June 19, 2011

Dig Dis Sci. 2011 Jun 2. [Epub ahead of print]
 
 
Gastroenterology Section, Department of Veterans Affairs Medical Center (VAMC), 4150 Clement Street (111B), San Francisco, CA, 94121, USA.

Abstract

BACKGROUND:
Studies of the retreatment with consensus interferon (CIFN) and ribavirin (RBV) of hepatitis C virus (HCV)-infected patients who failed prior pegylated interferon alfa/ribavirin (PEG-IFN/RBV) have found quite variable efficacy and tolerability of this therapy. As such, CIFN/RBV use and efficacy in clinical practice were evaluated within the Department of Veterans Affairs (VA), the largest national, integrated system for HCV care.

AIMS:
The purpose of this study was to determine rates of sustained virologic response (SVR) and patterns of CIFN/RBV use in the VA. Methods included retrospective review of national VA data in HCV-infected patients who had previously failed ≥12 weeks of PEG-IFN/RBV and were prescribed CIFN/RBV between October 1, 2003 and September 30, 2006.

RESULTS:
A total of 597 patients met the study criteria. CIFN was primarily dosed as 15 mcg subcutaneously daily combined with standard doses of RBV. Mean treatment duration was 21 weeks; CIFN was discontinued within 4 weeks in 24%. Hematological growth factors were used in 49%. Post-treatment viral loads were available in 385 patients. SVR to CIFN/RBV was achieved in 11%, and was significantly higher in prior PEG-IFN/RBV relapsers compared with nonresponders (31% vs. 6%, respectively; P < 0.0001). A 2-log(10) or greater drop in HCV RNA after 24 weeks of PEG-IFN/RBV was a predictor of subsequent SVR to CIFN/RBV.

CONCLUSIONS:
CIFN/RBV was used frequently in clinical practice for retreatment of PEG-IFN/RBV. In this setting, early treatment discontinuation was common. Overall SVR was low, although response was significantly better in prior PEG-IFN/RBV relapsers and those who had a 2-log(10) or greater decline than in nonresponders.

Source
N Engl J Med. 2011 Jun 9;364(23):2199-207. Epub 2011 Jun 1.
 
 
Department of Internal Medicine, University of New Mexico, Albuquerque, USA. sarora@salud.unm.edu

Abstract

BACKGROUND:
The Extension for Community Healthcare Outcomes (ECHO) model was developed to improve access to care for underserved populations with complex health problems such as hepatitis C virus (HCV) infection. With the use of video-conferencing technology, the ECHO program trains primary care providers to treat complex diseases.

METHODS:
We conducted a prospective cohort study comparing treatment for HCV infection at the University of New Mexico (UNM) HCV clinic with treatment by primary care clinicians at 21 ECHO sites in rural areas and prisons in New Mexico. A total of 407 patients with chronic HCV infection who had received no previous treatment for the infection were enrolled. The primary end point was a sustained virologic response.

RESULTS:
A total of 57.5% of the patients treated at the UNM HCV clinic (84 of 146 patients) and 58.2% of those treated at ECHO sites (152 of 261 patients) had a sustained viral response (difference in rates between sites, 0.7 percentage points; 95% confidence interval, -9.2 to 10.7; P=0.89). Among patients with HCV genotype 1 infection, the rate of sustained viral response was 45.8% (38 of 83 patients) at the UNM HCV clinic and 49.7% (73 of 147 patients) at ECHO sites (P=0.57). Serious adverse events occurred in 13.7% of the patients at the UNM HCV clinic and in 6.9% of the patients at ECHO sites.

CONCLUSIONS:
The results of this study show that the ECHO model is an effective way to treat HCV infection in underserved communities. Implementation of this model would allow other states and nations to treat a greater number of patients infected with HCV than they are currently able to treat. (Funded by the Agency for Healthcare Research and Quality and others.).

Comment in

J Infect Dis. 2011 Jul;204(1):84-93.
 

Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN.

Abstract

Background. Pegylated interferon, ribavirin, and telaprevir triple therapy is a new strategy expected to eradicate the hepatitis C virus (HCV) even in patients infected with difficult-to-treat genotype 1 strains, although adverse effects, such as anemia and rash, are frequent. Methods. We assessed efficacy and predictive factors for sustained virological response (SVR) for triple therapy in 94 Japanese patients with HCV genotype 1. We included recently identified predictive factors, such as IL28B and ITPA polymorphism, and substitutions in the HCV core and NS5A proteins. Results. Patients treated with triple therapy achieved comparatively high SVR rates (73%), especially among treatment-naive patients (80%). Of note, however, patients who experienced relapse during prior pegylated interferon plus ribavirin combination therapy were highly likely to achieve SVR while receiving triple therapy (93%); conversely, prior nonresponders were much less likely to respond to triple therapy (32%). In addition to prior treatment response, IL28B SNP genotype and rapid viral response were significant independent predictors for SVR. Patients with the anemia-susceptible ITPA SNP rs1127354 genotype typically required ribavirin dose reduction earlier than did patients with other genotypes. Conclusions. Analysis of predictive factors identified IL28B SNP, rapid viral response, and transient response to previous therapy as significant independent predictors of SVR after triple therapy.
J Hepatol. 2011 May 14. [Epub ahead of print]
 
 
Inserm, U748, Strasbourg, France; Université de Strasbourg, Strasbourg, France.

