 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. The Company disclaims any obligation to update the information contained in this press release as new information becomes available.
Investor Conference Call Today at 4:30 p.m. ET
Vertex Pharmaceuticals will host a conference call and webcast today, September 7, at 4:30 p.m. ET. This call and webcast will be broadcast via the Internet at www.vrtx.com/finances. It is suggested that webcast participants go to the web site at least 10 minutes in advance of the call to ensure that they can access the slides. The link to the webcast is available on the Events & Presentations button. To listen to the call on the telephone, dial (888) 634-7543 (U.S. and Canada) or (719) 457-2573 (International) and use conference ID number ID 5433422. Vertex is also providing a podcast MP3 file available for download on the Vertex website at www.vrtx.com.
The call will be available for replay via telephone commencing September 8, 2010 at 8:00 p.m. ET running through September 22, 2010 at 5:00 p.m. ET. To listen to the replay dial (888) 203-1112 (U.S. and Canada) or (719) 457-0820 (International) and use conference ID number 5433422. Following the live webcast, an archived version will be available on Vertex's website until 5:00 p.m. on September 15, 2010.
New York City Investor and Analyst Webcast Tomorrow, September 8, at 8:00 a.m. ET
Vertex Pharmaceuticals will also webcast its investor and analyst meeting from New York City on Wednesday, September 8, 2010 at 8:00 a.m. ET. This webcast will be broadcast via the Internet at www.vrtx.com/finances. The link to the webcast is available on the Events & Presentations button. The New York City webcast will not be available via telephone. It is suggested that webcast participants go to the web site at least 10 minutes in advance of the call to ensure that they can access the slides.
(VRTX-GEN)
Photos/Multimedia Gallery Available: http://www.businesswire.com/cgi-bin/mmg.cgi?eid=6419968&lang=en
SOURCE: Vertex Pharmaceuticals Incorporated
-17% of people achieved SVR with pegylated-interferon and ribavirin alone in the control arm-
press release
Sept. 7, 2010, 4:01 p.m. EDT
CAMBRIDGE, Mass., Sep 07, 2010 (BUSINESS WIRE) -- ---Safety and tolerability results were consistent with prior Phase 3 studies-
---Completion of rolling New Drug Application submission on track for the fourth quarter 2010-
Vertex Pharmaceuticals Incorporated /quotes/comstock/15*!vrtx/quotes/nls/vrtx (VRTX 35.60, +0.59, +1.69%) today announced that 65% of people overall achieved a sustained viral response (SVR or viral cure) with a telaprevir-based regimen in the pivotal Phase 3 REALIZE study, as compared to 17% of people in the control arm who received pegylated-interferon and ribavirin alone. REALIZE enrolled three groups of patients with genotype 1 hepatitis C who had undergone at least one prior treatment course with pegylated-interferon and ribavirin but did not achieve SVR: (1) those who relapsed, (2) those who achieved a partial response and (3) those who had almost no response, known as a null response. REALIZE is the only Phase 3 hepatitis C study to date of an investigational direct-acting antiviral therapy that was designed to evaluate all major subgroups of people whose prior treatment was unsuccessful, including those who had a null response. The safety and tolerability results were consistent with results from the other two Phase 3 studies of telaprevir. The REALIZE study was conducted by Vertex's collaborator, Tibotec.
"The REALIZE data represent a major milestone in the development of new treatments for hepatitis C, as patients who received telaprevir-based therapy had a viral cure rate almost four times greater than the cure rate in those treated with available medicines," said Stefan Zeuzem, M.D., Professor of Medicine and Chief of the Department of Medicine at the JW Goethe University Hospital, Frankfurt, Germany and Principal Investigator of the trial. "These results may provide hope to people who have not been cured and who are in need of new treatment options, including those with advanced liver disease."
"Along with results from ADVANCE and ILLUMINATE, the REALIZE data provide us with a strong understanding of telaprevir's potential role in helping many people with hepatitis C achieve a cure, regardless of their treatment history," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "With these data, we look forward to completing our rolling New Drug Application submission for telaprevir later this year."
Overview of SVR Results
The primary endpoint of the study was SVR in each of the two telaprevir arms compared to the control arm, as well as across the three subgroups of people included in the study. One of the telaprevir treatment arms was designed to evaluate, for the first time, whether there was any further improvement in viral cure rates when delaying the start of telaprevir by four weeks, during which time patients received four weeks of pegylated-interferon and ribavirin alone, compared to a simultaneous start. The SVR rates between these two arms were similar and there was no clinical benefit to the telaprevir delayed start treatment arm in any of the subgroups of patients. The table below combines the two telaprevir arms compared to the control.
Relapsers Partial Responders Null Overall (ITT)
(n=354) (n=124) Responders (n=662)
(n=184)
----------- --------------------- ---------- -------------
Telaprevir- 86%* 57%* 31%* 65%*
based (n=245/286) (n=55/97) (n=46/147) (n=346/530)
Treatment
Arms+
----------- ---------------------
Pooled Analysis: 78% (n=300/383)**
------------------------------------------
Control 24% 15% 5% 17%
Arm++ (n=16/68) (n=4/27) (n=2/37) (n=22/132)
----------- ----------- --------------------- ---------- -------------
Pooled Analysis: 21% (n = 20/95)**
--------------------------------
*Combined endpoint analysis: The SVR rates observed in
the overall combined telaprevir-based arms were statistically
significant when compared with the control arm (p
+Reflects SVR rates from the combined telaprevir-based
treatment groups. There were two telaprevir-based treatment groups:
1. 12 weeks of telaprevir (750 mg, q8h), pegylated-interferon
(Peg-IFN) & ribavirin (RBV), followed by 36 weeks of Peg-IFN & RBV
alone or
2. 4 weeks of Peg-IFN & RBV alone followed by 12 weeks of
telaprevir (750 mg, q8h), Peg-IFN & RBV, followed by 32 weeks of
Peg-IFN & RBV alone
++12 weeks of placebo, Peg-IFN & RBV, followed by 36
weeks of Peg-IFN and RBV alone
**Supplemental analysis
Null Responder: Defined as a
person who achieved a less than 2 log10 reduction in
HCV RNA at week 12 of a prior course of therapy.
