Spontaneous Weight Change during Chronic Hepatitis C Treatment: Association with Virologic Response Rates

Int J Med Sci. 2013 Oct 31;10(13):1830-6. doi: 10.7150/ijms.6184.

Alwakeel HR, Zaghla HE, Omar NA, Alashinnawy HA, Rewisha EA, Matarese LE, Taha AA, Kandil HM.

1. Hepatology Department, National Liver Institute, Monufia University, Shibin Alkom, Egypt.

Abstract

Objective : We examined weight changes during chronic hepatitis C (CHC) therapy and association with virologic response.

Methods : Weight changes were compared between subjects achieving rapid, early, and sustained virologic response rates (RVR, EVR, and SVR). RVR, EVR and SVR were compared among patients with or without weight loss of ≥ 0.5 body mass index (BMI) units (kg/m(2)) at 4, 12, 48 weeks.

Results : CHC therapy was initiated in 184 cases. Median pretreatment BMI was 27.7 (18.4-51.3) with 38% overweight and 31% obese (BMI ≥25 and ≥ 30, respectively). Among patients with liver biopsies (n = 90), steatosis was present in 31.6%; fibrosis grade of 1-2/6 in 46%, 3-4 in 37.3% and 5-6 in 14.7%. Mean weight loss at 4, 12, 24 and 48 weeks of therapy were 1.2, 2.6, 3.8 and 3.3 kg, respectively. After 4 and 12 weeks of treatment, 38% and 54.3% had a BMI decrement of ≥ 0.5 kg/m(2). For genotype 1, weight loss at 4 weeks was associated with significantly higher EVR (90.0% vs. 70%, p = 0.01) and a tendency towards better RVR and SVR (42.9% vs. 26.0% and 55.2% vs. 34.8%, respectively, p = 0.08). In multivariate analysis, weight loss at 4 weeks was independently associated with EVR (OR 6.3, p = 0.02) but was not significantly associated with RVR or SVR

Conclusions : Spontaneous weight loss at 4 and 12 weeks of CHC therapy was associated with improved EVR. Weight loss at 4 weeks was an independent predictor of EVR but not SVR.

KEYWORDS:

Weight change, hepatitis C, treatment outcomes, virologic response

PMID: 24324359 [PubMed - in process]

Source

Antivirals for HCV improve kidney and cardiovascular diseases in diabetic patients

PUBLIC RELEASE DATE: 11-Dec-2013

Contact: Dawn Peters
sciencenewsroom@wiley.com
781-388-8408
Wiley

Researchers from Taiwan reveal that antiviral therapy for hepatitis C virus (HCV) improves kidney and cardiovascular outcomes for patients with diabetes. Results of the study published in Hepatology, a journal of the American Association for the Study of Liver Diseases, show that incidences of kidney disease, stroke, and heart attack were lower in patients treated with pegylated interferon and ribavirin compared to HCV patients not treated with antivirals or diabetic patients not infected with the virus.

The World Health Organization (WHO) estimates that diabetes affects 347 million individuals worldwide and another 170 million people are living with chronic HCV. Previous research suggests a link between diabetes and chronic HCV, with HCV infected individuals having a greater chance of developing insulin resistance and diabetes. Moreover, HCV patients with insulin resistance, with or without diabetes, have a poor response to antiviral treatment, increased progression of liver fibrosis and greater risk of developing liver cancer (hepatocellular carcinoma).

"There is growing evidence of an association between diabetes and HCV," explains lead author, Chun-Ying Wu, MD, PhD, MPH from Taichung Veterans General Hospital in Taiwan. "Our study investigates if antiviral therapy used to treat HCV infection also improves diabetes outcomes."

For this population-based study researchers used data from the Taiwan National Health Insurance Research Database, which has collected healthcare details for all residents of the country since 1997. The team indentified 1, 411 patients with diabetes and HCV who were enrolled in the study, and received pegylated interferon plus ribavirin. There were also 1,411 individuals in the untreated group and 5,644 patients with diabetes and without HCV in the uninfected cohort. Follow-up for all participants was from 2003 to 2011.

Findings indicate that the 8-year cumulative incidences of end-stage renal disease in the treated, untreated and uninfected groups were 1.1%, 9.3%, and 3.3%, respectively. Further analysis found stroke incidence was 3.1% for treated patients, 5.3% for untreated and 6.1 for uninfected subjects. Acute coronary syndrome—an umbrella term the American Heart Association uses to define diseases, such as heart attack or angina, where blood to the heart is blocked—occurred in 4.1%, 6.6% and 7.4% of treated, untreated and uninfected patients.

"Our findings suggest that HCV may cause clinical complications related to diabetes. But these issues are mitigated by HCV antiviral therapy, specifically pegylated interferon plus ribavirin, which was found to reduce risks of kidney disease, stroke and cardiovascular diseases in diabetic patients," concludes Dr. Wu. The authors recommend further examination of the underlying relationship between HCV and diabetes.

###

This study was funded in part by grants from Taiwan's National Health Research Institutes (PH-100-PP-54, PH-101-PP-23) and Taiwan's National Science Council (NSC 101-2314-B-650 -003).

This study is published in Hepatology. Media wishing to receive a PDF of the article may contact sciencenewsroom@wiley.com.

Full citation: "Antiviral Treatment for Hepatitis C Virus Infection is Associated with Improved Renal and Cardiovascular Outcomes in Diabetic Patients." Yao-Chun Hsu, Jaw-Town Lin, Hsiu J. Ho, Yu-Hsi Kao, Yen-Tsung Huang, Nai-Wan Hsiao, Ming-Shiang Wu, Yi-Ya Liu and Chun-Ying Wu. Hepatology; (DOI: 10.1002/hep.26892).

URL: http://doi.wiley.com/10.1002/hep.26892

Author Contact: Media wishing to speak with Dr. Wu may contact dr.wu.taiwan@gmail.com or at +866-921388866. Dr. Yao-Chun Hsu, the first author of this article, may be reached at +886-988687726.

About the Journal

Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on is published by Wiley on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://wileyonlinelibrary.com/journal/hep.

About Wiley

Wiley is a global provider of content-enabled solutions that improve outcomes in research, education, and professional practice. Our core businesses produce scientific, technical, medical, and scholarly journals, reference works, books, database services, and advertising; professional books, subscription products, certification and training services and online applications; and education content and services including integrated online teaching and learning resources for undergraduate and graduate students and lifelong learners.

Founded in 1807, John Wiley & Sons, Inc. (NYSE: JWa, JWb), has been a valued source of information and understanding for more than 200 years, helping people around the world meet their needs and fulfill their aspirations. Wiley and its acquired companies have published the works of more than 450 Nobel laureates in all categories: Literature, Economics, Physiology or Medicine, Physics, Chemistry, and Peace. Wiley's global headquarters are located in Hoboken, New Jersey, with operations in the U.S., Europe, Asia, Canada, and Australia. The Company's website can be accessed at http://www.wiley.com.

Source

The Challenges of Caring for Newly Diagnosed Patients With HCV: Filling the Gap

Medscape Infectious Diseases

An Increasing Role for ID and Primary Care Clinicians?

Kaushal B. Shah, MD, Dawd S. Siraj, MD, MPH&TM

December 11, 2013

Hepatitis C Virus Infection

Hepatitis C virus (HCV) is an RNA virus causing major worldwide morbidity and mortality. If not diagnosed and treated early, HCV can have severe complications, including esophageal varices, liver cirrhosis with decompensation, and hepatocellular carcinoma. It is the leading indication for liver transplantation and a leading cause of hepatocellular carcinoma in the United States.^[1]

Since the discovery of HCV in 1989,^[2] remarkable progress has been made in its treatment. The newly approved direct-acting antiviral (DAA) protease inhibitor-based regimen has improved response rates, ushering in a new era in the management of patients with HCV. More effective, short course, and simpler regimens are expected in the near future. The recent update in the screening guidelines published by the US Preventive Services Task Force (USPSTF)^[3] is expected to increase the number of patients seeking care.

