HCV New Drug Research

Why Boomers Should Be Aware of Hepatitis

2012-01-28T09:28:00.000-05:00

Why Boomers Should Be Aware of Hepatitis

Related-

Babyboomers Most at Risk for Hepatitis C Virus

Montefiore Liver Specialists Urge Population to be Tested for This Potentially Deadly Virus

NEW YORK, Dec. 2, 2011 /PRNewswire-USNewswire/ -- Experts at Montefiore Medical Center urge the general public to be tested for the Hepatitis C virus, especially baby boomers, adults born between 1946-1964, who could be most at risk for this disease. Baby boomers are more likely to have been exposed to dangerous risk factors decades ago, such as sharing a drug needle, being tattooed or pierced with unsterilized tools or receiving a tainted blood transfusion. The disease often has no symptoms, and if untreated, can lead to chronic infection that can scar the liver, cause liver failure or cancer and potentially lead to liver transplantation.

Hepatitis C virus (HCV) is the most common chronic blood borne infection in the United States, with 35,000 to 185,000 new cases diagnosed per year. Worldwide, 180 million people are chronically infected with Hepatitis C, with an estimated 3-4 million new cases reported each year. The disease particularly affects minorities, Hispanics, Asian-Americans and African-Americans.
"This disease has grown to epidemic proportions, with 350,000 people around the world dying from Hepatitis C-related liver disease," said Milan Kinkhabwala, MD, Chief, Division of Transplantation at the Montefiore Einstein Center for Transplantation. "But it is called the 'silent killer' because many people don't even know they have it. This condition can be asymptomatic for decades and then present itself when it has already severely damaged the liver."

Individuals at risk can get a simple blood test to detect the virus before chronic infection leads to permanent liver damage. The Montefiore Medical Center Comprehensive Liver Disease Program offers simple and effective screenings. It is recommended that individuals talk to their primary care physician or contact 888-RX-LIVER (888-795-4837) for more information or to set up an appointment for a screening.
"This is a revolutionary time in the treatment of the disease and there is more hope than ever before," said Dr. Kinkhabwala. "The blood test is essential to detecting Hepatitis C, because now there are ways to treat the condition, and even reverse damage to the liver."
Two new anti-viral oral medications, boceprevir and teleprevir, received FDA approval in May 2011. Both drugs work by blocking an enzyme that helps the virus reproduce. The drugs are intended to improve on standard treatments using the injected drug pegylated interferon alpha and the pill rivavrin.

"So far, the new drugs have shown promise in clearing the virus from the body and almost doubling the cure rate of the disease," said Allan Wolkoff, MD, Professor of Medicine and of Anatomy and Structural Biology at Albert Einstein College of Medicine of Yeshiva University and Chief of the Division of Gastroenterology and Liver Diseases at Montefiore and Einstein. "Another key benefit is that they cut treatment time in half, thus reducing the time the patient has to endure the severe side effects, which include anemia, depression and flu-like symptoms like fatigue, fever and headache."
When symptoms do occur after the disease has progressed, they're generally mild and flu-like and may include fatigue, fever, nausea or poor appetite, muscle and joint pain, bruising, abdominal pain, jaundice and itching. At that point, chronic infection can lead to scarring of the liver (fibrosis) and then advanced scarring (cirrhosis). Scarring of the liver makes it difficult for the liver to function properly and can be devastating to the rest of the body, often causing liver failure or liver cancer.
If the liver disease progresses too far and the medications are not effective, then transplantation is the last resort. However, more than 16,000 people in the United States are currently waiting for a liver donor, and in New York State, there are 1,700 patients on the waiting list.

Factors that have been reported to accelerate the rate of HCV disease progression include age, gender (males have more rapid disease progression than females), alcohol consumption, HIV coinfection (approximately 35% of patients) and fatty liver (the presence of fat in liver cells caused by obesity).
Unlike Hepatitis B, there is no vaccine to prevent this disease. While the symptoms are similar, distinct differences exist between the two viruses. Hepatitis B is primarily transmitted through sexual intercourse and is less severe.
Dr. Kinkhabwala will be available for a live twitter chat to answer questions about Hepatitis C and liver disease on December 8, 2011 at noon. Follow @MontefioreNews to discuss #MonteHepC.

About Montefiore Medical CenterAs the University Hospital for Albert Einstein College of Medicine, Montefiore is a premier academic medical center nationally renowned for its clinical excellence, scientific discovery and commitment to its community. Recognized among the top hospitals nationally and ranked sixth out of 184 in the New York metropolitan area by U.S. News & World Report, Montefiore provides compassionate, patient- and family-centered care and educates the healthcare professionals of tomorrow. The Children's Hospital at Montefiore is consistently named in U.S. News' "America's Best Children's Hospitals," and is second among those in the New York metro area. With four hospitals, 1,491 beds and 93,000 annual hospital discharges, Montefiore is an integrated health system seamlessly linked by advanced technology. State-of-the-art primary and specialty care is provided through a network of nearly 100 locations across the region, including the largest school health program in the nation and a home health program. Montefiore's partnership with Einstein advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. The medical center derives its inspiration for excellence from its patients and community, and continues to be on the frontlines of developing innovative approaches to care. For more information please visit www.montefiore.org and www.montekids.org and follow us on Twitter @MontefioreNews.

SOURCE Montefiore Medical Center

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Once-weekly diabetes drug wins approval on third try

2012-01-28T09:11:00.002-05:00

Once-weekly diabetes drug wins approval on third try

Posted by Rebecca Hersher | Categories: Drugs, drugs and more drugs

Third time’s the charm for Amylin Pharmaceuticals. After two failed attempts in as many years, the San Diego-based drugmaker finally won approval today for its once-weekly diabetes medication Bydureon (exenatide).

Bydureon is a reformulation of the company’s own twice-daily injectable Byetta. Like Byetta and Novo Nordisk’s bestselling daily injectable Victoza (liraglutide), Bydureon mimics the gut hormone GLP-1 (glucagon-like peptide-1) to lower blood sugar levels. But Bydureon takes advantage of a controlled release technology developed by Alkermes, based in Cambridge, Massachusetts, to offer long-lasting diabetes care with fewer stabs of the needle and with an additional benefit over Byetta: weight loss.
That’s no small perk, notes Daniel Drucker, a diabetes researcher at Mount Sinai Hospital’s Samuel Lunenfeld Research Institute in Toronto. “This is a substantial advance for hundreds of thousands of patients who don’t like multiple injections and who are concerned struggle with weight gain on insulin therapy,” says Drucker, who led a phase 3 trial for Bydureon.

How many people currently taking daily injectables will decide to switch over to Bydureon is still unknown, but forecasts were not helped by a clinical trial reported last year showing that Bydureon was not as effective as the daily injectable Victoza at controlling blood glucose. Amylin hopes that benefits for weight and compliance will give Bydureon an edge where efficacy does not.

Bydureon may not have the weekly injectable field to itself for long, though. Indiana’s Eli Lilly and Britain’s GlaxoSmithKline both have long-acting GLP-1 analogs in phase 3 trials and Denmark’s Novo has a pair of weekly injectables in its pipeline, too.

See ‘Class of once-weekly diabetes drugs poised for approval’ from the December 2011 issue of Nature Medicine for more.

Once-Weekly Diabetes Treatment Gets FDA OK

By Crystal Phend, Senior Staff Writer
MedPage Today Published: January 27, 2012

WASHINGTON -- The delay is over for diabetes drug Bydureon (exenatide extended-release), with FDA approval making it the first once-weekly treatment for type 2 disease.
The announcement from drugmakers Amylin and Alkermes came after years of back and forth with the agency over the new formulation of the injectable glucagon-like peptide (GLP-1) receptor agonist.
Once-weekly exenatide was originally submitted for FDA review in 2009, but questions about the manufacturing process and a possible cardiovascular side effect, prolongation of the QT interval, proved to be a stumbling block.

The FDA approval came with a stipulation requiring Risk Evaluation and Mitigation Strategy (REMS) be put in place to address concerns over acute pancreatitis and potential risk of medullary thyroid cancer.

Amylin is also being required to conduct post-marketing studies to look at these issues and the impact on cardiovascular disease.

The most common adverse effect with Bydureon was nausea, at 14% in the DURATION-5 trial. Other common effects included diarrhea, upper respiratory tract infection, and injection site nodules.
But the DURATION-5 trial showed weight loss rather than gain -- a major plus from the patient perspective -- with the once-weekly drug and no major hypoglycemic events.
That trial also showed better glycemic control with Bydureon than with the once-daily version of exenatide (Byetta).

Byetta was approved for treatment of type 2 diabetes in 2005. The weekly formulation gained European regulatory approval in mid-2011. Lilly had been a partner in development of Bydureon until late 2011.

Muscle and Mortality in Cirrhosis

2012-01-27T17:45:00.001-05:00

Muscle and Mortality in Cirrhosis

Clinical Gastroenterology and Hepatology
Volume 10, Issue 2 , Pages 100-102, February 2012

Virginia Commonwealth University, Hunter Holmes McGuire Department of Veterans Affairs Medical Center, Richmond, Virginia

published online 11 November 2011.

Skeletal muscle wasting, accompanied by weakness and poor functional capacity, is a frequent finding in advanced liver disease. Many factors contribute to cachexia in cirrhosis. Loss of appetite is common and might be related to metabolic and hormonal alterations, medications, hepatic encephalopathy, or inflammatory cytokines. Poor diet is frequent in cirrhotic patients with active alcoholism and substance abuse and might be aggravated by poverty, poor social support, and iatrogenic restrictions. Postprandial discomfort associated with tense ascites might limit oral intake. Impaired gut motility with small intestinal bacterial overgrowth might contribute to altered digestion and nutrient malabsorption. Cirrhosis is a hypermetabolic state, increasing demand for calories and protein. The cirrhotic liver has reduced gluconeogenic capacity, and relatively short periods of fasting in cirrhotic patients lead to muscle breakdown with mobilization of skeletal muscle amino acids (Figure 1).

The prognostic significance of cachexia in chronic liver disease has been recognized for at least half a century. Malnutrition was a component of the original Child–Turcotte prognostic classification of cirrhosis severity.¹, ² An anthropometric study by Alberino et al³ identified low muscle mass (defined by mid-arm muscle circumference) as an independent predictor of survival in hospitalized cirrhotic patients. Gunsar et al⁴ found that malnutrition as measured by a variety of parameters predicted survival independently of Model for End-Stage Liver Disease (MELD) score in cirrhotic patients awaiting liver transplantation. In Japan, a prognostic index incorporating nutritional indexes (CONUT) has been proposed to assign priority for organ allocation in liver transplantation.⁵ Malnutrition also increases mortality after surgery in cirrhotic patients⁶ and predicts length of intensive care unit and hospital stay after liver transplantation.⁷ Despite these consistent findings, the general incorporation of cachexia into cirrhosis prognostic models has been limited by lack of a reliable, objective, generally accepted method to quantify muscle wasting.

The term sarcopenia has been proposed to describe objectively a condition of progressive and generalized loss of skeletal muscle mass and strength.⁸ Sarcopenia is not synonymous with cachexia, reduced functional capacity, or malnutrition, although there is considerable overlap among these conditions.⁹ Much of the literature on sarcopenia has focused on age-related decline in muscle mass leading to progressive frailty in elderly populations. Clinical trials examining sarcopenia in elderly people have used a variety of different measures to estimate muscle mass, including anthropometrics, tests of strength and endurance, measures of body composition, and imaging. A particular difficulty is determining for each technique what constitutes the normal range, because muscle mass in health is influenced strongly by gender, race, body habitus, and other variables. Definitions and diagnostic criteria for sarcopenia remain in flux. A recent European Society for Clinical Nutrition and Metabolism consensus statement concluded that imaging with computed tomography (CT) and magnetic resonance imaging should be the gold standards for determining muscle mass in clinical trials, with abnormally low muscle mass being defined as 2 standard deviations below the mean reference values for young adults.⁸ To date there has been limited application of these principles to areas outside of geriatrics.

In this issue of Clinical Gastroenterology and Hepatology, Montano–Loza et al¹⁰ report on the use of a novel CT-based method to diagnose sarcopenia and assess its prognostic significance in 112 consecutive cirrhotic patients undergoing initial listing for liver transplantation. Their technique for quantifying sarcopenia used abdominal CT images, which were obtained routinely as part of the transplant pre-evaluation. An axial image, selected consistently at the level of the L3 vertebra, was analyzed, and the cross-sectional area of skeletal muscle on this section was determined by an automated computer algorithm based on tissue radiodensity. This measurement has been shown in previous studies¹¹ to correlate with total body fat free mass, and norms for healthy men and women have been established. The authors found in this study that sarcopenia was present in 50% of cirrhotic men and 18% of cirrhotic women at time of listing for transplantation. Sarcopenia did not correlate with severity of liver dysfunction as measured by the MELD score. During follow-up, 46% of their patients died before transplantation. Sarcopenic patients, compared with those with normal muscle mass, had significantly poorer 6-month transplant-free survival (71% vs 90%, respectively; P < .005). The most common cause of death was liver failure (49%) or sepsis (25%). Sarcopenia was strongly associated with death from sepsis. In multivariable analysis, sarcopenia (as a dichotomous variable) and MELD were found to be independent predictors of pretransplant mortality.

Several notes of caution are in order. By the technique used here, normal values for women are substantially less than for men. Men with cirrhosis met the criteria for sarcopenia much more often than women. It is not clear whether these gender differences are associated with gender differences in prevalence of malnutrition and cachexia, or whether the technique is simply insensitive for detection of sarcopenia in women. Although the gender difference could confound the results, within the male subgroup sarcopenia also was associated with a higher mortality. Additional studies are needed to determine the ideal cutoff for sarcopenia as a determinant of functional impairment and survival in each gender. Racial and ethnic differences also need to be studied. In addition, the CT-based measure of sarcopenia needs to be correlated with other measures of nutritional and functional status to determine its ability to serve as an adequate surrogate marker. The effect of ascites and anasarca on the quantitative analysis of skeletal muscle area also needs to be examined systematically.
Despite these limitations, the findings of this study are intriguing because they suggest that information that is already routinely gathered in the course of evaluation of cirrhotic patients (abdominal CT axial images) can be used to objectively assess adequacy of muscle mass, and the finding of sarcopenia by this method might identify cirrhotic individuals who are at high risk of death from sepsis. Sarcopenia thus joins hyponatremia, uncontrolled ascites, hepatic encephalopathy, etiology of liver disease, and etiology of renal disease as supplemental factors that might add short-term prognostic information to the MELD model.¹², ¹³, ¹⁴ With the small numbers of patients studied to date, additional studies are needed to validate the methodology. If sarcopenia measured in this way is confirmed to be an independent predictor of survival in cirrhosis, then a case could be made to include CT-based estimation of skeletal muscle mass as a factor in determining “sickest first” priority for organ allocation in patients awaiting liver transplantation. However, before such a change could be adopted, it would be important to determine to what extent sarcopenia adversely affects survival after liver transplantation. Englesbe et al¹⁵ measured psoas muscle mass by CT in patients undergoing liver transplantation and reported a strong association between sarcopenia and post-transplant mortality. Thus, rather than increasing transplant priority, sarcopenia could represent a relative contraindication to liver transplantation. Application of measures of sarcopenia to other areas of hepatology, such as estimation of surgical risk or assessing ability to tolerate antiviral or anticancer therapy, also needs to be explored. The most important use of this new technique might lie in serial measurement of muscle mass, both to predict decompensation in cirrhosis and to assess objectively the response to interventions such as appetite stimulants, nutritional supplements, or physical conditioning.
We owe a debt of gratitude to our colleagues in geriatrics for advancing the concept of sarcopenia. Montano–Losa and colleagues have provided us with a promising tool, along with tantalizing evidence of its potential usefulness in management of cirrhosis. Now it is up to the rest of us to confirm the general validity of the technique, define its limitations, and explore its applications. Whether it will ultimately find a permanent place in the diagnostic armamentarium remains to be seen.

References

Turcotte JG , Wallin VW , Child CG . End to side versus side to side portacaval shunts in patients with hepatic cirrhosis . Am J Surg . 1969;117:108–116
Child CG , Turcotte JG . Surgery and portal hypertension . Major Probl Clin Surg . 1964;1:1–85
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Alberino F , Gatta A , Amodio P , et al. Nutrition and survival in patients with liver cirrhosis . Nutrition . 2001;17:445–450
Gunsar F , Raimondo ML , Jones S , et al. Nutritional status and prognosis in cirrhotic patients . Aliment Pharmacol Ther . 2006;24:563–572
Fukushima K , Ueno Y , Kawagishi N , et al. The nutritional index “CONUT” is useful for predicting long-term prognosis of patients with end-stage liver diseases . Tohoku J Exp Med . 2011;224:215–219
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Merli M , Nicolini G , Angeloni S , et al. Malnutrition is a risk factor in cirrhotic patients undergoing surgery . Nutrition . 2002;18:978–986
Merli M , Giusto M , Gentili F , et al. Nutritional status: its influence on the outcome of patients undergoing liver transplantation . Liver Int . 2010;30:208–214
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Cruz-Jentoft AJ , Baeyens JP , Bauer JM , et al. Sarcopenia: European consensus on definition and diagnosis—Report of the European Working Group on Sarcopenia in Older People . Age Ageing . 2010;39:412–423
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Muscaritoli M , Anker SD , Argilés J , et al. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) “cachexia-anorexia in chronic wasting diseases” and “nutrition in geriatrics” . Clin Nutr . 2010;29:154–159
Montano–Loza AJ , Meza–Junco J , Prado CMM , et al. Muscle wasting is associated with mortality in patients with cirrhosis . Clin Gastroenterol Hepatol . 2012;10:166–173
Mourtzakis M , Prado CM , Lieffers JR , et al. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care . Appl Physiol Nutr Metab . 2008;33:997–1006
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Heuman DM , Abou-Assi SG , Habib A , et al. Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death . Hepatology . 2004;40:802–810
Martín-Llahí M , Guevara M , et al. Prognostic importance of the cause of renal failure in patients with cirrhosis . Gastroenterology . 2011;140:488–496
Stewart CA , Malinchoc M , Kim WR , et al. Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease . Liver Transplant . 2007;13:1366–1371
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Englesbe MJ , Patel SP , He K , et al. Sarcopenia and mortality after liver transplantation . J Am Coll Surg . 2010;211:271–278

The 2012 AASLD Hepatitis Single Topic Conference (STC)

2012-01-27T17:32:00.000-05:00

Optimal Treatment Approaches to be Explored at Hepatitis STC

By Ann Haran, AASLD Staff

The 2012 AASLD Hepatitis Single Topic Conference (STC)

HCV Direct Antiviral Agents (DAA): Concepts, Development, and Optimal Use endeavors to advance understanding of the factors and tools available for successful treatment of chronic hepatitis C infection, with focus on the use of recently approved direct-acting antiviral drugs. The "brainchild" of the AASLD Clinical Research Committee, the course was organized by Raymond Chung, MD, and Warren Schmidt, MD, PhD. Committee member Dr. Schmidt was tasked with arranging a conference when the DAAs were first approved, so that researchers and practitioners could be brought together to investigate and optimize their approach to treatment. Dr. Schmidt stresses that the course was designed to target persistent treatment barriers with new drug discovery and management options.

The course directors encourage anyone involved in the care of patients with HCV to attend this conference. Practitioners who actively treat the disease will certainly benefit, as will those who are less deeply involved with treatment. Dr. Chung stresses that course participation is not limited to hepatologists; rather, gastroenterologists, infectious disease specialists, interested primary care providers, and midlevel providers are also encouraged to attend, as "direct acting antiviral regimens will surely expand care to many more patients and treaters." Presenters will discuss the new, better-tolerated interferon-free drug regimens and how these regimens can be tailored to both conventional and special hepatitis C populations, including those persons with HIV coinfection and those who have undergone liver transplantation. Case-based discussions with audience and panel involvement will highlight key messages. Attendees are also encouraged to submit abstracts detailing their own clinical, translational, or fundamental research in this area to be considered for poster presentation at the conference, as the course directors hope to foster collaboration and maximize the exchange of ideas.
The development of several classes of new therapies will be discussed at the conference, including HCV-specific protease inhibitors, nucleos(t)ide and non-nucleoside polymerase inhibitors, NS5A inhibitors, and host factor inhibitors. An up to date emphasis will be placed on novel pathways that may be fruitful for new drug development. As such, basic scientists from both academia and industry will also benefit from the program. The appropriate use of antiviral agents, either alone or in combination with one another, will be explored, as "there may be several roads to the same destination," according to Dr. Chung. Viral resistance presents a significant obstacle in treating HCV, so the question of how to optimally combine classes of agents to suppress resistance will be discussed. In addition, the FDA will be sending a representative to discuss the regulatory aspects of clinical trial design using these agents.

Dr. Chung predicts a "feverish increase in the number of clinical trials of all oral therapies in the coming years and even the coming months." This symposium should "provide clarity to researchers and practitioners in this early post-DAA period; this will be a rapidly evolving area with no doubt many more updates to come."

Advance Registration closes February 10, 2012.

Friday Round Up - Hepatitis News Ticker:

2012-01-27T09:56:00.001-05:00

This Weeks Updates:

Muscle and Mortality in Cirrhosis
The 2012 AASLD Hepatitis Single Topic Conference (STC)
Entry point of hepatitis C virus identified
Big Pharma:The Hepatitis C Race For Tolerable Therapies
Germany’s IQWiG sees added benefits for Incivo
Pharmasset's Hepatitis C Drug: How it Could Change Australia
Watch-Beware of Hepatitis B at the nail salon
Magic mushrooms point to new depression drugs
Pot-based prescription drug looks for FDA OK
Drop in effectiveness of HCV treatment in national VA practice
New Hepatitis C Regimen Stimulates Changes in Therapy Management
Hepatitis C Virus Infection In Non-Hodgkin’s Lymphoma: A Case Control Study
Dietary Fiber for the Treatment of Type 2 Diabetes Mellitus
Editorial-How to Optimize Treatment of Hepatitis C

Today In The News

Big Pharma

Biotech Stock Mailbag: Vical, Hep C Drugs

Two basic defining characteristics of nucs make them ideal drugs for hepatitis C. First, nucs are prodrugs, which means they're inactive until the body (in this case, the liver) metabolizes the drug into an active form. Having a drug that concentrates and activates in the liver is ideal for viral liver disease like hepatitis C.