---------------------------------------------------------------------------------------
Relapser: Defined as a
person whose hepatitis C virus was undetectable at the completion
of at least 42 weeks of a prior course of therapy but whose virus
became detectable during the follow-up period.
---------------------------------------------------------------------------------------
Partial Responder: Defined
as a person who achieved at least a 2 log10 reduction
at week 12, but whose hepatitis C virus never became undetectable
by week 24 of a prior course of therapy.
---------------------------------------------------------------------------------------
Backgrounders on hepatitis C treatment response and the REALIZE
http://investors.vrtx.com/press.cfm---------------------------------------------------------------------------------------
SVR rates for the telaprevir simultaneous start arm and the delayed start arm were 64% and 66%, respectively, overall, based on an intent-to-treat (ITT) analysis. For the primary analysis, the SVR rates for the telaprevir simultaneous start arm, delayed start arm and control arm, respectively, were 83%, 88% and 24% in relapsers (p<0.0001); 59%, 54% and 15% in partial responders, (p<0.0001); and 29%, 33% and 5% in null responders, (p<0.001).
Safety & Tolerability Results
The safety and tolerability results of the telaprevir-based regimens in the REALIZE study were consistent with results reported from the Phase 3 ADVANCE and ILLUMINATE studies. The most common adverse events, reported in any treatment arm during the telaprevir dosing periods and up to week 16 to account for the telaprevir delayed start arm in order of frequency, were fatigue, pruritis, headache, rash, flu-like symptoms, nausea and anemia, with the majority being mild to moderate. Of these, fatigue, pruritis, rash, flu-like symptoms, nausea and anemia were more common in the telaprevir-based treatment arms compared to control. Adverse events leading to discontinuation of all study drugs during the telaprevir dosing period and up to week 16 occurred in 4% of people in the combined telaprevir arms and 3% in the control arm during the same period. Discontinuation of all drugs due to anemia and rash during the telaprevir dosing period and up to week 16 occurred in 0.6% and 0.4% of patients, respectively, in the combined telaprevir arms, while discontinuation of all three drugs due to rash and anemia did not occur in the control arm during the same period. As in ADVANCE and ILLUMINATE, the use of erythropoiesis-stimulating agents (ESAs) was not allowed in this study.
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. With results from the three Phase 3 studies of telaprevir - ADVANCE, ILLUMINATE and REALIZE - Vertex is on track to complete its rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2010.
Patient Demographics
REALIZE enrolled people with hepatitis C who did not achieve a viral cure after receiving at least one course of prior treatment with pegylated-interferon and ribavirin. Patients in the study were enrolled based on their response to prior treatment: 53% were prior relapsers, 19% were prior partial responders and 28% were prior null responders. In this study, 26% of patients overall had cirrhosis and 89% of patients overall had a high viral load (HCV RNA greater-than or equal to 800,000 IU/mL) when entering the study. Specifically in the null responder population, there were an even greater number of people with cirrhosis (33%) and high viral load (95%). Approximately 50% of patients were genotype 1a and 50% were genotype 1b.
About the Study
REALIZE was a pivotal Phase 3, randomized, double-blind, placebo-controlled study conducted in 662 people at more than 100 international clinical trial sites with the majority in Europe and North America. The study was designed to evaluate the efficacy, safety and tolerability of telaprevir-based regimens in people infected with genotype 1 chronic hepatitis C who did not achieve a viral cure after at least one prior treatment with interferon-based therapy. There were two telaprevir-based arms (simultaneous and delayed start) and one control arm. Patients were randomized 2:2:1 to the two telaprevir arms and the control arm, respectively.
The primary endpoint of the REALIZE study was SVR, defined as the proportion of people who had undetectable HCV RNA (<25IU/mL undetectable by Roche COBAS Taqman HCV test) 24 weeks after the end of all treatment. REALIZE was designed to compare the SVR rates for each of the telaprevir-based regimens with the control arm, separately for the prior response subgroups of relapsers and non-responders (null and partial responders), and then for the two subgroups of non-responders. The secondary endpoint was to evaluate the safety and tolerability of telaprevir in combination with pegylated-interferon and ribavirin.
As in all Phase 3 studies of telaprevir, patients received no more than 12 weeks of telaprevir given in combination with pegylated interferon and ribavirin. In REALIZE, the telaprevir arms included 12 weeks of telaprevir in combination with pegylated-interferon and ribavirin with 36 weeks of pegylated-interferon and ribavirin alone for a total of 48 weeks of treatment.
About the Telaprevir Development Program
To date, more than 2,500 people with hepatitis C have received telaprevir-based therapy as part of Phase 2 studies and the Phase 3 ADVANCE, ILLUMINATE and REALIZE studies. Together, these studies enrolled people with genotype 1 hepatitis C who had not been treated for their disease previously as well as people who had been treated before but did not achieve a viral cure.
Vertex retains commercial rights to telaprevir in North America. Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.
About Hepatitis C
Hepatitis C is a liver disease caused by the hepatitis C virus, which is found in the 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 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 major 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.
References:
(1)Ghany, m.G., Strader, d.B., Thomas, d.L., Seeff, Leondard B. Diagnosis, Management and Treatment of Hepatitis C; An Update. 2009. 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. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Available at http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. 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 T.R, 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, Michael I., Tocco, Rachel, Saini, Sameer, Lok, Anna S.F. Public Health Impact of Antiviral Therapy for Hepatitis C in the United States. Hepatology.2009;50(6):1750-1755. (10) Veldt, B.J., 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. Milliman, Inc. This report was commissioned by Vertex Pharmaceuticals, Inc. May, 2009.