Epidemiology of HCV

HCV infects 170-200 million people around the globe, accounting for 3% of world's population. It is a much bigger problem compared with HIV, which has an overall prevalence of only about 34 million.^[4] In United States, approximately 3.2 million people are infected with HCV, and about two thirds are unaware of their diagnosis.^[5]

HCV is the most common chronic bloodborne pathogen in the United States. HCV antibody prevalence approaches 1.6%, and 78% of persons who test positive have detectable viremia.^[6]

Currently, 6 major genotypes and more than 80 subtypes have been identified worldwide.^[7] Genotype 1 is the most common type in the United States,^[8] where an estimated 16,000 new cases of HCV and 15,000 HCV-related deaths occur yearly.^[3]

HCV Screening and Diagnosis

Screening Guidelines

In the United States, the most important risk factor for HCV infection remains injection drug use. Other risk factors include past or current injection drug use, receipt of a blood transfusion before 1992, being born to an HCV-infected mother, incarceration, intranasal drug use, unregulated tattoos, and other unregulated percutaneous exposures. Previous guidelines recommended risk-based screening.

Unfortunately, as many as 45% of all HCV diagnosed patients report no known exposure risk.^[3] According to data from 1999 to 2008, about three fourths of patients in the United States living with HCV infection were born between 1945 and 1965, with a peak prevalence of 4.3% in persons aged 40-49 years.^[3,9] After conducting 2 systematic reviews of the evidence on HCV progression, complications, and available therapies, in June 2013, the USPSTF updated the screening guidelines by adding 1-time HCV screening of people born between 1945 and 1965.^[3]

With this change in the screening guideline, more than 800,000 people with chronic HCV will be identified.^[10] This will undoubtedly stress the already stretched field of HCV clinicians. By the end of 2007, only 21% of all estimated infected persons had received antiviral therapy. If this trend is not changed, it is projected that only 14.5% of liver-related deaths related to HCV during 2002-2030 would be prevented.^[11,12]

The reasons for these distressing statistics are multifactorial, with the lack of early screening with advanced disease at time of care and the limited number of specialists who treat patients with HCV being the main driving factors. The recently updated screening guideline is expected to improve this situation, but without a massive increase in HCV providers who will absorb the increased demand for care, its impact will be blunted.

Diagnostic Testing

For years, HCV treatment decisions have been based on stage of liver inflammation and fibrosis as determined by liver biopsy. Although considered the gold standard, liver biopsy is an invasive and expensive procedure that can be associated with morbidity and, rarely, mortality.^[13] Furthermore, this test is saddled by significant sampling error (30%-35%), poor and inadequate sampling, and inter- and intrareader variability of interpretation of results.^[13]

Noninvasive blood tests and ultrasonographic scanning of the liver are becoming increasingly precise in staging liver disease in patients with HCV.^[14] The US Food and Drug Administration (FDA) approved liver ultrasonographic elastography, the FibroScan® (Echosens, Paris, France), in mid-2013. In a recent meta-analysis, the sensitivity and specificity of FibroScan to detect fibrosis were 87% and 91%, respectively.^[15]

Paradigm Shift in Management of HCV

The main goal in the treatment of HCV is sustained virologic response (SVR). SVR is associated with a substantial (> 50%) reduction in risk for all-cause mortality^[16] and substantially lower rates of liver-related death and decompensated cirrhosis with ascites, variceal bleeding, encephalopathy, or impaired hepatic synthetic function.^[17]

In 2011, the first DAAs -- telaprevir and boceprevir -- were licensed in the United States for treatment of HCV genotype 1.^[18,19] The addition of DAAs to the management of HCV has improved the rates of SVR from 44% to 75%.^[20] Furthermore, approximately 20 new HCV treatments are undergoing phase 2 or phase 3 clinical trials.^[21] These new regimens have improved side-effect profiles and are expected to improve SVR rates and shorten the duration of therapy.

Increased Demand for HIV Care

Currently, clinical HCV care is primarily provided by hepatologists and gastroenterologists. When screening was limited and rates of SVR were low, most patients with HCV sought medical attention late in the disease process, when they required advanced specialist care. Moreover, the need for liver biopsy to stage disease has centered the care of patients with HCV among hepatologists. The changing guidelines for screening, the precision of noninvasive techniques for staging liver disease, and the approval of highly effective DAAs will probably change this paradigm gradually.

In the United States, there are approximately 14,000 practicing gastroenterologists.^[21] With no increase in fellowship positions, the surge in the HCV patient population will be an extraordinary burden on these already stretched HCV care providers. Furthermore, the multiple new drug combinations, complex drug/drug interactions and side-effect profiles, challenging socioeconomic issues, and comorbid conditions common in patients with HCV will require specialists who are familiar and comfortable with handling those complex issues.

There are many persuasive reasons for infectious diseases (ID) specialists to integrate HCV care into their practices. An estimated 15%-20% of patients with HIV are coinfected with HCV.^[22] In HIV practice, we formulate complex antiviral combinations, manage drug/drug interactions of fundamentally similar medications to the HCV regimen (protease inhibitors, nucleosides, non-nucleosides), interpret results of antiviral drug resistance testing, and devise salvage regimens. ID specialists care for patients with HIV who have complex social, financial, substance abuse, alcoholism, depression, and nonadherence issues that require sustained and involved long-term care. Experience with the same general principles would apply and serve us well if we gradually incorporate care of HCV-infected patients into our practice.

HCV, like HIV, is a public health issue that requires an integrated approach to care. The focus on risk factor identification, diagnosis, transmission prevention, education, and provision of access to care will require clinicians to work closely with public health systems. ID specialists can apply their expertise in this area to help patients with HCV and strengthen the public health system.

The needs and care of patients with HIV and HCV are similar, but at the same time, ID specialists must appreciate the differences and create working relationships with hepatologists, gastroenterologists, and transplant centers for more coordinated and effective care. This will foster a better transition of patient care when diagnostic and therapeutic services for such issues as variceal bleeding, ascites, hepatocellular carcinoma, or liver transplant are required.

With these issues in mind, the Infectious Diseases Society of America (IDSA) has created an HCV task force that is spearheading the training of ID physicians through increasing coverage at society meetings, preparing training webinars, and working on a curriculum for ID fellowship training in HCV patient care. In the long run, this will fill a crucial gap in the overall care of patients with HCV.^[23]

If HCV screening is implemented as recommended and the number of patients increases as anticipated, the addition of ID clinicians might not even be adequate to meet the demand. The reasons and rationale that justify the need for ID physicians could work as well for primary care physicians, internists, and family medicine specialists. With proper training, the fundamental changes on evaluation and management of HCV will make it possible for these primary care providers to be involved in direct care of patients with HCV.

Clinic Organization for HCV Care

Clinicians who are planning to add HCV care to their practices will need a clinic-wide plan to prepare for the increased patient load and work volume.^[24,25] Because staff resources and time are limited, healthcare providers will have to determine how best to allocate clinic resources and use support staff to maximize productivity without compromising the quality and safety of care. This is better handled if care is centered around a designated management team who will dedicate a portion of their time to HCV care.

Before offering the service and on an ongoing basis, the HCV management team should receive education on HCV and the current approved management of HCV. The complex drug/drug interaction profile, side effects, and dosing schedules make this education critical to providing quality standardized care. It would be advisable to prepare a manual or protocol to standardize knowledge and care among clinic staff.

Nurse practitioners, physician assistants, and pharmacists can be an integral part of the HCV management team. With proper supervision and education, they can play critical roles in the day-to-day care and follow-up of patients. Most of the issues that are brought by patients while undergoing HCV treatment can be addressed by these medical professionals, allowing physicians to use their time to evaluate new patients.

A New Era in HCV Care

A new era is dawning in HCV care. Multiple recent developments are playing a role in this change, including:

• Recent updates in the HCV screening guideline, which are expected to bring an unprecedented number of new patients;

• The approval of the FibroScan® and refinement of biochemical tests to noninvasively stage liver disease; and

• The approval of shorter, safer, more effective, and possibly all-oral DAA-based HCV treatment regimens.

As a result of these changes, not only we will see an increased number of patients who will be seeking care, but most will be at the early stage of their disease, further reducing the need for highly specialized tests and care. To meet this increased demand, more HCV care providers will be required in the near future. Considering their expertise in comprehensive HIV care, we believe that ID physicians are the ideal candidates to fill this critical gap. Collaborative training with hepatologists, modification of ID fellowship training to include HCV patient care, and multimedia continuous training of ID physicians by IDSA and the HCV task force should continue to pave the way for the new era.

References

1. Sanyal AJ; Governing Board the Public Policy, Clinical Practice, Manpower Committees of the AASLD. The Institute of Medicine report on viral hepatitis: a call to action. Hepatology. 2010;51:727-728.

2. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244:359-362.

3. Moyer VA; US Preventive Services Task Force. Screening for hepatitis C virus infection in adults: US Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013;159:349-357.

4. Marinho RT, Barreira DP. Hepatitis C, stigma and cure. World J Gastroenterol. 2013;19:6703-6709.

5. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-714.

6. US Preventive Services Task Force. Screening for hepatitis C virus infection in adults. September 13, 2013.http://effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=1698 Accessed November 30, 2013.

7. Bunchorntavakul C, Chavalitdhamrong D, Tanwandee T. Hepatitis C genotype 6: a concise review and response-guided therapy proposal. World J Hepatol. 2013;5:496-504.

8. Manos MM, Shvachko VA, Murphy RC, Arduino JM, Shire NJ. Distribution of hepatitis C virus genotypes in a diverse US integrated health care population. J Med Virol. 2012;84:1744-1750.

9. Smith BD, Morgan RL, Beckett GA, et al; Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61(RR-4):1-32.

10. Rein DB, Smith BD, Wittenborn JS, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in US primary care settings. Ann Intern Med. 2012;156:263-270.

11. Volk ML. Antiviral therapy for hepatitis C: why are so few patients being treated? J Antimicrob Chemother. 2010;65:1327-1329.

12. Godofsky E. Why should infectious disease physicians care for the hepatitis C-infected patient? Infect Dis Clin North Am. 2012;26:839-847.

13. Patel K, Friedrich-Rust M, Lurie Y. FibroSURE and FibroScan in relation to treatment response in chronic hepatitis C virus. World J Gastroenterol. 2011;17:4581-4589.

14. Poynard T, Imbert-Bismut F, Munteanu M, Ratziu V. FibroTest-FibroSURE: towards a universal biomarker of liver fibrosis? Expert Rev Mol Diagn. 2005;5:15-21.

15. Talwalkar JA, Kurtz DM, Schoenleber SJ, West CP, Montori VM. Ultrasound-based transient elastography for the detection of hepaticfibrosis: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2007;5:1214-1220.

16. Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol. 2011;9:509.e.1-516.e.1.

17. Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-1374.

18. Jacobson IM, McHutchison JG, Dusheiko G, et al; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.

19. Poordad F, McCone J Jr, Bacon BR, et al; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.

20. Asselah T, Marcellin P. Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow. Liver Int. 2012;32 Suppl 1:88-102.

21. Elta GH. GI training: where are we headed? Am J Gastroenterol. 2011;106:395-397.

22. Koziel MJ, Peters MG. Viral hepatitis and HIV infection. N Engl J Med. 2007;356:1445-1454.

23. McGovern BH. Hepatitis C virus and the infectious disease physician: a perfect match. Clin Infect Dis. 2012;55:414-417.

24. Levine CD, Nordenson NJ. Chapter 1: getting ready for direct-acting antiviral (DAA) therapy. In: HCV Care and Guidance. eHandbook. http://lmt.projectsinknowledge.com/2037/ Accessed November 30, 2013.

25. Infectious Diseases Society of America. Hepatitis C curriculum. http://www.idsociety.org/HCV_Curriculum/ Accessed November 23, 2013.

Source

 

Why Talk of a Hepatitis C Price War Should Act as a Warning to the Large Pharma Industry-at-Large

Provided by Forbes

Pharma & Healthcare 12/11/2013 @ 8:19AM |1,590 views

Bloomberg reporter Drew Armstrong may have broken one of the most important pharmaceutical news stories of the year on Tuesday when he revealed that a leading US pharmacy benefits manager (PBM) is to take an aggressive stance towards the pricing of new hepatitis C therapies.

The crux of the story is that Express Scripts ESRX -0.66% will not view the convenience of Gilead Sciences' GILD -2.8% proposed single-tablet, fixed-dose combination treatment – due to be approved in late 2014/early 2015 – as an adequate justification for higher pricing versus less convenient therapies (i.e. more tablets) that deliverer a similar level of efficacy.

Immediate reaction to the story saw Gilead’s share price fall (shares closed down 3.2 percent on Tuesday), primarily as the proposed convenience of its product is central to its entire hepatitis C strategy and is widely perceived to be a key factor in driving the company’s anticipated dominance of this market.

Express EXPR -2.12% Scripts has subsequently sought to play down the comments made by its chief medical officer Steve Miller, suggesting that they should not be viewed as being directed solely at Gilead. But it is not only Gilead – or those players competing in the hepatitis C space – that need to be concerned at the stance Express Scripts is taking.

The underlying narrative here has broader implications for the pharmaceutical industry, particularly as Express Scripts has already demonstrated itself to be taking an increasingly aggressive position towards the pricing of drugs that it believes offer minimal efficacy benefit over competing therapies, which it can secure at a cheaper cost.

Most significantly, the PBM announced earlier this year that from the beginning of 2014, Novo Nordisk's Novo Nordisk's diabetes treatment Victoza will no longer have a place on its preferred national formulary list. The decision to replace Victoza with AstraZeneca and Bristol-Myers Squibb’s Bydureon franchise also caused some consternation among industry commentators, given that Victoza is widely perceived to be a superior product.

“If you look at the actual primary efficacy and safety trial results, the gap between Bydureon and Victoza is modest, thus Express Scripts can fairly argue it is not providing an inferior medicine,” says Sanford C. Bernstein analyst Ronny Gal. “However, more refined arguments relating to factors such as the duration of side-effect, size of needle and physician experience are more debatable,” adds Gal.

Mirroring similar tactics that are emerging at other PBMs (such as CVS Caremark), the decision to block Victoza was not only a “shot across Novo’s bow,” says Gal, but a “testing tactic,” the success of which will likely be measured by both the Danish company’s response and the reaction of the market.

Novo Nordisk has provided a bullish riposte on a number of occasions, both indicating that it will not bow to unnecessary discounting pressure and suggesting that patients and physicians will rally against any significant lack of access to medicines.

Thus it is not surprising to see Express Scripts use the approval of new – and expensive – hepatitis C therapies as an opportunity to promote its stance. Indeed, while Armstrong’s article focused on the potential pricing competition of products that remain some 12 months from the market, payers face a more immediate concern in the hepatitis C market.

One element of Gilead’s proposed fixed-dose combination – Sovaldi (sofosbuvir) – was approved by the FDA on Friday with a wholesale price of $84,000 for a 12-week course. Its transition from regulatory to commercial arena has been supported by a somewhat laissez-fair attitude as to how the drug can be used by the FDA.

The administration has even signaled that use of sofosbuvir in combination with ribavirin (thus excluding interferon and its burdensome side-effect profile) can be used in “interferon-ineligible” patients over a 24-week period in the large genotype 1 population; a proposed use that simultaneously doubles the price of Sovaldi, but provides no real definition as to what constitutes interferon-ineligibility.

At FirstWord we polled 67 physicians this week and discovered that more than two-thirds would consider a patient ‘ineligible’ for interferon if that patient said they did not want to be treated with it. The message appears to be clear – physicians and patients are keen to use these new therapies, perhaps more aggressively than some analysts are forecasting, and this provides a real conundrum for payers, particularly given the level of patient warehousing that has preceded their availability.

The key statement made by Express Scripts’ Miller on Tuesday was arguably “we will identify which drugs can be pitted against each other and make some really tough formulary decisions” – rhetoric that clearly lays out how the PBM expects to assess drugs moving forward.

Also likely to strike fear into branded pharmaceutical manufacturers was Miller’s assertion that “when you look at the price of many new products coming to the marketplace, it’s just not going to be sustainable” – a statement that looks much more at home in the European pricing environment than the US.

Let’s not forget also the decision by Sanofi to reduce the price of its colorectal cancer treatment Zaltrap last year after a group of prominent physicians wrote a high-profile opinion piece in the New York Times saying that it was no more effective than an existing therapy available at roughly half the cost.

What appears to be a very aggressive stance towards the next generation of hepatitis C therapies indicates that Express Scripts is hardly holding fire on its strategy. The key question that the industry needs to ask is whether others will follow?

Source

Also See: Express Scripts Pushes Price Competition for Gilead Drug

Arrowhead Presents Phase 1 Data on ARC-520 at HepDART 2013

BY BUSINESS WIRE

DECEMBER 9, 2013 04:02 PM EST

Arrowhead Research Corporation (NASDAQ: ARWR), a biopharmaceutical company developing targeted RNAi therapeutics, today announced that COO and Head of R&D, Bruce Given, M.D., presented data on the Phase 1 clinical study of ARC-520, the company’s clinical candidate for the treatment of chronic hepatitis B infection, at the HepDART 2013 conference being held on The Big Island, Hawaii. New data including pharmacokinetics (PK) and adverse event (AE) attribution presented today in a poster and in an oral presentation tomorrow, support the previous findings that ARC-520 appears to be generally safe and well-tolerated at all six dose levels studied.

The Phase 1 study was designed to characterize the safety profile of ARC-520 across a range of doses and evaluate pharmacokinetics. It is a single-center, randomized, double-blind, placebo-controlled, single dose-escalation, first-in-human study of ARC-520 administered intravenously to healthy adult volunteers. 36 subjects have been enrolled in 6 groups randomized at a ratio of 2:1 to receive ARC-520 or placebo: Placebo (n=12), ARC-520 0.01 mg/kg (n=4), 0.1 mg/kg (n=4), 0.3 mg/kg (n=4), 0.6 mg/kg (n=4), 1.2 mg/kg (n=4), and 2.0 mg/kg (n=4). The placebo group included 7 male and 5 female subjects with average of 28.1 +/- 9.6 years. The treatment group included 12 male and 12 female subjects with average age of 26.9 +/- 6.7 years. Subjects were admitted to the unit overnight pre-dose and vital signs, telemetry, ECGs, safety labs, PK, and adverse events were monitored for 24 hours post-dose. Return visits occurred for repeat safety evaluations and recording of adverse events at 48 hrs, 72 hours, day 7, day 14 and day 28 post dosing.

Preliminary results from the phase 1 clinical study of ARC-520 indicate that to date there have been no serious AEs, no dose limiting toxicities, no discontinuations, and a modest occurrence rate of AEs with no dose related increase in frequency or severity, with the possible exception of mild lightheadedness which occurred in two subjects in the 2 mg/kg dose group. There were no general differences observed or findings rated clinically significant on vital signs, ECGs, physical examinations, or clinical laboratories in the ARC-520 groups relative to placebo. Adverse event frequency and severity did not differ between placebo and ARC-520, with 75% of both treated and placebo subjects reporting mild or moderate AEs. There was a low occurrence rate of abnormal laboratory tests, with no observed relationship to timing or dose. PK results appear to indicate that C₀(equivalent to C_Max) and AUC_0-∞ increase linearly with dose (r²=0.984).

The Phase 1 study has thus demonstrated that a single intravenous administration of ARC-520 appears to be safe and well tolerated up to and including a dose of 2 mg/kg, the highest dose tested. A copy of the poster presentation is available on the Presentations and Events page of Arrowhead website at http://www.arrowheadresearch.com/presentations.

About ARC-520

Approximately 350 million people worldwide are chronically infected with the hepatitis B virus. Chronic HBV infection can lead to cirrhosis of the liver and is responsible for 80% of primary liver cancers globally. Arrowhead’s RNAi-based candidate ARC-520 is designed to treat chronic HBV infection by reducing the expression and release of new viral particles and key viral proteins. The goal is to achieve a functional cure, which is an immune clearant state characterized by hepatitis B s-antigen negative serum with or without sero-conversion. The siRNAs in ARC-520 intervene at the mRNA level, upstream of where nucleotide and nucleoside analogues act. In transient and transgenic mouse models of HBV infection, a single co-injection of Arrowhead’s DPC delivery vehicle with cholesterol-conjugated siRNA targeting HBV sequences resulted in multi-log knockdown of HBV RNA, proteins and viral DNA with long duration of effect. In a chimpanzee chronically infected with HBV and high viremia and antigenemia, ARC-520 induced rapid reductions of 90-95% in HBV DNA, e-antigen, and s-antigen, which did not return to baseline until study day 43, 43, and 71 respectively. Data also suggested that a therapeutic immunological flare occurred, which is thought to be part of a cascade that under chronic therapy may lead to HBsAg seroconversion and functional cure. Arrowhead has completed enrollment in a phase 1 single ascending dose study in normal volunteers, which the company expects to follow with a phase 2a study in chronic HBV patients.

About Arrowhead Research Corporation

Arrowhead Research Corporation is a biopharmaceutical company developing targeted RNAi therapeutics. The company is leveraging its proprietary drug delivery technologies to develop targeted drugs based on the RNA interference mechanism that efficiently silence disease-causing genes. Arrowhead technologies also enable partners to create peptide-drug conjugates that specifically home to cell types of interest while sparing off-target tissues. Arrowhead’s pipeline includes clinical programs in chronic hepatitis B virus and obesity and partner-based programs in oncology.

For more information please visit http://www.arrowheadresearch.com, or follow us on Twitter @ArrowRes. To be added to the Company's email list to receive news directly, please send an email to ir@arrowres.com.

Source

Use of laser capture microdissection to map hepatitis C virus-positive hepatocytes in human liver

Gastroenterology. 2013 Dec;145(6):1404-1413.e10. doi: 10.1053/j.gastro.2013.08.034. Epub 2013 Aug 22.

Kandathil AJ, Graw F, Quinn J, Hwang HS, Torbenson M, Perelson AS, Ray SC, Thomas DL, Ribeiro RM, Balagopal A.

Department of Medicine, Johns Hopkins University Baltimore, Maryland.

Abstract

BACKGROUND & AIMS: Hepatitis C virus (HCV) predominantly infects hepatocytes, but many hepatocytes are not infected; studies have shown that HCV antigens cluster within the liver. We investigated spatial distribution and determinants of HCV replication in human liver samples.

METHODS: We analyzed liver samples from 4 patients with chronic HCV infection (genotype 1, Metavir scores 0-1) to estimate the proportion of infected hepatocytes and the amount of HCV viral RNA (vRNA) per cell. Single-cell laser capture microdissection was used to capture more than 1000 hepatocytes in grids, to preserve geometric relationships. HCV vRNA and interferon-induced transmembrane protein 3 (IFITM3) messenger RNA (the transcript of an interferon-stimulated gene) were measured in the same hepatocytes by quantitative polymerase chain reaction and assembled in maps to identify areas of high and low HCV replication.

RESULTS: Patients' serum levels of HCV RNA ranged from 6.87 to 7.40 log10 IU/mL; the proportion of HCV-infected hepatocytes per person ranged from 21% to 45%, and the level of vRNA ranged from 1 to 50 IU/hepatocyte. Infection was not random; we identified clustering of HCV-positive hepatocytes using infected-neighbor analysis (P < .0005) and distance to the kth nearest neighbor compared with random distributions, obtained by bootstrap simulations (P < .02). Hepatocytes that expressed IFITM3 did not appear to cluster and were largely HCV negative.

CONCLUSIONS: We used single-cell laser capture and high-resolution analysis to show that in human liver HCV infects hepatocytes in nonrandom clusters, whereas expression of antiviral molecules is scattered among hepatocytes. These findings show that quantitative single-cell RNA measurements can be used to estimate the abundance of HCV vRNA per infected human hepatocyte and are consistent with cell-cell propagation of infection in the absence of clustered IFITM3.

Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS: AIDS Linked to Intravenous Experience, ALIVE, HCV, HIV, IFITM3, ISG, Intrahepatic Infection, LCM, PCR, Virology, cDNA, complementary DNA, hepatitis C virus, human immunodeficiency virus, interferon-induced transmembrane protein 3, interferon-stimulated gene, laser-capture microdissection, mRNA, messenger RNA, polymerase chain reaction, qPCR, quantitative polymerase chain reaction, scLCM, single-cell laser-capture microdissection, vRNA, viral RNA

PMID: 23973767 [PubMed - in process]

Source

Express Scripts Pushes Price Competition for Gilead Drug

Provided by Bloomberg News

By Drew Armstrong Dec 10, 2013 4:07 PM ET

The biggest U.S. drug benefits manager plans to start a price war over a new generation of hepatitis C treatments that will cost $1,000 a pill, in a bid to drive down spending on the medicines.

Express Scripts Holding Co. (ESRX) will pit Gilead Sciences Inc. againstAbbVie Inc. (ABBV) and other drugmakers when the new treatments come to market next year or early in 2015. The new hepatitis C pills are projected to be among the biggest pharmaceutical sellers ever. While Gilead’s once-a-day drug may be the easiest to use, Express Scripts might block the pill from reimbursement if the competitors accept lower pricing.

“We will identify which drugs can be pitted against each other and make some really tough formulary decisions,” Steven Miller, chief medical officer of St. Louis-based Express Scripts, said in a telephone interview. “If the difference in convenience cannot be demonstrated to have a difference in outcomes, we often recommend coverage of the equally effective, less-convenient product.”

Miller spoke in part of an interview yesterday focused on the new hepatitis C medications, their cost, and how the benefits manager would approach covering the new drugs.

Gilead (GILD)’s drug Sovaldi may generate $9.5 billion in 2017, according to the average of six analysts’ estimates compiled by Bloomberg. Sovaldi is half of a two-drug combination pill expected to reach the market by early 2015. AbbVie is developing a treatment of four pills to be taken daily that may be approved for sale about the same time. Bristol-Myers Squibb Co. (BMY) and Achillion Pharmaceuticals Inc. also are developing medicines.

$84,000 Price

Gilead’s Sovaldi was approved Dec. 6 by U.S. regulators to be used with current medicines for patients with certain types of hepatitis C. Its $84,000 cost for a course of therapy will strain the health-care system, said Express Scripts’ Miller.

“When you look at the price of many new products coming to the marketplace, it’s just not going to be sustainable,” he said.

Pharmacy benefit managers like Express Scripts control the list of covered drugs, or formularies, that get reimbursed or are subject to lower co-payments for patients. The companies force drugmakers to compete in an effort to gain discounts in return for making it on to their list, or for having lower co-pays to drive patients to the drugs.

About 4 million Americans have hepatitis C, which attacks the liver and can cause cancer. The disease is passed through infected blood or body fluids and can be carried for years without symptoms. The U.S. Centers for Disease Control and Prevention recommends that baby boomers, defined by the agency as those born from 1945 to 1965, get tested for the infection.

Similar Benefits

The new medicines act faster than current therapies and eliminate weeks of injections that cause side effects such as the flu. Most have shown similar levels of effectiveness, said Mark Schoenebaum, an analyst with International Strategy & Investment Group LLC.

“They’re basically comparable,” he said in a telephone interview. “Wall Street is expecting price parity, but AbbVie might be more willing to wheel and deal.”

A more convenient dosing may not be enough to get preferred reimbursement, Miller said, especially with the high prices. “If a company is just relying on a convenience factor to get that product covered, they may end up being disappointed,” he said.

Gilead shares declined 3.2 percent to 72.81 at 4 p.m. New York time, the most since October. The Foster City, California-based company’s stock has almost doubled this year. AbbVie gained 1.8 percent to $52.14, its highest closing price this year. Express Scripts increased less than 1 percent to $67.73.

Cara Miller, a Gilead spokeswoman, didn’t respond to an interview request to discuss Miller’s remarks. Elizabeth Hoff, a spokeswoman for North Chicago, Illinois-based AbbVie, didn’t immediately provide a comment.

AbbVie released results today from a final-stage trial of 394 previously treated hepatitis C patients showing that its treatment cleared all signs of the virus in 96 percent of patients. In the second of three studies generally needed for U.S. approval, Gilead’s one-pill, two-drug treatment showed viral clearance rates of 95 percent to 100 percent.

To contact the reporter on this story: Drew Armstrong in New York atdarmstrong17@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

Source

Also See: Gilead HCV Drug May Face Price War; Rival AbbVie Up

Gilead’s HCV drug sofosbuvir approved by the FDA but accessible for how many? (Act Up-Basel, MSF, APN+, MDM, INPUD, ITPC)

Provided by ACT UP-Basel

Monday 9 December 2013
All the versions of this article: [English]

• Press Release • December 9 • Bangkok – Paris – Basel – London – New York • On December 6, the U.S. Food and Drug Administration approved Gilead’s sofosbuvir (Sovaldi), an oral medication for the treatment of hepatitis C virus (HCV). Sofosbuvir and other direct-acting antivirals (DAAs) coming out of the drug development pipeline are more potent, have fewer side effects, and can often be taken for a shorter duration than the current standard of care. In clinical trials, sofosbuvir demonstrated high cure rates of up to 100% when combined with other DAAs. Yet its anticipated price tag of USD $80,000 will ensure that this drug remains out of reach for the vast majority of people living with HCV.

At least 185 million people worldwide have been infected with hepatitis C virus (HCV). Each year, three to four million people are newly infected and HCV-related liver complications kill an estimated 350,000 people annually, even though HCV is treatable and curable. Currently, injectable pegylated interferon is the backbone of the standard of care and, in combination with the oral drug Ribavirin (RBV), has a cure rate of between 50 and 75% of cases, depending on the HCV genotype; however, it is associated with significant side effects. Drugs like sofosbuvir — Gilead’s “blockbuster” nucleotide polymerase inhibitor — show much-improved cure rates (reaching up to 90-100% in clinical trials) and shorter treatment duration when combined with pegylated interferon or other DAAs. Using newer DAAs, especially if they can be used without the addition of pegylated interferon, may result in a drastically lower incidence of side effects and adverse reactions. Many more DAAs will enter the market over the next couple of years.

Ninety percent of people who have hepatitis C live in low- and middle-income countries (LMICs); most are not aware of their HCV status, nor do they have access to testing and counselling. Most people with chronic HCV do not have access to treatment, even under the current standard of care, as pegylated interferon can cost up to USD $18,000 per treatment course, or ten times their country’s per capita Gross Domestic Product. Advocates are already fighting for better accessibility to treatment programs and more affordable prices of pegylated interferon. Accordingly, now is the time to ensure affordable DAAs and optimized DAA combinations that reduce treatment duration and improve both adherence and treatment outcomes for everyone who needs them.

The price of sofosbuvir in high-income countries is expected to be very high, between USD $80,000 – 90,000. Like other DAAs, sofosbuvir is used in combination with other drugs, thus the total cost of a treatment course will be even higher. In France, where sofosbuvir is approved for early access, the 12-week course of treatment costs more than USD $76,000 (USD $905 per pill). Analysts expect Gilead’s drug to generate sales of USD $1.73 billion in 2014 alone.

Sofosbuvir and other DAAs coming out of late-stage development do not have to cost this much. They can be produced generically for a tiny fraction of that price, just like HIV antiretrovirals (ARVs). For example, a 12-week course of sofosbuvir, produced generically, may cost in the range of USD $68-136. Ensuring universal access to affordably priced and generic DAAs could help eradicate HCV globally.

The HIV/AIDS pandemic demonstrated that corporate greed, rather than the cost of drug development and production, caused originator drug prices to be scandalously inflated. Generic competition led to radical decreases in HIV drug prices: for some molecules they dropped by 99% once generic versions became available, allowing millions more people to access life-saving ARVs. Generic production also led to the development of optimized fixed-dose combinations that have simplified treatment, ensured access to ideal treatment combinations, and enabled the development of pediatric versions and heat stable formulations.

We, people living with HCV, HIV/AIDS, people who use drugs, and our advocates, demand that:

• Companies, Gilead specifically, as well as generics producers must price their products close to the cost of production for all patients in all LMICs; considering the cost of production per 12-week treatment course (Ribavirin plus two DAAs) is estimated to range from USD $100 to 250.
• Companies should not hinder the production of generic medicines and should not interfere with the obligation of governments to guarantee the access to health for their population; including the right to grant patents for real therapeutic inventions only, the right to revoke abusive patents, and the right to issue compulsory licenses in order to protect public health interests as clearly allowed by the World Trade Organization’s TRIPS agreement (Agreements on Trade related Aspects of Intellectual property rights) and reaffirmed in the Doha Declaration.
• Governments must ensure that their intellectual property (IP) laws promote, not impede, their obligation to their people’s right to health. In particular, governments must use all safeguards to protect public health, and where IP laws are not written to promote public health, they should be revised accordingly.

We cannot allow more people to die from a treatable and curable disease and must learn the lessons from HIV advocacy by demanding affordable drug pricing for all, now! Failure to learn these lessons would be an unforgiveable scandal.

Act Up-Basel – Médecins sans Frontières – Asia Pacific Network of People Living with HIV/AIDS – Médecins du Monde – International Network of People who Use Drugs – International Treatment Preparedness Coalition

Source

Gilead HCV Drug May Face Price War; Rival AbbVie Up

By AMY REEVES, INVESTOR'S BUSINESS DAILY

Posted 03:08 PM ET

Gilead Sciences' (GILD) newly approved hepatitis C drug Sovaldi came under fire for its price from pharmacy benefit manager Express Scripts (ESRX) Tuesday, as rival AbbVie (ABBV) reported good data for its competing drug candidate. Gilead's stock dropped while AbbVie's rose on the stock market today.

Bloomberg reporter Drew Armstrong said on Twitter that Express Scripts' chief medical officer, Steve Miller, told him that the convenience of Sovaldi's one-pill-a-day regimen won't necessarily justify the $84,000 price tag for a 12-week regimen. "We will identify which drugs can be pitted against each other and make some really tough formulary decisions," Armstrong quoted him as saying.

This was a positive sign for AbbVie's regimen, which has so far performed as well as Sovaldi in clinical trials but involves four different drugs. Coincidentally, early Tuesday AbbVie released a second round of data from the regimen's phase-three program, showing a 96% sustained response rate among patients with the most common genotype of the virus who'd failed previous treatments.

ISI Group analyst Mark Schoenebaum wrote in an email to clients that while Express Scripts' size (around 100 million lives covered) gives it considerable leverage on these matters, the impact on Gilead might not be felt for a few years out.

"A big price differential would likely be necessary to block GILD's regimen," he wrote. "In a two-player market (before other competitors reach the market), whether ABBV would be willing to take a large price cut is not clear. Thus, the larger risk to price could be pushed out until 2017 when other competitors are able to reach the market."

Gilead stock, which hit a new high Monday after Sovaldi was approved, shed 3.5% in afternoon trading Tuesday. AbbVie spiked briefly to a new high above 54, but in afternoon trading was up 2%. Its partner Enanta Pharmaceuticals (ENTA), which developed the technology behind the drugs, got a much bigger lift and was up 27% in afternoon trading, to what is by far an all-time high for the stock.

RELATED: Gilead Hep C Drug Wins EU Panel Approval.

Source

Charles Gore - why it's important to get diagnosed

From Catching The Virus

Charles Gore - why it's important to get diagnosed from Catching The Virus on Vimeo.

Source

Beyond the Hype: What Sofosbuvir Means—and Doesn’t—for Global Hepatitis C Treatment

PUBLICATIONS

December 2013 by Azadeh Momenghalibaf Public Health Program

 Beyond the Hype: What sofosbuvir means—and doesn’t—for global hepatitis C treatment Download the report. 429.37 KB PDF

In December 2013, authorities in the United States and Europe approved Gilead’s highly anticipated hepatitis C drug, sofosbuvir. This drug and other new treatments for hepatitis C, called direct-acting antivirals (DAAs), have created a buzz among medical and research communities, patients, and financial analysts. Taken in pill form rather than by injection, and with cure rates and side-effect profiles better than previously seen for hepatitis C, many are hailing sofosbuvir and other new oral medicines as “miracle cures.”

The new drugs, however, come with a major limitation—price. Business analysts currently estimate that Gilead could charge $80,000 USD for a single course of treatment of sofosbuvir. With nearly 90 percent of the estimated 185 million people living with hepatitis C worldwide residing in low- and middle-income countries, where government health budgets are small and where most patients have to pay for medi ines out of pocket, this price tag means that sofosbuvir and the other new hepatitis C medicines will remain out of reach for the majority of those in need.

In this new report, Beyond the Hype: What Sofosbuvir Means—And Doesn’t—For Global Hepatitis C Treatment, we examine the new hepatitis C treatment market and projected revenues, and look back at what we can learn from the fight for access to HIV medicines in the 2000s to help secure reductions in the price of these promising new hepatitis C treatments.

Cross-posted from Open Society Foundations

------------------

American Liver Foundation Hails Promise of Cure Signaled by FDA's Approval of New Hepatitis C Treatments

 

Treatments With Few Serious Side Effects Strengthen Case for Increased Screening, Which Could Save Many Lives

NEW YORK, Dec. 10, 2013 /PRNewswire/ -- The American Liver Foundation fully welcomes FDA approval of two new treatments for Hepatitis C, one of which is a new class of drug. This liver disease affects approximately 3.2 million people inthe United States, and roughly 75% of those infected are unaware they carry the virus. Often referred to as a silent epidemic, those infected include baby boomers that may have contracted the virus from surgeries, blood transfusions, and other contaminated blood products before the disease was known to exist.

Sovaldi, known generically as Sofosbuvir, is the first polymerase inhibitor to be approved for treatment of Hepatitis C, in combination with other anti-virals. Olysio, known generically as Simeprevir, is the first once-daily protease inhibitor to be approved.

"This is the beginning of a new, gentler, era in the treatment of Hepatitis C," states Tom Nealon, National Board Chair of the American Liver Foundation. "We know that thousands of patients have been awaiting new, less invasive, treatment options, and this is exciting news, but we are concerned that millions of cases of infections remain undetected and therefore untreated. These new treatments give hope to existing patients, and strengthen the case for systematically screening all baby boomers," he adds.

New data from the manufacturers of these and other new drugs for Hepatitis C was presented at the recent AASLD conference in Washington DC, indicating that there are many more new treatments in the pipeline, and promising the possibility of cure.

"With these new treatments just approved, and many more being developed, we have every reason to be optimistic about the potential to cure and even eradicate this deadly virus," states Hillel Tobias, MD, a liver transplant specialist and Co-Chair of the American Liver Foundation's National Medical Advisory Committee. "With these new treatments, it may be possible to lower the overall cost of treatment due to less side effects and hospitalizations that occurred from previous treatments. If we identify and treat patients with these new medications, it will be possible to prevent the need for many thousands of liver transplants," he adds.

Both newly approved drugs promise shorter duration of treatment and reduced side-effects, with treatment regimens for some strains of Hepatitis C no longer requiring injections of Interferon, which has been the mainstay of treatment for many years, but is associated with some challenging side effects which can impact a person's ability to work outside the home.

Between 3 and 4 million Americans are infected with Hepatitis C. Many of them are baby boomers who contracted the virus before Hepatitis C was known to exist, in the decades before the commencement of identification and screening in 1992. Other risk factors include tattoos, body piercings, and intravenous drug use.

Left untreated, Hepatitis C leads to liver cirrhosis and liver failure. 75% of patients do not know they have the disease, and 90% do not get treated. The American Liver Foundation hopes that awareness of these new, better-tolerated treatments will bring increased Hepatitis C screenings, testing and treatments.

Additional Resources:

• ALF Hep C 123 Program: http://hepc123.liverfoundation.org/

ABOUT THE AMERICAN LIVER FOUNDATION
The American Liver Foundation's (ALF) mission is to facilitate, advocate and promote education, support and research for the prevention, treatment and cure of liver disease. It carries out its mission through education to promote liver health and disease prevention. Three national core programs are targeted to reach the public, at-risk groups, and patients with liver disease. ALF is the leading source of information on liver health and liver disease, through printed materials and www.liverfoundation.org. A toll-free national HelpLine at (800) GO-LIVER and 16 chapters across the country provide support to newly diagnosed patients, families, and the general public, through phone, email, and community outreach. It funds research that has helped to begin the careers of more than 750 scientists in the field of liver health in hopes of finding treatments and cures that will lead to a world free of liver disease. ALF is on twitter at @liverUSA

SOURCE The American Liver Foundation

RELATED LINKS
http://www.liverfoundation.org

Source

Fair Pricing Coalition Condemns Gilead for Exorbitant Price of New Hepatitis C drug

December 9, 2013

The Fair Pricing Coalition (FPC) today condemned Gilead Sciences for the price set for its direct acting antiviral (DAA) Sovaldi™ (sofosbuvir), a once-daily, first-in-class nucleotide polymerase inhibitor approved by the U.S. Food and Drug Administration on December 6, 2013, for the treatment of chronic hepatitis C, including those co-infected with HIV. While FPC believes that all hepatitis C virus (HCV) drugs are priced too high, the coalition of HIV and viral hepatitis treatment activists is especially dismayed by the wholesale acquisition cost (WAC) of $84,000 for a 12-week course of Sovaldi™. For comparison purposes, the FPC notes the 12-week WAC for the recently approved NS3/4A protease inhibitor Olysio™ (simeprevir) is $66,360.

"Sovaldi™ is a very safe and highly effective drug that will significantly shorten HCV therapy and either reduce or eliminate the need for injected pegylated interferon," explained FPC Co-Chair Lynda Dee. "However, this does not give Gilead unconscionable pricing carte blanche, particularly when considering that Sovaldi™ still needs to be combined with ribavirin for the treatment of HCV genotype 2 for 12 weeks or genotype 3 for 24 weeks. Twelve weeks of therapy with Sovaldi™ plus both pegylated interferon and ribavirin is required for the treatment of HCV genotype 1, the most common genotype in the US, and HCV genotype 4."

The WAC for 12 weeks of HCV treatment with pegylated interferon and ribavirin is approximately $9,000, resulting in a combined WAC of $93,000 for a Sovaldi™-inclusive regimen to effectively treat a single person living with HCV genotypes 1 or 4. To treat HCV genotype 3, 24 weeks of Sovaldi™ plus ribavirin is required, resulting in a Sovaldi™ WAC of $168,000.

Advertisement

Price Portends an Ominous Future

"Gilead has set the bar dangerously high as other companies determine prices for similar hepatitis C drugs as they enter the market," Dee said. The effectiveness of Sovaldi™ as a component of future pegylated interferon-free regimens for the treatment of HCV will ultimately depend on co-administration with other DAAs currently in development, and are anticipated to come with their own high price tags.

"Sovaldi™ is expected to transform the curative landscape for hundreds of thousands of people living with hepatitis C in the U.S. who require therapy or responded poorly to previous treatment," said Lorren Sandt, FPC Co-Chair. "Yet the high price will result in significant barriers to treatment access, particularly in limited and fixed-budget programs, such as Medicare and state Medicaid programs, AIDS Drug Assistance Programs, the Veterans Administration, and in correctional systems."

The high price may also lead to access challenges imposed by private insurance plans and Qualified Health Plans in the new Affordable Care Act (ACA) Marketplaces, notably those with high co-payment and other out-of-pocket requirements.

"There may be reluctance to add Sovaldi™ to formularies quickly and payers may force people living with HCV to engage in step therapy in which they are first required to try less expensive options that are less effective," Sandt added. "These options take longer to complete and are associated with serious side effects, which present a serious impediment to adherence and, ultimately, to being cured of hepatitis C."

Concessions Where They Count

Although Gilead refused FPC's demand for fair pricing of Sovaldi™, the company has agreed to all FPC requests for concessions regarding Sovaldi™ access programs. These include:

• The SupportPath™ (www.supportpath.com) patient assistance program (PAP), with a $100,000 maximum income allowance for a household of three and 500% of the federal poverty level (FPL) eligibility criteria for larger households.
• The SupportPath™ Sovaldi™ co-pay coupon program will provide co-pay assistance for eligible patients with private insurance, including ACA Marketplace exchange patients, who need assistance paying for out-of-pocket medication costs. Most patients will pay no more than $5 per co-pay. Co-pay assistance of up to 20% ($16,000) of the WAC price for Sovaldi™ can also be applied toward prescription deductibles and co-insurance obligations.
• Gilead has made a contribution to the Patient Access Network (PAN) for co-pay assistance for Medicare Part D clients.
• Gilead has initiated an emergency Sovaldi™ supply program for patients that may lose their prescriptions.

Gilead has agreed to ensure access to its PAP and co-pay assistance programs for AIDS Drug Assistance Program (ADAP) patients who are co-infected with HIV, even in states with ADAP programs that will not include Sovaldi™ on their formularies.

The FPC urges Gilead to widely disseminate the details of its SupportPath™ PAP and co-pay coupon program, which must include providing written SupportPath™ information for prescribers, prominently featured SupportPath™ information in its professional and direct-to-consumer advertisements, and clear links to www.supportpath.com via the Gilead and Sovaldi™ websites.

From The Fair Pricing Coalition

“There are decades where nothing happens; and there are weeks where decades happen.” - Vladimir Ilyich Lenin

(March 2014 Issue, Journal of Hepatology)
FOCUS 

Scott L. Friedman MD
Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY

Correspondence:
Scott L. Friedman, M.D.
Division of Liver Diseases
Box 1123, Mount Sinai School of Medicine
1425 Madison Ave., Room 1170C
New York, NY 10029
Tel 212-659-9501
Fax 212 849-2574
Email: scott.friedman@mssm.edu

PII: S0168-8278(13)00839-8
DOI: http://dx.doi.org/10.1016/j.jhep.2013.12.002
Reference: JHEPAT 4964

To appear in: Journal of Hepatology

Received Date: 3 December 2013
Accepted Date: 4 December 2013

Please cite this article as: Friedman, S.L., “There are decades where nothing happens; and there are weeks where decades happen.” - Vladimir Ilyich Lenin, Journal of Hepatology (2013), doi: http://dx.doi.org/10.1016/j.jhep. 2013.12.002

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Lenin could have hardly imagined that his words describing the Bolshevik revolution almost 100 years ago could be applied to the breathtaking approvals in HCV therapies in the past few weeks. Yet, if one defines ‘revolution’ (from the Latin revolutio, "a turnaround") as “a significant change that usually occurs in a short period of time”, there is little doubt that we are experiencing a revolutionary epoch in hepatology, and practitioners would be wise to mark this watershed in their collective memories. After over a decade of only modest improvements upon standard interferon-based therapies, the recent FDA approval and anticipated EMA approval of sofosbuvir and simeprevir – albeit currently in combination with interferon and ribavirin - represent the leading edge of what will be a new era of interferon-free regimens that promise to cure more than 90% of genotype 1 patients, using regimens that are well tolerated and will rescue many patients in whom interferon is either unsafe or not tolerable. These advances have generated excitement among the lay and scientific press [1, 2], patients, providers, pharmaceutical and biotech companies, and investors.

A study by Younossi et al in this month’s issue of the Journal estimates the predicted economic and clinical windfall of this revolution using Markov modeling. In this study, the authors compared the calculated incremental cost-effectiveness ratio (ICER) between patients treated with standard interferon based triple therapy (interferon, ribavirin and either telaprevir or boceprevir) with those treated with all oral regimens for 12 weeks, based on published distributions of fibrosis stage, current costs of therapy and health care, and drug efficacies. They also distinguished between predictions based on whether patients were first screened with transient elastography (e.g. Fibroscan) as the staging method in order to limit therapy to only those with more advanced fibrosis; estimates that included the cost of liver biopsy were restricted to the sensitivity analysis. Of note, the study was performed before Fibroscan was approved in the US, and as of this writing the cost is still not determined, so the authors used the cost of ultrasound as a surrogate. The authors also made the estimate that the average total treatment cost of oral therapy was equal to the average total treatment cost of triple therapy, since the actual costs were not known at the time of their study.

The model’s findings clearly favor the use of all oral regimens in all patients with HCV over the use of triple therapy, and also predict that treating all patients would be cost-effective compared to using staging-guided therapies. The all oral regimen without staging would yield an ICER of $15,709 quality-adjusted life years (QALY), well below the threshold of $50,000 often used to provide justification for new therapies. Moreover, neither a significant reduction in the cost of boceprevir / telaprevir, nor the cost of staging would have any impact on the predicted advantage to using all oral therapy without staging guidance.

As the authors point out, the findings take on added significance with an expected increase in detection of HCV in the United States following the endorsement of recommendations by the CDC and US Preventive Services Task Force to conduct widespread one-time HCV screening in patients between 45 and 65 years old. Modeling predictions like this study’s supporting the use of a ‘test and treat’ strategy could greatly simplify the linkage to care following HCV diagnosis that is so vital for effective disease eradication in at-risk populations [3].

Of course, the analysis by Younossi et al relies on major assumptions regarding drug efficacy, costs and adverse events, which could well be higher in the real world than that seen in clinical trials. This was the experience in the use of triple therapy that includes boceprevir or telaprevir, where the incidence of adverse events in clinical practice after the drugs were approved was much higher, and the events more severe than what was experienced in pre-approval studies [3, 4]. This unexpected problem arose in part because after the drugs were approved they were first given to those with the most urgent need for cure (ie., cirrhotics), even though these same patients had the least capacity to tolerate adverse events.

Moreover, treatment with all oral regimens may not be so straightforward in every patient, particularly those who previously failed interferon-based regimens or with HCV genotype 1a. For example, in the article by Lok at al, also in this issue of the Journal, the results of a phase II trial that included two experimental direct-acting antivirals (daclatasvir and asunaprevir) underscores the more labor-intensive and customized treatments that will be required in prior null responders, especially the need to distinguish between genotypes 1a and 1b. In the Lok et al study, which was a randomized open label trial testing a series of combinations with or without interferon, 99% of the patients had the non-CC IL-28 genotype associated with interferon resistance, which explains their prior non-responses. In these difficult-to-treat patients, those with genotype 1a required interferon-based combinations to achieve an SVR. Thus, prior non-response was a tipoff to the need for more detailed diagnosis (e.g, viral and possible IL-28 genotyping) and customized therapy, yet as we screen and uncover more untreated HCV, some will also have genotype 1a and a non-CC IL-28 genotype and will possibly fail an all oral combination. Indeed, the simeprevir drug label will indicate that in genotype 1a patients resistance testing should be performed for the ‘Q80K’ mutation. If present, then “other therapies should be considered.” Thus, should our initial algorithm include both HCV and IL-28 genotyping, or should we wait until such patients fail initial therapy and then consider retreatment with an interferon-based regimen? If so, will viral resistance from initial therapy limit efforts to retreat? These are the kinds of nuanced questions, which color the interpretation of the Markov modeling used by Younossi, although they do not undermine it.

As we enter this momentous transition towards an ‘interferon-free’ world, it is also worth looking back to ask which advances were absolutely critical to bringing us to this juncture. I would contend that three seminal discoveries were essential: 1) The discovery of the HCV agent by Houghton, Choo, Kuo, Bradley and colleagues [5], a Nobel-worthy achievement both because of its public health impact and for the brilliant new methodology they formulated to clone the virus; 2) The development of cell based culture systems that supported HCV, first using the replicon [6] and then later the infectious JFH1 virus systems [7, 8], which enabled high throughput drug screening and the discovery of obligate cellular receptors for HCV [9]; 3) The characterization of HCV protein structures, which greatly facilitated the design of direct-acting antiviral drugs.

Does this mean that all the other investments in HCV research were irrelevant? Not at all. The discovery of HCV could not have happened without years of clinical characterization of non-A non-B hepatitis cases and studies in non-human primates, among others. Similarly, revealing how HCV evades immune clearance and how it drives intracellular innate immune signaling have already borne fruit in helping us understand the pathogenesis of other viral infections, and will also be vital in developing a prophylactic HCV vaccine.

Another important implication of these three seminal discoveries is that they reflect a healthy synergy between the academic and commercial research spaces. Both the discovery of the virus and the development of new drugs took place in the biotech/pharmaceutical sphere, yet they could not have happened without equally important discoveries in academia, including the clinical studies before and after the discovery of the virus, and the characterization of cell culture systems to enable drug screening. In fact, one could argue that the HCV success story represents an ideal consequence of a healthy, interdependent ecosystem between academic and commercial research.

This brings us back to the words of Lenin and the exciting times we live as investigators or clinicians devoted to liver disease. We can only hope that decades do not pass again before witnessing another revolution in our specialty, but just in case let’s enjoy this rare view while we can.

Acknowledgement

I greatly appreciate the helpful advice of Drs. Douglas Dieterich and Jean Michel Pawlotsky in writing this article.

References

[1] Pollack A. Hepatitis C, a Silent Killer, Meets its Match. New York Times. November 4, 2013.

[2] Mole B. Targeted drugs to tackle hepatitis C. Nature 2013;497:18-19.

[3] Hezode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, et al. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol 2013;59:434-441.

[4] Bichoupan K, Schwartz JM, Martel-Laferriere V, Giannattasio ER, Marfo K, Odin JA, et al. Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir. Aliment Pharmacol Ther 2013 (in press).

[5] Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244:359-362.

[6] Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 1999;285:110-113.

[7] Lindenbach BD, Meuleman P, Ploss A, Vanwolleghem T, Syder AJ, McKeating JA, et al. Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro. Proc Natl Acad Sci U S A 2006;103:3805-3809.

[8] Sainz B, Jr., Chisari FV. Production of infectious hepatitis C virus by welldifferentiated, growth-arrested human hepatoma-derived cells. J Virol 2006;80:10253- 10257.

[9] Evans MJ, von Hahn T, Tscherne DM, Syder AJ, Panis M, Wolk B, et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 2007;446:801-805.

Source

Effects of Sofosbuvir-based Treatment, With and Without Interferon, on Outcome and Productivity of Patients With Chronic Hepatitis C

Clinical Gastroenterology and Hepatology

Article in Press

Zobair M. Younossi,Maria Stepanova, Linda Henry, Edward Gane Ira M. Jacobson, Eric Lawitz, David Nelson, Lynn Gerber, Fatema Nader,  Sharon Hunt

Received 7 November 2013; accepted 17 November 2013. published online 09 December 2013.
Accepted Manuscript

Abstract

Background

& Aims: Interferon-based treatment of chronic hepatitis C virus (HCV) infection can negatively affect patient-reported outcomes (PROs) and work productivity (WP). We assessed these factors in patients with chronic hepatitis C treated with sofosbuvir and ribavirin, with or without pegylated interferon.

Methods

The HCV-specific Quality of Life (CLDQ-HCV), Functional Assessment of Chronic Illness Therapy-Fatigue, and WP and Activity Index: Specific Health Problem questionnaires were completed before, during, and after treatment of patients infected with HCV genotypes 2 or 3 who received sofosbuvir and ribavirin for 16 or 12 weeks (the FUSION study, n=201), or patients infected with HCV genotype 1 who received pegylated interferon, sofosbuvir, and ribavirin for 12 weeks (the NEUTRINO study, n=327).

Results

Patients in each group of the FUSION study had similar PRO and WP scores at each time point (all comparisons, P>.05). Compared to baseline, patients had modest reductions in fatigue, HCV-specific quality of life, and WP and Activity Index scores during treatment (P=.02 to <.0001). However, by 4 weeks after treatment, all scores returned to baseline levels or higher. Subjects in the NEUTRINO study had greater reductions in these scores during treatment; most remained significant through 4 weeks after treatment (P<.05). Significant improvements in PROs were observed among patients with sustained virologic responses 12 weeks after treatment (SVR12) in the FUSION and NEUTRINO studies (all P<.05). In multivariate analyses, after adjustment for confounders, interferon therapy was independently associated with worse PROs after 12 weeks of treatment.

Conclusions

Based on an analyses of 2 large clinical trials (FUSION and NEUTRINO), patient outcome and productivity are more negatively affected by the inclusion of pegylated interferon in treatment than by interferon-free regimens. Patients with SVR12 had significant reported improvements in outcome in both studies.

Key Words: CLDQ-HCV, WPAI, FACIT-F, quality of life, liver disease, hepatitis C

No full text is available. To read the body of this article, please view the PDF online.

Source