Abstract

COMMENTARY ON:: A humanized mouse model to study hepatitis C virus infection, immune response and liver disease. Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger JA, Barry W, Ploss A, Rice CM, Su L. Gastroenterology. 2011 Apr;140(4):1334-44. Copyright (2011). Abstract reprinted with permission from the American Gastroenterological Association. http://www.ncbi.nlm.nih.gov/pubmed/21237170. ABSTRACT: Background & Aims: Studies of hepatitis C virus (HCV) infection, immunopathogenesis, and resulting liver diseases have been hampered by the lack of a small animal model. We developed humanized mice with human immune system and liver tissues to improve the studies of hepatitis C pathogenesis and treatment. Methods: To promote engraftment of human hepatocytes, we expressed a fusion protein of the FK506 binding protein (FKBP) and caspase 8 under the control of the albumin promoter (AFC8), which induces liver cell death, in Balb/C Rag2(-/-) γC-null mice. Co-transplantation of human CD34(+) human hematopoietic stem cells (HSC) and hepatocyte progenitors into the transgenic mice led to efficient engraftment of human leucocytes and hepatocytes. We then infected these humanized mice (AFC8-hu HSC/Hep) with primary HCV isolates and studied HCV-induced immune responses and liver diseases. Results: AFC8-hu HSC/Hep mice supported HCV infection in the liver and generated a human immune T-cell response against HCV. HCV infection induced liver inflammation, hepatitis, and fibrosis, which correlated with activation of stellate cells and expression of human fibrogenic genes. Conclusions: AFC8-hu HSC/Hep mice are a useful model of HCV infection, the immune response, and liver disease, because they contain human immune system and liver cells. These mice become infected with HCV, generate a specific immune response against the virus, and develop liver diseases that include hepatitis and fibrosis. This model might also be used to develop therapeutics for HCV infection.

Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Source
Hepatology. 2011 May 29. doi: 10.1002/hep.24460. [Epub ahead of print]
 
 
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.

Abstract

Telaprevir is a potent inhibitor of hepatitis C virus (HCV) NS3-4A protease. However, emergence of drug resistant strains during therapy is a serious problem, and the susceptibility of resistant strains to interferon (IFN), as well as the details of the emergence of mutant strains in vivo is not known. We previously established an infectious model of HCV using human hepatocyte chimeric mice. Using this system, we investigated the biological properties and mode of emergence of mutants by ultra-deep sequencing technology. Chimeric mice were injected with serum samples obtained from a patient who had developed viral breakthrough during telaprevir monotherapy with strong selection for resistance mutations (A156F [92.6%]). Mice infected with the resistant strain (A156F [99.9%]) developed only low-level viremia, and the virus was successfully eliminated with interferon therapy. As observed in patients, telaprevir monotherapy in viremic mice resulted in breakthrough, with selection for mutations that confer resistance to telaprevir (e.g., a high frequency of V36A [52.2%]). Mice were injected intrahepatically with HCV genotype 1b clone KT-9 with or without an introduced resistance mutation, A156S, in the NS3 region, and treated with telaprevir. Mice infected with the A156S strain developed lower level viremia compared to the wild type strain but showed strong resistance to telaprevir treatment. Although mice injected with wild type HCV showed a rapid decline in viremia at the beginning of therapy, a high frequency (11%) of telaprevir-resistant NS3 V36A variants emerged two weeks after the start of treatment. Conclusion: Using deep sequencing technology and a genetically engineered HCV infection system, we showed that the rapid emergence of telaprevir-resistant HCV was induced by mutation from the wild type strain of HCV in vivo. (HEPATOLOGY 2011.).

Copyright © 2011 American Association for the Study of Liver Diseases.

Source
For many patients with the hepatitis C virus (HCV), direct antiviral agents (DAA) offer a potential cure for the disease. The Food and Drug Administration (FDA) has recently approved two new DAAs, telaprevir and boceprevir, and with that clinicians must now decide who should be the first to receive this treatment. Discussion of this timely topic is now available in the June issue of Hepatology.