Special Note Regarding Forward-looking Statements
This press release contains forward-looking statements, including statements regarding (i) the Company being on track to complete the NDA for telaprevir in the fourth quarter of 2010 and (ii) the REALIZE data providing the Company with a strong understanding of telaprevir's potential role in helping many people with hepatitis C achieve a cure, regardless of their treatment history. While the Company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the Company could experience unforeseen delays in submitting the NDA for telaprevir and/or obtaining approval to market telaprevir; that there may be varying interpretations of the data from the telaprevir clinical trials; that future outcomes from clinical trials of telaprevir may not be favorable; and that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir-based combination therapy and the 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. The Company disclaims any obligation to update the information contained in this press release as new information becomes available.
Investor Conference Call Today at 4:30 p.m. ET
Vertex Pharmaceuticals will host a conference call and webcast today, September 7, at 4:30 p.m. ET. This call and webcast will be broadcast via the Internet at www.vrtx.com/finances. It is suggested that webcast participants go to the web site at least 10 minutes in advance of the call to ensure that they can access the slides. The link to the webcast is available on the Events & Presentations button. To listen to the call on the telephone, dial (888) 634-7543 (U.S. and Canada) or (719) 457-2573 (International) and use conference ID number ID 5433422. Vertex is also providing a podcast MP3 file available for download on the Vertex website at www.vrtx.com.
The call will be available for replay via telephone commencing September 8, 2010 at 8:00 p.m. ET running through September 22, 2010 at 5:00 p.m. ET. To listen to the replay dial (888) 203-1112 (U.S. and Canada) or (719) 457-0820 (International) and use conference ID number 5433422. Following the live webcast, an archived version will be available on Vertex's website until 5:00 p.m. on September 15, 2010.
New York City Investor and Analyst Webcast Tomorrow, September 8, at 8:00 a.m. ET
Vertex Pharmaceuticals will also webcast its investor and analyst meeting from New York City on Wednesday, September 8, 2010 at 8:00 a.m. ET. This webcast will be broadcast via the Internet at www.vrtx.com/finances. The link to the webcast is available on the Events & Presentations button. The New York City webcast will not be available via telephone. It is suggested that webcast participants go to the web site at least 10 minutes in advance of the call to ensure that they can access the slides.
(VRTX-GEN)
Photos/Multimedia Gallery Available: http://www.businesswire.com/cgi-bin/mmg.cgi?eid=6419968&lang=en
SOURCE: Vertex Pharmaceuticals Incorporated
Proteome‐Wide Anti–Hepatitis C Virus (HCV) and Anti‐HIV Antibody Profiling for Predicting and Monitoring the Response to HCV Therapy in HIV
Proteome‐Wide Anti–Hepatitis C Virus (HCV) and Anti‐HIV Antibody Profiling for Predicting and Monitoring the Response to HCV Therapy in HIV‐Coinfected Patients
JID Sept 15 2010
"Declining anti‐HCV core and envelope‐specific antibody responses at the end of therapy were observed only in the SVR group, suggesting that these antibody responses could be used to discriminate between those who experience relapse and SVR at the end of therapy. The SVR group showed the largest and most consistent decrease in titers of antibodies against the core, E1, and NS4 proteins after 48 weeks of treatment. In contrast, the NR and relapse groups showed minimal decreases in antibody titers. Despite the less than detectable levels of HCV RNA at the end of HCV treatment in the relapse and SVR groups, significant decreases in anti‐HCV antibody titers do frequently occur among patients with SVRs. Given that HCV loads in the relapse and SVR groups were clinically indistinguishable and below the level of detection, it is possible that the decrease in levels of antibodies in the SVR group reflects a marked decline in antigen load in the liver rather than in the plasma. Regardless of the mechanism, the differential response in antibody titers between the SVR and relapse groups at the end of treatment offers a novel tool to predict who will experience relapse after treatment is stopped. This could lead to the development of novel therapeutic strategies, such as extended therapy for those with relapse. Studies addressing whether these antibodies and/or other biomarkers show robust differences at earlier time points may provide practical tools for monitoring therapy."
"Titers of antibodies against the panel of HCV proteins were also evaluated before and after treatment for their value in monitoring HCV therapy. The Wilcoxon sign ranked test revealed that 4 of the 6 HCV proteins (core, E1, E2, and NS4) showed statistically significant (p<.05) decreases in antibody titer between the pre‐ and posttreatment samples (Figure 3). In contrast, antibody responses to the NS3 and NS5A antigens did not significantly change between before and after treatment (p>.44). Substratification by treatment outcome revealed that the SVR group showed the most consistent and largest decrease (p=.02) in titers of antibodies against the 3 most informative antigens (core, E1, and NS4) after treatment (Figure 3). In contrast, the NR and relapse groups had relatively stable titers of antibodies against these 3 antigens between before and after treatment (p=.70 and p=.43, respectively)"
Peter D. Burbelo,1
Joseph A. Kovacs,2
Kathryn H. Ching,1
Alexandra T. Issa,1
Michael J. Iadarola,1
Alison A. Murphy,3
Joerg F. Schlaak,4
Henry Masur,2
Michael A. Polis,3 and
Shyam Kottilil3
1Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, 2Critical Care Medicine Department, National Institutes of Health Clinical Center, and 3Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; 4University Hospital of Essen, Essen, Germany
We quantified antibody responses to the hepatitis C virus (HCV) proteome that are associated with sustained virologic response (SVR) in human immunodeficiency virus (HIV)/HCV–coinfected patients treated with pegylated interferon and ribavirin. Analysis of pre‐ and posttreatment samples revealed significant decreases in the combined anti‐core, anti‐E1, and anti‐NS4 HCV antibody titers in those with SVRs but not in those who experienced relapse or who did not respond. Furthermore, anti–HIV p24 antibody titers inversely correlated with treatment response. These results suggest that profiling anti‐HCV antibody is useful for monitoring HCV therapy, especially in discriminating between those who experience relapse and those who have SVRs at 48 weeks.