Second, nucs, unlike PIs, have a high barrier to viral resistance, meaning the virus has a difficult time mutating or changing into forms that can fight off the drug. Nucs probably can't effectively cure hepatitis C on their own (at least not the current nucs) but Gilead's PSI-7977 (obtained from Pharmasset) may only need to be combined with ribavirin for a short time to be highly effective in treating genotype 2/3 patients -- and perhaps genotype 1 patients as well.

Drawbacks to nucs are that these drugs are generally less potent than PIs (although again, PSI-7977 surprised a lot of people by having PI-like potency) and the risk of serious side effects. Recently, Pharmasset had to shelve another of its nucs due to unacceptable liver toxicity.
Researchers -- and investors -- are so excited about nucs (more so than PIs) these days because the nucs' high barrier to viral resistance means combinations of all-oral drugs can be designed that exclude the need for weekly injections of interferon.

An all-oral therapy against hepatitis C is the golden ticket that every drug company involved in the field is shooting for. At this point, nucs more so than PIs, appear to have the edge as the backbone of future all-oral regimens, and that explains the billions of dollars spent recently to acquire nucs.

Two updates on old friends of the Mailbag who may be nearing their respective ends:
Generex Biotechnology(GNBT _) disclosed in a regulatory filing Tuesday night that it took out second mortgages on company-owned property to raise money to remain in business. I've seen a lot of crazy financing schemes in my days covering biotech, but I've never seen a company resort to real-estate loans (with a 10% annual interest rate, mind you) to keep the lights on.

Read Complete Article Here

Ex-doc to have fitness hearing in Vegas hep C case

By: The Associated Press | 01/27/12 7:02 AM
The Associated Press

A Nevada judge is due to consider the fitness of a once prominent Las Vegas physician to stand trial on criminal charges in a 2008 hepatitis outbreak.
Clark County District Court Judge Kathleen Delaney is scheduled to hear arguments Friday whether 62-year-old Dipak Desai (DEE'-pak des-EYE') is mentally competent for trial with two former employees on felony racketeering, fraud and patient neglect charges.
The three men have pleaded not guilty. They could face decades in prison.
Each is accused of infecting patients at Desai clinics with incurable hepatitis C by reusing endoscopy scopes and vials of an injected anesthetic during outpatient procedures.
Defense lawyer Richard Wright says Desai is incapacitated by strokes and can't help his defense.
Prosecutor Michael Staudaher contends Desai is exaggerating his ailments to avoid trial.

HCV Management for Individuals on Methadone Maintenance
This article takes an in-depth look at hepatitis C treatment options in a specialized community of people on methadone maintenance.
Journal of Viral Hepatitis, January 2012

Effect of IL28B Genotype on Early Viral Kinetics during Interferon-Free Treatment of Patients with Chronic Hepatitis C
Kulkarni R, Gane EJ, Roberts SK, Stedman C, Angus PW, Ritchie B, Lu XY, Ipe D, Lopatin U, Germer S, Iglesias VA, Elston R, Smith PF, Shulman NS; Gastroenterology (Jan 2012)

Abstract
Background & Aims
Although IL28B genotype affects the response of patients with chronic hepatitis C (CHC) to peginterferon and ribavirin, little is known its effect on response to direct-acting antivirals in interferon-free combinations. We analyzed the effects of IL28B genotype on the viral kinetic (VK) response to an interferon-free combination of the nucleoside polymerase inhibitor mericitabine (RG7128) and hepatitis C virus (HCV) protease inhibitor danoprevir.
Methods
We performed a double-blind, dose-escalation study of patients with chronic HCV genotype 1 infection who were interferon treatment-naive or had not responded to previous therapy with peginterferon and ribavirin. Patients were sequentially assigned to 1 of 7 cohorts, then randomly assigned to groups that received up to 13 days of treatment with mericitabine (500 or 1000 mg, twice daily) plus danoprevir (100 or 200 mg, every 8 hrs or 600 or 900 mg, twice daily) or placebo. Eighty-three of 87 patients were genotyped for the IL28B single-nucleotide polymorphism rs12979860. VKs were analyzed only in patients who received 13 days of treatment, at optimal doses, using a bi-phasic model to describe first- and second-phase slopes of viral decay during therapy.
Results
At day 14 (the end of interferon-free treatment), the mean reduction in the serum level of HCV RNA was slightly greater in patients with the CC polymorphism (5.01 log₁₀ IU/mL) than those without (4.59 log₁₀ IU/mL). Modeling revealed that patients with the CC polymorphism had slightly better early VKs, most apparent in the β-phase of viral decay. A mixed effect on the α-phase was observed, which was reduced in magnitude but prolonged in patients with CC, who also had better on-treatment response to peginterferon and ribavirin during follow up.
Conclusions
IL28B genotype appears to affect early VKs in patients with CHC receiving interferon-free treatment.

Minimal Hepatic Encephalopathy Does Not Impair Health-related Quality of Life in Patientswith Cirrhosis
A Prospective Study

Ewa Wunsch; Barbara Szymanik; Michał Post; Wojciech Marlicz; Marta Mydłowska; Piotr Milkiewicz

Discussion Only
Click Here To View-Abstract,Patients,Methods and Results

In order to clarify the real impact of minimal HE on daily functioning, we have studied HRQoL in cirrhotic patients without clinical evidence of overt HE, but with abnormal neurophysiological profile. We noted that patients with minimal HE experienced HRQoL similar to other cirrhotics without minimal HE, an observation in contrast with other studies.^[4,6] Only one study indicated unimpaired daily functioning in subjects with minimal HE when assessed with specific CLDQ.^[17] Two main reasons may explain these observations. Firstly, there is no standard diagnostic procedure for minimal HE.^[18] Electrophysiological tools such as the electroencephalogram, evoked potentials and single psychometric tests have been used to identify patients with minimal HE.^{[5, 6, 17, 19–21]} The electroencephalogram has fallen behind psychomotor tests, mainly because of the lower diagnostic sensitivity.^[22] Psychometric tests are now recommended for the diagnosis of minimal HE; nevertheless, a standardized battery of such tools should be used to counteract the poor sensitivity of a single test.^[1,23,24] To date, PHES has been used in none of the studies of HRQoL.
Secondly, the majority of studies have assessed HRQoL with general questionnaires, such as Sickness Impact Profile or SF-36.^[4–6] These widely used instruments measure an overall impact of a disease on the patient's well-being but do not evaluate symptoms specific for liver disease and are less responsive to small but clinically significant changes. Therefore, disease-specific questionnaires perhaps should be more appropriate in establishing the effect of liver disease on daily functioning. CLDQ was developed for the assessment of HRQoL in chronic liver damage and contains questions that are specific for advanced liver disease such as ascites, fatigue or pruritus.^[15] It is possible, however, that this tool is not sensitive enough to measure the real effect of mild hepatic dysfunction and subclinical condition such as minimal HE. So far, however, no specific instrument was developed for the evaluation of HRQoL in minimal HE. In summary, this study showed no significant effect of minimal HE on patients' HRQoL measured both with SF-36 and CLDQ. This finding requires validation in larger cohorts of patients with minimal HE.
This project was supported by grant N402-100-31/3038 from the Ministry of Science and Higher Education.

FDA

FDA Supplement Guidance Not Strict Enough, MD Says
An FDA proposal to require dietary supplement manufacturers to submit data proving their product is safe doesn't go far enough, according to a physician writing in the New England Journal of Medicine.
More than 100 million Americans spend more than $28 billion on vitamins, minerals, herbal ingredients, amino acids and other natural products in the form of dietary supplements each year, "assuming they are both safe and effective," wrote Pieter A. Cohen, MD, of Harvard Medical School and the Cambridge Health Alliance.

But they have no assurance that the products are safe because FDA regulation of supplements is too weak, Cohen wrote in a Perspective piece.

By law, ingredients that were used and sold in supplements prior to 1994 can be marketed without any proof that they are safe or effective. But under a law called the Dietary Supplement Health and Education Act (DSHEA), manufacturers of any ingredient introduced after 1994 must provide the FDA with evidence supporting "a reasonable expectation of safety."
Cohen said that part of the law "has thus far not been enforced."

Since DSHEA became law more than 15 years ago, the number of supplements on the market has gone from 4,000 to more than 55,000. Since 1994, the FDA has received proper notification for 170 new supplement ingredients, "undoubtedly a small fraction of the ingredients for which safety data should have been submitted," Cohen said.

The FDA has mounted a new effort to discourage the sale and use of nutritional supplements that contain ingredients that are regulated as drugs. Last year, the agency issued draft guidance meant to inform supplement manufacturers about what information they must submit to the FDA, including spelling out when an ingredient is considered old and when it's considered new. (A synthetically produced replica of a botanical product, for instance, would be considered new).
In addition, the FDA is proposing that the guidance call for in vitro, animal, and long-term tolerability testing for supplements that would be marketed at higher doses than those historically ingested.
"The FDA's guidance provides a thoughtful framework for evaluating the safety of new ingredients and if implemented it would lead to substantial improvement in safety," Cohen wrote, but he said he didn't think the FDA goes far enough.

He said under the guidance, companies can use historical data (instead of clinical trials) to prove that a supplement is safe, and Cohen said that the FDA can't assess the safety of new products scientifically without experimental data.

Cohen also said that under the guidance, manufacturers would not be required to submit both favorable and unfavorable data to the FDA, so they could cherry-pick only positive data to submit.
The dietary supplement industry largely opposes the draft regulation.

One opponent is the Natural Products Association, whose 1,900 members include small health food stores and large supplement manufacturers. The group submitted its official response to the FDA's proposal in November and said the agency is "overstepping" and that the rules would have a "chilling effect" on the dietary supplement industry.

"The draft guidance as currently written sets up inappropriate barriers to market entry, imposes food additive criteria, and requires multiple ... notifications beyond those required by law," the group wrote.

Cohen said it's true that the proposed requirements would impose similar standards on supplements and food additives.

"Industry advocates are correct insofar as DSHEA does not hold established (pre-1994) supplement ingredients to the same safety standards as food additives: a chemical preservative sprayed inside a can of tomato soup or the purple dye in Jell-O requires much more evidence of safety than ingredients used in supplements," Cohen wrote.

Cohen urged the FDA to not change its proposal because of protests from industry.
"If the FDA succumbs to industry pressure, the public health consequences will be significant, as hundreds of thousands of Americans continue to turn to new supplements to sustain their health and treat their ailments," he said.

The FDA is accepting comments on the draft guidance until Feb. 1

Women And Chronic Pain

Stanford study of electronic medical records that found women reported more-intense pain than men may in virtually every disease category..

Entry point of hepatitis C virus identified

2012-01-25T09:46:00.000-05:00

The cholesterol receptor offers a promising new target for anti-viral therapy, for which an approved drug may already exist, say the researchers, whose findings were reported online in advance of publication in Nature Medicine.

An estimated 4.1 million Americans are infected with hepatitis C virus, or HCV, which attacks the liver and leads to inflammation, according to the National Institutes of Health. Most people have no symptoms initially and may not know they have the infection until liver damage shows up decades later during routine medical tests.

Previous studies showed that cholesterol was somehow involved in HCV infection. The UIC researchers suspected that a receptor called NPC1L1, known to help maintain cholesterol balance might also be transporting the virus into the cell.

The receptor is common in the gut of many species -- but is found on liver cells only in humans and chimpanzees, says Susan Uprichard, assistant professor in medicine and microbiology and immunology and principal investigator in the study. These primates, she said, are the only animals that can be infected by HCV.

Uprichard and her coworkers showed that knocking down or blocking access to the NPC1L1 receptor prevented the virus from entering and infecting cells.

Bruno Sainz, Jr., UIC postdoctoral research associate in medicine and first author of the paper, said because the receptor is involved in cholesterol metabolism it was already well-studied. A drug that "specifically and uniquely targets NPC1L1" already exists and is approved for use to lower cholesterol levels, he said.

The FDA-approved drug ezetimibe (sold under the trade-name Zetia) is readily available and perfectly targeted to the receptor, Sainz said, so the researchers had an ideal method for testing NPC1L1's involvement in HCV infection.

They used the drug to block the receptor before, during and after inoculation with the virus, in cell culture and in a small-animal model, to evaluate the receptor's role in infection and the drug's potential as an anti-hepatitis agent.

The researchers showed that ezetimibe inhibited HCV infection in cell culture and in mice transplanted with human liver cells. And, unlike any currently available drugs, ezetimibe was able to inhibit infection by all six types of HCV.

The study, Uprichard said, opens up a number of possibilities for therapeutics.
Hepatitis C is the leading cause for liver transplantation in the U.S., but infected patients have problems after transplant because the virus attacks the new liver, Uprichard said.
While current drugs are highly toxic and often cannot be tolerated by transplant patients taking immunosuppressant drugs, ezetimibe is quite safe and has been used long-term without harm by people to control their cholesterol, Uprichard said. Because it prevents entry of the virus into cells, ezetimibe may help protect the new liver from infection.

For patients with chronic hepatitis C, ezetimibe may be able to be used in combination with current drugs.

"We forsee future HCV therapy as a drug-cocktail approach, like that used against AIDS," Uprichard said. "Based on cell culture and mouse model data, we expect ezetimibe, an entry inhibitor, may have tremendous synergy with current anti-HCV drugs resulting in an improvement in the effectiveness of treatment."

Source

Germany’s IQWiG sees added benefits for Incivo

2012-01-25T09:38:00.000-05:00

Germany’s IQWiG sees added benefits for Incivo

Article | 24 January 2012

In an early benefit assessment pursuant to Germany’s Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG), has examined whether Incivo (telaprevir) offers an added benefit compared with the present standard therapy.

According to the findings of the assessment, telaprevir offers advantages in various groups of patients with chronic hepatitis C infection of genotype 1. The available studies provide proof, indications or "hints” of an added benefit. However, not only the probability but also the extent of added benefit varies, said the IQWiG.

The European Commission has approved Johnson & Johnson (NYSE: JNJ) subsidiary Janssen’s Incivo, a direct acting antiviral (DAA) protease inhibitor, for the treatment of genotype-1 chronic hepatitis C virus (HCV), in combination with peginterferon alfa and ribavirin, in adults (The Pharma Letter September 21, 2011). The drug was developed in collaboration with the USA’s Vertex and Japan’s Mitsubishi Tanabe and is approved and marketed under the trade name Incivek in the USA and Canada (TPLs May 24 and August 23).

In accordance with the approval status, different patient groups are treated for different periods, which was allowed for in the assessment. The dual combination of peginterferon alfa and ribavirin is the present standard therapy, and this was compared with the triple combination of these two standard drugs and telaprevir.

Studies largely only provide data on morbidity and adverse effects
Overall three relevant studies were identified. The outcomes considered were "mortality,” "secondary complications of treatment (morbidity)” measured in the studies by means of the surrogate outcome "SVR,” as well as "health-related quality of life” and "adverse effects.”
The quality-of-life results for treatment-naive (ie, previously untreated) patients without cirrhosis were not statistically significant. No evaluable data on this outcome were available for other patient groups. Due to the too short study duration, the event rates for mortality were too low in all patient groups to be able to draw robust conclusions.

Extent of added benefit cannot be classified on the basis of the surrogate outcome for morbidity
The extent of added benefit cannot be classified on the basis of the surrogate outcome "SVR,” the agency noted. This parameter is not a patient-relevant outcome in itself and there are no studies in which SVR is validated as a surrogate outcome in accordance with the usual criteria employed by IQWiG. Nevertheless, the Institute accepts SVR in the context of this assessment as a surrogate for the reduced incidence of liver cancer. This is because it is currently accepted that patients with no detectable hepatitis C virus in the blood are at lower risk of liver cancer. However, it is not known how many cases of liver cancer can in fact be prevented by telaprevir and it is therefore unclear whether the added benefit can be classified as "minor” "considerable” or "major.” According to the corresponding legal ordinance, the added benefit is thus "unquantifiable.”.Under consideration of the beneficial and harmful effects of telaprevir, overall IQWiG reaches different conclusions for different patient groups.

Advantages for treatment-naive patients without cirrhosis who have a high viral load
Different results for morbidity were shown for treatment-naive patients without cirrhosis, depending on the viral load in the blood at the start of treatment. Proof of an added benefit of telaprevir was only determined for patients with a high viral load. However, the extent of the added benefit is unquantifiable as it refers to the surrogate outcome "SVR.”
For treatment-naive patients without cirrhosis, the data also provide proof and an indication of greater harm due to the adverse effects anaemia and rash, respectively, the extent being classified as "considerable” in the former and "minor” in the latter case. In the consideration of the beneficial and harmful effects of telaprevir, this did not lead to a restriction in the overall conclusion for patients with a high viral load, as these side effects were nearly exclusively classified as "not serious,” said the IQWiG.
In contrast, for treatment-naive patients without cirrhosis who have a low viral load at baseline, the data provide an indication of lesser benefit of telaprevir versus the comparator therapy. This is due to the fact that an added benefit regarding SVR is not proven, so that only the harmful effects are taken into account. An added benefit of telaprevir is not proven for treatment-naive patients with cirrhosis, as the manufacturer dossier did not contain any evaluable data.

Indication of an advantage also in patients with unsuccessful pre-treatment
Depending on the cirrhosis status, different results were shown for patients in whom treatment had so far been unsuccessful (non-responders). Regarding morbidity, the data provide an indication of an added benefit of telaprevir in patients without cirrhosis. The data only provide a "hint” of an added benefit in non-responders with cirrhosis. In this context, "indication” and "hint” refer to the surrogate outcome "SVR.” Therefore the extent of added benefit is unquantifiable. As in the case of treatment-naive patients without cirrhosis, indications of greater harm due to the side effects "anaemia” and "rash” did not lead to a restriction in the overall conclusion.

No additional benefit for relapsed patients
In patients without cirrhosis who relapsed after standard therapy, the treatment regimen deviated from the approval status. Consequently, the added benefit cannot be assessed on the basis of the available data so that an added benefit is not proven, noted the IQWiG.
In patients with cirrhosis who relapsed, the data provide an indication of an added benefit regarding SVR. However, at the same time they also provide an indication of greater harm (extent: considerable) regarding serious adverse events. Under consideration of the beneficial and harmful effects of telaprevir, the IQWiG concluded that overall an added benefit is not proven for this patient group.

Big Pharma:The Hepatitis C Race For Tolerable Therapies

2012-01-25T09:31:00.001-05:00

On The Blog: Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow

Source : Jules Levin @ NATAP

Curing HCV For Many Coming - (01/23/12)

Today In The News

Vertex Vows to Fight On With Alios Drugs in High-Stakes Hepatitis C Race

Vertex Pharmaceuticals went from king of the hill in the treatment of hepatitis C to yesterday’s news in about six wild months. But while many on Wall Street say Vertex’s big drug will soon become obsolete, Vertex and its small partner in South San Francisco have quietly put themselves in position to defend a big share of this future multi-billion dollar market.

Cambridge, MA-based Vertex (NASDAQ: VRTX), which has significant operations in San Diego, is running a series of small clinical trials this year that will mix and match combinations of antiviral medicines against hepatitis C. These trials will help determine whether Vertex and its partner, South San Francisco-based Alios Biopharma, have hit upon a combination of drugs that can raise the cure rate, and reduce side effects, for millions of patients with this liver-damaging virus.

While Vertex’s new drug has been a huge step forward in the past year, the ultimate way to fight the fast-mutating virus, many scientists believe, will be by putting together a cocktail of antivirals that attack hepatitis C from multiple angles like with HIV.

“There isn’t one magic pill that will solve the problem,” says Vertex CEO-to-be Jeff Leiden. “It’s clear the HCV space will evolve into different combination treatments for different patients. It’s not yet clear what the best combination is going to be. What you want is to have the component parts in your company so you can put them together.”

The hepatitis C world saw dramatic upheaval in the past year as researchers learned more about antivirals in development. Vertex won FDA approval in May for its new protease inhibitor, telaprevir (Incivek), which doubled the cure rate to about 80 percent for new patients when given in tandem with standard pegylated interferon alpha and ribavirin. About 25,000 people rushed in to get treated with the new combo regimen in its first seven months on the market, generating hundreds of millions in cash flow per quarter for Vertex, and pushing it into the black.

Exciting as it all was for physicians, patients, and Vertex shareholders, the company was soon upstaged. Researchers have long been looking for a way to get rid of the injectable interferon part of the regimen, which causes nasty flu-like symptoms that people must endure for months. To go beyond combo therapies (like the one from Vertex and another from Merck that include injectable interferon), the next step is to hit the hepatitis C virus with not just protease inhibitors, but also drugs from other classes—nucleotide polymerase inhibitors, and non-nucleotide polymerase inhibitors.

Princeton, NJ-based Pharmasset (NASDAQ: VRUS) stole the show last November at the American Association for the Study of Liver Disease when it said its nucleotide polymerase inhibitor cured all 40 patients with certain hepatitis C genotypes in a small study—a result that led to its $11 billion acquisition by Foster City, CA-based Gilead Sciences (NASDAQ: GILD). A few weeks later, another maker of drugs in that class, Alpharetta, GA-based Inhibitex (NASDAQ: INHX), got bought by Bristol-Myers Squibb for $2.5 billion. Separately, Bristol-Myers Squibb released some more promising clinical results from its own pipeline just last week.