The World Health Organization (WHO) estimates up to 170,000 million individuals worldwide are infected with chronic HCV. In the U.S., HCV is the leading cause of liver-related mortality and most common cause for liver transplantation. Medical evidence has shown that for the past ten years response rates to pegylated interferon and ribavirin treatment have been stagnant, with less than half of patients achieving a sustained virologic response. Now with the introduction of new DAA therapy, it is expected to significantly improve virus clearance rates, particularly in patients with genotype 1, compared to the current standard of care.

"The availability of DAA therapy will forever change the landscape of HCV," explains Andrew Aronsohn, MD, from the University of Chicago Medical center and co-author of the current paper. "We will now be able to cure patients of HCV disease who we were unable to cure in the past." However, as the authors note, the medical breakthrough with DAAs is coupled with resource scarcity and an equitable distribution based upon medical need is essential.

DAA therapy and its promise to improve efficacy has been well publicized for a number of years, prompting clinicians and patients to defer standard care in cases where there was a low risk of HCV progressing to severe liver disease. The authors point out that in one large study of 4084 patients evaluated for HCV therapy with interferon and ribavirin, of those that declined therapy more than half did so in anticipation of more effective therapy.

The advent of DAAs will likely create a surge in requests to initiate treatment given the number of patients who deferred treatment, along with those patients who failed to respond to standard HCV regiments. The authors performed a time analysis study at their institution to understand the time needed to treat patients with DAA therapy. They found that on average, a health care provider could initiate therapy on three patients each week, and at least 500 requests for evaluation of HCV therapy are anticipated during the first few weeks of DAA availability. "Current staffing will be unable to meet the demands of all HCV patients requesting treatment," concluded co-author, Donald Jensen, MD. "We propose a plan to educate patients and triage therapy to the neediest patients first, thereby fulfilling the moral framework of distributive justice."

Reference: Andrew Aronsohn and Donald Jensen. Distributive Justice and the Arrival of Direct Acting Antivirals. Who Should be First in Line? Hepatology. June 2011.

Source
Gastroenterology
Volume 140, Issue 7, June 2011, Pages 1961-1969

Neal D. Freedmanlow asterisk , Teresa M. Curto, Karen L. Lindsay§, Elizabeth C. Wrightshort parallel, Rashmi Sinhalow asterisk, James E. Everhart and HALT-C TRIAL GROUP

New England Research Institutes, Watertown, Massachusetts
low asterisk Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland
short parallel Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
§ Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California
Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland

Received 20 November 2010;
accepted 18 February 2011.
Available online 2 March 2011.

Background & Aims

High-level coffee consumption has been associated with reduced progression of pre-existing liver diseases and lower risk of hepatocellular carcinoma. However, its relationship with therapy for hepatitis C virus infection has not been evaluated.

Methods

Patients (n = 885) from the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial recorded coffee intake before retreatment with peginterferon α-2a (180 μg/wk) and ribavirin (1000–1200 mg/day). We assessed patients for early virologic response (2 log10 reduction in level of hepatitis C virus RNA at week 12; n = 466), and undetectable hepatitis C virus RNA at weeks 20 (n = 320), 48 (end of treatment, n = 284), and 72 (sustained virologic response; n = 157).

Results

Median log10 drop from baseline to week 20 was 2.0 (interquartile range [IQR], 0.6–3.9) among nondrinkers and 4.0 (IQR, 2.1–4.7) among patients that drank 3 or more cups/day of coffee (P trend <.0001). After adjustment for age, race/ethnicity, sex, alcohol, cirrhosis, ratio of aspartate aminotransferase to alanine aminotransferase, the IL28B polymorphism rs12979860, dose reduction of peginterferon, and other covariates, odds ratios for drinking 3 or more cups/day vs nondrinking were 2.0 (95% confidence interval [CI]: 1.1–3.6; P trend = .004) for early virologic response, 2.1 (95% CI: 1.1–3.9; P trend = .005) for week 20 virologic response, 2.4 (95% CI: 1.3–4.6; P trend = .001) for end of treatment, and 1.8 (95% CI: 0.8–3.9; P trend = .034) for sustained virologic response.

Conclusions

High-level consumption of coffee (more than 3 cups per day) is an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with hepatitis C.

Keywords: Liver Fibrosis; Diet; Risk Factor; Caffeine


Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; FFQ, food frequency questionnaire; HALT-C, Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial; HCV, hepatitis C virus; HOMA2, homeostatic model assessment score of insulin resistance; IQR, interquartile range; LDL, low-density lipoprotein


Article Outline

Materials and Methods
Patient Population
Assessment of Coffee and Tea Consumption
Assessment of Outcomes
Statistical Analysis
Results
Discussion
Acknowledgements
References
Conflicts of interest This author discloses the following: Dr Lindsay was a consultant and received research support from Hoffmann-La Roche, Inc. (now Genentech) during this study and is now an employee of Tibotec, Inc. (a subsidiary of Johnson and Johnson), Titusville, NJ.The remaining authors disclose no conflicts.