Infection with hepatitis C virus (HCV) is seen in 15%–30% of all human immunodeficiency virus (HIV)–infected individuals in the United States, as a result of the shared routes of viral transmission [1, 2]. The introduction of antiretroviral therapy has improved clinical outcomes in patients infected with HIV. However, liver disease has become a leading cause of morbidity and mortality in this population [3, 4]. HIV/HCV coinfection is also associated with higher HCV levels in serum [5, 6], rapid progression of liver disease [7], and lower efficacy of treatment with pegylated interferon plus ribavirin [5, 8]. Development of biomarkers that can accurately predict therapeutic responses are needed to optimize HCV therapy in this coinfected population. Previously, HIV/HCV‐coinfected patients who were not responsive to HCV therapy with pegylated interferon plus ribavirin were found to have a gene‐activation signature present before treatment indicative of the activation of many immune‐related molecules, including interferon‐stimulated genes [9]. Quantitative and qualitative humoral responses over the course of HCV therapy among HIV/HCV‐coinfected subjects have never been studied, to our knowledge. The ability to clearly predict and monitor outcomes of HCV infection in a robust and simple serological test would have obvious clinical utility. Recently, luciferase immunoprecipitation system (LIPS) assays have been used to accurately quantify antibody responses to various viral pathogens [10]. In the present study, we used LIPS profiling of antibodies against the whole proteome of HCV and part of the proteome of HIV to evaluate its utility in predicting and monitoring the response to HCV therapy in HIV/HCV‐coinfected individuals.
Methods. This was a prospective, open‐label trial performed at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, Maryland. All 29 patients provided written informed consent approved by the NIAID Institutional Review Board. HIV/HCV‐coinfected patients were treated with pegylated interferon alfa‐2b at 1.5 μg/kg subcutaneously every week (PegIntron; Schering‐Plough) and ribavirin daily (Rebetol; Schering‐Plough; 400 mg every morning and 600 mg every evening for those <75 kg or 600 mg twice per day for those >75 kg) for 48 weeks and followed up for 24 weeks after the end of treatment. All patients irrespective of virologic response were treated for 48 weeks. One patient discontinued ribavirin at week 24 because of refractory anemia but continued pegylated interferon until week 48.
Patients were eligible for the study if they were >18 years of age and had a CD4 T cell count of >100 cells/μL, an absolute neutrophil count of >1000 cells/μL, an HCV load of >2000 copies/mL, histologic evidence of chronic hepatitis C, and stable HIV disease with or without antiretroviral therapy. Patients with other causes of liver disease, advanced cirrhosis or severe liver decompensation, and several other conditions were excluded. These patients included 11 who experienced no response (NR group), 9 end‐of‐treatment responders who experienced relapse after 48 weeks of therapy (relapse group), and 9 who experienced sustained virologic responses (SVR group). All patients (except for 1 of the patients in the relapse group who was enrolled in the study and 1 of the previous patients in the NR group who was omitted because of lack of a serum sample) have been described elsewhere [9].
Renilla luciferase (Ruc) antigen fusions—including HCV core, HCV NS3, HCV NS5A, HIV p24 Gag, and HIV Tat—have been described elsewhere [10]. Four additional HCV proteins were generated as Ruc antigen fusions, including E1, E2, NS3, and NS4. One HCV protein, NS5B, was tested, but it was not found to be useful and was not used further. LIPS assays with these different HCV and other Ruc antigens were performed as described elsewhere [11]. All of the light unit (LU) data represent the average of 2 independent experiments and were corrected for background LU values.
Prism software (version 5; GraphPad) was used for statistical analyses. The Mann‐Whitney U test was used for comparison of antibody titers between groups, and the Wilcoxon signed rank test was used to evaluate statistical differences between values before and after HCV therapy.
Results.
Antibody titers in serum samples from all patients and in 2 control samples were evaluated for 6 different recombinant HCV antigens, essentially derived from the whole proteome of HCV. A heat map, constructed with log10‐transformed antibody titers, was used to display the differing antibody responses to the 6 antigens in individual samples from these subgroups (Figure 1A). As shown by the heat map, LIPS profiling of responses to these 6 HCV antigens clearly distinguished the 29 HCV‐infected serum samples from the 2 uninfected control serum samples. The most useful antibody response was directed against the HCV core, for which all but 1 of the 29 HIV/HCV‐coinfected samples was positive. The second most useful antibody response was against NS3 (Figure 1A). The other 4 HCV proteins (E1, E2, NS4, and NS5) showed variable immunoreactivity with HIV/HCV‐coinfected serum samples (Figure 1A). Of interest, 1 patient in the NR group was completely negative for anti‐core, anti‐E1, and anti‐E2 antibodies but showed strong immunoreactivity to 3 other nonstructural HCV proteins (Figure 1A). Titers of antibodies against the 6 HCV antigens correlated poorly with each other (r8>0.60), suggesting marked heterogeneity in humoral responses (Table 1).
Titers of antibodies against these HCV antigens in pretreatment serum samples showed no significant differences between the NR, relapse, and SVR groups (figure 2). For example, the mean anti‐core antibody titers in the NR, relapse, and SVR groups were 497,200 LUs (95% confidence interval [CI], 279,800–714,700 LUs), 483,400 LUs (95% CI, 292,500–674,200 LUs), and 545,600 LUs (95% CI, 299,400–791,900 LUs), respectively, and the Mann‐Whitney U test showed no statistically significant differences ( ). These results suggest that anti‐HCV antibody titers in the pretreatment HIV/HCV‐coinfected serum samples have no obvious predictive value for response to treatment.
Because of the known effect that HIV/HCV coinfection has on HCV therapy, antibody responses to several HIV proteins were also evaluated in the 3 groups. As shown in Figure 1B, all 29 pretreatment serum samples were robustly seropositive for anti–HIV p24 Gag antibodies by previously determined cutoffs [10], whereas the 2 uninfected control samples were negative. The mean anti‐p24 antibody titers in the NR, relapse, and SVR groups were 2.77x10(6) , 2.17x10(6), and 1.71x10(6) LUs, respectively. The anti‐p24 antibody titer in the relapse group did not significantly differ from that in either the NR or SVR group (p>.47, Mann‐Whitney U test); the NR and SVR groups showed a statistically significant difference in anti‐p24 antibody titer (p=0.23). Anti‐p24 antibody titers did not correlate (p>.05) with HIV or HCV load, genotype, or CD4 T cell count (data not shown). However, anti‐p24 antibody titers paralleled the cumulative group scores for the interferon‐associated gene‐expression signature previously reported by Lempicki et al [9] for the same patients. Titers of antibodies against the Tat protein of HIV did not significantly differ between the NR, relapse, and SVR groups (p>.26) (data not shown). Because statistically higher anti‐p24 antibody titers were detected in the NR group versus the SVR group and correlated with failure of HCV therapy, a cutoff based on 2.2 million LUs was determined to optimally separate these 2 groups. By this approach, 9 of the 11 patients in the NR group were above the cutoff, compared with only 2 of the 9 patients in the SVR group (Figure 1B). On the basis of this analysis, anti‐p24 antibody titers provide 82% positive predictive value in identifying patients who will experience therapy failure. Although anti‐p24 antibody titers had value only in distinguishing NR from SVR (and none for relapse), there is little practical predictive value for this test in HIV/HCV‐coinfected individuals.
Titers of antibodies against the panel of HCV proteins were also evaluated before and after treatment for their value in monitoring HCV therapy. The Wilcoxon sign ranked test revealed that 4 of the 6 HCV proteins (core, E1, E2, and NS4) showed statistically significant (p<.05) decreases in antibody titer between the pre‐ and posttreatment samples (Figure 3). In contrast, antibody responses to the NS3 and NS5A antigens did not significantly change between before and after treatment (p>.44). Substratification by treatment outcome revealed that the SVR group showed the most consistent and largest decrease (p=.02) in titers of antibodies against the 3 most informative antigens (core, E1, and NS4) after treatment (Figure 3). In contrast, the NR and relapse groups had relatively stable titers of antibodies against these 3 antigens between before and after treatment (p=.70 and p=.43, respectively) (Figure 3). Anti–HIV p24 and anti–BRLF2 Epstein‐Barr virus antibody titers also did not change with HCV therapy (data not shown). There was heterogeneity in response to the different HCV antigens in the SVR group, in which some patients showed the largest decrease in anti–HCV core antibody titers, whereas other patients showed more pronounced decreases in anti‐ENV1 and anti‐NS4 antibody titers. Because decreasing levels of antibodies against these 3 HCV antigens was a common feature of the SVR group versus the NR and relapse groups, the relative decrease in antibody titer between the pre‐ and posttreatment samples was the most useful approach for distinguishing SVR from NR and relapse. With an antibody titer decrease of >1.5‐fold between the pre‐ and posttreatment samples used as a marker of HCV therapy success, 6 of the 9 patients in the SVR group were positive, compared with only 1 of the 9 patients in the relapse group and none of the patients in the NR group. Overall, this LIPS assay measuring differences in titers of antibodies against these 3 HCV antigens between the pre and posttreatment samples showed an 86% positive predictive value in identifying a response to therapy.
Figure 3. Informative antibody titers before and after hepatitis C virus (HCV) treatment in human immunodeficiency virus–coinfected patients in the no‐response (NR; n=11), relapse (n=9), and sustained virologic response (SVR) (n=9) groups. Shown are anti‐core, anti‐E1, and anti‐NS4 antibodies levels at baseline and after treatment in individual patients. The solid horizontal bars reflect the mean titer in each group for the pre‐ and posttreatment sample. Statistical differences between pre‐ and posttreatment values were calculated using the nonparametric Wilcoxon signed rank test. The P values derived from summation of the light unit (LU) antibody titers for the 3 antigens are shown at bottom.
Screen shot 2010-09-03 at 1.29.59 PM.png
Discussion.
Our study suggests that highly quantitative HCV proteome–wide antibody responses can be a valuable tool for monitoring and predicting HCV therapeutic responses among HIV‐coinfected patients. Few studies have examined the utility of anti‐pathogen antibodies for predicting and monitoring drug therapy. Our LIPS assay provided a clearer summary of the marked patient variability in humoral responses to the whole HCV proteome than has been previously reported. None of the baseline antibody responses to the 6 different HCV proteins predicted response to HCV therapy. This suggests that preexisting host humoral responses to HCV generally do not affect the response to HCV therapy. Previously, it has been shown that, among HCV‐monoinfected patients, those with SVRs had higher pretreatment anti‐NS4A and anti‐NS5a antibody titers (without normalization for HCV load) than did those with NRs [12]. It should be noted that our study differs from this published study in that our patient population was coinfected with HIV and HCV, and HCV loads were controlled for. Nevertheless, 1 patient in the NR group completely lacked anti‐core, anti‐E1, and anti‐E2 antibodies but had high levels of other HCV antibodies, possibly explaining the lack of responsiveness to HCV therapy. Given that this patient (infected with HCV genotype 1) had ample antibodies against HIV and nonstructural HCV proteins, it is likely that selective B cell exhaustion or deletion of certain populations of plasma B cells occurred [13, 14]. Intriguingly, anti–HIV p24 antibodies detected in the pretreatment samples inversely correlated with response to treatment. The highest anti‐p24 antibody titers were observed in the NR group, intermediate titers were observed in the relapse group, and the lowest titers were observed in the SVR group. The higher anti‐p24 antibody titers in the NR group compared with the SVR group suggests that some of the patients in the NR group who responded poorly to interferon treatment may have had an abnormal immune response to HIV.
Declining anti‐HCV core and envelope‐specific antibody responses at the end of therapy were observed only in the SVR group, suggesting that these antibody responses could be used to discriminate between those who experience relapse and SVR at the end of therapy. The SVR group showed the largest and most consistent decrease in titers of antibodies against the core, E1, and NS4 proteins after 48 weeks of treatment. In contrast, the NR and relapse groups showed minimal decreases in antibody titers. Despite the less than detectable levels of HCV RNA at the end of HCV treatment in the relapse and SVR groups, significant decreases in anti‐HCV antibody titers do frequently occur among patients with SVRs. Given that HCV loads in the relapse and SVR groups were clinically indistinguishable and below the level of detection, it is possible that the decrease in levels of antibodies in the SVR group reflects a marked decline in antigen load in the liver rather than in the plasma. Regardless of the mechanism, the differential response in antibody titers between the SVR and relapse groups at the end of treatment offers a novel tool to predict who will experience relapse after treatment is stopped. This could lead to the development of novel therapeutic strategies, such as extended therapy for those with relapse. Studies addressing whether these antibodies and/or other biomarkers show robust differences at earlier time points may provide practical tools for monitoring therapy.
JID Sept 15 2010
"Declining anti‐HCV core and envelope‐specific antibody responses at the end of therapy were observed only in the SVR group, suggesting that these antibody responses could be used to discriminate between those who experience relapse and SVR at the end of therapy. The SVR group showed the largest and most consistent decrease in titers of antibodies against the core, E1, and NS4 proteins after 48 weeks of treatment. In contrast, the NR and relapse groups showed minimal decreases in antibody titers. Despite the less than detectable levels of HCV RNA at the end of HCV treatment in the relapse and SVR groups, significant decreases in anti‐HCV antibody titers do frequently occur among patients with SVRs. Given that HCV loads in the relapse and SVR groups were clinically indistinguishable and below the level of detection, it is possible that the decrease in levels of antibodies in the SVR group reflects a marked decline in antigen load in the liver rather than in the plasma. Regardless of the mechanism, the differential response in antibody titers between the SVR and relapse groups at the end of treatment offers a novel tool to predict who will experience relapse after treatment is stopped. This could lead to the development of novel therapeutic strategies, such as extended therapy for those with relapse. Studies addressing whether these antibodies and/or other biomarkers show robust differences at earlier time points may provide practical tools for monitoring therapy."
"Titers of antibodies against the panel of HCV proteins were also evaluated before and after treatment for their value in monitoring HCV therapy. The Wilcoxon sign ranked test revealed that 4 of the 6 HCV proteins (core, E1, E2, and NS4) showed statistically significant (p<.05) decreases in antibody titer between the pre‐ and posttreatment samples (Figure 3). In contrast, antibody responses to the NS3 and NS5A antigens did not significantly change between before and after treatment (p>.44). Substratification by treatment outcome revealed that the SVR group showed the most consistent and largest decrease (p=.02) in titers of antibodies against the 3 most informative antigens (core, E1, and NS4) after treatment (Figure 3). In contrast, the NR and relapse groups had relatively stable titers of antibodies against these 3 antigens between before and after treatment (p=.70 and p=.43, respectively)"
Peter D. Burbelo,1
Joseph A. Kovacs,2
Kathryn H. Ching,1
Alexandra T. Issa,1
Michael J. Iadarola,1
Alison A. Murphy,3
Joerg F. Schlaak,4
Henry Masur,2
Michael A. Polis,3 and
Shyam Kottilil3
1Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, 2Critical Care Medicine Department, National Institutes of Health Clinical Center, and 3Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; 4University Hospital of Essen, Essen, Germany
We quantified antibody responses to the hepatitis C virus (HCV) proteome that are associated with sustained virologic response (SVR) in human immunodeficiency virus (HIV)/HCV–coinfected patients treated with pegylated interferon and ribavirin. Analysis of pre‐ and posttreatment samples revealed significant decreases in the combined anti‐core, anti‐E1, and anti‐NS4 HCV antibody titers in those with SVRs but not in those who experienced relapse or who did not respond. Furthermore, anti–HIV p24 antibody titers inversely correlated with treatment response. These results suggest that profiling anti‐HCV antibody is useful for monitoring HCV therapy, especially in discriminating between those who experience relapse and those who have SVRs at 48 weeks.
Infection with hepatitis C virus (HCV) is seen in 15%–30% of all human immunodeficiency virus (HIV)–infected individuals in the United States, as a result of the shared routes of viral transmission [1, 2]. The introduction of antiretroviral therapy has improved clinical outcomes in patients infected with HIV. However, liver disease has become a leading cause of morbidity and mortality in this population [3, 4]. HIV/HCV coinfection is also associated with higher HCV levels in serum [5, 6], rapid progression of liver disease [7], and lower efficacy of treatment with pegylated interferon plus ribavirin [5, 8]. Development of biomarkers that can accurately predict therapeutic responses are needed to optimize HCV therapy in this coinfected population. Previously, HIV/HCV‐coinfected patients who were not responsive to HCV therapy with pegylated interferon plus ribavirin were found to have a gene‐activation signature present before treatment indicative of the activation of many immune‐related molecules, including interferon‐stimulated genes [9]. Quantitative and qualitative humoral responses over the course of HCV therapy among HIV/HCV‐coinfected subjects have never been studied, to our knowledge. The ability to clearly predict and monitor outcomes of HCV infection in a robust and simple serological test would have obvious clinical utility. Recently, luciferase immunoprecipitation system (LIPS) assays have been used to accurately quantify antibody responses to various viral pathogens [10]. In the present study, we used LIPS profiling of antibodies against the whole proteome of HCV and part of the proteome of HIV to evaluate its utility in predicting and monitoring the response to HCV therapy in HIV/HCV‐coinfected individuals.
Methods. This was a prospective, open‐label trial performed at the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, Maryland. All 29 patients provided written informed consent approved by the NIAID Institutional Review Board. HIV/HCV‐coinfected patients were treated with pegylated interferon alfa‐2b at 1.5 μg/kg subcutaneously every week (PegIntron; Schering‐Plough) and ribavirin daily (Rebetol; Schering‐Plough; 400 mg every morning and 600 mg every evening for those <75 kg or 600 mg twice per day for those >75 kg) for 48 weeks and followed up for 24 weeks after the end of treatment. All patients irrespective of virologic response were treated for 48 weeks. One patient discontinued ribavirin at week 24 because of refractory anemia but continued pegylated interferon until week 48.
Patients were eligible for the study if they were >18 years of age and had a CD4 T cell count of >100 cells/μL, an absolute neutrophil count of >1000 cells/μL, an HCV load of >2000 copies/mL, histologic evidence of chronic hepatitis C, and stable HIV disease with or without antiretroviral therapy. Patients with other causes of liver disease, advanced cirrhosis or severe liver decompensation, and several other conditions were excluded. These patients included 11 who experienced no response (NR group), 9 end‐of‐treatment responders who experienced relapse after 48 weeks of therapy (relapse group), and 9 who experienced sustained virologic responses (SVR group). All patients (except for 1 of the patients in the relapse group who was enrolled in the study and 1 of the previous patients in the NR group who was omitted because of lack of a serum sample) have been described elsewhere [9].
Renilla luciferase (Ruc) antigen fusions—including HCV core, HCV NS3, HCV NS5A, HIV p24 Gag, and HIV Tat—have been described elsewhere [10]. Four additional HCV proteins were generated as Ruc antigen fusions, including E1, E2, NS3, and NS4. One HCV protein, NS5B, was tested, but it was not found to be useful and was not used further. LIPS assays with these different HCV and other Ruc antigens were performed as described elsewhere [11]. All of the light unit (LU) data represent the average of 2 independent experiments and were corrected for background LU values.
Prism software (version 5; GraphPad) was used for statistical analyses. The Mann‐Whitney U test was used for comparison of antibody titers between groups, and the Wilcoxon signed rank test was used to evaluate statistical differences between values before and after HCV therapy.
Results.
Antibody titers in serum samples from all patients and in 2 control samples were evaluated for 6 different recombinant HCV antigens, essentially derived from the whole proteome of HCV. A heat map, constructed with log10‐transformed antibody titers, was used to display the differing antibody responses to the 6 antigens in individual samples from these subgroups (Figure 1A). As shown by the heat map, LIPS profiling of responses to these 6 HCV antigens clearly distinguished the 29 HCV‐infected serum samples from the 2 uninfected control serum samples. The most useful antibody response was directed against the HCV core, for which all but 1 of the 29 HIV/HCV‐coinfected samples was positive. The second most useful antibody response was against NS3 (Figure 1A). The other 4 HCV proteins (E1, E2, NS4, and NS5) showed variable immunoreactivity with HIV/HCV‐coinfected serum samples (Figure 1A). Of interest, 1 patient in the NR group was completely negative for anti‐core, anti‐E1, and anti‐E2 antibodies but showed strong immunoreactivity to 3 other nonstructural HCV proteins (Figure 1A). Titers of antibodies against the 6 HCV antigens correlated poorly with each other (r8>0.60), suggesting marked heterogeneity in humoral responses (Table 1).
Titers of antibodies against these HCV antigens in pretreatment serum samples showed no significant differences between the NR, relapse, and SVR groups (figure 2). For example, the mean anti‐core antibody titers in the NR, relapse, and SVR groups were 497,200 LUs (95% confidence interval [CI], 279,800–714,700 LUs), 483,400 LUs (95% CI, 292,500–674,200 LUs), and 545,600 LUs (95% CI, 299,400–791,900 LUs), respectively, and the Mann‐Whitney U test showed no statistically significant differences ( ). These results suggest that anti‐HCV antibody titers in the pretreatment HIV/HCV‐coinfected serum samples have no obvious predictive value for response to treatment.
Because of the known effect that HIV/HCV coinfection has on HCV therapy, antibody responses to several HIV proteins were also evaluated in the 3 groups. As shown in Figure 1B, all 29 pretreatment serum samples were robustly seropositive for anti–HIV p24 Gag antibodies by previously determined cutoffs [10], whereas the 2 uninfected control samples were negative. The mean anti‐p24 antibody titers in the NR, relapse, and SVR groups were 2.77x10(6) , 2.17x10(6), and 1.71x10(6) LUs, respectively. The anti‐p24 antibody titer in the relapse group did not significantly differ from that in either the NR or SVR group (p>.47, Mann‐Whitney U test); the NR and SVR groups showed a statistically significant difference in anti‐p24 antibody titer (p=0.23). Anti‐p24 antibody titers did not correlate (p>.05) with HIV or HCV load, genotype, or CD4 T cell count (data not shown). However, anti‐p24 antibody titers paralleled the cumulative group scores for the interferon‐associated gene‐expression signature previously reported by Lempicki et al [9] for the same patients. Titers of antibodies against the Tat protein of HIV did not significantly differ between the NR, relapse, and SVR groups (p>.26) (data not shown). Because statistically higher anti‐p24 antibody titers were detected in the NR group versus the SVR group and correlated with failure of HCV therapy, a cutoff based on 2.2 million LUs was determined to optimally separate these 2 groups. By this approach, 9 of the 11 patients in the NR group were above the cutoff, compared with only 2 of the 9 patients in the SVR group (Figure 1B). On the basis of this analysis, anti‐p24 antibody titers provide 82% positive predictive value in identifying patients who will experience therapy failure. Although anti‐p24 antibody titers had value only in distinguishing NR from SVR (and none for relapse), there is little practical predictive value for this test in HIV/HCV‐coinfected individuals.
Titers of antibodies against the panel of HCV proteins were also evaluated before and after treatment for their value in monitoring HCV therapy. The Wilcoxon sign ranked test revealed that 4 of the 6 HCV proteins (core, E1, E2, and NS4) showed statistically significant (p<.05) decreases in antibody titer between the pre‐ and posttreatment samples (Figure 3). In contrast, antibody responses to the NS3 and NS5A antigens did not significantly change between before and after treatment (p>.44). Substratification by treatment outcome revealed that the SVR group showed the most consistent and largest decrease (p=.02) in titers of antibodies against the 3 most informative antigens (core, E1, and NS4) after treatment (Figure 3). In contrast, the NR and relapse groups had relatively stable titers of antibodies against these 3 antigens between before and after treatment (p=.70 and p=.43, respectively) (Figure 3). Anti–HIV p24 and anti–BRLF2 Epstein‐Barr virus antibody titers also did not change with HCV therapy (data not shown). There was heterogeneity in response to the different HCV antigens in the SVR group, in which some patients showed the largest decrease in anti–HCV core antibody titers, whereas other patients showed more pronounced decreases in anti‐ENV1 and anti‐NS4 antibody titers. Because decreasing levels of antibodies against these 3 HCV antigens was a common feature of the SVR group versus the NR and relapse groups, the relative decrease in antibody titer between the pre‐ and posttreatment samples was the most useful approach for distinguishing SVR from NR and relapse. With an antibody titer decrease of >1.5‐fold between the pre‐ and posttreatment samples used as a marker of HCV therapy success, 6 of the 9 patients in the SVR group were positive, compared with only 1 of the 9 patients in the relapse group and none of the patients in the NR group. Overall, this LIPS assay measuring differences in titers of antibodies against these 3 HCV antigens between the pre and posttreatment samples showed an 86% positive predictive value in identifying a response to therapy.
Figure 3. Informative antibody titers before and after hepatitis C virus (HCV) treatment in human immunodeficiency virus–coinfected patients in the no‐response (NR; n=11), relapse (n=9), and sustained virologic response (SVR) (n=9) groups. Shown are anti‐core, anti‐E1, and anti‐NS4 antibodies levels at baseline and after treatment in individual patients. The solid horizontal bars reflect the mean titer in each group for the pre‐ and posttreatment sample. Statistical differences between pre‐ and posttreatment values were calculated using the nonparametric Wilcoxon signed rank test. The P values derived from summation of the light unit (LU) antibody titers for the 3 antigens are shown at bottom.
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Discussion.
Our study suggests that highly quantitative HCV proteome–wide antibody responses can be a valuable tool for monitoring and predicting HCV therapeutic responses among HIV‐coinfected patients. Few studies have examined the utility of anti‐pathogen antibodies for predicting and monitoring drug therapy. Our LIPS assay provided a clearer summary of the marked patient variability in humoral responses to the whole HCV proteome than has been previously reported. None of the baseline antibody responses to the 6 different HCV proteins predicted response to HCV therapy. This suggests that preexisting host humoral responses to HCV generally do not affect the response to HCV therapy. Previously, it has been shown that, among HCV‐monoinfected patients, those with SVRs had higher pretreatment anti‐NS4A and anti‐NS5a antibody titers (without normalization for HCV load) than did those with NRs [12]. It should be noted that our study differs from this published study in that our patient population was coinfected with HIV and HCV, and HCV loads were controlled for. Nevertheless, 1 patient in the NR group completely lacked anti‐core, anti‐E1, and anti‐E2 antibodies but had high levels of other HCV antibodies, possibly explaining the lack of responsiveness to HCV therapy. Given that this patient (infected with HCV genotype 1) had ample antibodies against HIV and nonstructural HCV proteins, it is likely that selective B cell exhaustion or deletion of certain populations of plasma B cells occurred [13, 14]. Intriguingly, anti–HIV p24 antibodies detected in the pretreatment samples inversely correlated with response to treatment. The highest anti‐p24 antibody titers were observed in the NR group, intermediate titers were observed in the relapse group, and the lowest titers were observed in the SVR group. The higher anti‐p24 antibody titers in the NR group compared with the SVR group suggests that some of the patients in the NR group who responded poorly to interferon treatment may have had an abnormal immune response to HIV.
Declining anti‐HCV core and envelope‐specific antibody responses at the end of therapy were observed only in the SVR group, suggesting that these antibody responses could be used to discriminate between those who experience relapse and SVR at the end of therapy. The SVR group showed the largest and most consistent decrease in titers of antibodies against the core, E1, and NS4 proteins after 48 weeks of treatment. In contrast, the NR and relapse groups showed minimal decreases in antibody titers. Despite the less than detectable levels of HCV RNA at the end of HCV treatment in the relapse and SVR groups, significant decreases in anti‐HCV antibody titers do frequently occur among patients with SVRs. Given that HCV loads in the relapse and SVR groups were clinically indistinguishable and below the level of detection, it is possible that the decrease in levels of antibodies in the SVR group reflects a marked decline in antigen load in the liver rather than in the plasma. Regardless of the mechanism, the differential response in antibody titers between the SVR and relapse groups at the end of treatment offers a novel tool to predict who will experience relapse after treatment is stopped. This could lead to the development of novel therapeutic strategies, such as extended therapy for those with relapse. Studies addressing whether these antibodies and/or other biomarkers show robust differences at earlier time points may provide practical tools for monitoring therapy.
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