Those developments got everyone talking about a new paradigm in hepatitis C, which many on Wall Street believe will leave Vertex in the dust. Jason Kantor, an analyst with RBC Capital Markets in San Francisco, said in a Dec. 19 note to clients that “the consensus view is that Vertex’s HCV franchise will essentially go to zero beyond 2015.” Vertex stock has dropped almost 40 percent in the past year, down from its 52-week high of $58.87 to $35.86 at yesterday’s close.

While Leiden has spent much time talking with investors about Vertex’s other drugs in development—particularly one expected to hit the market this year for cystic fibrosis—he says the company isn’t about to surrender in the hepatitis C market. He has a plan intended to allow Vertex to compete beyond 2015, when the first all-oral, interferon-free regimens are expected to could come along and replace today’s standard of care.

Sometime before the end of March, Vertex expects to see results from an early-stage study of an all-oral combo regimen of telaprevir (a non-nucleotide polymerase inhibitor called VX-222 that it acquired from a Canadian company in 2009) and the usual ribavirin. If Vertex can cure about 75 percent to 80 percent of patients with this cocktail, and reduce side effects by eliminating interferon, Leiden says the company would be ready to go to pivotal clinical trials this year with its own all-oral combination.

“If we can do that, it will be a very exciting result. If you take that regimen into pivotal trials, now we’re talking about 2014 to finish those trials,” Leiden says.

And that isn’t the only combo Vertex has in mind. Within weeks--Continue Reading … Next Page »

Luke Timmerman is the National Biotech Editor of Xconomy, and the Editor of Xconomy Seattle. E-mail him at ltimmerman@xconomy.com or follow him on Twitter at twitter.com/ldtimmerman.

Top Hepatitis C Virus Biotech Picks By The World's Largest Fund Managers

Seeking Alpha

The announcement by Bristol-Myers Squibb (BMY), just over two weeks ago, on January 7th, of an agreement to buy Inhibitex (INHX) for $2.5 billion at a massive buyout premium of over 160%, has ignited a rally among biotech companies that are currently active in developing products targeting hepatitis C virus (HCV). In this article, we examine based on our research of their latest available Q3 institutional 13-F filings, the investment activities of the world's largest funds or mega funds among a dozen pharmaceutical and biotech companies that are active in the HCV space.

These mega fund managers hold between $100 billion and over a trillion dollars in assets, such as Fidelity Investments, Goldman Sachs, and Vanguard Group, and together they control almost a third of the assets invested in the U.S. equity markets, but number just over 30 out of the tens of thousands of funds that invest in the U.S. equity markets. Individually, and collectively, they pack enough firepower to move stocks based on their trading activities.

Taken together, these mega managers were bullish on the group, adding a net $427 million in Q3 to their prior $178.84 billion prior quarter holdings in the group. However, taking out the big pharmaceutical companies, mega funds still added a net $530 million in Q3 to their $47.46 billion prior quarter position among the biotech companies that are active in the HCV field. (for more general information on these mega funds, please look at the end of the article).

The following are the HCV group companies that mega fund managers are bullish about (see Table):

Idenix Pharmaceuticals (IDIX): IDIX engages in the discovery and development of drugs for the treatment of human viral and other infectious diseases, including a focus on hepatitis C virus, hepatitis B virus (HBV), human immunodeficiency virus (HIV) type-1, and acquired immune deficiency syndrome (AIDS). Mega funds added a net $45 million in Q3 to their $380 million prior quarter position, and together they hold 29.7% of the outstanding shares, higher than their 26.3% weighting in the group. The top mega fund buyers in Q3 was by Fidelity Investments ($50 million), and the top holders were Fidelity Investments ($131 million), T Rowe Price ($114 million) and Vanguard Group ($50 million).

IDIX shares have mounted a strong rally recently, up more than 100% in the past twelve trading days, benefiting from both the January 9th announcement of the acquisition of rival INHX by BMY that has ignited a rally in the group, as well as positive interim phase 2b clinical trial data on its HCV Nucleotide Inhibitor, IDIX 184, that was released the same day by the company.

Dynavax Technologies (DVAX): DVAX is a clinical-stage biotech company that is engaged in the discovery and development of novel products to prevent and treat infectious and inflammatory diseases. Its lead clinical stage product candidate is HEPLISAV™, a phase 3 investigational adult hepatitis B vaccine designed to provide protection with fewer doses than current licensed vaccines. In addition it has early stage product candidates, including a universal flu vaccine in phase 1, TLR inhibitor for lupus in phase 1, and then hepatitis B and hepatitis C therapies, also in phase 1 development.

Mega funds added a net $7 million in Q3 to their $102 million prior quarter position, and taken together they hold 25.8% of outstanding shares. The top mega fund buyers were Fidelity Investments ($3.3 million) and Bank of America Corp. ($1.6 million), and the top holder by far was also Fidelity Investments ($64 million). DVAX is currently engaged in preparing to submit its first Biologics License Application (BLA) for HEPLISAV™ Hepatitis B Vaccine to the FDA in the first quarter of 2012, followed soon by a submission of Marketing Authorization Application (MAA) for European approval.

Peregrine Pharmaceuticals (PPHM): PPHM is a clinical-stage biotech company developing and manufacturing innovative monoclonal antibody therapeutics to treat cancers and viral infections such as hepatitis C virus. In the hepatitis C space, the company is evaluating bavituximab combined with ribavirin in a randomized phase 2 trials in treatment native patients with genotype-1 HCV infection. Earlier, the company released preliminary phase 2 trial results from this study on December 29th last year that showed antiviral activity and a positive safety profile, with patients reporting fewer side effects than in the interferon-containing arm. Mega funds added a net $1 million in Q3 to their $8 million prior quarter position, and taken together mega funds hold 11.4% of the outstanding shares, with the top holders at the end of Q3 being Barclays Global Investors ($2.7 million) and Blackrock ($1.7 million).

The following are the HCV group companies that mega fund manager are most bearish about (see Table):

Vertex Pharmaceuticals (VRTX): VRTX engages in the discovery, development, and commercialization of small molecule drugs for the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases. It has two FDA-approved drugs, INCIVEKTM for treat chronic hepatitis C genotype-1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatments, and Lexiva for HIV that it co-discovered with GlaxoSmithKline (GSK).

It has five other drugs in clinical development, including VX-222 in phase 2 development for hepatitis C, VX-765 in phase 2 development for epilepsy, VX-509 in phase 2 development for immune-mediated inflammatory disease, and VX-770 and VX-809 in phase 3 and phase 2 development respectively for Cystic Fibrosis. Mega funds cut a net $110 million in Q3 form their $3.89 billion prior quarter position. The top sellers were Fidelity Investments ($91 million) and T Rowe Price ($34 million), and the top holders were Fidelity Investments ($966 million) and Capital World Investors ($653 million).

Achillion Pharmaceutical (ACHN): ACHN is a clinical-stage biotech focused on developing new treatments to patients with infectious diseases, including HCV and resistant bacterial infections. It currently has five compounds in various stages of clinical development targeting HCV, including one in phase 2, two in phase 1 and two others in pre-clinical development. Mega funds cut a net $6 million from their $280 million prior quarter position, with the top seller being Bank of New York Mellon Corp. ($18 million), and the top holder being Fidelity Investments ($111 million). ACHN shares rallied strongly after the announcement of the INHX acquisition by BMY, up over 50% in the five trading days after the January 7th announcement; while they have given back part of their gains, they are still up over 35% on the news.

Inhibitex Inc. and Bristol-Myers Squibb Co.: INHX, a developer of differentiated anti-infective products to prevent and treat serious viral and bacterial infections, including primarily shingles and chronic infections caused by hepatitis C virus, is under agreement to be acquired by BMY, a developer of branded pharmaceuticals for the treatment of cardiovascular, virological and other infectious diseases. Mega funds cut $28 million in Q3 from a $512 million prior quarter position in INHX, and they added a net $711 million to their $20.51 billion prior quarter position in BMY.

Other pharmaceutical and biotech companies that are players in the HCV space that mega funds are bearish on (see Table) include Gilead Sciences Inc. (GILD), that has multiple product candidates in phase 1 and phase 2 trials targeting hepatitis C, in which mega funds cut a net $306 million in Q3 from their $17.68 billion prior quarter position, and Abbott Laboratories (ABT), that has a product candidate in phase 2 clinical trials for HCV in collaboration with Enanta Pharmaceuticals, in which mega funds cut a net $16 million in Q3 from their $26.63 billion prior quarter position.

Also, additional HCV players that mega funds are bullish about include Merck & Co. (MRK), that has an FDA-approved product Victrelis for HCV in the market, and several in phase 2 and 3 development for hepatitis B and C, in which mega funds added a net $530 million to their $47.46 billion prior quarter position; and Pfizer Inc. (PFE), that has a compound in phase 2 development for HCV, in which mega funds added a net $60 million to their $54.03 billion prior quarter position. Furthermore, mega funds have a $1 million position, unchanged in Q3, in Inovio Pharmaceuticals (INO), that has compounds in phase 2 and preclinical development targeting HCV....Continue Reading...

Hepatitis C Pill Makes BioLineRx Buyout Target: Israel Overnight

By Tal Barak Harif

Jan. 25 (Bloomberg) -- BioLineRx Ltd. surged in New York trading, widening the premium versus its Tel Aviv shares to a record, on bets the biopharmaceutical company will be acquired following its licensing agreement for a hepatitis C treatment.

BioLineRx’s American depositary receipts jumped 69 percent on the Nasdaq Stock Market yesterday, swelling the premium to the Israeli stock to 28 percent. The Tel Aviv shares soared 25 percent at 10:28 a.m. in Tel Aviv today. The Bloomberg Israel-US 25 Index of the largest Israeli companies traded in New York rose 0.1 percent to 92.53. Check Point Software Technologies Ltd. led gains after Topeka Capital Markets Inc. recommended buying shares of the maker of network security equipment.

BioLineRx’s agreement with French company Genoscience to develop and sell a hepatitis C pill treatment boosts the odds that the Jerusalem-based company will be bought, according to Morgan Joseph TriArtisan Group. Bristol-Myers Squibb Co. and Gilead Sciences Inc. announced $13.3 billion of acquisitions in the past two months to buy developers of hepatitis treatments.

“The fact that BioLineRx now has a highly novel hepatitis C drug in its armory should make the company an appealing target for strategic partners,” Raghuram Selvaraju, a New York-based equity analyst at Morgan Joseph TriArtisan, said by e-mail yesterday. “The hepatitis C viral infection space is an area that has been particularly hot recently.”

The Bloomberg Israel-US 25 Index has gained 10 percent this year, outperforming the Nasdaq Composite Index’s 7 percent advance and the Standard & Poor’s 500 Index’s 4.5 percent increase. A 14 percent jump in Teva Pharmaceutical Industries Ltd., the world’s largest maker of generic drugs, has helped pushed the Israel-US 25 higher. The TA-25 stock index rose 0.3 percent to 1,126.06 today.

BioLineRx ‘Euphoria’

Bristol-Myers, a biopharmaceutical company based in New York, said on Jan. 7 it would pay about $2.5 billion in cash to buy Inhibitex Inc., which is developing an oral drug called INX-189 for treating hepatitis C. Pharmasset Inc., based in Princeton, New Jersey, agreed to be acquired by Gilead Sciences for $10.8 billion in a deal announced on Nov. 21.

Gilead, the world’s largest maker of HIV drugs, offered the highest premium on record for a drug takeover of comparable size, according to data compiled by Bloomberg.

As many as 170 million people worldwide carry the hepatitis C virus, a blood-borne disease that can lead to liver cirrhosis and cancer, according to the Centers for Disease Control and Prevention in Atlanta. The market for medicines to treat the disease is about $3 billion worldwide, said Andrew Berens, a senior health-care analyst with Bloomberg Industries.

“The euphoria you’re seeing is mostly related to the fact that the announcement makes the company an acquisition target,” Berens said in a phone interview from Skillman, New Jersey. “An oral drug is what everyone is trying to develop because the current injection treatments are toxic and cumbersome.”

Volumes Surge

BioLineRx’s ADRs rose to $5.55 yesterday after the shares in Tel Aviv climbed 37 percent to 1.65 shekels, or the equivalent of 44 cents. One ADR represents 10 shares. The Tel Aviv shares rose to 2.06 shekels, or 55 cents, today.

Phone messages and e-mails sent to Garth Russell, a spokesman for BioLineRx from an external public-relations company, seeking comments on a potential buyout weren’t returned.

Trading volumes on the stock soared yesterday, with more than 6 million BioLineRx ADRs exchanging hands, compared with an average of 7,000 trades a day, according to Bank of New York Mellon Corp.

The Israeli biopharmaceutical company, whose largest shareholder is Teva, listed the ADRs on the Nasdaq Stock Market on July 25... Continue Reading...

Pharmasset’s Hepatitis C Drug: How it Could Change Australia
By Lord Jorrel Polintan | January 25, 2012 2:41 PM EST

Finding cures for diseases is always a tall order to take up on, but to have a drug that can cure a disease without fail is almost too good to be true. That is why when the news that Pharmasset Inc. is working on a drug that can cure hepatitis C without fail, people started buzzing, and wondered how a sure fire drug could affect the world, but more importantly, Australia.

Hepatitis C is infamous world-wide for being a virus that can cause liver inflammation and liver disease. With more and more people getting the disease, especially in Australia, a cure for it would be a heaven sent. In response to this problem, a new drug is being developed.

And in the study that was conducted by the company, 40 patients who received the experimental drug were responsive after 12 weeks, and that just after 24 hours, around half of the patients were all cured of hepatitis C, Bloomberg reported. Though being criticized by the number of patients it was tested on, the results are still very impressive and promising.

At present, some cases of hep C infection may clear up without treatment and are only asked to avoid alcohol and medications that might affect the liver. However, generally, those with liver abnormalities due to the infection undergo 24 to 48 weeks of treatment consisting of pegylated interferon alpha and the antiviral drug ribavirin, according to the American Family Physician.

What with a drug that can cure hepatitis C and Australia's growing problem with the disease, the drug could significantly change the playing field. According to the Australian Hepatitis C Support, in 2006, about 1% of the population, or 271,000 people, were exposed to the virus, and that there were 12,500 people diagnosed with hepatitis C infection.

But now, things have changed. According to the Annual Surveillance Report 2011 of the University of New South Wales, there is an estimated 221,000 people living in the country with chronic hepatitis C infection, which includes 48,000 with moderate to severe liver disease.

Even with the various programs and efforts in Australia, such as the Fourth Community Pharmacy Agreement which funded $10.3 million for the preventions and reduction of the transmission of the virus, or the Hepatitis C Public Health Promotion Program which was developed to increase awareness and accessibility of information about the virus, the number of those with the virus is rising.
And with current treatments lasting longer periods of time than that of the drug being developed, the sooner the drug comes out, the sooner will the numbers go down.

In trying to reach out for comments, Gilead Sciences, now the mother company of Pharmasset Inc., told International Business Times that having just completed acquisition of Pharmasset, Gilead is now in the process of integrating the hepatitis C drug into their pipeline and determining timelines and their next step.

After all is said and done, the world could soon see a readily available drug in the market that can cure hepatitis C completely.

Pharmasset's Hepatitis C Drug: How it Could Change Australia

2012-01-25T09:07:00.000-05:00

Pharmasset’s Hepatitis C Drug: How it Could Change Australia

By Lord Jorrel Polintan | January 25, 2012 2:41 PM EST

Finding cures for diseases is always a tall order to take up on, but to have a drug that can cure a disease without fail is almost too good to be true. That is why when the news that Pharmasset Inc. is working on a drug that can cure hepatitis C without fail, people started buzzing, and wondered how a sure fire drug could affect the world, but more importantly, Australia.

Hepatitis C is infamous world-wide for being a virus that can cause liver inflammation and liver disease. With more and more people getting the disease, especially in Australia, a cure for it would be a heaven sent. In response to this problem, a new drug is being developed.

And in the study that was conducted by the company, 40 patients who received the experimental drug were responsive after 12 weeks, and that just after 24 hours, around half of the patients were all cured of hepatitis C, Bloomberg reported. Though being criticized by the number of patients it was tested on, the results are still very impressive and promising.

Watch-Beware of Hepatitis B at the nail salon

2012-01-24T09:06:00.001-05:00

Beware of Hepatitis B at the nail salon

Nearly 5 million Americans have chronic hepatitis, and believe it or not, many don't know it because they don't show symptoms. Now a new study shows customers in nail salons could be putting themselves at risk for the deadly disease.

Nancye Swanson does her own nails these days. Six months ago, she almost died from Hepatitis B, a serious liver infection, which doctors say she picked up at a salon.

"It felt like the flu," she said.

Her skin turned yellow, a symptom of Hepatitis B. It happened while she was getting a pedicure.

"A lot of these places use sharp instruments and they could be reusing those," said Dr. Robert Gish, a clinical professor at University of California San Diego.

Dr. Gish is writing a health policy for the Vietnamese government on the spread of Hepatitis B. That's because anyone born in the Asian Pacific region is at a high risk of already having it. That includes the thousands of people working in salons across the U.S. --and they may not even know it.

"Ninety-five percent of people with Hepatitis B have no symptoms," said Dr. Gish. "That's the problem."

While there is no cure, Nancye takes a pill once a day to control it.

"I cannot believe I was that close to death," she said.

To protect yourself, the Hepatitis B foundation recommends:

Bringing your own tools since disinfectants may not be 100 percent effective
If you have cuts, bug bites or a skin infection -- reschedule the appointment
Don't shave your legs before a pedicure since that increases your risk of infection
Ask how often footbaths are disinfected
It's not just nail salons to watch out for. Anyplace where you can get tattoos, ear piercing, body piercing, even barbershops, can put you at risk for Hepatitis B, according to Dr. Gish.

There is a Hepatitis B vaccine available which has been routinely given to infants since 1991. It's now recommended that adults who are at high-risk be immunized so check with your doctor.

Magic mushrooms point to new depression drugs

2012-01-24T08:26:00.000-05:00

LONDON — The brains of people tripping on magic mushrooms have given the best picture yet of how psychedelic drugs work and British scientists say the findings suggest such drugs could be used to treat depression.

Two separate studies into the effects of psilocybin, the active ingredient in magic mushrooms, showed that contrary to scientists' expectations, it does not increase but rather suppresses activity in areas of the brain that are also dampened with other anti-depressant treatments.

"Psychedelics are thought of as 'mind-expanding' drugs so it has commonly been assumed that they work by increasing brain activity," said David Nutt of Imperial College London, who gave a briefing about the studies on Monday. "But, surprisingly, we found that psilocybin actually caused activity to decrease in areas that have the densest connections with other areas."

These so-called "hub" regions of the brain are known to play a role in constraining our experience of the world and keeping it orderly, he said.

"We now know that deactivating these regions leads to a state in which the world is experienced as strange."

In the first study, published in the Proceedings of the National Academy of Sciences (PNAS) journal, 30 volunteers had psilocybin infused into their blood while they were inside magnetic resonance imaging (MRI) scanners, which measure changes in brain activity.

It found activity decreased in "hub" regions and many volunteers described a feeling of the cogs being loosened and their sense of self being altered.

The second study, due to be published in the British Journal of Psychiatry on Thursday, involved 10 volunteers and found that psilocybin enhanced their recollections of personal memories.

Robin Carhart Harris from Imperial's department of medicine, who worked on both studies, said the results suggest psilocybin could be useful as an adjunct to psychotherapy.

Nutt cautioned that the new research was very preliminary and involved only small numbers of people.

"We're not saying go out there and eat magic mushrooms," he said. "But...this drug has such a fundamental impact on the brain that it's got to be meaningful -- it's got to be telling us something about how the brain works. So we should be studying it and optimizing it if there's a therapeutic benefit."

The key areas of the brain identified -- one called the medial prefrontal cortex (mPFC) and another called the posterior cingulate cortex (PCC) -- are the subject of debate among neuroscientists, but the PCC is thought by many to have a role in consciousness and self-identity.

The mPFC is known to be hyperactive in depression, and the researchers pointed out that other key treatments for depression including medicines like Prozac, as well as cognitive behavioral therapy (CBT) and deep brain stimulation, also appear to suppress mPFC activity.

Psilocybin's dampening action on this area may make it a useful and potentially long-acting antidepressant, Carhart-Harris said.

The studies also showed that psilocybin reduced blood flow in the hypothalamus - a part of the brain where people who suffer from a condition known as cluster headaches often have increased blood flow. This could explain why some cluster headache sufferers have said their symptoms improved after taking the psychedelic drug, the researcher said.

The studies, which are among only a handful conducted into psychedelic substances since the 1960s and 1970s, revive a promising field of study into mind-altering drugs which some experts say can offer powerful and sustained mood improvement and relief from anxiety.

Other experts echoed Nott's caution: "These findings are very interesting from the research viewpoint, but a great deal more work would be needed before most psychiatrists would think that psilocybin was a safe, effective and acceptable adjunct to psychotherapy," said Nick Craddock, a psychiatry professor from Cardiff University.

Kevin Healy, chair of the Royal College of Psychiatrists' faculty of medical psychotherapy said it was interesting research "but we are clearly nowhere near seeing psilocybin used regularly and widely in psychotherapy practice."

Copyright 2012 Thomson Reuters

Pot-based prescription drug looks for FDA OK

2012-01-23T11:06:00.000-05:00

LISA LEFF, Associated Press
Updated 02:09 p.m., Sunday, January 22, 2012

SAN FRANCISCO (AP) — A quarter-century after the U.S. Food and Drug Administration approved the first prescription drugs based on the main psychoactive ingredient in marijuana, additional medicines derived from or inspired by the cannabis plant itself could soon be making their way to pharmacy shelves, according to drug companies, small biotech firms and university scientists.

A British company, GW Pharma, is in advanced clinical trials for the world's first pharmaceutical developed from raw marijuana instead of synthetic equivalents— a mouth spray it hopes to market in the U.S. as a treatment for cancer pain. And it hopes to see FDA approval by the end of 2013.

Sativex contains marijuana's two best known components — delta 9-THC and cannabidiol — and already has been approved in Canada, New Zealand and eight European countries for a different usage, relieving muscle spasms associated with multiple sclerosis.

FDA approval would represent an important milestone in the nation's often uneasy relationship with marijuana, which 16 states and the District of Columbia already allow residents to use legally with doctors' recommendations. The U.S. Drug Enforcement Administration categorizes pot as a dangerous drug with no medical value, but the availability of a chemically similar prescription drug could increase pressure on the federal government to revisit its position and encourage other drug companies to follow in GW Pharma's footsteps.

"There is a real disconnect between what the public seems to be demanding and what the states have pushed for and what the market is providing," said Aron Lichtman, a Virginia Commonwealth University pharmacology professor and president of the International Cannabinoid Research Society. "It seems to me a company with a great deal of vision would say, 'If there is this demand and need, we could develop a drug that will help people and we will make a lot of money.'"

Possessing marijuana still is illegal in the United Kingdom, but about a decade ago GW Pharma's founder, Dr. Geoffrey Guy, received permission to grow it to develop a prescription drug. Guy proposed the idea at a scientific conference that heard anecdotal evidence that pot provides relief to multiple sclerosis patients, and the British government welcomed it as a potential way "to draw a clear line between recreational and medicinal use," company spokesman Mark Rogerson said.
In addition to exploring new applications for Sativex, the company is developing drugs with different cannabis formulations.

"We were the first ones to charge forward and a lot of people were watching to see what happened to us," Rogerson said. "I think we are clearly past that stage."

In 1985, the FDA approved two drug capsules containing synthetic THC, Marinol and Cesamet, to ease side-effects of chemotherapy in cancer patients. The agency eventually allowed Marinol to be prescribed to stimulate the appetites of AIDS patients. The drug's patent expired last year, and other U.S. companies have been developing formulations that could be administered through dissolving pills, creams and skin patches and perhaps be used for other ailments.

Doctors and multiple sclerosis patients are cautiously optimistic about Sativex. The National Multiple Sclerosis Society has not endorsed marijuana use by patients, but the organization is sponsoring a study by a University of California, Davis neurologist to determine how smoking marijuana compares to Marinol in addressing painful muscle spasms.

"The cannabinoids and marijuana will, eventually, likely be part of the clinician's armamentarium, if they are shown to be clinically beneficial," said Timothy Coetzee, the society's chief research officer. "The big unknown in my mind is whether they are clearly beneficial."

Continue Reading Here.....

Drop in effectiveness of HCV treatment in national VA practice

2012-01-23T10:57:00.002-05:00

J Hepatol 2012: 56(2): 320-325
23 January 2012

The most recent issue of the Journal of Hepatology investigates gaps in the achievement of effectiveness of HCV treatment in national VA practice.

Antiviral treatment for hepatitis C virus (HCV) has high efficacy rates for achieving sustained viral response in randomized controlled trials.

However, it can be lower in community-based practice settings.
Dr Jennifer Kramer and colleagues from Texas, USA determined the effectiveness of HCV treatment in Veterans Administration (VA) hospitals nationwide.
Using the nationwide VA HCV Clinical Case Registry, the researchers examined a cohort of veterans who had HCV viremia between 2000 and 2005, and identified patients who received pegylated-interferon (PEG-INF) and ribavirin.

The duration of treatment and proportion of patients completing treatment was calculated.

The team measured the effectiveness of treatment as the proportion of patients who achieved SVR in the entire cohort, and among patients who initiated and completed treatment.
The researchers identified 99,166 patients with HCV viremia.

Of those, 12% received PEG-INF with ribavirin, and 6% completed treatment.

The team observed contraindications in 57% of the patients that did not receive treatment.

Sustained virologic response was documented in 40% and 58% of patients who completed treatment, 24% and 51% of patients who initiated treatment, and 4% and 11% of the entire HCV cohort for genotype 1 or 4 and 2 or 3, respectively.

Overall, the team found that only 4% of the entire HCV viremic cohort had a documented sustained virologica response.

Dr Kramer's team concludes, "Treatment effectiveness for HCV is low."
"In addition to fixed factors, such as race and virus genotype, the drop in effectiveness is due to low rates of antiviral treatment initiation and treatment completion."

Journal of Hepatology
February 2012

Jennifer R. Kramer1,2,, Fasiha Kanwal4, Peter Richardson1,2, Minghua Mei1,2, Hashem B. El-Serag1,2,3

1Houston VA Health Services Research and Development Center of Excellence, Michael E. DeBakey VA Medical Center, Houston, TX, United States;

2Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, United States; 3Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States; 4John Cochran VA Medical Center, Department of Gastroenterology and Hepatology, St. Louis University School of Medicine, St. Louis, MO, United States

ABSTRACT

Background & Aims
Antiviral treatment for hepatitis C virus (HCV) has high efficacy rates for achieving sustained viral response (SVR) in randomized controlled trials (RCTs) (40-80%); however, it can be lower in community-based practice settings. We wanted to determine the effectiveness of HCV treatment in Veterans Administration (VA) hospitals nationwide.

Methods
Using the nationwide VA HCV Clinical Case Registry (CCR), we examined a cohort of veterans who had HCV viremia between 2000 and 2005 and identified patients who received pegylated-interferon (PEG-INF) and ribavirin. The duration of treatment and proportion of patients completing treatment was calculated. The effectiveness of treatment was measured as the proportion of patients who achieved SVR (negative viremia at least 12weeks after the end of treatment) in the entire cohort, and among patients who initiated and completed treatment.

Results
We identified 99,166 patients with HCV viremia. Of those, 11.6% received PEG-INF with ribavirin and 6.4% completed treatment. Contraindications were present in 57.2% of the patients that did not receive treatment. SVR was documented in 39.9% and 58.3% of patients who completed treatment; 23.6% and 50.6% of patients who initiated treatment; and 3.9% and 11.2% of the entire HCV cohort for genotype 1 or 4 and 2 or 3, respectively. Overall, only 3.5% of the entire HCV viremic cohort had a documented SVR.

Conclusions
Treatment effectiveness for HCV is low. In addition to fixed factors, such as race and virus genotype, the drop in effectiveness is due to low rates of antiviral treatment initiation and treatment completion.

Introduction
The major goal of treating patients with hepatitis C virus (HCV) is to achieve a sustained viral response (SVR). This has been associated with improvement in health-related quality of life; hepatic histological features; and even a reduction in long-term outcomes such as cirrhosis, hepatocellular carcinoma, and mortality [1], [2], [3], [4]. Currently, the recommended antiviral treatment for HCV is a combination of pegylated-interferon (PEG-INF) and ribavirin. This combination has relatively high efficacy in achieving SVR, with rates in patients with genotype 1 from randomized controlled trials (RCTs) ranging from 41% to 52% [5], [6], [7].

Despite its high efficacy in clinical trials, the effectiveness of antiviral therapy in community-based practices is unclear. Clinical trials typically evaluate carefully selected participants with few or no contraindications; closely monitor patients; and have less ethnic and racial diversity than would be seen in most clinical practice settings [8]. A few studies in Europe, Canada, and Australia reported SVR rates among community-based patients that were comparable to those reported in clinical trials. However, these studies did not incorporate the uptake of treatment among all patients presenting to these setting. In addition, the treated patients had favorable features for achieving SVR (e.g., predominantly Caucasian with a high prevalence of HCV genotypes 2 or 3) [9], [10], [11], [12], [13]. On the other hand, studies of drug users and racial and ethnic minorities have shown substantially lower SVR rates in clinical practice settings [14], [15]. No study has examined the overall effectiveness of care among all patients presenting with chronic HCV in a national healthcare system, while examining various steps in clinical care such as HCV genotype testing; contraindications to treatment; initiation of treatment; completion rates; and SVR.

It is important to understand the current state of treatment effectiveness so we can identify the gaps along the spectrum of care and the magnitude with which each of these gaps contributes to the drop in effectiveness. Such knowledge is essential for a rational and efficient approach to ensuring that more patients get access to treatment and ultimately, achieve SVR. In addition, with the anticipated release of newer, more efficacious therapies, addressing the gaps of effectiveness in clinical practice is very timely [16].

The Veterans Administration (VA) has the largest integrated healthcare system in the United States. It provides care for more than 190,000 chronically infected HCV patients [17], which is approximately 6% of the estimated 3.2 million HCV-infected individuals in the United States [18]. In this study, we sought to determine the overall effectiveness of HCV treatment in the VA, focusing on receipt of treatment and SVR rate in all patients with chronic HCV diagnosed from 2000 to 2005. We determined contraindications in patients with chronic HCV infection who did not receive treatment. We also examined SVR stratified by HCV genotype and race, among patients who received treatment.

Discussion

This is one of the largest studies examining HCV treatment effectiveness in a community practice setting. We showed that, compared to efficacy estimates obtained in RCTs, PEG-INF and ribavirin treatment effectiveness was low in a national sample of veterans with chronic HCV. Overall effectiveness for HCV treatment in achieving SVR was only 3.6% for the entire study population. Thus, nearly 96,000 of the 99,166 veterans with HCV diagnosed between FY2000 and FY2005 have either not been treated or have not cleared the virus. Since the benefits of treatment are limited to patients with SVR, our data show that antiviral treatment has been minimally effective in reducing the burden of HCV-related chronic liver disease. Most of the drop in effectiveness resulted from low treatment rates (12.7%); high treatment discontinuation rates (16.3%); and low response to therapy (23.6% and 50.6%).

There is a chasm between efficacy and effectiveness of antiviral treatment in the VA. Among patients who received at least one PEG-IFN treatment, we found SVRs of 23.6% for genotype 1 or 4 and 50.6% for genotype 2 or 3, whereas RCTs with combination therapy have published SVR rates as high as 52% in genotype 1 and 80% for genotype 2 or 3 [5], [6], [7]. However, the patients in our study were older (49 vs. 43years old); disproportionately African Americans and Hispanics; and adhered less to treatment (as suggested by lower treatment completion rates) than patients enrolled in clinical trials.

Previous effectiveness studies in other populations have also demonstrated that HCV antiviral therapy in clinical practice is substantially less effective than was previously published. A recent single-center study by Feuerstadt et al. conducted in urban minority patients that were predominantly Hispanic, reported SVR rates of 14% in genotype 1 patients, 37% in genotype 2 or 3 patients, and an overall effectiveness rate of 3.3% in HIV-antibody negative patients [14]. Our results are similar to those from a study conducted with the same data source by Backus et al., who found an SVR rate of 20% in genotype 1, 52% in genotype 2, and 43% in genotype 3 [20]. Our study also extended previous findings by examining more recently available data and other treatment outcomes, such as non-response and relapse, as well as overall effectiveness of antiviral treatment in the VA.

Race/ethnicity has been shown to be an important predictor of SVR in clinical trials, where only 19-28% of African Americans with genotype 1 and 57% of those with genotype 2 or 3 had SVR [22], [23], [24]. In our study, African Americans had SVR rates lower than those of Caucasians, and lower than those of African Americans in previous studies (15.8% for genotype 1 or 4 and 47.9% for genotype 2 or 3). For Hispanics, published SVR rates are 34-47% for patients with genotype 1 and 66% for patients with genotype 2 or 3 [25], [26]. In our study, Hispanics had SVR rates lower than those of Caucasians, and lower than those of Hispanics in previous publications (17.5% for genotype 1 or 4 and 47.3% for genotype 2 or 3).

Starting patients on antiviral treatment remains the most important obstacle in improving the effectiveness of HCV antiviral treatment in the VA. The underutilization of therapy shown in this study can be reasonably explained in just over half of the patients, who had contraindications to treatment. However, even among these patients, some contraindications are potentially reversible or manageable. Efforts toward management of drug and alcohol use and psychiatric disorders, such as depression, could increase treatment rates. The lack of treatment in the remaining patients is potentially concerning. While inappropriate underutilization of treatment is likely occurring in a considerable proportion of these patients, some may have unrecorded contraindications, while others may be refusing treatment or not adhering to recommended prescriptions. Further study of this group is required. In addition, a majority of patients never received a biopsy as part of their evaluation process, and therefore their fibrosis stage remains unknownÑthus lack of significant fibrosis does not seem to explain the low treatment rates in this population of HCV patients.

The low effectiveness of HCV therapy in achieving SVR among patients in our cohort could be due to several factors, including low treatment completion rates; large proportion of African Americans; and lack of appropriate documentation of viral load following initiation and completion of treatment. The study highlights the sporadic testing for viral counts among patients started on antiviral treatment, which does not allow for classifying patients to the conventional randomized trial definition. The lack of viral count testing at conventional times not only hampers the ability to examine the true outcomes of therapy, but also makes prognostic estimates and hence decision making about re-treatment difficult (i.e. patients who are true non-responders have a lower response rate to re-treatment than patients who relapse).

In addition, HCV genotype was unknown in 8.8% of the patients who received treatment. We cannot exclude the fact that some of these patients may have been tested for genotype at a non-VA institution and not retested at the VA. Since genotype 1 is the most common HCV genotype in the United States, it is likely that the majority of these patients have genotype 1, resulting in a slight underestimation of SVR rates for patients with genotype 1 or 4.

There are several limitations to this study. First of all, patient-physician interactions and some of the decisions that result from them (e.g., patient declining treatment, physician discouraging treatment, or physician prescribing treatment but patient not filling the prescription) was not captured by this study. In addition, there could be variability in the knowledge and care of patients with HCV by facility and we did not examine rates by facility. These factors could explain some of the apparently inappropriate underutilization of treatment. In addition, dosage/adherence information for PEG-INF/ribavirin therapy were not known. We used prescription release date rather than fill date to improve the capture of actual receipt of the drug, but we could not determine whether a patient actually took the medication. We were also unable to determine the reason for treatment discontinuation for the patients in the undetermined group. This could include inability to tolerate it, refusal to take it, improper RNA monitoring, or simple loss to follow-up. The reasons behind low completion of treatment rates were not examined in this study; it is important to examine this issue further in order to intervene accordingly.

An additional limitation of this study is that contraindications were defined by ICD-9 codes, which may not be valid and may result in over- or under-ascertainment of the condition. However, these definitions have been used in previously published work [27], [28]. If underestimation of contraindications occurred, this may explain the high proportion of untreated patients that appeared treatment eligible; however, we do not believe this underestimation would affect everyone and feel many patients are eligible who are not receiving treatment. Also, there was information missing from the dataset for some of the study variables, such as genotype and race. Finally, our study population was overrepresented with African American men who are generally more difficult to cure compared to the general population, thus, generalizability to other medical systems may be limited. However, the study population of close to 100,000 patients represents more than 3% of the estimated number of patients with chronic HCV infection in the United States and close to 10% of patients with known infection since only one-third to one-half of patients with HCV infection have been identified. The VA also represents the largest integrated healthcare system in the United States and with the availability of the comprehensive HCV registry data it is an ideal population for this "real world" descriptive study.

In conclusion, overall effectiveness of HCV therapy is low in a national sample of veterans with chronic HCV. When studying only patients who completed treatment, it improves, but remains lower than that seen in RCTs. Potential explanations for this include racial diversity and low treatment receipt and completion rates. We can use this knowledge to target interventions such as, improving depression management to increase treatment rates, or introducing a clinical reminder to conduct genotype testing with the hope that these efforts will improve the effectiveness of HCV treatment and, ultimately, reduce the burden of liver disease in the VA.

Results

Study cohort

There were 99,166 patients in the study cohort. Most were men (97%) with a mean age of 51.2years (SD=7.9). The racial/ethnicity composition of the cohort was 55.2% white, 29.9% African American, 3.5% Hispanic, 1.1% other, and 10.2% unknown. Almost half had HCV genotypes 1 or 4 (48.0%; of which approximately 1% were genotype 4), 12.2% had genotypes 2 or 3, and 39.8% were not tested for genotype. Only 11.6% of patients had a liver biopsy in the VA during the two years before and two years after their HCV index date. Approximately 16.5% (n=16,381) had any prescription for interferon or ribavirin before September 30, 2005, while 83.5% (n=82,785) had no prescription for any antiviral treatment. Patients who were not tested for genotype were significantly less likely to receive any antiviral treatment (3.3% vs. 25.2%, p <0.0001). Untreated patients were significantly older (51.6 vs. 49.5years old, p <0.001 and more likely to be African American (26.0% vs. 16.7%, p <0.001) than patients who received treatment. Approximately 43% of patients who did not receive antiviral treatment had none of the contraindications to treatment listed in Materials and methods and in Table 1. The remaining 57% had at least one contraindication, with 37.2% having at least one absolute contraindication and 38.3% having at least one relative contraindication. The most common contraindication was current use of drugs or alcohol (29.7%), followed by depressive illness (16.3%), COPD (11.5%), poorly controlled diabetes (8.1%), and significant coronary artery disease (7.5%) (Table 1). All contraindications were significantly different across racial/ethnic groups (p <0.05). African Americans were less likely to have a diagnosis of depression, severe coronary artery disease, severe COPD, and decompensated cirrhosis than whites. However, African Americans were more likely to be diagnosed with severe hypertension, severe heart failure, poorly controlled diabetes, HIV, chronic renal disease, and uncontrolled psychiatric disease than whites. African Americans and Hispanics had slightly fewer absolute contraindications overall compared to whites, but more relative contraindications.

Treatment cohort

The treatment cohort consisted of a total of 11,479 (11.6%) patients with at least two released prescriptions for PEG-INF and ribavirin. The mean age was 49.4years (SD=6). Race/ethnicity distribution was 68.0% white, 18.2% African American, 4.1% Hispanic, and 1.3% other racial groups. Race was unknown in 8.4% of patients. There were 7792 (67.9%) patients with genotype 1 or 4, 2670 (23.3%) with genotype 2 or 3, and 1017 (8.8%) with unknown genotype.

Overall, 16.3% of patients discontinued treatment after less than 12weeks. This was very similar across genotypes. Approximately 47.7% (n=3719) and 27.2% (n=2121) of patients with genotype 1 or 4 completed at least 38.2 and 48weeks of treatment, respectively. On the other hand, 75.2% (n=2007) and 50.1% (n=1338) of patients with genotypes 2 or 3 completed 19.2 and 24weeks of treatment, respectively. Table 2 displays the treatment outcomes by HCV genotype. Of those patients with genotype 1 or 4, 23.6% achieved SVR, 30.7% had no response, 15.4% had a relapse, and 30.2% were undetermined. Of the patients with undetermined treatment response, 36.6% discontinued treatment before 12weeks, while nearly half discontinued treatment before 24weeks. For patients with genotype 2 or 3, 50.6% achieved SVR and only 6.1% had no response; 13.6% had a relapse, and 29.7% were undetermined. Of the patients with undetermined treatment response, 32.0% discontinued treatment before 12weeks, while 43% discontinued treatment before 19.2weeks.

Table 3 shows the treatment outcomes stratified by race and HCV genotype. For genotype 1 or 4, whites had the highest SVR at 27.0% vs. 15.8% in African Americans and 17.5% in Hispanics. Whites were also more likely to have a relapse and African Americans were more likely to have non-response. For genotype 2 or 3, there were no statistically significant differences in SVR rates across races/ethnicities.

Overall effectiveness

We examined SVR among VA patients who initiated treatment (n=11,479), patients who completed treatment (n=5723), and the entire cohort of veterans with chronic HCV (n=99,166) diagnosed in FY2000-2005. For genotype 1 or 4, 23.6% of patients who initiated treatment achieved SVR; 39.9% of patients who completed at least 38.4weeks of treatment achieved SVR; and 3.9% of the entire cohort achieved SVR. For genotype 2 or 3, 50.6% of patients who initiated treatment achieved SVR; 58.3% of patients who completed at least 19.2weeks of treatment achieved SVR; and 11.2% of the entire cohort achieved SVR. Fig. 1 displays the gaps in care that are partly responsible for low overall effectiveness of HCV antiviral therapy in the VA. Based on the entire cohort, for every 100 patients with chronic HCV, 60 had a genotype test; 12 received PEG-INF and ribavirin; six completed treatment; and only three achieved SVR.

Materials and methods

Data sources

This study was approved by Baylor College of Medicine's Institutional Review Board and all procedures conform to the ethical guidelines of the 1975 Declaration of Helsinki. We used data from the VA HCV Clinical Case Registry (CCR), which contains health information for all known HCV-infected patients from 128 VA facilities nationwide. The CCR automatically identifies patients with positive HCV antibody tests as well as HCV-related ICD-9 codes. Data elements in the CCR include demographics; laboratory test results; outpatient and inpatient VA pharmacy data; and inpatient and outpatient diagnoses codes. These data are extracted all the way back to the mid 1990s through December 31, 2006. Additional details of the CCR data are published elsewhere [17]. We examined datasets obtained from the VA HCV CCR database for patients diagnosed in the VA between January 1, 2000 and January 1, 2005. For patients with missing race/ethnicity, we linked the CCR to the VA Patient Treatment File and the Outpatient Care File to identify additional race/ethnicity information.

Study population

Patients had to have at least one positive HCV RNA test or HCV genotype test result; at least one visit at a VA facility; and an HCV index date between 2000 and 2005 to be included in the study cohort. The index date for HCV diagnosis reflected the date of the earliest positive HCV test or the first appearance of an ICD-9 code for HCV (070.51, 070.54, 070.41, 070.44, or V02.62). To be included in the treatment cohort, patients had to have at least two prescriptions for PEG-INF plus ribavirin with the first one occurring before September 30, 2005. This date was chosen based on the fact our CCR database ended on December 31, 2006 which ensured at least four months of follow-up time to determine SVR after a 48-week treatment course.

Definitions of study variables

We identified sociodemographic characteristics such age at HCV index; gender; and race/ethnicity (African American, white, Hispanic, other, or unknown) for all patients in the study cohort. We also defined variables based on ICD-9 codes (see Supplementary material for definitions) indicative of conditions that constitute absolute, or relative contraindications to treatment, based on the American Association for the Study of Liver Disease guidelines [19]. We used diagnoses in the two years before or after the HCV index date to define these conditions. Absolute contraindications included major depressive illness; renal, heart, or lung transplant; autoimmune hepatitis; severe hypertension; severe heart failure; significant coronary artery disease; poorly controlled diabetes; and severe chronic obstructive pulmonary disease (COPD). Relative contraindications included drug or alcohol use; HIV co-infection; chronic renal disease; decompensated cirrhosis; liver transplant; and uncontrolled psychiatric disease.

Treatment outcomes

All prescriptions for any interferon and/or ribavirin, including prescriptions dispensed as part of a clinical trial, were identified. Antiviral treatment initiation was defined by the date of the earliest prescription for PEG-INF released from any VA pharmacy. Duration of treatment was calculated from the earliest prescription date to the most recent prescription date plus days of supply. Prescriptions separated by time gaps of more than 45days were not included as part of the treatment course. This definition has been used in previous studies [20]. Overlapping prescriptions were not considered. Treatment completion was defined as at least 48weeks for genotypes 1 or 4 and at least 24weeks for genotypes 2 or 3. Since patients in the clinical setting may have a shorter treatment course, we also considered patients who completed at least 80% of expected treatment duration to have completed therapy as done in a previous study (i.e. 38.4weeks for genotypes 1 or 4 and 19.2weeks for genotypes 2 or 3) [21]. The proportion of patients who discontinued treatment before 12weeks was also examined. SVR was defined as all RNA tests being negative after treatment completion with one being recorded at least 12weeks after treatment completion. Non-response to antiviral treatment was defined by all RNA tests during treatment being positive. Relapse was defined as any negative RNA test after treatment initiation, followed by a positive test at anytime. Undetermined response status was defined by the absence of an RNA test required to define SVR, non-response, or relapse.

Data analysis

We calculated the proportion of patients with SVR out of those who initiated treatment, those who completed treatment, and the entire cohort (all veterans with chronic HCV diagnosed in FY2000-2005). Among patients who did not receive treatment, we calculated the proportion with the contraindications defined above. Among treated patients, we calculated the treatment response outcomes (SVR, non-response, relapse, and undetermined) stratified by viral genotype (1 or 4 vs. 2 or 3) and further stratified by patient race (African American, white, and Hispanic). For all proportions of treatment response outcomes, we calculated 95% confidence intervals and used Chi-square tests and t-tests to determine statistical significance when appropriate.

New Hepatitis C Regimen Stimulates Changes in Therapy Management

2012-01-23T10:10:00.001-05:00

New Hepatitis C Regimen Stimulates Changes in Therapy Management

MANAGED CARE December 2011. ©MediMedia USA

Costly protease inhibitors work well in many patients, but call for careful monitoring

Thomas Reinke

Contributing Editor

In less than a year, two new protease inhibitors — telaprevir (Incivek) and boceprevir (Victrelis) — have changed the standard of care for hepatitis C by introducing a new mechanism of action, but their significance goes beyond that.

They are the first new medications for the disease in 10 years and they have brought dramatic improvements in outcomes by knocking out this infection in many more patients, including previous poor responders. They have also complicated care by adding a third agent to the previous standard regimen of two agents.

“We took a step back ... to make sure we could capitalize on the value of these medications,” says David Lassen, PharmD, chief clinical officer at Prime Therapeutics.

The new agents are examples of how therapy management for new and costly medications is moving from traditional utilization and outcomes management to more sophisticated strategies. The focus on adherence and medication possession rates is giving way to patient selection criteria and close monitoring of clinical results.

Approximately 3.9 million people in the United States have chronic hepatitis C virus (HCV) infection, and about 5,000 acute cases surface annually.

Boceprevir and telaprevir are direct-acting agents that block the growth of viruses by directly disrupting essential viral functions. They were approved only as supplements to the previous standard treatment, a combination of ribavirin (Rebetol, Copegus) plus peginterferon alfa-2a (Pegasys) or peginterferon alfa-2b (PegIntron).

Both are also approved only for use in one subset of patients: genotype 1 patients. HCV has at least 6 genotypes and 50 different subtypes, with genotype 1 being the most common.
In trials, the new drugs increased cure rates, known as sustained viral response (SVR) rates, by 30 to 40 percentage points over control groups receiving peginterferon and ribavirin. SVR means that no HCV is detected in the blood.

For telaprevir in one study, a SVR at 24 weeks was achieved in 75 percent of patients, compared with 44 percent for control patients. For boceprevir, in one study the success rate for triple therapy was 66 percent, compared with 38 percent for control patients.

Based on these results, the American Association for the Study of Liver Diseases updated its clinical guidelines to recommend triple therapy with a protease inhibitor, interferon, and ribavirin as the standard of treatment for hepatitis C.

“The hope for improved outcomes produced an immediate demand for these medications,” says David Lassen, PharmD, chief clinical officer of Prime Therapeutics, a pharmacy benefit manager. “Previously the utilization of medications used to treat hepatitis C was on the decline, causing an overall decrease in the pharmacy cost trend over time. With the entrance of these two new agents, we have seen a significant increase in drug trend driven by increased use and cost.”

Doubling the cost of HCV management
An article in the November 2011 issue of the Journal of Managed Care Pharmacy by Prime’s pharmacy experts says that the new regimen will more than double the cost of HCV management. Telaprevir costs $49,200 for its 12-week regimen. The required peginterferon and ribavirin add $17,175 for 24 weeks and $34,349 for 48 weeks of therapy.
Boceprevir costs $26,410 for a 24-week duration and $35,213 for 32 weeks. Peginterferon and ribavirin add $20,037 or $34,349 to the total.

Complexities
The protease inhibitors add to the complexity of treatment for hepatitis C. Poor response and anemia were problems with the previous peginterferon-ribavirin regimen.
Anemia has increased significantly with the new agents. In studies of telaprevir it increased from 17 percent to 36 percent, and in studies of boceprevir it increased from 20–30 percent to 45–50 percent. The increased anemia may stimulate more frequent therapy with erythropoiesis-stimulating agents, further driving up costs.
The new agents have many drug interactions, including conflicts with statins, and there are new side effects, such as the skin rash that is associated with telaprevir. This is in addition to flu-like symptoms that are associated with peginterferon.
There are other implications for the new medications. Both have demonstrated success and are approved for use in poor responders, so the demand for the new agents may spike until this cohort is resolved.
The new regimen requires monitoring of viral loads at specific points, and there are parameters for discontinuing therapy when treatment is futile.

Lassen says that Prime Therapeutics planned ahead to be able to handle the protease inhibitors. “In anticipation of the approvals we took a step back to revise our management strategies to be sure we could capitalize on the value of these medications in an evidence-based manner,” he says.
Prime Therapeutics made significant changes in its utilization and therapy management activities. It expanded the patient-specific data it captures. For initial authorizations, it asks about comorbidities such as HIV/AIDS and about the extent of liver disease. It also asks about previous treatments with protease inhibitors for HCV.

For renewing authorizations, the company is going further. “We are looking at the viral load component to ensure that the therapy is on track because some of the patients are not naïve to treatment,” says Lassen. Providers are asked to report the specific HCV RNA levels from lab tests at 4 or 12 weeks, depending on which new drug is being used.

While Prime, like other PBMs and even health plans, is interested in capturing more clinical data to improve its quality and cost management, Lassen emphasizes that this has to be done appropriately. “We were careful and thoughtful in our approach. Any request for additional information as part of prior authorization or utilization management can have a negative impact on providers.”

He adds: “It is also important that requests like lab results as part of renewals do not interrupt therapy. There can be legitimate delays in getting tests done, and we make it a point to provide continued coverage while tests are being arranged.”

For health plans
The protease inhibitors are game changers in the treatment of hepatitis C — the first new medications in 10 years with a new mechanism of action.
“Triple therapy is complex, “Lassen says. “Patients cannot be switched to a different agent once a course of therapy is started, and it is critical that therapy be completed. Up front, you need a clear set of criteria for patient selection, and then there needs to be close monitoring and a clear set of supportive care activities as patients move through therapy.”

How well did that new drug work?

Health plans and PBMs are collecting more patient-specific clinical data as part of their prior-authorization and therapy management. These data are increasingly important in ensuring the appropriate use of new, more complex, targeted medications.

The questions below are asked by Prime Therapeutics, a pharmacy benefit manager owned by several Blue Cross Blue Shield plans, when a renewal authorization is being considered for telaprevir (Incivek) and boceprevir (Victrelis). HCV RNA results indicate the level of hepatitis C infection and the progress of therapy.

The questions are taken from the prior-authorization form used by Blue Cross Blue Shield of Texas.

Incivek requests
Was the patient’s HCV RNA level measured at four weeks of treatment?	___ Yes	___ No
If yes, what was the viral load?	_______ IU/mL
Victrelis requests
Was the patient’s HCV RNA level measured at 12 weeks of treatment?	___ Yes	___ No
If yes, what was the viral load?	_______ IU/mL
Was the patient’s HCV RNA level measured at 24 weeks of treatment?	___ Yes	___ No
If yes, what was the viral load?	_______ IU/mL

MANAGED CARE December 2011. ©MediMedia USA

Your liver is for life - so treat it well

2012-01-23T10:08:00.001-05:00

Your liver is for life - so treat it well

As the Love Your Liver roadshow hits the streets of the UK health correspondent Rachel Allen finds out why liver disease – one of the UK’s biggest killers – is rising each year.
THE biggest misconception of liver disease (cirrhosis) is that it is automatically associated with alcohol abuse.

Of course alcohol is the biggest culprit – accounting for 35 per cent of all cases – but it can also develop from hepatitis viruses (25 per cent of all cases), non-alcoholic fatty liver disease, which is linked to obesity (20 per cent), autoimmune liver diseases (10 per cent) and genetic disorders and other rare causes, also 10 per cent.
Obesity is the other big offender – something which people often forget about despite the number of health problems it leads to.

In a bid to combat the rising numbers of cirrhosis cases, which lead to 4,000 deaths a year, The British Liver trust has launched a Love Your Liver Campaign for January – the first of its kind.
Dr Alexander Gimson is a consultant physician and hepatologist at the Liver Unit at Addenbrooke’s and he’s keen to emphasise the importance of taking care of your liver.
He said: “Cirrhosis is the name given by doctors to a certain pattern of scarring within the liver which eventually damages the liver’s functions, which progressively fail over a number of years and may eventually be fatal.

“Compared to most other major conditions like heart disease and cancer, liver disease continues to be a major cause of death in this country.
“It’s increasing, whereas the number of people dying from heart disease and cancer is getting less and less.

“Also, deaths from liver disease continue to rise in this country in contrast to reductions in Europe.
“People need to be aware that obesity causes liver disease, not just alcohol abuse.
“Obesity is prevalent in about one in five of the population and that can be associated with diabetes and, less well known, with cirrhosis.”

And some people are afflicted with liver disease due to rare genetic conditions – like Vicky Fenton.
The 34-year-old mother-of-two was diagnosed with primary sclerosing cholangitis (PSC), an autoimmune liver disease, as a child.

In autoimmune diseases the patient’s own immune system starts to attack their organs – in some cases the liver, resulting in inflammation and eventually cirrhosis.
She said: “It’s quite rare and more common in middle-aged men but I was critically ill when I was just 12 before I was diagnosed.

“I became really tired and got really itchy skin, which is one of the main symptoms, and I went quite yellow as well.

“I was put in isolation in Addenbrooke’s because doctors didn’t know what it was, as it was so rare.
“It was Dr Gimson who diagnosed me and has treated me ever since.

“They put me on loads of different sorts of medication at the time and gave me lots of blood transfusion and told me that one day I would need a transplant.

“I was well for years after that really. They told me I might not have children but I went on to have two daughters.

“I only went into hospital a couple of times but when I hit 30 my health started to deteriorate and I was getting more and more tired.

“I’m quite an energetic, vibrant person but I was just tired all the time.”
Vicky was put on the organ donor list in September 2010 and had a 70 per cent chance of dying within a year.

Dr Gimson said: “Everyone who goes on the transplant list has a 0 per cent chance of surviving five years without one. Some will die in the first year.”

Vicky, of Cambridge, said: “I couldn’t receive the initial liver that I was offered in December 2010 as I had started to show signs of pneumonia. It was quite difficult because I was really ill and you usually only get one chance to get a donor organ.

“It’s a really strange time, you are always waiting for the phone to ring but you are scared of having the operation at the same time. You can never relax.
“You have to think about what is going to happen to your children if you are not around and make plans in case you are not.”

However, she received a call on June 15 last year asking her to go to the hospital as another organ had become available.

She said: “I remember shaking uncontrollably. I felt relief and excitement but as I was going into theatre I kept crying uncontrollably and apologising.”

She had a long road to recovery, spending six weeks in hospital, and her body rejected the organ twice, despite being on high levels of immunosuppressant drugs.
One of the first things she did on leaving the hospital was go to the seaside with her daughters Lola, 7 and Poppy, 5.

Vicky is just one of many grateful patients who has been given a new lease of life and is passionate about making people aware of organ donation to reduce the shortage.

She said: “I just enjoy life now and live in the moment. Just enjoying being a mum and running round the park with my kids is wonderful.”

Even if you sign up to become an organ donor to save the lives of others your next of kin can refuse to release your organs. So both Dr Gimson and Vicky want to make sure people talk about the topic.
Vicky said: “Currently 30 per cent of the population are on the register but considering 98 per cent would accept an organ if needed that is such a low figure – the numbers should match.”
Dr Gimson said: “I think the problem is that it is a taboo subject.

“Nobody wants to talk about death and organ donation but if it is your wish to be an organ donor you should tell your next of kin because they may go against your wishes.”
For more information and to register visit www.organdonation.nhs.uk.
rachel.allen@cambridge-news.co.uk

Cirrhosis facts and figures
Cirrhosis is a certain pattern of scarring within the liver which eventually damages the liver’s functions, which fail over a number of years and may eventually be fatal.
Every year over 4,000 people in the UK die from cirrhosis.
Around 700 people have to have a liver transplant each year to survive.
Survival after a liver transplant is good – 90 per cent are alive after one year and 75 per cent after five years.

Causes of Cirrhosis:
– Alcohol 35%
– Hepatitis viruses 25%
– Non-alcoholic fatty liver disease
– Autoimmune liver diseases 10%
– Genetic disorders and other rare causes 10%.

Hepatitis C Virus Infection In Non-Hodgkin’s Lymphoma: A Case Control Study

2012-01-22T15:13:00.001-05:00

Hepatitis C Virus Infection In Non-Hodgkin’s Lymphoma: A Case Control Study

[ID:1491, in press, available in 2012][DOI: 10.5812/kowsar.1735143X.801]
Authors: Muhammad SK,Chandio MA, Soomro MA, Shaikh BA
Correspondence:
Shaikh Khalid Muhammad

Abstract:

Background:
Hepatitis C virus (HCV) is the most common cause of chronic liver disease in Pakistan{%1%} Globally an estimated 170 million persons are infected with HCV and around 3-4 million are newly infected each year with HCV {%2%}{%3%} Currently the prevalence of HCV in Pakistan is 4-7%.{%4%}{%5%}{%6%}HCV is a hepatotropic virus, causing chronic hepatitis in at least 80% of infected with it. If left untreated, 20-30% will eventually develop Cirrhosis with average latency of 15-25 years and Hepato-Cellular Carcinoma at rate of 1-5% per year with average latency of 20-30 years. {%3%}{%7%}.

Objectives: To determine the association between hepatitis C virus (HCV) infection and Non-Hodgkin's Lymphoma (NHL).

Methods & Materials: This 2 year case control study was started on 1st January 2009. 292 cases of NHL underwent staging according to Ann Arbor staging and were graded according to working formulation classification. Blood samples from 292 NHL cases and 1168 age and sex matched controls (2 groups) meeting our selection criteria, were sent for detection of anti-HCV Ab on ELISA. Chi-square test was applied to compare anti-HCV Ab seropositivity in cases and controls and odd ratios were computed. NHL cases were divided in anti-HCV Ab seronegative and seropositive groups to compare the effect of anti-HCV Ab seropositivity on stage and grades of NHL. P value of 0.05 was taken as statistically significant.

Results: 52 (17.8%) cases, 45 (7.7%) controls in group 1(10 Relatives) and 50 (8.6%) controls in group 2 (Non Hematological Malignancy) were anti-HCV Ab positive, with odd ratios of 2.59 (95%CI: 1.69 - 3.97) for group 1 and 2.31 (95%CI: 1.52 - 3.50) for group 2 with P value of 0.000 for both. Anti-HCV Ab positive NHL cases were more likely to be in middle age (40-60years) with odds of 3.68 (95%CI: 2.07 - 6.50). There was no significant effect of anti-HCV Ab seropositivity on grades and stages of NHL.

Conclusion: NHL is strongly associated with Anti-HCV Ab seropositivity, with 2 to 2.5 odd risk and seropositive cases tend to be in middle and young age.

Keywords: Hepatitis C Virus (HCV); Hepatitis C Antibodies; Association; Lymphoma, Non-Hodgkin (NHL).

Discussion Only
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This was first study conducted in Pakistan to observe the association between HCV and NHL and to observe the impact of anti-HCV Ab seropositivity on the stages and grades of NHL. In our study, we excluded NHL patients who had experienced exposure to any known risk factor for lymphoma development such as irradiation exposure, HIV infection, HBV infection, exposure to cytotoxic or immunosuppressive drugs, autoimmune disorders, and connective tissue disorders. We also excluded patients with a history of transfusion or parenteral medication or surgical procedures in the last 6 months as well as known patients with hemophilia or thalassemias since these disorders may falsely elevate the number of patients in the anti-HCV Ab-positive group. After exclusion, a total of 292 patients were enrolled in our study. For the cases, we used age- and sex-matched controls.
Advantages in selecting 1st degree relatives as control group 1 were that the relative belonged to the same locality of origin, experienced the same environmental factors, and had a genetic makeup similar to that of the patient.

Control group 2 consisted of patients with non-hematological malignancy and was used to compute the odds of NHL n HCV, as compared to other non-hematological malignancies. In our study, we identified statistically significant (P <0.000) odds ratio values for HCV in NHL patients. The HCV-infected NHL patients were younger (P < 0.000) than the non-infected individuals, but the risk was higher in young (< 20 years) and middle-aged (40–60 years) patients. There was no significant impact of HCV seropositivity on the stages and grades of NHL. Similar results were reported by researchers in Egypt and Saudi Arabia. In Egypt, Cowgill et al. (30) observed a significant association between NHL and HCV, but they did not evaluate the impact of HCV infection on the stages and grades of NHL. HCV infection in NHL patients is reportedly independent of age. Polymerase chain reaction, which was used in a previous study, was better than ELISA for the detection of HCV infection. In Saudi Arabia, Harakati et al. (31) reported that HCV-infected NHL patients were more likely to have intermediate-grade NHL than non-infected patients. Researchers in Europe also documented a similar association between NHL and HCV infection, but few studies have been conducted to evaluate the impact of the stages and grades of NHL in detail. Mele et al. (32) documented a strong association and concluded that in Italy, 1 of 20 instances of B-NHL may be attributable to HCV infection, and thus, the patients may benefit from antiviral treatment. In Turkey, Isikdogan et al. (33) observed that HCV-seropositive NHL patients were more likely to have intermediate-grade NHL. In France, Seve et al. (34) documented a positive but non-significant trend
towards an association between NHL and HCV infection (odds ratio, 1.31; 95% CI, 0.51–3.36). In Spain, De Sanjose et al. (35) found no significant difference in HCV seropositivity between nodal and extranodal NHL cases.

Similar to our study, all these studies reported a positive association between NHL and HCV. A Spanish study reported results similar to those of our study regarding the impact on the grades of NHL, but a Turkish study reported contradictory results. Studies performed in other countries have also reported a strong association between HCV and NHL. Spinelli et al. (36) in Canada, Takeshita et al. (37) in Japan, Masami et al. (38) and Nieters et al. (39) in a European multicenter case-control study (EPILYMPH), and El-Sayed et al. (40) in Egypt also reported similar results.

Most of these studies did not examine the impact of HCV seropositivity on the stages, grades, and B symptoms of NHL. Our study not only studied the association between NHL and HCV but also examined its impact on the stages and grades of NHL. In addition, this was the first study performed in Pakistan on this issue. The literature supports the concept that hepatitis C and NHL are associated.
However, limited studies have been conducted in Pakistan to explore this issue. The incidences of these disorders are currently increasing. The primary reasons for increase in HCV infections in developing countries such as Pakistan include poverty, lack of public awareness, non-availability of vaccines, and lack of health care facilities. Furthermore, the incidence of NHL is also increasing
at a rate of 1–4% per year. This association of HCV with NHL may put the public at risk of an NHL epidemic, particularly in developing countries such as Pakistan. This may ultimately result in decreased life expectancy and loss of young people in developing nations.

In conclusion, HCV infection is strongly associated with NHL. HCV was 2–3 times more prevalent in NHL patients than in the controls. HCV infection in NHL patients was more frequently observed in young and middle-aged subjects. No statistically significant impact was observed regarding anti-HCV Ab seropositivity on the stages and grades of NHL.

On the basis of our results, larger epidemiological studies can be conducted. Our study results also provide information for health policy and decision makers that can be used to control a combined epidemic.

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Off Topic- 6 Devices That Could Change the Standards of Medical Care

2012-01-22T12:36:00.001-05:00

video platform video management video solutions video player

Can we be better at diagnosing and preventing illnesses?

Dr. David Agus, author of "The End of Illness" and oncologist for the late Steve Jobs, says not only can we do better, but we can do it through changing the way we analyze the human body and using more advanced technologies. After spending years conducting research and clinical studies at various medical centers across the country, Agus wrote his book as a guide to how we can personalize health care.

Together, "Nightline" and Dr. Agus developed a medical "lab of the future" -- a group of advanced machines, tests and technologies Agus says could help slow the onset of illness or even prevent some diseases entirely.

Dr. Agus offers a timeline for when he suggests these devices and tests will likely be standard in medicine – some even in your homes – in the next decade. His theory is that we should be proactive, not reactive about our health. To do this, the future of medicine must become personalized.

It remains to be seen if the following practices will be implemented at doctors' offices and hospitals on a wider scale, though some are used today. Dr. Agus also recommends that you consult your physician before undergoing certain tests.

View Slideshow of all devices here

Dietary Fiber for the Treatment of Type 2 Diabetes Mellitus

2012-01-22T12:03:00.005-05:00

Dietary Fiber for the Treatment of Type 2 Diabetes Mellitus: A Meta-Analysis

doi: 10.3122/jabfm.2012.01.110148 J Am Board Fam Med January-February 2011 vol. 25 no. 1 16-23

+ Author Affiliations

From the Department of Family Medicine, Medical University of South Carolina, Charleston.

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Abstract

Background:
The evidence of the relationship between fiber intake and control of diabetes is mixed. The purpose of this study was to determine if an increase in dietary fiber affects glycosylated hemoglobin (HbA1c) and fasting blood glucose in patients with type 2 diabetes mellitus.

Methods:
Randomized studies published from January 1, 1980, to December 31, 2010, that involved an increase in dietary fiber intake as an intervention, evaluated HbA1c and/or fasting blood glucose as an outcome, and used human participants with known type 2 diabetes mellitus were selected for review.

Results:
Fifteen studies met inclusion and exclusion criteria. The overall mean difference of fiber versus placebo was a reduction of fasting blood glucose of 0.85 mmol/L (95% CI, 0.46–1.25). Dietary fiber as an intervention also had an effect on HbA1c over placebo, with an overall mean difference of a decrease in HbA1c of 0.26% (95% CI, 0.02–0.51).

Conclusion:
Overall, an intervention involving fiber supplementation for type 2 diabetes mellitus can reduce fasting blood glucose and HbA1c. This suggests that increasing dietary fiber in the diet of patients with type 2 diabetes is beneficial and should be encouraged as a disease management strategy.

Diabetes mellitus is an ever increasing problem in the United States. As of 2010, the Centers for Disease Control and Prevention estimates that there are 18.8 million people affected with this disease in the United States with another 7 million people with undiagnosed diabetes.¹ Furthermore, almost 2 million people older than the age of 20 were newly diagnosed with diabetes in 2010.¹ Diabetes was estimated to cost more than $174 billion in 2007 in the United States when taking into account medical costs and loss of productivity.² Diabetes increases mortality by almost 2-fold and increases mortality by cardiovascular disease by 2- to 3-fold.³

Lifestyle modification is an important part of the management of diabetes. One of the main strategies for this is known as “medical nutrition therapy.” The goals of medical nutrition therapy include improving control of blood glucose levels, lipid profiles, and blood pressure to reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus.⁴ Medical nutrition therapy has been shown to reduce glycosylated hemoglobin (HbA1c) by 1% to 2% in patients with type 2 diabetes mellitus.⁵ It also has been shown to cause improvements in low-density lipoprotein cholesterol, an important marker in controlling the risk of cardiovascular disease.⁶ The American Diabetes Association recommends a specific diet as part of medical nutrition therapy for secondary and tertiary prevention in patients with type 2 diabetes mellitus. This diet includes the consumption of fiber-rich foods.⁴

Fiber has been studied in the treatment of diabetes for many years because increased fiber content decreases the glycemic index of foods.^7–9 The theory, then, is that the decreased glycemic index would lead to smaller increases in blood glucose, and thus reduced blood glucose and HbA1c levels. Although high fiber intake has been linked to a decreased risk of diabetes,^10,11 the evidence on fiber intake and control of diabetes is mixed. Specifically, many of the studies focused on fiber intake and glycemic control are small and have conflicting results; some studies show an improvement in diabetes control and others show no improvement.^12–17 Therefore, the purpose of this study was to perform a meta-analysis of these studies to determine to what extent an increase in dietary fiber affects HbA1c and fasting blood glucose in patients with type 2 diabetes mellitus.

Methods

Data Sources and Searches

A search of PubMed materials dated January 1, 1980, to December 31, 2010, was performed on February 9, 2011, using the keywords “dietary fiber” and “diabetes mellitus.” A search of OVID, the Cochrane Clinical Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature also was performed using the same keywords. The references within studies that met inclusion criteria were searched for any possible relevant articles that may have been missed by these queries.

Study Selection

Inclusion criteria for this meta-analysis included randomized trials that involved an increase in dietary fiber intake as an intervention, evaluated HbA1c and/or fasting blood glucose as an outcome, used human participants with known type 2 diabetes mellitus, and was written in English. Exclusion criteria included are detailed in Figure 1.

If a study included multiple arms, where one arm included diet and a medication versus another arm of just dietary intervention, then only the dietary intervention arm was included in the analysis. Patients in crossover trials, in which patients are their own controls, were treated as separate control and intervention arms for analysis.

Data Extraction

Data were extracted from each study and entered into an Excel spreadsheet (Microsoft, Corp., Redmond, WA). Demographic factors included sample population, mean age, mean body mass index, and sex distribution of the control and treatment groups. Outcome measures included final means for HbA1c and fasting blood glucose of the control and intervention groups. For studies that reported standard deviation of the mean, those data were used. For studies that reported standard error of the mean, standard error was multiplied by the square root of the sample population to obtain the appropriate standard deviations. If studies reported fasting blood glucose in units of mg/dL, this was converted to the standardized international unit of mmol/L by multiplying the fasting blood glucose value in mg/dL by 0.0555.

Study quality was assessed using the GRADE assessment as detailed in the Cochrane Handbook.¹⁸ This assessment takes into account the bias of studies as well as their methodology (eg, randomized vs observational) and their limitations to determine a quality grade of high, moderate, low, or very low.

Data Synthesis and Analysis

Meta-analysis for the mean differences was performed with Review Manager (version 5.0.23, The Nordic Cochrane Center, Copenhagen, Denmark). Separate analyses were performed for fasting blood glucose and HbA1c. Because measures of fasting blood glucose are on the same scale (mmol/L), and measures of HbA1c are on the same scale (percent of glycohemoglobin), a standardized mean difference was not necessary. The final means in the control and intervention groups were compared by computing a mean difference using the inverse variance method, where studies with less variance in their effect estimate are given more weight. Both fixed- and random-effects models were used for analysis. Comparison of final means is considered an appropriate analysis method in randomized trials because, in theory, the baseline data of the control and intervention groups in a randomized trial are not statistically different, and therefore final values for each trial arm would be representative of a change from a common baseline.¹⁸ A test of heterogeneity was performed to determine if results from a fixed-effect model could be considered valid. If the test of heterogeneity exhibited P < .05, then only the results of a random effect model would be considered valid. Forest plots each for fasting blood glucose and HbA1c were created. Funnel plots for each analysis to assess publication bias visually were created as well.

Results

Studies

The search initially yielded 1623 studies. Of these, 28 met inclusion criteria. Of these 28 studies, 13 were excluded for meeting one of the exclusion criteria, resulting in a total of 15 studies Figure 1.Of the 15 included studies, 5 were randomized controlled trials^19–23 and 10 were randomized crossover trials.^24–33 Among these 15 articles, 13 contained data for fasting blood glucose that could be extracted and 10 contained data for HbA1c that could be extracted. Further details regarding the types of fiber and the specific interventions used in each study are listed in Table 1. Using the GRADE assessment, 11 of the studies were of high quality and 4 were of moderate quality.

Table 1.

Intervention Details of Included Studies

Study	Specific Fiber Type	Soluble Fiber	Intervention
Karlstrom 1984	Cereal and unknown	Soluble and insoluble	A high-fiber diet (42.4 g) versus a control diet (18.9 g fiber). Diets were identical in the proportion of carbohydrate, fat, protein, and cholesterol.
Hollenbeck 1986	Unknown	Unknown	A high-fiber diet (27 g/1000 kcal) versus a control diet (11 g fiber/1000 kcal). Diets were identical in the proportion of carbohydrate, fat, protein, and cholesterol.
Holman 1987	Guar gum	Soluble	Guar minitablets (5 g), taken 3 times a day taken immediately before the first mouthful of each meal and washed down with water. Of note, all patients had achieved near-normal fasting plasma glucose levels before study began.
Hagander 1988	Cereal, beet, and leguminous	Soluble and insoluble	High-fiber versus low-fiber diets without changing energy intake or proportions of protein, fat, and carbohydrates.
Uusitupa 1989	Guar gum	Soluble	Guar gum granules (5 g), premixed with juice, milk, or water (1–2 dL), 3 times a day before main meals.
Lalor 1990	Guar gum	Soluble	Guar gum granules (5 g) at meal times 3 times daily.
Karlander 1991 (diet only arm)	Beet fiber	Soluble	Beet fiber (16 g) mixed into meals divided over 3 meals a day.
Chuang 1992	Guar gum	Soluble	Guar gum (5 g) taken before or with meals in a liquid form 3 times a day.
Chandalia 2000	Unfortified foods (e.g. cantaloupe, sweet potato, oatmeal)	Soluble and insoluble	A high-fiber diet (50 g) versus a control diet (24 g fiber). Diets were identical in the proportion of carbohydrate, fat, protein, and cholesterol.
Jenkins 2002	Cereal fiber	Soluble and insoluble	Bread and breakfast cereals high in cereal fiber were provided to add 19 g/day of additional cereal fiber compared with an additional 4 g/day of additional cereal fiber in the control group.
Feldheim 2003	Wheat fiber	Soluble and insoluble	Consumption of bread and crescents enriched with a dietary fiber concentrate.
Lu 2004	Arabinoxylan-rich fiber	Soluble and insoluble	Usual diet supplemented with arabinoxylane fiber-enriched bread and muffins compared with non–fiber-enriched bread and muffins in the control group.
Cho 2005	Cassia tora fiber	Soluble	Two 2-g packets per day ingested after meals, i.e., one packet each after morning and evening meal.
Ziai 2005	Plantago ovata Forsk (Psyllium)	Soluble and insoluble	Fiber supplement (5.1 g) in 250 mL of water twice a day, 20–30 minutes before the morning and evening meals.
Ikem 2007	Unknown	Unknown	A high-fiber diet (40 g of fiber added) versus a control diet. Diets were similar in the proportion of carbohydrate, fat, and protein.

Demographics

Table 2 lists the demographic features of each study. The total number of participants for fasting blood glucose was 400 and for HbA1c was 324. Mean ages ranged from 52.1 to 69.1 years. The proportion of female participants ranged from 7.7% to 73.4%. Mean body mass index ranged from 23.4 to 32.5. Fiber interventions ranged from 4 to 40 g/d of additional fiber, with a mean increase in fiber for the intervention of 18.3 g/d. No studies reported any bias.

Fasting Blood Glucose

Results for the meta-analysis of fasting blood glucose are shown in Figure 2. Because the test for heterogeneity was not statistically significant (P = .40), the fixed-effects model was considered valid for the analysis. Overall, fiber intervention was more effective than placebo in reducing fasting blood glucose. The overall mean difference was a reduction of fasting blood glucose by fiber of 0.85 mmol/L (95% CI, 0.46–1.25) more than the reduction from placebo. This is equivalent to a reduction over placebo of 15.32 mg/dL (95% CI, 8.29–22.52). The funnel plot for fasting blood glucose data are fairly symmetrical, with 7 studies favoring fiber and 6 favoring control, indicating low risk of publication bias for this data.

Glycosylated Hemoglobin

Results for the meta-analysis of HbA1c are shown in Figure 3. Because the test for heterogeneity was not statistically significant (P = .25), a fixed-effects model was considered valid for analysis. Overall, fiber intervention was more effective on HbA1c than placebo, with an overall reduction in HbA1c by fiber of 0.26% (95% CI, 0.02–0.51) more than the reduction from placebo. The funnel plot for HbA1c data is asymmetrical, indicating that there may be a risk of publication bias for this data.

Discussion

The results of the meta-analysis show a statistically significant improvement in fasting blood glucose and HbA1c when an increase in dietary fiber was used as an intervention in patients with type 2 diabetes mellitus. However, the effect for HbA1c was more modest than that for fasting blood glucose. A possible cause for this is that the time period for 8 of the 10 interventions for HbA1c was less than 12 weeks, and HbA1c is representative of an overall glycemic control for a 12-week period. Therefore, most of the studies evaluating HbA1c were of a length less than the recommended testing period between HbA1c measurements. More studies evaluating HbA1c for a duration of longer than 12 weeks would be warranted.

Some may suggest that the effect on HbA1c, though statistically significant, my not be clinically significant. Metformin, one of the oral medications most commonly used to treat diabetes, has shown HbA1c reductions anywhere from the range of 0.2% to 2%.³⁴ Comparatively, making a change in diet to reduce HbA1c by about 0.3% could be useful as an adjunctive therapy to medication as part of an overall treatment strategy for controlling diabetes. Again, this effect may be tempered by short follow-up durations of the majority of these studies, so fiber may truly have a larger affect on HbA1c than what is reported in this study.

These results suggest that increasing dietary fiber in the diet of patients with type 2 diabetes is beneficial and should be encouraged as a disease management strategy. High-fiber versions of traditionally low-fiber foods have been shown to be palatable for patients with type 2 diabetes.³⁵ Consequently, this disease management strategy should not be particularly onerous for patients and may be easier to comply with than some other more intense lifestyle changes. The mean increase in fiber in the included studies was approximately 18 g/d. To implement this in one's diet would include eating a bowl of high-fiber cereal and adding a few more servings of vegetables a day.

The studies in this analysis used a variety of grams of fiber per day in their interventions, comprising a large range, from as little as an additional 4 g/d to as much as 40 g/d. The most commonly used fiber intervention dose was a 15-g/d supplement to usual diet. However, the American Diabetes Association recommends fiber consumption of at least 14 g/1,000 kcal/d or a range of 25 to 30 g/d, the values recommended by the United States Department of Agriculture,⁴ whereas the American Dietetic Association's position statement recommends 30 to 50 g of dietary fiber per day for patients with type 2 diabetes mellitus.³⁶ Dietary fiber intake from a variety of sources has been associated with a significantly decreased risk of coronary events in epidemiologic studies in patients with and without diabetes. For example, in the Nurses Health Study, women with the highest fiber intake (median, 22.9 g/d) had an age-adjusted relative risk for major coronary events that was almost 50% lower than women in the group with the lowest fiber intake (11.5 g/d).³⁷ Another study showed that fiber intake more than 20 g/d is associated with lower risk of coronary heart disease among women.³⁸ Large epidemiologic studies have demonstrated an inverse relationship between fiber intake and cardiovascular disease rates in men as well.^39,40 More studies of those specifically with type 2 diabetes mellitus with larger fiber doses as an intervention would aid in supporting or refuting recommendations for diabetics.

Limitations

The authors did not examine unpublished data, studies not in English, or any studies that were not published in peer-reviewed journals. One can argue that there is publication bias and that many negative studies are not published; however, many of the studies included in this analysis showed non-statistically significant effects. Also, the authors were trying to find studies of the highest quality, and these types of studies usually are published in English language, peer-reviewed journals. The studies exhibited a wide range of intervention amounts of fiber and lengths of time, but these differences are inherent in any meta-analysis.

Conclusions

Overall, an intervention involving fiber supplementation for type 2 diabetes mellitus can reduce fasting blood glucose and HbA1c. Further studies of more than 12 weeks' length are warranted for testing fiber's effect on HbA1c. Also, studies involving larger doses of fiber are warranted to help support current diabetes dietary fiber recommendations.

Notes

This article was externally peer reviewed.
Current affiliation: Virtua Family Medicine Residency, Voorhees, NJ (REP).
Funding: none.
Conflict of interest: none declared.

Received for publication April 29, 2011.
Accepted for publication August 9, 2011.

Previous Section

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Editorial-How to Optimize Treatment of Hepatitis C

2012-01-22T11:36:00.004-05:00

Editorial-Journal of Viral Hepatitis

Massimo Colombo

Article first published online: 10 JAN 2012

DOI: 10.1111/j.1365-2893.2011.01520.x

Special Issue: How to Optimize Treatment of Hepatitis C

Volume 19, Issue Supplement s1, pages 1–2, January 2012

Chronic carriers of the hepatitis C virus (HCV) constitute a huge reservoir of cirrhosis and hepatocellular carcinoma which, ultimately, are a growing cause of liver-related mortality worldwide [1]. Treatment with pegylated interferon (PegIFN) combined with ribavirin (Rbv) is the only option for preventing HCV-related end stage liver disease.

Currently, sustained virological response (SVR) rates, the surrogate definition of a cure of the disease, of up to 90% are achievable in patients infected with HCV genotypes 2 and 3, but the SVR rate is about 50% for patients infected with HCV genotype 1, the most common form [2]. Therefore, patients infected with HCV genotypes 1 and 4 who fail to respond to IFN-based therapies represent a very important unmet clinical need in the HCV arena, as highlighted also by the unsatisfactory success rate of re-treatment with Peg IFN/Rbv [3,4]. Therefore, it was with understandably great anticipation that hepatologists awaited the final reports on triple therapy with the orally bio-available protease inhibitors (PI) telaprevir and boceprevir, known to improve SVR rates to 75% in this difficult-to-cure population [5,6]. Even more welcomed were the final reports of the Prove 3 (telaprevir) and Respond 2 (boceprevir) studies, which demonstrated that re-treatment of relapsing or nonresponding HCV genotype 1 infections with standard therapy plus a PI significantly increases the likelihood of HCV eradication [7,8].

Now that we have confirmation that the new direct-acting antiviral agents will provide a major breakthrough in the treatment of patients with HCV genotype 1 infections, although at the cost of increased treatment-related side effects and discontinuation rates, we must adopt new therapeutic algorithms based on careful pretreatment patient stratification.

This purpose might be served by the recent description of a set of polymorphisms in the interleukin 28B (IL28B) gene region, which encodes interferon λ3 and is associated with response to Peg IFN/Rbv therapy in HCV patients [9,10]. In fact, the link between IL28B genotype and treatment outcome might allow for pretreatment stratification aimed at refining not only decisions regarding the initiation of current therapy, but also the design of clinical trials with new direct antiviral agents. Indeed, it is worthwhile to test both a strategy restricting dual therapy to patients with the favourable IL28B genotype (CC), while administering triple therapy to those with unfavourable genotypes (TT or CT), and also a strategy in which patients are stratified by IL28B genotype for dosing and duration of antiviral therapy. This strategy might be even more cost-effective once ‘second wave’ direct antiviral agents, endowed with higher genetic barriers and broader antiviral activity against different HCV genotypes, become available.

Indeed, we should acknowledge that the applicability of first generation antivirals is jeopardized by a very high risk of generating resistant HCV mutants with variable degrees of replicative fitness and by low tolerability, which could translate into higher rates of treatment discontinuation compared to dual therapy with PegIFN/Rbv alone [11].

Cutaneous rash, pruritus and anaemia following telaprevir versus anaemia and disgeusia following boceprevir were more common in the triple regimen than in the standard of care groups. Undoubtedly, the management and treatment of patients with chronic HCV infection will become more complicated, requiring increased scientific and clinical expertise to meet the new challenges that this first generation of direct-acting antivirals will provide. Although the development of viral resistance to PIs occurs in a minority of patients receiving the triple therapy regimens, it is important to outline that those mutant strains will likely preclude or delay our patients from receiving other class-specific direct antiviral agents [12].

Related:Dermatological side effects of hepatitis C and its treatment: Patient management in the era of direct-acting antivirals
Boceprevir and telaprevir for hepatitis C: safety management in clinical practice

Because alternative anti-HCV agents such as nucleoside or nonnucleoside NS5B polymerase inhibitors are in the early stages of development, patients with resistant disease will be left waiting for future drugs to enter the market before an effective anti-HCV regimen can be started. Thus, when a patient is considered for treatment with PIs, a careful risk/benefit evaluation must be conducted at the individual level; careful patient selection for triple therapy is mandatory. This is even more important when re-treating patients with genotype-1 infections, where breakthrough rates are higher among nonresponders (particularly those with < 1 log decline of HCV-RNA at week 4 of treatment) than among relapsers and among patients infected with subtype 1a compared with subtype 1b.

The clinical implication of these observations is clear: PIs require some degree of viral response to PegIFN and Rbv to maximize their antiviral activity, therefore suggesting that treatment be prioritized in relapsing patients and in those primary nonresponders experiencing a ≥1 log decline in HCV-RNA at week 4 of lead in treatment with PegIFN+Rbv. In addition, an updating of HCV genotype definition is mandatory to avoid false positive diagnosis of 1b using tests based on sequence analysis or reverse hybridization of only the 5′ noncoding region of HCV, a risk that can be avoided using a second generation reverse hybridization assay that targets both the 5′ noncoding and the core-coding region of HCV [13]. Last but not least, the landscape of therapeutic effectiveness needs to be reshaped in terms of reducing HCV-related mortality at the population level.

Given that HCV-related mortality in the general population can only be reduced by increasing the number of HCV patients on treatment (only 1% in Italy) and that most of the infected patients are unaware of their liver disease because of its symptomless course, more effort should be made to identify infected patients to be treated.

Although the implementation of screening of persons at risk for HCV is an important step in this direction, we must realize that in many European countries including Italy, more than half of the patients with chronic hepatitis C lack a history of exposure to known risk factors and, therefore, will escape identification based on such a case-finding strategy [14]. As it is estimated that the health burden of HCV-related complications will continue to grow in most countries, in May 2010 the World Health Organization declared hepatitis a global and urgent health issue to be combated through prevention campaigns and widespread treatment of patients with the aim of avoiding progression to cirrhosis in individuals already infected.

To offer anti-HCV therapy to every eligible patient, efforts should be geared toward improving the currently available screening programs for HCV infection, such as in individuals born between 1950 and 1960, as was recently suggested by the American Association for the Study of the Liver. A Markov model analysis clearly shows that increasing the number of patients currently treated with dual therapy by 50% would prevent 30% of liver-related deaths because of HCV by 2030 [15]. The advent of a rapid point-of-care test for HCV exposure that can be performed without phlebotomy needs to be recognized as a major breakthrough in this field [16]. Obviously, an agreement between local health authorities and big pharma to significantly decrease drug costs is necessary to make an expanded HCV therapy program affordable.

Declaration of personal interests:
Massimo Colombo received grants and research support from Merck, Roche, BMS, Gilead Science and participated in Advisory Committees organized by Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex and moreover acted as a speaker and as a teacher for Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex.

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Surveillance for Hepatocellular Carcinoma in Patients With Cirrhosis

2012-01-22T11:16:00.001-05:00

From Clinical Gastroenterology and Hepatology,

Surveillance for Hepatocellular Carcinoma in Patients With Cirrhosis

Authors and Disclosures

Ju Dong Yang and W. Ray Kim
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota

Posted: 01/19/2012; Clin Gastroenterol Hepatol. 2012;10:16-21. © 2012 AGA Institute

Clinical Scenario
A59-year-old man was referred to liver transplantation clinic for the evaluation of enlarging abdominal girth and swelling of feet during the preceding 2 months. The patient was a Cambodian native who immigrated to the United States 5 years ago. The patient was first diagnosed with chronic hepatitis B virus (HBV) infection shortly after his entry into the United States. However, he was not further evaluated, treated, or followed. He had no personal or family history of liver disease or liver cancer. Physical examination of the abdomen showed mild hepatosplenomegaly with positive shifting dullness from a moderate amount of ascites. There was no abdominal tenderness. Laboratory results included platelet count, 95,000/μL; aspartate aminotransferase, 100 U/L; alanine aminotransferase, 45 U/L; and Model for End-Stage Liver Disease score, 13. Viral serology showed hepatitis B surface antigen–positive and eantigen– positive and HBV DNA of 5 million IU/mL. Serum alpha-fetoprotein (AFP) was normal at 4 ng/mL. An abdominal ultrasound (US) showed cirrhotic liver contour and evidence of portal hypertension. An esophagogastroduodenoscopy showed large esophageal varices. The patient was started on the following medications: spironolactone and furosemide for the ascites, propranolol for the varices, and entecavir for HBV. Patient was further assessed and then listed for liver transplantation.

During the ensuing 12 months, the patient had substantial clinical improvement including resolution of ascites as well as hepatitis B e seroconversion. He also underwent abdominal US and serum AFP measurement on a 6-month interval. An abdominal US performed 18 months after his presentation showed a new 2.1-cm hyperechoic nodule in the right lobe of the liver along with mild elevation of serum AFP at 22 ng/mL. A subsequent triphasic abdominal computed tomography (CT) scan showed a 2.2-cm well-circumscribed vascular mass that had arterial enhancement and venous washout, thus meeting the radiographic diagnosis criteria for hepatocellular carcinoma (HCC) of the American Association for the Study of Liver Disease (AASLD). The patient underwent transarterial chemoembolization and subsequently received a liver transplant. Four years later, the patient is doing well with satisfactory liver function with no evidence of recurrent HBV or HCC.

The Problem
Our patient represents a case in which implementation of HCC surveillance likely improved his ultimate outcome. HCC is a major global health problem because it is the third leading cause of cancer-related death in the world. GloboCan reported that the incidence and mortality of HCC continued to increase as of 2008. In general, HCCs tend to be asymptomatic until the tumor is in an advanced stage. Although there has been substantial progress in the treatment of HCC, long-term survival is only achievable in a small proportion of patients— those presenting in an early stage where potentially curative modalities such as liver transplantation and surgical resection are feasible. Therefore, it is widely held and recommended that early detection of HCC is imperative in improving the prognosis.

Screening is defined as application of diagnostic tests in patients at risk for a condition (eg, HCC) without a high index of suspicion that the condition is already present. Surveillance is conducted by repeated application of screening tests. In the case of HCC, the stated goal of surveillance is to decrease HCC mortality or at least to increase the meaningful duration of life through the early detection of HCC in asymptomatic patients. Existing evidence indicates that HCCs detected by surveillance are more likely to be amenable to curative treatment. Because long-term survival can be achieved in a majority of patients eligible for liver transplantation or resection, surveillance might decrease HCC mortality. This is a main rationale for which HCC surveillance is recommended in high-risk individuals.

There have been 2 randomized controlled trials that investigated the efficacy of surveillance. Both studies were conducted in China in patients with HBV infection. The first study, involving 19,000 patients, showed that surveillance is efficacious in reducing HCC mortality. Patients assigned to semiannual surveillance with serum AFP and abdominal US had a 37% decrease in HCC mortality compared with patients not under surveillance. Although the study was limited by a high dropout rate of study participants and suboptimal randomization and concealment schemes, it provides the best evidence to date that has shown the benefit of surveillance on "hard end points" in HCC. The other study was performed with 5581 HBV patients. In contrast to the first study, it used serum AFP as the primary tool for surveillance. This study showed that surveillance increased the detection of early-stage tumors but did not affect overall survival and liver cancer mortality. Besides these trials, a number of observational studies have suggested that surveillance improves survival in HCC patients (Table 1).

Click On Image To Enlarge

Although HCC surveillance is generally accepted, its implementation is suboptimal in real-life practices. In the United States, a study that used the Surveillance Epidemiology and End Results-Medicare database showed that only 17% of cirrhotic patients were under regular surveillance 3 years before the diagnosis of HCC. In a more recent study involving 13,000 cirrhotic hepatitis C virus patients at Veterans Administration health care facilities throughout the United States, only 12% received routine HCC surveillance.

Who Are the Candidates for Hepatocellular Carcinoma Surveillance?
Hepatocellular carcinoma surveillance should be performed in a group of patients whose risk for HCC development is sufficiently high to make it cost-effective Table 2-below- Surveillance is considered effective if it increases life expectancy by more than 3 months and considered cost-effective if less than $50,000 is needed to increase 1 quality-adjusted life-year. Under this concept, the incidence of HCC is the primary determinant of the cost-effectiveness of surveillance.

The first category of candidates for surveillance is patients with cirrhosis. Cirrhosis is the single most important risk factor for HCC, and most patients with HCC have underlying liver cirrhosis. According to a guideline from AASLD, surveillance is recommended when the HCC incidence is higher than 1.5% in a patient with cirrhosis. This category of patients includes those with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, and primary biliary cirrhosis, and thus these patients should be under a surveillance program. In addition, experts recommend patients with other types of cirrhosis to receive surveillance, although firm data about the incidence of HCC in this group of patients are lacking.

In implementing surveillance, one of the common challenges is to identify patients with cirrhosis. Because viral hepatitis is easily recognizable, patients at risk for chronic viral hepatitis infection need to be screened for HBV and/or hepatitis C virus according to the established guidelines. It is also important to have a high index of suspicion of chronic liver disease in patients with abnormal liver function test, significant alcohol history, or metabolic syndrome.

The diagnosis of cirrhosis is straightforward in patients with hepatic decompensation, on the basis of the characteristic symptoms of portal hypertension and liver failure. Hepatocellular carcinoma surveillance in this group of patients would be most meaningful if liver transplantation is available. Under the current allocation system, an early-stage HCC within the socalled Milan criteria increases the priority of receiving a liver transplant from a deceased donor. In contrast, if liver transplantation is not available, surveillance in patients with hepatic decompensation severe enough to disallow meaningful therapy is unlikely to be beneficial.

Diagnosing patients with compensated liver cirrhosis might present a challenge because patients are usually asymptomatic without an overt sign of portal hypertension. Although histology is considered the gold standard for the diagnosis of cirrhosis, a liver biopsy is invasive and subject to sampling variability. Various laboratory data and mathematical models have been proposed to noninvasively identify patients with cirrhosis. Transient elastographic techniques with magnetic resonance imaging (MRI) or US measure the stiffness of the liver, which correlates with hepatic fibrosis. As data accumulate in support of accuracy of these techniques in identifying asymptomatic cirrhotic patients, they are gaining wider acceptance in clinical practice.

The other category of candidates for surveillance is HBV carriers who might develop HCC without cirrhosis. In those subjects, surveillance is warranted when the HCC incidence is higher than 0.2%/year. These high-risk hepatitis B carriers include Asian men older than 40 years and Asian women older than 50 years. Although the annual incidence of HCC in individuals of African race or those with family history of HCC cannot be firmly established, they are also recommended to undergo surveillance starting at an earlier age(Table 2 ).

Table 2. Target Subjects for HCC Surveillance

Cirrhosis, threshold incidence (>1.5%	Incidence	Noncirrhotic HBV carrier, threshold incidence (>0.2%)	Incidence
HBV cirrhosis	3%–8%/y	Asian men >40 y	0.4%–0.6%/y
HCV cirrhosis	3%–5%/y	Asian women > 50 y	0.3%–0.6%/y
Primary biliary cirrhosis	3%–5%/y	Family history of HCC	Unknown
Nonalcoholic steatohepatitis	2.6%/y	African race	Unknown
Other cause of cirrhosis	Unknown

What Modality is to be Used for Surveillance?
Most guidelines advocate abdominal US as the standard surveillance test for HCC. It has sensitivity greater than 60% and specificity greater than 90% as a screening test for HCC. It is widely available and less expensive than CT or MRI. It does not expose patients with repeated radiation. However, there are several weaknesses of US as a surveillance test for HCC. Abdominal US is highly dependent on the operator. Because small HCC often presents with a nonspecific appearance, detecting an early HCC nodule can be challenging, particularly in a patient with a nodular cirrhotic liver. Sensitivity of US is further decreased in obese subjects. Because of the high prevalence of obesity in the United States, the utility of US as an HCC surveillance test in those patients has been questioned.
These limitations of US have prompted some clinicians to use abdominal CT or MRI in select patient groups, eg, those waiting for liver transplantation. However, the risk of repeated radiation and contrast exposure and high cost are obvious limitations that prevent its routine use in the broader population at risk. Finally, serum AFP is commonly used as an adjunct to abdominal US, although its use as a surveillance test for HCC remains controversial.

What is the Next Step if a Suspicious Lesion is Found by a Surveillance Test? (Recall Policy)
Once a suspicious lesion is found on US, a systematic algorithm, also known as the recall policy, can be followed to appropriately and expeditiously diagnose an HCC (Figure 1). If the nodule is smaller than 1 cm, a close follow-up with a repeat US at 3 months is recommended. If the lesion is found to enlarge to a size larger than 1 cm, a dynamic imaging study (CT or MRI) should be performed. If the size of the lesion remains the same for more than 2 years, the original 6-month follow-up might be resumed.

Figure 1. Lesions on surveillance US: recall policy.

Click On Image To Enlarge

For lesions that appear larger than 1 cm on US, a contrastenhanced dynamic CT or MRI must be performed. If characteristic vascular features (arterial enhancement and venous washout) are seen, a diagnosis of HCC is established. If the imaging characteristics are not typical, a second dynamic scan should be performed (if the first modality was CT, then MRI, and vice versa). If it shows the characteristic vascular features, a diagnosis of HCC might be made. If not, a percutaneous biopsy of the lesion should be considered, although the biopsy might not always be diagnostic. Finally, if there is considerable increase in serum AFP in the absence of a demonstrable lesion on US, a contrast-enhanced dynamic CT or MRI should be performed.

Areas of Uncertainty

Is Serum Alpha-Fetoprotein Beneficial?
There is broad agreement that serum AFP alone is inadequate as an independent tool for HCC surveillance and must not be used. For example, investigators of the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial serially measured the serum AFP every 3 months before the diagnosis of HCC and reported that serum AFP has inadequate efficacy as a surveillance test. Many other studies investigating the performance of AFP were in the setting of diagnosis rather than surveillance, where pretest probabilities are higher and the performance of the test is overestimated. The biggest limitation of serum AFP, when used alone, is its low sensitivity. Whereas the test might be made sufficiently specific if a high cutoff value is used, modest elevations might be seen in patients with viral hepatitis especially hepatitis C, pregnant women, and in those with tumors other than HCC, most notably gonadal tumors. Thus, depending on the cutoff value, serum AFP has suboptimal sensitivity and/or specificity. More recent serum markers such as des-carboxy prothrombin and the ratio of lecithinbound AFP to total AFP are even less sensitive than AFP for the detection of early-stage HCCs and have not been shown to be useful for surveillance.

Compared with US alone, the combination of US and serum AFP might slightly enhance the sensitivity to detect an HCC lesion. A study from China showed that the combination of US and serum AFP increases the liver cancer detection rate by 9%. However, the combination was associated with a 2.4-fold increase in false positivity and a 2.2-fold decrease in the positive predictive value. A cost-effectiveness analysis performed in the United States showed abdominal US is most cost-effective, and addition of AFP to US in HCC surveillance provides a small gain at a significant increase in cost. This increase in cost stems not only from adding the cost of AFP testing but also from the expenses needed to investigate false-positive results. For this reason, the AASLD guideline recommends the use of US alone for the surveillance of HCC.

Despite these limitations of serum AFP, a recent study that used the Surveillance Epidemiology and End Results-Medicare database reported that the combination of serum AFP and US, followed by serum AFP alone, is most commonly used for HCC surveillance in the United States. The reality in practice is that AFP is widely available and inexpensive. Proponents point out that given the poor adherence to US-based surveillance, even a suboptimal test might still be better than complete lack of any surveillance. This might be more relevant in settings with limited health care access and resources, such as in Alaskan natives with chronic HBV infection in whom serum AFP was found to be beneficial.

How Often Should Tests be Repeated?
Most guidelines recommend surveillance to be conducted every 6 months. The principle for determining the interval for surveillance is that it should not be based on the anticipated incidence of HCC, but on the rate of tumor growth. Even if the incidence is high, if all of the tumors grow slowly, infrequent surveillance would be sufficient. On the other hand, if many tumors grow fast, frequent surveillance is needed for any hope of early diagnosis to exist. Thus, the absolute risk (incidence) of HCC determines whether surveillance should be performed, whereas the rate of tumor growth dictates the interval for surveillance.

It is currently uncertain whether surveillance every 6 months is superior to every 12 months in decreasing HCC mortality and improving patient survival ( Table 3 ).

Table 3. Comparison Between 6-Month and 12-Month Surveillance

Study	Study design	Patient population	Definition of surveillance	Main outcome	Result
Santi et al, 2010	Cohort	Italian cirrhotic patients with HCC, n = 595	Abdominal US ± AFP	Overall survival	5-y survival: 57% vs 21% in semiannual surveillance and annual surveillance, respectively (P <.0001)
Santagostino et al, 2003	Cohort	Italian hemophiliac with HCV, n = 559	Abdominal US ± AFP	HCC-related death	At 6-follow-up: 1/210 (0.5%vs 2/349 (0.6%died of HCC in semiannual surveillance and annual surveillance, respectively (P >.05)
Trevisani et al, 2002	Cohort	Italian cirrhotic patients with HCC, n = 821	Abdominal US ± AFP	Overall survival	Median survival: 36 vs 34 mo in semiannual surveillance and annual surveillance, respectively (P <.05)

Several retrospective studies showed that there is no difference in survival between 6-month and 12-month surveillance intervals. However, the most recent study showed that surveillance every 6 months improved patient survival compared with that every 12 months. In short, to date, there is no robust evidence from a randomized controlled trial to determine the optimal surveillance interval. Most hepatologists tend to err on being more conservative with frequent (ie, semiannual) surveillance.

Published Guidelines and Summary

Most practice guidelines suggest that patients at risk of HCC undergo surveillance. Published guidelines for HCC surveillance are summarized in - Table 4

Table 4. HCC Surveillance in Published Guidelines

	AASLD	EASL	APASL	NCI
Target subjects	All patients with cirrhosis, certain individuals with HBV infection	All patients with cirrhosis	High-risk population: cirrhotic patients with HBV and HCV	No recommendation on HCC surveillance
Modality	US	US	US and AFP
Interval	6 mo	6 mo	6 mo

APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; NCI, National Cancer Institute.

Although not ideal, US is the preferred modality for surveillance. The AASLD guideline recommends patients with cirrhosis from any cause to undergo HCC surveillance by using abdominal US at 6-month intervals. AFP is inadequate as a surveillance test. The European Association for the Study of the Liver recommends that the ideal target population is Child–Pugh class A cirrhotic patients without severe comorbid conditions. Patients not suitable for curative therapy might be excluded from surveillance. The Asian Pacific Association for the Study of the Liver specifies cirrhotic patients with HBV and HCV as candidates for surveillance in whom the combination of US and AFP is to be used every 6 months. In contrast to these liver societies, the National Cancer Institute calls for additional data before HCC surveillance is routinely recommended, even in high-risk patients. They note that data to date suffer from several methodological flaws and limited generalizability and thus have not proved that surveillance decreases HCC mortality.

Against the backdrop of these recommendations, in the particular case of our patient, we have little doubt that he benefited from the surveillance because it led to detection of an early HCC lesion, followed by successful liver transplantation. He was "fortunate" to have experienced hepatic decompensation that drew close medical attention to his liver disease, which resulted in institution of surveillance for HCC. Because he had not been followed for his HBV, he could very well have presented with advanced HCC, if his liver disease had remained compensated. Although our patient would have been a candidate for surveillance according to most guidelines, he belonged in the majority of patients in whom surveillance is not practiced as a result of patient preference, lack of socioeconomic or health insurance support, or poor awareness of or adherence to guideline recommendations by the physician.

Among human malignancies, HCC is unique in that cirrhosis or advanced fibrosis is essentially a prerequisite condition, which makes it relatively straightforward to identify subjects who should be subjected to surveillance. However, it is obvious that not all patients with cirrhosis develop HCC, and the best informed surveillance strategy should include accurate risk stratification. As of today, we lack detailed knowledge for individualized risk stratification, which prevents formulation of an optimal surveillance program. Clearly, more high-quality data are needed to improve the outcome of patients with HCC, whose incidence is rising in the United States and globally. In the meantime, the clinician is encouraged by cases like ours that careful adherence to surveillance in at-risk individuals provides opportunities to make a meaningful difference in the patient's outcome.

References

Bruix J, Aasld SM. AASLD practice guideline, management of hepatocellular carcinoma: an update. Available at: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf. Accessed August 02, 2010.
Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236.
Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL Conference—European Association for the Study of the Liver. J Hepatol 2001;35:421–430.
Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417–422.
Davila JA, Morgan RO, Richardson PA, et al. Use of surveillance for hepatocellular carcinoma among patients with cirrhosis in the United States. Hepatology 2010;52:132–141.
Marrero JA, Feng Z, Wang Y, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 2009;137:110–118.
Lok AS, Sterling RK, Everhart JE, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology 2010;138:493–502.
Santi V, Trevisani F, Gramenzi A, et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J Hepatol 2010;53:291–297.
Chen JG, Parkin DM, Chen QG, et al. Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen 2003;10:204–209.
Davila JA, Henderson L, Kramer JR, et al. Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States. Ann Intern Med 2011;154:85–93.

Diabetes-Biochip measures glucose in saliva, not blood

2012-01-21T10:01:00.000-05:00

Engineers at Brown University have designed a biological device that can measure glucose concentrations in human saliva. The technique could eliminate the need for diabetics to draw blood to check their glucose levels. The biochip uses plasmonic interferometers and could be used to measure a range of biological and environmental substances. Results are published in Nano Letters.

PROVIDENCE, R.I. [Brown University] — For the 26 million Americans with diabetes, drawing blood is the most prevalent way to check glucose levels. It is invasive and at least minimally painful. Researchers at Brown University are working on a new sensor that can check blood sugar levels by measuring glucose concentrations in saliva instead.

The technique takes advantage of a convergence of nanotechnology and surface plasmonics, which explores the interaction of electrons and photons (light). The engineers at Brown etched thousands of plasmonic interferometers onto a fingernail-size biochip and measured the concentration of glucose molecules in water on the chip. Their results showed that the specially designed biochip could detect glucose levels similar to the levels found in human saliva. Glucose in human saliva is typically about 100 times less concentrated than in the blood.

“This is proof of concept that plasmonic interferometers can be used to detect molecules in low concentrations, using a footprint that is ten times smaller than a human hair,” said Domenico Pacifici, assistant professor of engineering and lead author of the paper published in Nano Letters, a journal of the American Chemical Society.

The technique can be used to detect other chemicals or substances, from anthrax to biological compounds, Pacifici said, “and to detect them all at once, in parallel, using the same chip.”
To create the sensor, the researchers carved a slit about 100 nanometers wide and etched two 200 nanometer-wide grooves on either side of the slit. The slit captures incoming photons and confines them. The grooves, meanwhile, scatter the incoming photons, which interact with the free electrons bounding around on the sensor’s metal surface. Those free electron-photon interactions create a surface plasmon polariton, a special wave with a wavelength that is narrower than a photon in free space. These surface plasmon waves move along the sensor’s surface until they encounter the photons in the slit, much like two ocean waves coming from different directions and colliding with each other. This “interference” between the two waves determines maxima and minima in the light intensity transmitted through the slit. The presence of an analyte (the chemical being measured) on the sensor surface generates a change in the relative phase difference between the two surface plasmon waves, which in turns causes a change in light intensity, measured by the researchers in real time.

“The slit is acting as a mixer for the three beams — the incident light and the surface plasmon waves,” Pacifici said.

The engineers learned they could vary the phase shift for an interferometer by changing the distance between the grooves and the slit, meaning they could tune the interference generated by the waves. The researchers could tune the thousands of interferometers to establish baselines, which could then be used to accurately measure concentrations of glucose in water as low as 0.36 milligrams per deciliter.

“It could be possible to use these biochips to carry out the screening of multiple biomarkers for individual patients, all at once and in parallel, with unprecedented sensitivity,” Pacifici said.
The engineers next plan to build sensors tailored for glucose and for other substances to further test the devices. “The proposed approach will enable very high throughput detection of environmentally and biologically relevant analytes in an extremely compact design. We can do it with a sensitivity that rivals modern technologies,” Pacifici said.

Tayhas Palmore, professor of engineering, is a contributing author on the paper. Graduate students Jing Feng (engineering) and Vince Siu (biology), who designed the microfluidic channels and carried out the experiments, are listed as the first two authors on the paper. Other authors include Brown engineering graduate student Steve Rhieu and undergraduates Vihang Mehta, Alec Roelke.
The National Science Foundation and Brown (through a Richard B. Salomon Faculty Research Award) funded the research.

Editors: Brown University has a fiber link television studio available for domestic and international live and taped interviews, and maintains an ISDN line for radio interviews. For more information, call (401) 863-2476.

Source : Brown University

Gender Differences in Liver Cancer Risk Explained by Small Changes in Genome, Penn Study Finds

2012-01-21T09:45:00.001-05:00

The Foxa factors control liver cancer risk. When mice are exposed to a liver carcinogen, normally male mice develop many tumors, while female mice are protected (left part of the figure). However, in mice lacking the Foxa genes, the situation is reversed (right part of the figure). Thus, the Foxa genes are essential determinants of the sexual dimorphism in liver cancer risk.
Credit: Klaus Kaestner, PhD, Perelman School of Medicine, University of Pennsylvania, Cell Press

Gender Differences in Liver Cancer Risk Explained by Small Changes in Genome, Penn Study Finds

PHILADELPHIA - Men are four times more likely to develop liver cancer compared to women, a difference attributed to the sex hormones androgen and estrogen. Although this gender difference has been known for a long time, the molecular mechanisms by which estrogens prevent -- and androgens promote -- liver cancer remain unclear.

Now, new research, published in Cell this week from the lab of Klaus Kaestner, PhD, professor of Genetics in the Perelman School of Medicine at the University of Pennsylvania, has found that the difference depends on which proteins the sex hormones bind next to. Specifically a group of transcriptional regulatory proteins called Foxa 1 and 2.

Normally, when mice are given a liver carcinogen, male mice develop many tumors while females get very few. Strikingly, this gender-related incidence of liver cancer was completely reversed in mice genetically engineered by the team to lack the Foxa genes after the team induced cancer. Using complex genomic analyses, the researchers could show that the actions of both estrogens and androgens in the liver are Foxa dependent, explaining the reversal in cancer risk.

But how does this translate to human liver cancer when there are 5,000 places in the human genome where Foxa factors can bind? The team looked for genetic markers called SNPs that intersect with Foxa protein binding. A SNP is a DNA sequence variation occurring when a single nucleotide, or DNA building block, differs between members of a biological species or paired chromosomes in an individual. Knowing that in women the estrogen receptor protects against liver cancer, they looked for SNP markers within Foxa binding sites in tissue samples from women with and without liver cancer.

Strikingly, women with liver cancer frequently had SNPs within specific Foxa binding sites. The researchers then showed that the mutated SNP acts not only to abolish binding of the Foxa proteins, but also of the estrogen receptor to its target sites nearby. This impairment of estrogen receptor binding is thought to result in loss of the protective effect of estrogens, and increased liver cancer risk. Future research will have to determine if the same holds true in reverse in men. In addition, if the human data are validated in larger cohorts of patients, this research might lead to tests for predicting the genetic risk of liver cancer.

This study was funded through the National Institute of Diabetes and Digestive and Kidney Diseases (P01 DK049210).

Hepatitis C Friday News Ticker: How far is noninvasive assessment of liver fibrosis from replacing liver biopsy in hepatitis C?

2012-01-20T13:03:00.015-05:00

Bowl & Newspaper Artist Marie Fox

New On The Blog

How far is noninvasive assessment of liver fibrosis from replacing liver biopsy in hepatitis C?

New developments in HCV therapy

Boceprevir and telaprevir for hepatitis C: safety management in clinical practice

Dermatological side effects of hepatitis C and its treatment: Patient management in the era of direct-acting antivirals

Hepatitis C-From Clinical Guidelines to Clinical Practice

Steatosis and insulin resistance in response to treatment of chronic hepatitis C

Today's Updates

Clinical Trials

Study of DEB025/Alisporivir Plus Pegylated Interferon alfa2a and Ribavirin and Boceprevir Plus Pegylated Interferon alfa2a and Ribavirin in African American Chronic Hepatitis C Genotype 1 Patients That Have Never Received Treatment for Their Hepatitis C

This study will assess the safety and efficacy of alisporivir plus pegylated interferon alfa2a and Ribavirin as well as boceprevir plus pegylated interferon alfa2a and Ribavirin in African American chronic hepatitis C genotype 1 patients that have never received treatment for their hepatitis C.

Alisporivir With pegIFN/RBV in Protease Inhibitor (PI) Treatment Failure Patients With Chronic Hepatitis C: Open Label -

The purpose of this study is to evaluate the overall efficacy, and safety profile, of triple combination therapy of DEB025/pegIFN/RBV in chronic hepatitis C patients who failed prior treatment with PI.

Clinical Trials
To learn more about Hepatitis C virus clinical trials or to find out if a study is enrolling patients in your area, please click here

Treatment of Hepatitis C

Posted by Sara Fazio • January 19th, 2012

In a new study of 21 patients with hepatitis C virus genotype 1 infection who had had no response to prior treatment, sustained virologic responses were achieved in 4 of 11 who were treated with two antiviral agents alone and in 9 of 10 who were treated with the antiviral agents plus peginterferon and ribavirin.

Approximately 180 million people worldwide are infected with hepatitis C virus (HCV), including 4.1 million in the United States. HCV infection is the most common cause of chronic liver disease in the United States and a leading cause of cirrhosis and hepatocellular carcinoma globally. HCV is classified into six major genotypes; genotype 1 is predominant in the United States and is the most difficult to treat.

Clinical Pearls

• What is the conventional treatment and associated outcomes for Hepatitis C genotype 1 infection?

Treatment of HCV genotype 1 infection with peginterferon alfa and ribavirin for 48 weeks results in sustained virologic response (undetectable HCV RNA 24 weeks after the end of therapy) in 40 to 50% of patients who have not received previous treatment. Patients are considered as not having had a response if they do not have a reduction in HCV RNA levels by at least 2 log10 IU per milliliter after a minimum of 12 weeks of treatment with peginterferon and ribavirin. Retreatment with triple therapy — a protease inhibitor, peginterferon, and ribavirin — yields rates of sustained virologic response of only 14 to 33%.

• In patients with HCV genotype 1 infection who have not had a response to prior therapy, what new regimens may be effective?

In this week’s Journal, a preliminary study of patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents alone [the NS5A replication complex inhibitor BMS-790052 (60 mg once daily) and the NS3 protease inhibitor BMS-650032 (600 mg twice daily)]. In addition, a high rate of sustained virologic response at 24 weeks was achieved when the two direct-acting antiviral agents were combined with peginterferon and ribavirin.

Table 2. Virologic Response during and after Treatment.

Morning Report Questions

Q: What medication-related adverse effects were most commonly reported in patients receiving treatment in this study?

A: All the patients completed at least 24 weeks of therapy. The most common adverse events were diarrhea, fatigue, headache, and nausea, and were reported in both groups. Most adverse events were mild to moderate. There were no deaths, serious adverse events, or discontinuations due to adverse events during the analysis period.

Q: What was the pattern of resistance seen in patients treated only with direct-acting antiviral agents?

A: A high frequency of resistance to two classes of drugs was seen in patients with HCV genotype 1a infection who were treated with direct-acting antiviral agents alone. Although there were only two patients with HCV genotype 1b infection in this group, the observation that both of the patients had a sustained virologic response after treatment with two direct-acting antiviral agents alone may reflect a higher resistance barrier for this combination of drugs in patients with HCV genotype 1b infection than in patients with HCV genotype 1a infection. In contrast to the former group, no viral breakthrough occurred in patients in the group receiving quadruple therapy

Source- NEJM Blog
Hope for Hepatitis C
Posted by John Staples • January 18th, 2012

Imagine, for a moment, that you recently received a brand new Time-O-Matic Time Machine as a gift. How far back would you have to set the dial to see that meaningful progress has been made in the treatment of hepatitis C?

First, let’s say you set the dial to January 2011 and –- Puff-kachunk! — you’re there. Standard treatment for chronic hepatitis C genotype 1 infection consisted of 48 weeks of pegylated interferon-alpha and ribavirin, an approach more likely to produce adverse effects than clearance of the virus.

Your next trip (Zing-kersplat!) takes you to May 2011. The oral serine protease inhibitors boceprevir and telaprevir have just become available for treatment of chronic HCV genotype 1 infection. When added to pegylated interferon and ribavirin, these direct-acting antivirals dramatically improve the rate of sustained virologic response (SVR). But many patients still do not respond to treatment, and medication intolerance remains an issue. You step into your Time-O-Matic and return to January 2012 feeling somewhat discouraged.

Fortunately, this week’s NEJM might raise your spirits. In it, Dr. Anna S. Lok (University of Michigan, Ann Arbor, MI) and colleagues report on an open-label, phase 2a study that used a combination of two direct-acting antivirals to treat chronic HCV genotype 1 infection.

Twenty-one ‘null responders’ (patients who failed to achieve ≥2log10 decline in HCV RNA after ≥12 weeks of peginterferon and ribavirin) were randomized to 24 weeks of treatment in one of two treatment arms:
• Group A received BMS-790052 (an oral, first-in-class, NS5A replication complex inhibitor) and BMS-650032 (an oral NS3 protease inhibitor);

• Group B received BMS-790052 and BMS-650032 plus peginterferon alfa-2a and ribavirin.
Four of eleven (36%) patients in Group A and ten of ten (100%) of patients in Group B achieved an undetectable HCV RNA twelve weeks after completion of study treatment (SVR12, the primary end point). There were no deaths, serious adverse events, or discontinuations. The most common mild-to-moderate adverse effects were diarrhea, fatigue, headache, and nausea.

These results are exciting. The high rate of SVR12 achieved in Group B suggests that more effective treatment regimens may soon be available for null responders. But for editorialist Dr Raymond T. Chung (Massachusetts General Hospital, Boston, MA), it’s the Group A proof-of-concept results that really put HCV therapy “on the threshold of a treatment revolution.” The 36% of Group A patients achieving SVR12 demonstrate that combination direct-acting antivirals with non-overlapping resistance profiles can achieve HCV clearance without the use of interferon. If interferon and its adverse effects can be avoided, there is hope that treatment might be offered and accepted by a much greater number of patients.

“Current HCV treatment regimens are far from perfect,“ says primary care physician and NEJM deputy editor Dr. Mary Beth Hamel, “so it’s satisfying to see encouraging results from this kind of early-phase trial. It will be exciting to see what the future brings.”
Curious? Go ahead. Step into the Time-O-Matic and set the dial to see how far HCV therapy has progressed by January 2017. The rest of us, however, will just have to wait.

Medscape--

Immunosuppression, Liver Injury and Post-transplant HCV
Even after a liver transplant, patients can often experience a recurrence of hepatitis C. How should it be treated in this setting?
Journal of Viral Hepatitis, January 2012

FYI

Fake Pharmaceutical Websites Promoted through LinkedIn Spam

Spam mails apparently circulating across LinkedIn the business-related website for social networking inform recipients of somebody who has written to them, but actually conceal a sinister scheme for promoting a pharmaceutical website, which sells shady or illegitimate items, published softpedia.com dated January 12, 2012.

The fake electronic mail tells the recipient that [Name] has written one message for him. By following the web-link embedded underneath the message, the recipient can read it. The web-link given asks to view or answer the message. Meanwhile, to avoid getting e-mail notifications the user requires adjusting its configurations, the e-mail concludes.

But, when the web-link is clicked, the user is led onto one traditional pharmaceutical site that offers wonderful opportunities for buying medical items, a few illicit alternatively possible for acquiring solely through physician-prescribed certificates.

Essentially pharmacy scams aren't infrequent; however, they appear as highly successful, else their perpetrators would've deserted them in favor of something more effective.

A number of the fake Internet sites do not get displayed within search engine returns; therefore, cyber-crooks devise additional methods for advertising them. Hence the use of spam mails here as the more efficient tactic.

Nevertheless, according to security experts, it's quite imprudent as also potentially harmful for purchasing drugs or medicines from any such fake pharmaceutical website.

For, even suppose an ordered drug actually reaches the spam mail receiver, he has no way about verifying its authenticity as it could also be a harmful substitute.

Further, bogus pharmaceutical websites frequently have un-protected pages for manipulating transactions based on credit cards that can surely lead to theft of those cards' particulars. Besides, if anyone is suspected of intentionally using such spurious spam tricks, that person shouldn't be believed so far as giving him personal info or credit card particulars are concerned. Lastly, these fake online medicinal stores occasionally host malware too.

Additionally, the spam mails in question utilize HTML for masking the true online sites their implanted web-links exhibit. However, by brushing the mouse over such web-links the underlying URLs will get exhibited, thus letting users to conveniently know whether or not the said web-links are camouflaged.

SPAMfighter News - 20-01-2012

For Your Reading Pleasure

Grand Rounds

Grand Rounds is a weekly summary of the best health blog posts on the Internet. Each week a different blogger takes turns hosting Grand Rounds, and summarizing the best submissions for the week.

Hosted this week by Codeblog

Grand Rounds: Volume 8, No. 17

How’d we get to Volume 8 already?! I think hosting this Grand Rounds finally ties me up with GruntDoc, who has hosted 7 times. Grand Rounds is the weekly round-up of blog posts by medical bloggers.

Whereas in the past the host would post nearly every link they received, it appears that we are now moving towards more curated content. I said in my previous post that I wasn’t going to institute a theme, but I was definitely more drawn to the personal-story type posts. Thanks to everyone that submitted!

I shamelessly grabbed this next post from Twitter – Jordan, who blogs at In My Humble Opinion, wrote a touching post about mothers. In Praise of Mothers wasn’t quite the post that I was expecting (and apparently the first commenter wasn’t expecting it either); it was even better. And I’ve tried several times here to explain why, but I can’t.

And I shamelessly grabbed this one from Google Reader – Dr. V at 33 Charts shares his answer to the question, “How Often Should A Physician Blog?“ You could easily take the word “physician” out and apply the answer to any blogger. I have been blogging for over 9 years now. My posting frequency in the very beginning was about once a week. Now it’s more like once a month. He has some great insights that I found myself completely agreeing with.

Continue Reading Here.....

Are Religious People Better Adjusted Psychologically?

Psychological research has found that religious people feel great about themselves, with a tendency toward higher social self-esteem and better psychological adjustment than non-believers. But a new study published in Psychological Science, a journal of the Association for Psychological Science, finds that this is only true in countries that put a high value on religion.

The researchers got their data from eDarling, a European dating site that is affiliated with eHarmony. Like eHarmony, eDarling uses a long questionnaire to match clients with potential dates. It includes a question about how important your personal religious beliefs are and questions that get at social self-esteem and how psychologically well-adjusted people are. Jochen Gebauer of the Humboldt-Universität zu Berlin, Constantine Sedikides of the University of Southampton, and Wiebke Neberich of Affinitas GmbH in Berlin, the company behind eDarling, used 187,957 people’s answers to do their analyses.

As in other studies, the researchers found that more religious people had higher social self-esteem and where psychologically better adjusted. But they suspected that the reason for this was that religious people are better in living up to their societal values in religious societies, which in turn should lead to higher social self-esteem and better psychological adjustment. The people in the study lived in 11 different European countries, ranging from Sweden, the least religious country on the planet, to devoutly Catholic Poland. They used people’s answers to figure out how religious the different countries were and then compared the countries.

On average, believers only got the psychological benefits of being religious if they lived in a country that values religiosity. In countries where most people aren’t religious, religious people didn’t have higher self-esteem. “We think you only pat yourself on the back for being religious if you live in a social system that values religiosity,” Gebauer says. So a very religious person might have high social self esteem in religious Poland, but not in non-religious Sweden.

In this study, the researchers made comparisons between different countries, but another study found a similar effect within one country, between students at religious and non-religious universities. “The same might be true when you compare different states in the U.S. or different cities,” Gebauer says. “Probably you could mimic the same result in Germany, if you compare Bavaria where many people are religious and Berlin where very few people are religious.”

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For more information about this study, please contact: Jochen E. Gebauer at mail@JochenGebauer.info.

The APS journal Psychological Science is the highest ranked empirical journal in psychology. For a copy of the article "Religiosity, Social Self-Esteem, and Psychological Adjustment: On the Cross- Cultural Specificity of the Psychological Benefits of Religiosity" and access to other Psychological Science research findings, please contact Divya Menon at 202-293-9300 or dmenon@psychologicalscience.org.

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Lee started sleepwalking at the age of four. In this video he describes his sleepwalking episodes, including doing artwork despite having no interest in art, plus the physical side effects when he wakes up.

Healthy You

Sweet News About Chocolate

Several recent large-scale research reviews have provided the best evidence yet that chocolate, derived from the seeds of the cocoa tree (Theobroma cacao), is good for your heart.

In one review, in the British journal BMJ in August, researchers analyzed data from seven observational studies, which included more than 100,000 people. Those who ate the most chocolate had a 37 percent lower risk of heart disease, compared to those eating the least, after controlling for weight, physical activity, education and other dietary factors that could influence the results. They were also 29 percent less likely to have a stroke.

In a second review, in the European Journal of Clinical Nutrition in August, Harvard researchers looked at 10 clinical studies from the last decade, with a total of 320 people. Consuming dark chocolate or cocoa products for 2 to 12 weeks modestly lowered cholesterol. And another review of clinical trials, in BMC Medicine, found that cocoa-rich products had a small blood-pressure-lowering effect in people with hypertension and prehypertension.

Behind the benefits

Chocolate’s health benefits are largely attributed to polyphenol compounds called flavonoids—the same family of substances that are in tea, red wine, grape juice and other plant foods—which have antioxidant, anti-inflammatory and anti-clotting properties. In particular, flavonoids increase production of nitric oxide, which helps relax and dilate blood vessels, and this may help lower blood pressure and have other cardiovascular effects. Cocoa flavonoids may also inhibit cholesterol absorption as well as oxidation of LDL (“bad”) cholesterol, making it less harmful.

But before you reach for a chocolate bar, there are some caveats. First, not all studies have had positive results. And many—including all of those in the recent BMJ analysis—are observational studies, meaning that they don’t prove cause and effect (that chocolate, rather than something else about chocolate eaters, is responsible for the benefits seen).

Moreover, no one knows what type or amount of chocolate is optimal. Studies have used different formulations (with widely varying flavonoid levels) and intakes (from tiny daily amounts to impractically large quantities); some have not distinguished between milk and dark chocolate. Chocolate may affect people differently, too, depending on a variety of factors.

Keep in mind also that the chocolate confections that Americans love most are loaded with sugar, fat and calories (235 in a typical 1.5-ounce bar). Many have caramel, nougat and other unhealthy fillings and ingredients. Eat too much of any kind of chocolate and you can gain weight, which would likely cancel out the heart benefits.

Chocolate morsels

• Not all chocolate is created equal. Processing of cocoa beans into commercial chocolate candy greatly reduces flavonoid levels. In fact, a main manufacturing objective is to remove these compounds because they have a bitter taste. Some companies use—or claim to use—methods that better preserve the heart-healthy compounds.
• Dark chocolate generally has more flavonoids than milk chocolate, but it’s hard to know how much a particular bar has. The percent cocoa (or cacao) listed on a label is not a reliable indicator of flavonoid content, and a bar that is, say, 70 percent cocoa from one manufacturer is not necessarily better than one that is 60 percent from another manufacturer. In addition to processing, the type of cocoa beans used and the manufacturer’s “recipe” also play a significant role in determining final flavonoid content. At the very least, the darker the chocolate, as indicated by a higher percent of cocoa solids, the less room there is for sugar.

• Though chocolate is high in saturated fat (from cocoa butter), this is mostly stearic acid, which has a neutral effect on blood cholesterol. On the other hand, milk chocolate has added fats that are not good for your heart, as well as more added sugar than dark chocolate. Milk chocolate has twice as much sugar as the darkest chocolate.
• Cocoa powder is highest in cocoa solids and has the most flavonoids—though “Dutch” (or alkali) processing destroys them. If you use cocoa powder, look for unsweetened natural versions. Next highest in flavonoids is unsweetened baking chocolate.
• Chocolate contains small amounts of caffeine—about 20 milligrams in an ounce of dark chocolate, and 6 milligrams in milk chocolate (compared to about 100 to 150 milligrams in a cup of coffee).

• It’s not clear whether adding milk to cocoa interferes with the absorption of flavonoids. A 2009 study in the American Journal of Clinical Nutrition, for instance, found reduced flavonoid absorption when people drank cocoa made with milk compared to cocoa made with water. Still, other studies have found no effect of milk on cocoa flavonoids and no difference in blood antioxidant levels. It’s possible that milk interferes with some, but not all, cocoa flavonoids. Some studies that found no milk interactions used cocoa with much higher flavonoid levels than those in commercial cocoa, which could make any flavonoid-reducing effect of the milk less apparent.

Chocoholic advice

Chocolate may provide some heart-health benefits, especially if you eat it in place of other snacks or desserts that are high in calories and saturated fat. Choose the darkest chocolate that you like. