February 6, 2014

Blood Purification

Vol. 36, No. 3-4, 2013
Issue release date: January 2014

Free Access

Blood Purif 2013;36:231-236
(DOI:10.1159/000356362)

Bianco T.d · Cillo U.b · Amodio P.c · Zanus G.b · Salari A.d · Neri D.b ·Bombonato G.c · Schiff S.c · Baggio G.a · Ronco C.e, f · Brocca A.e, f · Soni S.f ·Minazzato L.d

aStudy Center of National Health and Gender Medicine, Padua Operating Unit, bUnit of Hepatobiliary Surgery, cDepartment of Clinical and Experimental Medicine, anddAntalgic Therapy, Institute of Anesthesiology and Reanimation, University of Padua, Padua, eDepartment of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, and fInternational Renal Research Institute Vicenza (IRRIV), Vicenza, Italy

Key Words Gender differences  Hepatitis C  Liver transplantation  Pain perception Quality of life  SF-36

Abstract

Background: Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, which adversely affects the quality of life (QoL) of the patient. The gender of the patient may be an important variable in the way severity of the disease is perceived. The aim of our study is to evaluate the effect of the gender variable on QoL in HCV-positive patients.Methods: This study included a total of 52 patients (26 men and 26 women) whocompleted a 1-year follow-up after liver transplantation. QoL was assessed using the SF-36 questionnaire. Results: Male subjects have significantly higher scores on physical role functioning, bodily pain and physical activity compared with females. Females have a better QoL compared to males with regard to the emotional state and mental health.Conclusions: These results show a significant effect of the gender variable on QoL in HCV patients.

© 2013 S. Karger AG, Basel

Introduction

The diagnosis of chronic liver disease has important implications on the patient's life, as it often marks the beginning of frequent medical checkups and treatment. It also involves the formalities related to enrolment into the liver transplant waiting list. In addition to the clinical effects of the liver disease, the psychological stress related to the continuous monitoring and assessments can affect health-related quality of life (HRQoL).

The World Health Organization (WHO) refers to ‘quality of life' as an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns [1]. In this sense, the HRQoL is defined as the set of physical, mental and social diseases assessed by somatic symptoms, psychological status and social interactions from the perspective of the patient, regardless of their medical condition. The international scientific community is increasingly interested in the QoL concept, particularly for the patients with chronic diseases. QoL studies can involve many different factors, ranging from the evaluation of the different effects of different diseases on daily activities and the identification of problems specific to each disease, to evaluate the effectiveness of different treatments and the specific factors that, in addition to patient compliance, determine treatment effectiveness.

In recent years, there have been numerous investigations on the QoL in patients with liver disease related to health, with particular attention to hepatitis C virus (HCV) positivity. This increased interest is justified by the significant spread of HCV in the world's population. In fact, the WHO estimated that worldwide there are about 140 million people affected by HCV, which corresponds to 2.2% of the global population. In Italy, about 2% of the general population is infected with HCV with a gradient that increases from north to south and the islands and with age (60% of patients with hepatitis) [2].

Even in the absence of overt liver disease, chronic HCV compromises HRQoL, with a negative impact on both mental health and physical well-being of the patient [3,4]. In fact, the vast majority of HCV patients present with nonspecific symptoms, such as fatigue, irritability, general malaise, abdominal pain, joint pain and headache [5]. In most cases, medical intervention is not required, however, physical and emotional health of the patient is affected. This in turn leads to inferior HRQoL for HCV patients [6]. Even if the patient is not aware of the seriousness of the disease, his psychological state is altered [7].

QoL in Patients with Liver Disease

Several studies seem to confirm a direct adverse effect of chronic HCV on HRQoL. Some recent reviews illustrate actual prospects of research in the field of QoL in patients with chronic liver disease. In a study from Britain, 72 unselected, consecutive patients with chronic HCV were compared with 30 consecutive patients with chronic hepatitis B infection and HBsAg positivity [4]. Patients with evidence of cirrhosis were excluded. SF-36 scores were markedly reduced in patients with chronic HCV infection, indicating that these patients perceived themselves as unwell and they reported a significant reduction in their QoL. Other researchers have shown that a significant percentage of HCV patients suffer from fatigue [8,9,10,11]. In one of the largest studies from France, Poynard et al. [12] reported that among 1,614 patients with HCV, 53% reported fatigue at their initial visit and the fatigue was severe in 17% of these patients. This study also found that fatigue was independently associated with female gender, age >50 years, cirrhosis, depression and purpura. In another study, HCV patients unaware of their HCV serostatus scored significantly worse in 3 parameters of general health, vitality and mental health [13]. Those aware of their serostatus did not differ demographically, clinically, virologically or serologically from those who were unaware, nor was there a link between QoL scores and objective measures of ill health. Numerous observations suggest that HCV may exert a direct effect on HRQoL through unknown mechanisms [14,15,16]. One possibility is that HCV may act within the central nervous system, since replicating viruses have been found within the nervous system tissue. Moreover, neuropsychiatric symptoms like fatigue, malaise, depression and cognitive impairment are among the most common complaints of patients with chronic hepatitis C and occur independently of liver disease or treatment status.

Importance of the Gender Variable

Over the past 30 years, medicine has reached incredible goals, including the description of the human genome, the ability to intervene at the beginning and end of life, the application of newest technologies for betterment of the patients, to name only a few. The achievements in many fields of medicine are based on evidence connected with guidelines. However, female gender has been inadequately represented in many of the epidemiological studies, which limits meaningful statistical analysis in many disorders.

The ‘woman question' emerged in 1991 when Bernadine Healy, the first female director of the National Institute of American Public Health, wrote a famous editorial in the New England Journal of Medicine [17]. She coined the term ‘Yentl syndrome' to highlight the gender-based disparities in the treatment and outcome of coronary artery disease in the intensive care unit (Yentl was a heroine of a Jewish story where a girl shaved her hair and disguised herself as a boy to enter religious training). Women in the intensive care unit were subjected to less diagnostic and therapeutic procedures than men and fewer invasive procedures such as cardiac catheterization and coronary artery bypass surgery [18,19]. Moreover, large prevention trials in patients with myocardial infarction did not include women at all. A clear discrimination by the cardiologists against the female patient was aptly emphasized. This editorial stirred basic researchers and clinicians around the world and was followed by a series of publications and studies designed to examine gender differences in various aspects of cardiovascular disease.

Another cornerstone of gender medicine was the Fourth World Conference on Women held in Peking in 1995, where the conviction to apply the principle of gender equality in all activities, including those for health, was considered a basic human right.

In 2002, the WHO established the Department for Gender and Women's Health to recognize the differences in disease burden and treatment between men and women. In 1999, the Italian Ministry for Equal Opportunities formally established a new group with the aim of working on gender disparities in medicine through a project entitled ‘A measure of health to a woman'. In 2001, a report on women's health was presented to the parliament and in 2003 a ‘Guide to women's health' was published. In Italy, the attention to the gender variable is now supported by the National Center for Health and Gender Medicine. The Center aims to gather information, impart training and encourage research in all fields of medicine. It also aims to network all Italian centers interested in these issues.

With regard to QoL in patients with chronic liver disease, the gender variable is not systematically studied so far. The aim of the present study is to assess the effect of the gender variable on the subjective evaluation of QoL in patients with chronic HCV infection.

Patients and Methods

SF-36 Questionnaire

SF-36 is the best-known, patient-oriented questionnaire for the assessment of one's general health condition. This test is the short form of the Medical Outcome Study questionnaire, which was developed by John Ware (the principal investigator) and his colleagues in the 1980s and was subject to successive modifications by researchers from various medical specialties [20]. The SF-36 is a generic instrument that proposes to evaluate the QoL from the patient's point of view. It is made up of 36 items divided into 8 scales (table 1) whose purpose is to evaluate the various aspects related to the patient's health and thereby furnish a global assessment of the patient's mental and physical well-being. To each question, a rough score is assigned; this initial score is further elaborated to furnish a final ranking only after evaluation of all answers given. The final response is given and the relationship between specific answers is evaluated to determine the score on each scale. Scoring on each scale is from 1 to 100, with higher values being indicative of a better-perceived QoL relative to one's health status (fig. 1). Scoring and standard deviations will vary from scale to scale and are also dependent on age. Its validity is recognized by the international community.

356362a

356362

Patients

This study included a total of 52 patients (26 men and 26 women) who completed a 1-year follow-up after liver transplantation. The HRQoL was assessed using the SF-36 questionnaire. The scores in the various domains of the questionnaire were compared using Student's t test. Analyses were performed using the statistical software SPSS 11.0.

Results

Male subjects have significantly higher scores on physical role functioning (daily activities or work is less impaired by physical health than in females), bodily pain (minor limitations due to pain) and physical activity (fewer constraints on the execution of physical activity in general) compared with females. On the other hand, females have a better QoL compared to males with regard to emotional role functioning (less impaired at emotional level) and mental health (self-satisfied and better mood stability).

Discussion

The way to deal with a disease and recovery will vary from person to person but there are gender differences that are often overlooked or incorrectly addressed. The significant difference between males and females with respect to ‘bodily pain' may be explained by the effects of various hormones on the body. Current research shows that estrogen would increase nervous system activity; this effect manifests itself in the increased transmission of pain stimuli and pain sensitivity of women. Conversely, testosterone has an analgesic effect and can reduce pain sensitivity in men [21]. Many previous studies dealing with behavioral responses evoked by nociceptive stimuli have demonstrated an increased sensitivity of females [22].

In our study, male patients scored higher in the category of ‘physical functioning' and ‘physical role functioning', which are the parameters related to physical activity and perceived limitations. The female patients scored less in both parameters, suggesting impaired QoL. This may partly be explained by the effect of ‘fatigue' in the posttransplant period. In an elegant cross-sectional study, van den Berg-Emons et al. [23] investigated the incidence, etiology, severity and factors of influence of fatigue in liver transplant recipients and concluded that the female gender perceives fatigue with greater severity.

In addition, sociocultural factors have to be considered. In fact, recent studies highlight the issue of gender difference in pain perception. It has been observed that for the same objective disease women report more pain than men [24]. These observations emphasize the fact that QoL assessment in liver transplant patients should not only include the clinical and biological condition of the patient but also psychosocial and cultural aspects. In this regard, it is also interesting to note that although female patients score less in the parameters ‘physical functioning' and ‘physical role functioning', they score better in the parameters of ‘emotional role functioning' and ‘mental health'. This highlights a better ability of females to manage stress and psychoemotional demands in the posttransplant setting. This could indicate differences in the ability of coping with stress between males and females of the study population.

Studies in the experience of pain in patriarchal ideology have highlighted ‘the central role of etiologic and coping strategies (‘being a good mother' to the female gender), suggesting that the patient needs pain to give meaning to their symptoms. It also helps to avoid negative feelings of despair and isolation. In this study, both males and females reported the common belief that a woman is better able to cope with painful events. This belief is also supported by the importance of the maternal role in women (experience of childbirth, breastfeeding, primary involvement in child rearing and emotional aspects of children) and explanations relating to the increased use of emotional expressiveness and the likelihood of seeking help and support of females. Recent studies have demonstrated sex differences in response to painful situations in teenagers and adolescents. It has been observed that males would mostly use distracting behavior while females make greater use of social support and positive self statements [25].

Studies on coping styles in the course of chronic diseases have shown that being active, thinking positively and expressing emotions positively correlated with significantly higher levels of functioning, with more positive scores in the clinical measures of disease and higher levels of psychological adjustment. The ability to adequately manage the transplant event and its consequences may foster greater satisfaction and improve QoL and HRQoL. In this sense, the gender differences in the QoL questionnaire identified in this study can help to direct attention to the most problematic and often neglected aspect for a patient undergoing a liver transplant by directing care and interventions in the posttransplant period in relation to an important variable such as gender.

Conclusion

HCV confers an inferior QoL to the patients. This effect is perceived by males and females in different ways.

References

Source

Provided by Zitter Health

Lee Goldberg, Director, Syndicated Research, Zitter Health Insights

FEBRUARY 5, 2014

The HCV category is certainly dynamic enough, with numerous agents poised for approval in the next 18 to 24 months. Still, the release last Wednesday of the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis Cadded another variable for payers and manufacturers to consider before determining their strategies. The recommendations were both confirmatory and surprising and it remains to be seen how payers will ultimately integrate them into management.

The Recommendations fully endorse new oral agents as the standard of care, advocating sofosbuvir first among treatment-naïve, genotype 1 patients who are eligible for interferon, followed by a simeprevir-based regimen as an alternative. The panel made a comparable recommendation for genotype 4 patients, then endorsed sofosbuvir for treatment of patients with genotypes 2 and 3, per label. Endorsements for telaprevir and boceprevir-based regimens were withdrawn as being “markedly inferior to the preferred and alternative regimens.”

However, not all endorsements followed the obvious path, namely those for patients intolerant to interferon. Labeling for sofosbuvir permits usage “in combination with ribavirin for 24 weeks . . . for CHC patients with genotype 1 infection who are interferon ineligible.” Nonetheless, the AASLD/IDSA made its primary treatment an off-label regimen of sofosbuvir plus simeprevir in combination for treatment-naïve, interferon-ineligible genotype 1 patients. It’s a safe assumption the panelists were impressed with the 90%-plus SVR rates achieved in the ongoing phase 2 COSMOS study, but it’s less clear payers will hold the same opinion.

Early research from the Hepatitis C Impact Monitor, a multi-stakeholder view of this rapidly changing area, published by Zitter Health Insights, indicates a majority of payers (52%) hold the guidelines as meaningfully or significantly influential on their determination of utilization management of the HCV category.  By itself that finding would indicate positive coverage of the sofosbuvir/simeprevir pairing.  But an even larger majority of the same payer sample, this time 80%, indicated they’re more unlikely than likely to cover those drugs in combination.  But that was before the guidelines were released.

To begin developing an understanding of how payers and doctors expect to change their behavior as events occur, we asked four pharmacy directors from national payers (in aggregate representing approximately 25 million commercial lives) how they anticipate their organizations will react.  While it’s still early for many to have determined final policies, reactions were evenly split.  One participant commented, “We try to support evidence based guidelines, but, the evidence is not there to support use at phase 2.  We’ll need more evidence development.” However, another pharmacy director was more resigned, commenting, “We won’t have a choice.  There’s no way to combat the recommendation.”
Combat may be a strong word, but may not be far from an accurate description because physicians appear on board. Prior to publication nearly a majority (47%) of specialists were more likely than unlikely to prescribe the combination. We expect those figures to increase because seventy-three percent of them grant the guidelines meaningful or significant influence in their prescribing decisions.

Perhaps beneficially for pharmacy directors, the conundrum about off-label sofosbuvir/simeprevir coverage comes with an expiration date. The AASLD/IDSA includes the caveat that “This regimen should be considered only in those patients who require immediate treatment, because it is anticipated that safer and more effective IFN-free regimens will be available by 2015.”  Which means payers will have new guidelines to digest upon the approval of Gilead’s sofosbuvir/ledipasvir, or of AbbVie’s triple therapy, or of Boehringer’s faldaprevir/deleobuvir. In the interim, payers will weigh the nature of Phase 2 results against the imprimatur of the AASLD.  Each of the four pharmacy directors we spoke with on Monday indicated their organization is currently reviewing the Recommendations document but hadn’t yet made a final policy determination.  Zitter’s Hepatitis C Impact Monitor will continue to examine the changing HCV landscape, providing timely, deep insights into non-clinical factors that influence agent access and adoption.

Hep-C-Feb-2014-Image-1

Source

Hepatitis C treatment shifts as new drugs emerge

Kim Painter, Special for USA TODAY 6:29 p.m. EST January 29, 2014

Treatment for liver-damaging virus is changing fast. Experts release new guidelines.

1391030010000-Sofosbuvir-bottle-with-pill-on-Gray

Sofosbuvir, with the brand name Sovaldi, is among new medications changing the treatment of hepatitis C.(Photo: Gilead Sciences Inc.)

John Billeris has tried and failed four grueling rounds of treatment for his chronic hepatitis C infection over the past 15 years. He is not convinced that his fifth try — with what he jokingly calls "magic medicine" — will be the charm. But he says the three-drug regimen he started on Christmas is definitely easier to take.

"I saw the doctor a couple of weeks ago… and I told him this (stuff) is not working because I don't feel anything," says the 59-year-old semi-retired real estate agent from Oyster Bay, N.Y. Since then, Billeris says, he's developed a familiar "anemic feeling," but still nothing like the persistent flu-like symptoms he has endured in the past.

That's because Billeris' new treatment does not include one drug that, until now, has been essential for patients like him: interferon, a medication known for causing fevers, headaches, fatigue, mood swings and other unpleasant and sometimes dangerous side effects. It does include two drugs approved by the Food and Drug Administration in late 2013, sofosbuvir from Gilead Sciences, Inc., and simeprevir from Janssen Therapeutics.

Those medications, and others the FDA is expected to consider soon, are part of what experts are calling a revolution in treatment for 3 million people in the USA chronically infected with hepatitis C, the nation's leading cause of liver cancer and liver transplants.

Changes in treatment are coming so fast that several medical groups on Wednesday took an unusual step: posting preliminary online treatment guidelines that will evolve as more medications become available.

Those medications could soon eliminate the need for interferon injections for most patients. They also are expected to make treatment faster, easier and more effective than older regimens, which last at least six months and succeed about 75% of the time, experts say.

"The ideal would be a single pill once a day, for eight or 12 weeks, with success rates of greater than 90%," says Donald Jensen, a liver disease specialist from the University of Chicago and co-chair of the committee behind the guidelines posted at HCVguidelines.org by the American Association for the Study of Liver Diseases, the Infectious Diseases Society of America and the International Antiviral Society-USA.

While single-pill therapies are not yet available and the FDA has not yet approved an interferon-free regimen for the majority of patients, the experts say doctors can combine drugs on the market to get faster, easier, more effective treatment for many patients who need care now. In some cases, that will mean using combinations not explicitly approved by the FDA — including the interferon-free cocktail Billeris is using. The guidelines say it is an option for hepatitis C patients with genotype 1 (the most common strain) who can't tolerate interferon or have certain conditions, including depression.

The guidelines don't carry the same weight as those that go through formal reviews to be published in medical journals, "but we are saying that if these were our patients, this is how we would handle them," says committee co-chair David Thomas, a liver specialist at Johns Hopkins School of Medicine, Baltimore.

The guidelines will be "enormously valuable" in convincing more insurers to cover the very expensive emerging treatments, says Douglas Dieterich, a liver specialist at Mount Sinai Hospital, New York. He says some have been refusing to pay for the combination of sofosbuvir, which costs $84,000 for 12 weeks, and simeprevir, which costs $66,000 for 12 weeks, according to manufacturers.

The prices for the new drugs, especially, sofosbuvir, at $1,000 a pill, also have drawn criticism from patient advocates who say high prices will limit access in the USA and worldwide.

"Gilead is exploiting the fact that this is essentially a cure for a deadly disease," says Michael Weinstein, president of the AIDS Healthcare Foundation.

Gilead believes the price of sofosbuvir "is fair, based on the value it represents" to patients, company president John Milligan said in a statement. Most private insurers are covering the drug in FDA-approved combinations, he says, and the company is working with Medicaid and Medicare to set terms for access under those plans. The company also has an assistance plan for uninsured patients and those who need help with co-pays.

The new expert guidelines "are not designed to address cost," Jensen says. "Our recommendations are based on what we think is best for patients."

The new guidelines also do not say which patients doctors should treat now and which patients can wait — a crucial issue since hepatitis C can cause varying degrees of harm and take decades to cause symptoms. A future version will address that issue, Thomas says.

Many people don't even know they have the infection. But the federal Centers for Disease Control and Prevention says it is so common among Baby Boomers that everyone born between 1945 and 1965 should be tested. The virus spreads through shared needles, birth and, sometimes, sex. About 5% of people with chronic infections eventually die of cancer or cirrhosis, the CDC says.

Getting tested is especially crucial now, Thomas says. "All the major advances in treatment are insignificant if a person doesn't even know they have the infection."

Of course, those advances in treatment still need to pass the test of real-world use — a test that some previous medical advances have failed. Billeris, for one, says, "I'm not optimistic — but I am hopeful."

Source

PUBLIC RELEASE DATE: 5-Feb-2014

Contact: Lee-Ann Landis Donegan
leeann.donegan@uphs.upenn.edu
215-349-5660
University of Pennsylvania School of Medicine

Findings could influence process for allocation of scarce organ resources

(PHILADELPHIA) – Patients waiting for liver transplants who develop hepatopulmonary syndrome (HPS), a lung disorder associated with end-stage liver disease, are eligible to move up on the wait list. In a new paper published in Gastroenterology, however, Penn Medicine researchers argue the so-called "exception points" given to these patients award some HPS patients unnecessary priority over others on the list, which includes about 17,000 patients.

The current U.S. transplant allocation system prioritizes patients based on medical urgency using the Model for End Stage Liver Disease (MELD) score, which takes into account the expected three-month survival due to end-stage liver disease, but does not consider other, unrelated medical complications. As a result, a system that allows wait-list candidates with certain conditions, HPS among them, to be eligible for exception points to increase their waitlist priority has been developed.

"To examine the impact of HPS MELD exception points on outcomes, we examined the relationship between patients' blood oxygen levels and outcomes in a national cohort of patients who received HPS exception points, and compared survival in HPS vs. non-HPS patients," says David Goldberg, MD, MSCE, instructor of Medicine at the Perelman School of Medicine of the University of Pennsylvania and lead author on the study.

HPS is found in approximately 20 percent of patients awaiting liver transplant and is associated with a worse health-related quality of life. The condition is known to double the risk of death among patients evaluated for liver transplantation.

The Penn researchers looked at data from February 2002, the date the exception point program commenced, to December 2012. During this time, 973 patients on the liver transplant list received HPS exception points. While post-transplant survival was similar in HPS vs. non-HPS patients, post-transplant survival in HPS patients varied based on the severity of pre-transplant oxygen saturation levels.

The team found that patients with the poorest oxygen saturation levels (lower than 44 mm Hg) had a significantly lower three-year post-transplant patient survival rate.

Comparatively, significantly more non-HPS waitlisted patients, who did not receive exception points, died on the waitlist or within 90 days of waitlist removal, while a great proportion of HPS waitlist candidates were transplanted (73 percent vs. 43 percent). In addition, the study showed that only 49 percent of HPS transplant recipients had clear evidence of clinical indications for transplantation aside from HPS, as compared with 89 percent of non-HPS transplant recipients.

The findings refute recent reports and demonstrate an association between pre-transplant oxygen levels and post-transplant mortality, suggesting that the criteria for doling out exception points be adjusted based on patients' oxygenation, and suggesting an over-prioritization of all HPS patients in the current system.

This study represents the largest analysis of liver transplant waitlist candidates with HPS to date.

"These data, we hope, can provide some guidance to UNOS, as the exception point policy comes under revision," says Goldberg. "As organs are a scarce resource, we want to make it easier for the patients in the most urgent need to be prioritized as such, according to evidence-based criteria."

###

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community.

Source

PRESS RELEASE February 6, 2014, 7:06 a.m. ET

CF102 has Orphan Drug Designation from U.S. FDA

Global Liver Cancer Drug Market is Expected to Exceed $2 Billion by 2015

PETACH TIKVA, Israel, Feb. 6, 2014 /PRNewswire/ -- Can-Fite BioPharma (TASE: CFBI), (OTC: CANFY), a biotechnology company with a pipeline of proprietary small molecule drugs that address inflammatory and cancer diseases, announced today that a Phase II study protocol for the treatment of advanced liver cancer with its CF102 drug candidate has been submitted.

The company plans to conduct the Phase II study in Israel, Europe and the US and will include 78 subjects (less than what has been reported previously since the company is treating a patient population with a more advanced disease) with second-line treatment of advanced hepatocellular carcinoma with Child-Pugh Class B cirrhosis. The study will investigate the efficacy and safety of CF102 vs. placebo. The protocol has been submitted to the ethics committee in Israel and the company intends to follow up with European and US submissions shortly. The study protocol was developed with the assistance of Dr. Keith Stuart, MD, Chairman, Department of Hematology and Oncology Professor of Medicine, Tufts University School of Medicine a well-known internationally expert in Liver Cancer.

The US Food and Drug Administration (FDA) has granted Orphan Drug designation for CF102, for the treatment of hepatocellular carcinoma.

According to Global Industry Analysts, the global liver cancer drug market is expected to exceed $2 billion by 2015.

The company reported earlier that data from the Phase I/II study was published recently in The Oncologist, one of the leading journals in this field, and was presented at the 18th World Congress on Advances in Oncology. The company reported that the Phase 1/II study data demonstrated that the trial objectives were successfully achieved, demonstrating a very favorable safety profile for CF102 in a patient population with hepatocellular carcinoma and Child-Pugh cirrhosis classes A and B. In addition, the median overall survival time was very encouraging given that most patients were treated in the second-line setting and some were Child-Pugh Class B. Another finding indicated that the A3 adenosine receptor, which is the target of CF102, can serve as a biomarker to predict the patients' reaction to treatment with CF102. Interestingly, one of the patients included in the Phase 1/II study has been treated for 4 years with CF102 and is continuing to be treated, with CF102.

About CF102

CF102 is a small orally bioavailable drug which binds with high affinity and selectivity to the A3 adenosine receptor. The latter is highly expressed in tumor cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug. In our pre-clinical and clinical studies, CF102 induces a robust anti-tumor effect via de-regulation of the Wnt signaling pathway, resulting in apoptosis of liver cancer cells.

About Can-Fite BioPharma Ltd.

Can-Fite BioPharma Ltd is an Israeli public company, the ordinary shares of which are traded on the Tel Aviv Stock Exchange (the "TASE") (TASE: CFBI). Level II American Depository Receipts of the Company currently trade on the NYSE MKT (NYSE MKT: CANF). Can-Fite, which commenced business activity in 2000, was founded by Pnina Fishman, Ph.D., researcher in the Rabin Medical Center, and Ilan Cohn Ph.D., patent attorney and senior partner at Reinhold Cohn Patent Attorneys in Israel. Dr. Fishman serves as the Chief Executive Officer of Can-Fite. Dr. Fishman founded Can-Fite on the basis of her scientific findings, and Can-Fite is focused on the development of small molecule orally bioavailable drugs, in particular, ligands that bind to the A3 adenosine receptor. Such drugs mediate anti-inflammatory and anti-cancer effects and the A3AR is developed as a biological predictive marker. Can-Fite's lead drug candidate, CF101, is in clinical development for the treatment of autoimmune inflammatory diseases including Rheumatoid Arthritis and Psoriasis. Can-Fite's CF102 drug candidate is being developed for the treatment of liver diseases and CF602 is being developed for the treatment of inflammation and sexual dysfunction. To date, more than 1000 patients have participated in clinical trials conducted by Can-Fite. Can-Fite previously spun off it's activity in the ophthalmic field to OphthaliX Inc., in which it holds 82%, and is currently listed on the U.S. Over-the-Counter Markets (OTCQB: OPLI).

Contact:

IRTH Communications, LLC

Robert Haag

canfy@irthcommunications.com

Forward-Looking Statements

This press release contains forward-looking statements, about Can-Fite's expectations, beliefs or intentions regarding, among other things, its product development efforts, business, financial condition, results of operations, strategies or prospects. In addition, from time to time, Can-Fite or its representatives have made or may make forward-looking statements, orally or in writing. Forward-looking statements can be identified by the use of forward-looking words such as "believe," "expect," "intend," "plan," "may," "should" or "anticipate" or their negatives or other variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical or current matters. These forward-looking statements may be included in, but are not limited to, various filings made by Can-Fite with the U.S. Securities and Exchange Commission (the "SEC"), press releases or oral statements made by or with the approval of one of Can-Fite's authorized executive officers. Forward-looking statements relate to anticipated or expected events, activities, trends or results as of the date they are made. Because forward-looking statements relate to matters that have not yet occurred, these statements are inherently subject to risks and uncertainties that could cause Can-Fite's actual results to differ materially from any future results expressed or implied by the forward-looking statements. Many factors could cause Can-Fite's actual activities or results to differ materially from the activities and results anticipated in such forward-looking statements, including, but not limited to, the factors summarized in Can-Fite's filings with the SEC and in its periodic filings with the TASE. In addition, Can-Fite operates in an industry sector where securities values are highly volatile and may be influenced by economic and other factors beyond its control. Can-Fite does not undertake any obligation to publicly update these forward-looking statements, whether as a result of new information, future events or otherwise.

SOURCE Can-Fite BioPharma

/Web site: http://www.canfite.com/

Source

Thu Feb 6, 2014 4:28am IST

(Reuters) - Gilead Sciences plans to license its breakthrough hepatitis C drug Sovaldi to a number of Indian generic pharmaceutical manufacturers, allowing for lower-priced sales of the medication in that developing nation, according to the company.

Although prices for the drug have not been set, company spokesman Nick Francis said in an emailed statement on Wednesday that Gilead aims to establish "tiered pricing."

For example, the price discussed for 24 weeks of Sovaldi therapy would run about $2,500 for certain patients at public hospitals, community clinics and non-governmental agencies in India, the Hindu Business Line reported earlier this week.

"Providing treatment in resource-limited settings presents complex challenges, and we will work with partners in multiple sectors around the world to ensure our access program reaches as many patients as possible," Francis said.

Gilead said final details of the program in India will be announced in coming months. The company has a similar program in place for lower-cost versions of its HIV/AIDS drugs.

In the United States, where Sovaldi was approved by regulators in December, the drug costs $84,000 for 12 weeks of therapy or $1,000 for a daily pill.

The Foster City, California-based company has said the price is fair because the treatment offers a potential cure for the liver-destroying virus without injections of interferon, which can cause severe side effects that compromise patient outcomes.

Prices in Europe are also lower than in the United States. The cost for treatment in the United Kingdom is about $57,000 while the price in Germany is around $66,000, the company has said.

Analysts have estimated that the drug will eventually generate billions of dollars in annual sales. Sanford Bernstein has forecast sales this year alone of $6.7 billion.

But some have questioned whether that is achievable. Many patients including those in the United States, where more than half of hepatitis C patients are estimated to rely on public funding, could have difficulty securing reimbursement for such a high-priced drug.

Other companies including Johnson & Johnson, AbbVie and Merck & Co are also working to develop new hepatitis C treatments with some in advanced stages of clinical studies.

Gilead, which reported 2013 earnings on Tuesday, declined to include an estimate for hepatitis C sales in its 2014 sales forecast, saying only that Sovaldi sales so far have been strong and broadly based.

Sales of Sovaldi in the last three weeks of 2013 totaled more than $139 million.

The World Health Organization estimates that about three percent of the world's population has been infected with the hepatitis C virus and that more than 170 million chronic carriers are at risk of developing liver cirrhosis, liver cancer or both.

Shares of Gilead fell $3.87, or nearly five percent, to close at $78.15 in Nasdaq trading on Wednesday. Over the past two years, the stock has nearly tripled.

(Reporting By Deena Beasley; Editing by Diane Craft)

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Journal of Hepatology

Article in Press

Hamish Innes, David Goldberg, Geoffrey Dusheiko, Peter Hayes, Peter R. Mills, John F. Dillon, Esther Aspinall, Stephen T. Barclay,Sharon J. Hutchinson

Received 7 August 2013; received in revised form 20 January 2014; accepted 27 January 2014. published online 06 February 2014.
Accepted Manuscript

Abstract

Background & Aims

Given an appreciable risk of adverse-effects, current therapies for chronic hepatitis C virus (HCV) infection pose a dilemma to patients. We explored, via simulation modelling, patient-important benefits of attaining a Sustained Viral Response (SVR).

Methods

We created the HCV Individualised Treatment-decision model (the HIT-model) to simulate, on a per patient basis, the lifetime course of HCV-related liver disease according to two distinct scenarios: (i) SVR attained, and (ii) SVR not attained. Then, for each model subject, the course of liver disease under these alternative scenarios was compared. The benefit of SVR was considered in terms of two patient-important outcomes: (1) The percent-probability that SVR confers additional life-years; and (2) The percent-probability that SVR confers additional healthy life-years, where “healthy” refers to years spent in compensated disease states (i.e. the avoidance of liver failure).

Results

The benefit of SVR varied strikingly. It was lowest for patients aged 60 years with initially mild fibrosis; 1.6% (95% CI: 0.8-2.7) and 2.9% (95% CI: 1.5-4.7) probability of gaining life-years and healthy life-years, respectively. Whereas it was highest for patients with initially compensated cirrhosis aged 30 years; 57.9% (95%CI: 46.0-69.0) and 67.1% (95%CI: 54.1-78.2) probability of gaining life-years and healthy life-years, respectively.

Conclusions

For older patients with less advanced liver fibrosis, SVR is less likely to confer benefit when measured in terms of averting liver failure and premature death. These data have important implications. Foremost, it may inform the contemporary patient dilemma of immediate treatment with existing therapies (that have poor adverse effect profiles) versus awaiting future regimens that promise better tolerability.

Abbreviations: HCV, Hepatitis C Virus, SVR, Sustained Viral Response, HIT model, Hepatitis-C Individual-based Treatment-decision model,HCC, Hepatocellular Carcinoma, NSS, Number need to attain SVR, NNT, Number needed to treat, SA, Sensitivity Analysis

Keywords: Hepatitis C, Chronic Hepatitis C, Patient-centred, Patient-important outcomes, Markov model, Simulation model, Antiviral treatment,Adverse effects, Risk-benefit ratio

Source

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original

Constance E. Ruhl M.D., Ph.D.1,*, Andy Menke Ph.D.1, Catherine C. Cowie Ph.D.2,  James E. Everhart M.D., M.P.H.2

DOI: 10.1002/hep.27047

Copyright © 2014 American Association for the Study of Liver Diseases

Publication History
Accepted manuscript online: 5 FEB 2014 10:25AM EST
Manuscript Accepted: 31 JAN 2014
Manuscript Revised: 5 DEC 2013
Manuscript Received: 20 SEP 2013

Keywords: insulin resistance; alanine aminotransferase;  gamma glutamyltransferase;  National Health and Nutrition Examination Survey;  epidemiology

ABSTRACT

An association of hepatitis C virus (HCV) infection with diabetes has been reported in many studies, but few have been population-based and applied standard criteria for diabetes diagnosis. We examined this relationship using recent population-based data from the U.S. National Health and Nutrition Examination Survey. 15,128 adult participants in the 1999-2010 surveys had data on diabetes status and serum HCV antibody (anti-HCV) or HCV RNA. Using American Diabetes Association criteria, diabetes was defined as a health care provider diagnosis, serum hemoglobin A1C (A1C) ≥6.5%, or fasting plasma glucose (FPG) ≥126 mg/dL; pre-diabetes as A1C 5.7%-<6.5% or FPG 100-<126 mg/dL; and normal glucose as A1C <5.7% and FPG <100 mg/dL. Odds ratios (OR) for diabetes and pre-diabetes, comparing persons with HCV infection to those without, were adjusted for demographics, BMI, C-reactive protein, smoking, drinking, and blood transfusion before 1992. Among participants without diabetes, we compared mean insulin resistance, estimated using homeostasis model assessment (HOMA-IR), by HCV status. The overall prevalence of anti-HCV+ was 1.7%, of HCV RNA+, 1.1%, of diabetes, 10.5%, and of pre-diabetes, 32.8%. The prevalence of diabetes and pre-diabetes did not differ by HCV status. In multivariate-adjusted analysis, diabetes remained unassociated with anti-HCV (OR=1.0, 95% confidence interval (CI), 0.6-1.7) or with HCV RNA (OR=1.1, 95% CI, 0.6-1.9). In contrast, elevated alanine aminotransferase and gamma glutamyltransferase activities were associated with diabetes regardless of HCV status. HOMA-IR was not associated with HCV markers in unadjusted or multivariate-adjusted analyses (p>0.05). Conclusion. In the U.S. population, HCV was not associated with diabetes, or with insulin resistance among persons with normal glucose. Previously reported relationships of HCV with diabetes were possibly attributable to the effect of elevated liver enzymes. (Hepatology 2014;)

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