Funding This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (contract numbers are listed in the Acknowledgments). Additional support was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed in the Acknowledgments). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc. (now Genentech), through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health. This research was also supported in part by the Intramural Research Program of the National Cancer Institute. The funding organizations had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Reprint requests Address requests for reprints to: Neal Freedman, PhD, MPH, Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS/320, MSC 7232, Rockville, Maryland 20852. fax: (301) 496-682.

Source
Gastroenterology. 2011 Apr 14. [Epub ahead of print]
 
 
Department of Hepatology, Division of Medicine, Imperial College London, London, United Kingdom.

Abstract

BACKGROUND & AIMS:
Polymorphisms in the IL28B gene are associated with outcomes from infection with hepatitis C virus (HCV). However, the role of these polymorphisms in protecting injection drug users who are at high risk for HCV infection but do not have detectable antibodies against HCV or HCV RNA (exposed uninfected) has not been demonstrated. We investigated whether these individuals have the IL28B genotype rs12979860-CC, which protects some individuals against HCV infection.

METHODS:
Seventy-four exposed uninfected individuals, 89 spontaneous resolvers, and 234 chronically infected individuals were genotyped to determine single nucleotide polymorphisms at IL28B.rs12979860.

RESULTS:
Exposed, uninfected individuals had a significantly lower frequency of the protective genotype (rs12979860-CC) than anti-HCV-positive spontaneous resolvers (41.9% vs 69.7%, respectively; P = .0005; odds ratio [OR], 0.31; 95% confidence interval [CI]: 0.16-0.60) but a similar frequency to patients who were chronically infected (41.9% vs 43.6%, respectively; P = ns). However, exposed, uninfected individuals had a significantly higher frequency of homozygosity for KIR2DL3:HLA-C1 than those with chronic infection (31.1% vs 13.3%, respectively; P = .0008; OR, 2.95; 95% CI: 1.59-5.49). For patients who spontaneously resolved infection, IL28B and KIR:HLA protected, independently, against chronic HCV infection, based on logistic regression and synergy analyses (synergy factor, 1.3; 95% CI: 0.37-4.75; P synergy = .6).

CONCLUSIONS:
IL28B and KIR2DL3:HLA-C1 are independently associated with spontaneous resolution of viremia following HCV exposure. Resistance to HCV infection in exposed uninfected cases is associated with homozygosity for KIR2DL3:HLA-C1 but not the single nucleotide polymorphisms IL28B.rs12979860. Uninfected individuals are therefore a distinct population from patients who spontaneously resolve HCV infection. Distinct, nonsynergistic innate immune mechanisms can determine outcomes of HCV exposures.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Source

Fair Pricing Coalition Says Vertex’s Incivek Price 'Outrageous'

May 25, 2011

The Fair Pricing Coalition is again sounding the alarm regarding the price of newly approved treatments for hepatitis C, this time questioning the cost of Vertex’s protease inhibitor Incivek (telaprevir). The advocacy group is concerned that Incivek’s price tag of $49,200 per 12-week course will adversely affect the ability of people with HCV to access the drug, while also setting an excessively unreasonable future price point for the many hepatitis C virus (HCV) drugs in the pipeline.

“Merck’s Victrelis costs $48,400 for 48 weeks of treatment,” said FPC member Lynda Dee in a statement from the organization. “Now Vertex has set a price approximately four times greater than Victrelis for 12 weeks of Incivek treatment. While we welcome a shorter course of Incivek treatment, both price points are outrageous. What is worse, you can bet that no future HCV drugs will be priced less than Victrelis and Incivek. What a terrible way to begin!”

According to FDA labeling for Incivek, approved May 23, the drug should be taken for 12 weeks with either 24 or 48 weeks of pegylated interferon and ribavirin, depending on a patient’s response to the regimen. The wholesale price for 48 weeks of HCV treatment with pegylated interferon and ribavirin is about $30,000. The $49,200 WAC price for 12 weeks of Incivek, the FPC wrote, “will more than double the already exorbitant 48 week price” of hepatitis C treatment.

“Although the addition of Incivek to pegylated interferon and ribavirin should significantly increase the HCV cure rate, it will be impossible to sustain these prices in light of the current U.S. health care crisis,” Dee said.

“The HCV community is anxiously awaiting interferon-sparing regimens because of the terrible side effects caused by interferon as well as ribavirin,” said FPC member Murray Penner. “An encouraging number of these drugs are currently in development. It will take three and maybe even four of these new drugs in a combination regimen to effectively cure HCV in the future. Future HCV drugs will invariably be more expensive than Victrelis and Incivek.

“If each of the new drugs costs $50,000, we are looking at regimens that will ultimately cost between $150,000 and $200,000 in the very near future. This is unsustainable and will unacceptably limit access to the regimens.”

Other costs need to be considered as well, the FPC states. According to a paper presented at the annual conference of the American Association for the Study of Liver Diseases (AASLD), the costs of treating the side effects of HCV protease inhibitors such as Victrelis are expected to be 30 percent higher than for existing treatments. And many of those with hepatitis C suffer from other illnesses. Some have diabetes or bleeding disorders; others are coinfected with HIV. All of these add completely new sets of medical expenses.

“We were very disappointed by the cost set by Merck for Victrelis earlier this month. Our fears about Vertex’s price for Incivek have now unfortunately come to pass,” Dee said. “How will this all end? We fear it will end in a lack of patient access to promising new HCV treatments that will result in morbidity and mortality for hundreds of thousands of Americans.

“Both Merck and Vertex have pledged to make their new drugs available to patients who cannot afford these exorbitant prices through their co-pay and patient assistance programs (PAP). Vertex’s PAP is particularly generous,” Dee pointed out. “The FPC will continue to advocate for people with HCV to ensure that both companies keep their word. We have kept a tight watch on HIV drug manufacturers in this regard. We intend to do the same thing in the viral hepatitis arena.”

Journal of Viral Hepatitis

T. Kawaoka1,2, H. Aikata1, S. Takaki1, A. Hiramatsu1, K. Waki1, N. Hiraga1, D. Miki1,2, M. Tsuge1, M. Imamura1, Y. Kawakami1, S. Takahashi1, H. Ochi1,2, H. Tashiro3, H. Ohdan3, K. Chayama1,2

Article first published online: 23 MAY 2011
DOI: 10.1111/j.1365-2893.2011.01468.x
© 2011 Blackwell Publishing Ltd

Author Information

1 Department of Medicine and Molecular Science, Division of Frontier Medical Science, Minami-ku, Hiroshima University, Hiroshima, Japan
2 Laboratory for Digestive Diseases, Centre for Genomic Medicine, RIKEN (The Institute of Physical and Chemical Research), Minami-ku, Hiroshima, Japan
3 Department of Surgery, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan

* Correspondence: Hiroshi Aikata, MD, Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail: aikata@hiroshima-u.ac.jp

Abstract

Keywords:
curative treatment; hepatitis C virus; hepatocellular carcinoma; interleukin-28B; pegylated interferon-alpha plus ribavirin combination therapy

Summary.  The present study was designed to determine the predictive factors for the viral response to pegylated interferon-alpha plus ribavirin combination therapy (PEGIFN/RBV) administered after curative treatment for hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). The study group was 78 patients treated between January 2005 and January 2009. The sustained viral response (SVR) rate was 25.8% (15/58) in patients infected with HCV-genotype 1 and 55.0% (11/20) in those with genotype 2. Among the 78 patients, 32 (41.0%) could not complete the treatment protocol, and this was because of HCC recurrence in 17 (53%) of them. Multivariate analysis identified partial early viral response (pEVR) as the only independent determinant of SVR [odds ratio (OR) 14.73, P = 0.013] for patients with genotype 1. Multivariate analysis identified male gender (OR 8.72, P = 0.001) and interleukin-28B (IL-28B) genotype (rs8099917) TT (OR 7.93, P = 0.007) as independent predictors of pEVR. Multivariate analysis also identified IL-28B genotype GG+TG (OR 14.1, P = 0.021) and α-fetoprotein >30 (OR 5.4, P = 0.031) as independent predictors of null response. Patients with SVR showed a better survival rate than those without SVR (P = 0.034). The second HCC recurrence rate tended to be lower in patients with SVR than in those without SVR (P = 0.054). With regard to the prognosis of patients with SVR, it is desirable to achieve SVR with interferon therapy even when administered after HCC treatment. IL-28B genotype is a potentially useful marker for the response to PEGIFN/RBV therapy administered after curative treatment of HCV-related HCC.

Source

FDA Approves INCIVEK™ (telaprevir) for People with Hepatitis C

I realize that this is not new news, yet I wanted to post the press release from Vertex for those that have not read it.

May 23, 2011

-79% of people treated for the first time achieved a SVR (viral cure) with INCIVEK combination treatment-
-Vertex launches a comprehensive financial assistance and patient support program-
-Conference call today at 11:00 a.m. ET to provide more information on the commercialization of INCIVEK-

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that the U.S. Food and Drug Administration (FDA) has approved INCIVEK™ (telaprevir) tablets for a broad group of people with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK (in-SEE-veck) is approved for people who are new to treatment, and for people who were treated previously but who did not achieve a viral cure (relapsers, partial responders and null responders). INCIVEK is given for 12 weeks in combination with pegylated-interferon and ribavirin, two other medicines approved to treat hepatitis C. After the first 12 weeks, all patients stop receiving INCIVEK and continue treatment with pegylated-interferon and ribavirin alone for an additional 12 weeks or 36 weeks of treatment. With INCIVEK combination treatment, more than 60 percent of people treated for the first time, as well as those who relapsed after previous therapy, are expected to complete all treatment in 24 weeks — half the time needed if they were to take pegylated-interferon and ribavirin alone. All other patients will receive a total of 48 weeks of treatment. INCIVEK will arrive in pharmacies this week.  

The approval of INCIVEK was based on data from three Phase 3 studies, which showed that people who received INCIVEK combination treatment achieved significantly higher rates of sustained viral response (SVR, or viral cure) compared to those who received pegylated-interferon and ribavirin alone, regardless of their prior treatment experience:

People new to treatment:
79 percent vs. 46 percent

People who were treated previously but did not achieve a viral cure:
-- Relapsers:
86 percent vs. 22 percent
-- Partial responders:
59 percent vs. 15 percent
-- Null responders:
32 percent vs. 5 percent
INCIVEK (750 mg) is given as two 375-mg tablets three times daily. It is packaged in weekly boxes that include daily blister strips to help patients keep track of their doses.

Rash and anemia are the most serious side effects associated with INCIVEK. The most common side effects reported with INCIVEK combination treatment include fatigue, itching, nausea, diarrhea, vomiting, anal or rectal problems, and taste changes.

"Hepatitis C can lead to liver failure, cancer and the need for a transplant, and for the past decade, the best we could offer patients was a year of difficult treatment that resulted in a viral cure for fewer than half of them," said Ira Jacobson, M.D., Chief of the Division of Gastroenterology and Hepatology, Weill Cornell Medical College and principal investigator for a Phase 3 study of INCIVEK. "With INCIVEK, 79 percent of people new to treatment achieved a viral cure."

"Today marks a turning point in the fight against hepatitis C, particularly for people who have been living with this silent disease for decades, hoping for a better chance of a viral cure," said Matthew Emmens, Chairman, President and Chief Executive Officer of Vertex. "The approval of INCIVEK was only possible thanks to more than 4,000 people who volunteered for our clinical studies, the doctors, nurses and coordinators who managed the studies, and our own pioneering scientists who have worked for more than 15 years to bring this new medicine to people with hepatitis C."

Vertex has 200 field-based employees across the United States, including a 115-person sales team, who are ready to support the introduction of INCIVEK. The sales team has an average of more than 14 years of experience bringing medicines to people who need them, including eight years of direct experience with antiviral medicines for diseases such as hepatitis C.

Helping People with Hepatitis C Get INCIVEK

The people who work at Vertex understand that medicines can only help patients who can get them. With that in mind, the company today introduced a comprehensive financial assistance and patient support program to help people get INCIVEK who might not otherwise be able to afford it. The program will help people with hepatitis C learn about insurance benefits for their medicines, give INCIVEK for free to eligible patients who do not have insurance and provide coverage for co-pay or co-insurance costs associated with INCIVEK for people who meet certain program criteria. Additionally, patients will have access to nurses through a 24-7 hotline by which they can receive support, guidance and educational materials about hepatitis C and its treatment. Vertex will also provide nurses and doctors with educational tools and resources so they can offer support and care to people with hepatitis C before, during and after the treatment process.

For eligible patients, the program includes the following:
  • Insurance Benefits Research and Support: Vertex case managers will research patients' insurance benefits for INCIVEK combination treatment, assist people with insurance appeals and help guide them to other forms of financial support, including Vertex's free medicine and co-pay programs;
  • Free Medicine Program: Vertex will give INCIVEK for free to people who do not have insurance and have an annual household income of $100,000 or less; and
  • Co-Pay Support: Vertex will cover co-pay or co-insurance costs up to 20 percent of the total cost of INCIVEK for people who have private insurance plans that cover INCIVEK, regardless of their household income. For people covered by government insurance, Vertex will also make donations to the independent, non-profit Patient Access Network Foundation, which has a fund to provide co-pay support to people taking hepatitis C medicines.
More information about this program is available by calling 1-855-837-8394 or visiting www.INCIVEK.com.

About INCIVEK

INCIVEK is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication. The Phase 3 registration studies evaluated INCIVEK in combination with Pegasys®(pegylated-interferon alfa-2a) and Copegus® (ribavirin) in people with hepatitis C who were new to treatment as well as those who were treated previously with pegylated-interferon and ribavirin but who did not achieve a viral cure, including:
  • Prior Relapsers: Defined as people whose hepatitis C virus was undetectable after a full course of previous treatment, but whose virus became detectable during the follow-up period;
  • Prior Partial Responders: Defined as people who achieved at least a 2 log10 reduction in hepatitis C virus at week 12, but whose hepatitis C virus never became undetectable by week 24 of a prior course of therapy; and
  • Prior Null Responders: Defined as people who achieved a less than 2 log10 reduction in hepatitis C virus at week 12 of a prior course of therapy.
Vertex developed telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, 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. In the United States, telaprevir will be marketed with the brand name INCIVEK.

Indication

INCIVEK™ (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment.

It is not known if INCIVEK is safe and effective in children under 18 years of age.

IMPORTANT SAFETY INFORMATION

Who should not take INCIVEK?

Do not take INCIVEK if you are pregnant or may become pregnant, or if you are a man with a sexual partner who is pregnant.

Do not take INCIVEK if you are taking certain medicines as there could be serious side effects. If these drugs are taken together, this can cause you to have too much or not enough INCIVEK or your other medicines in your body. It can also cause side effects that can be serious or life-threatening.

These medicines include: alfuzosin hydrochloride (Uroxatral®), atorvastatin (Lipitor®, Caduet®), ergot containing medicines such as methylergonovine (Methergine®), lovastatin (Advicor®, Altoprev®, Mevacor®), pimozide (Orap®), rifampin (Rifadin®, Rifamate®, Rifater®), sildenafil citrate (Revatio®) or tadalafil (Adcirca®) for the lung problem pulmonary artery hypertension (PAH), simvastatin (Zocor®, Vytorin®, Simcor®), St. John's wort (Hypericum perforatum), or triazolam (Halcion®).

Talk to your healthcare provider before taking INCIVEK if any of the above applies to you. Your healthcare provider may need to change the amount of medicines you take.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. INCIVEK and other medicines can affect each other.

Serious Side Effects

INCIVEK can cause serious side effects, including:
  • Birth defects or death of an unborn baby
    INCIVEK combined with peginterferon alfa and ribavirin may cause birth defects or death of your unborn baby. If you or your sexual partner is pregnant or plan to become pregnant, do not take these medicines. You or your partner should not become pregnant while taking INCIVEK with peginterferon alfa and ribavirin and for 6 months after treatment is over.

    You must have a negative pregnancy test before starting treatment, every month during treatment, and for 6 months after your treatment ends. You must use 2 effective methods of birth control during treatment and for 6 months after all treatment has ended. These 2 forms of birth control should not contain hormones, as these may not work as well during treatment with INCIVEK. Talk to your healthcare provider about the forms of birth control you should use during this time.

    Two weeks after stopping INCIVEK, you can use a hormonal form of birth control as one of your two forms of birth control.

    If you or your partner becomes pregnant during treatment or within 6 months after stopping these medicines, tell your healthcare provider right away. Contact the Ribavirin Pregnancy Registry right away by calling 1-800-593-2214. The Registry collects information about what happens to mothers and their babies if the mother takes ribavirin while pregnant.
  • Skin reactions: Mild skin rashes are common with INCIVEK combination treatment. Sometimes these skin rashes and other skin reactions can become severe and require treatment in a hospital.

    Call your healthcare provider right away if you develop any skin changes with these symptoms: rash with or without itching, blisters or skin lesions, mouth sores or ulcers, red or inflamed eyes like "pink eye" (conjunctivitis), swelling of your face, or fever.

    Your healthcare provider will decide if these changes may be a sign of a serious skin reaction. Your healthcare provider will also decide if you need treatment for your rash or to stop INCIVEK or your other medicines. Never stop taking INCIVEK combination treatment without talking to your healthcare provider first.
  • Do not take INCIVEK alone to treat chronic hepatitis C infection. It must be used with peginterferon alfa and ribavirin to treat chronic hepatitis C infection.
  • Low red blood cell count (anemia) that can be severe. Tell your healthcare provider if you have any of these symptoms of anemia: dizziness, shortness of breath, tiredness, or weakness.

    Your healthcare provider will do blood tests regularly to check your red blood cell count during treatment. If your anemia is severe your healthcare provider may tell you to stop taking INCIVEK. If this happens, do not start taking it again.
What should I tell my healthcare provider before taking INCIVEK?

Tell your healthcare provider if you:
  • have certain blood problems such as anemia
  • have liver problems other than hepatitis C infection
  • have hepatitis B, HIV infection, or any problems with your immune system
  • have a history of gout or high uric acid levels in your blood
  • have had an organ transplant
  • plan to have surgery
  • have any other medical condition
  • are breastfeeding
How should I take INCIVEK?

Take INCIVEK exactly as your healthcare provider tells you. Take 2 INCIVEK pills 3 times a day, 7 to 9 hours apart, with food. Eat a meal or snack containing about 20 grams of fat within 30 minutes before you take each dose. Talk to your healthcare provider about examples of food you can eat. If you miss a dose within 4 hours of when you usually take it, take your dose with food as soon as possible. If you miss a dose and it is more than 4 hours after the time you usually take it, skip that dose only and take the next dose at your normal time. Do not stop taking INCIVEK unless your healthcare provider tells you to. If your healthcare provider tells you to stop, you should not start taking it again, even if the reason for stopping goes away. If you take too much INCIVEK, call your healthcare provider or local Poison Control Center, or go to the nearest emergency room right away.

Common Side Effects of INCIVEK Combination Treatment

The most common side effects include itching, nausea, diarrhea, vomiting, anal or rectal problems (including hemorrhoids, discomfort or burning around or near the anus, itching around or near the anus), taste changes, and tiredness. Tell your healthcare provider about any side effect that bothers you or doesn't go away.

These are not all the possible side effects of INCIVEK. For more information, ask your healthcare provider or pharmacist.

You are encouraged to report negative side effects of prescription drugs to the FDA at 1-800-FDA-1088 or 1-800-332-1088 begin_of_the_skype_highlighting 1-800-332-1088 end_of_the_skype_highlighting or www.fda.gov/medwatch.   

You may also report side effects to Vertex Pharmaceuticals Incorporated at 1-877-824-4281 begin_of_the_skype_highlighting 1-877-824-4281 end_of_the_skype_highlighting.

Please see full Prescribing Information for INCIVEK including the Medication Guide available at www.INCIVEK.com.

For healthcare providers who are interested in information about INCIVEK, you can also call 1-877-824-4281 begin_of_the_skype_highlighting 1-877-824-4281 end_of_the_skype_highlighting.

Conference Call Information

Vertex will host a conference call and webcast today, May, 23, 2011 at 11:00 a.m. ET to provide more information about today's approval, the price of INCIVEK and Vertex's new financial assistance and patient support program. The conference call will be webcast live and a link to the webcast may be accessed from the ‘Events & Presentations' page of Vertex's website at www.vrtx.com. To listen to the call on the telephone, dial 1-866-501-1537 begin_of_the_skype_highlighting 1-866-501-1537 end_of_the_skype_highlighting (United States and Canada) or 1-720-545-0001 begin_of_the_skype_highlighting 1-720-545-0001 end_of_the_skype_highlighting (International). Vertex is also providing a podcast MP3 file available for download on the Vertex website at www.vrtx.com. The conference ID number for the live call and replay is 68267164. The call will be available for replay via telephone commencing May 23, 2011 at 5:00 p.m. ET running through 5:00 p.m. ET on May 30, 2011. The replay phone number for the United States and Canada is 1-800-642-1687 begin_of_the_skype_highlighting 1-800-642-1687 end_of_the_skype_highlighting. The international replay number is 1-706-645-9291 begin_of_the_skype_highlighting 1-706-645-9291 end_of_the_skype_highlighting. Following the live webcast, an archived version will be available on Vertex's website until 5:00 p.m. ET on June 6, 2011. To ensure a timely connection, it is recommended that users register at least 15 minutes prior to the scheduled webcast.

INCIVEK™ is a trademark of Vertex Pharmaceuticals Incorporated.

PEGASYS® and COPEGUS® are registered trademarks of Hoffmann-La Roche.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1

Unlike HIV and hepatitis B virus, chronic hepatitis C is curable.2 However, approximately 60 percent of people do not achieve SVR,3,4,5 or viral cure,6 after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8

More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.9 Hepatitis C is four times more prevalent in the United States compared to HIV.9 The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.10 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.9

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives. Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements, as defined in the Private Securities Litigation Reform Act of 1995, as amended, including statements regarding (i) Vertex's sales team being ready to support the introduction of INCIVEK, (ii) Vertex's financial assistance and patient support programs and its commitment to help people who might not otherwise be able to afford INCIVEK receive it and (iii) the use of INCIVEK as a treatment for people with genotype 1 chronic hepatitis C virus infection. 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, risks related to the commercialization of INCIVEK 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 Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

For more information and to view Vertex's press releases, please visit www.vrtx.com.
(VRTX - GEN)

1 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 March 21, 2011.
2 Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.
3 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.
4 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.
5 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.
6 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
8 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
9Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. 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. Updated January 11, 2010. Accessed March 21, 2011.
10 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed March 21, 2011. This report was commissioned by Vertex Pharmaceuticals, Inc.
11 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
12 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.

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Vertex::
Media:
Dawn Kalmar
Amy Pasqua
Zachry Barber
617-444-6992 begin_of_the_skype_highlighting 617-444-6992 end_of_the_skype_highlighting or mediainfo@vrtx.com
or
Investors:
Michael Partridge, 617-444-6108 begin_of_the_skype_highlighting 617-444-6108 end_of_the_skype_highlighting
Lora Pike, 617-444-6755 begin_of_the_skype_highlighting 617-444-6755 end_of_the_skype_highlighting
Matthew Osborne          617-444-6057 end_of_the_skype_highlighting

Source: Vertex Pharmaceuticals Incorporated

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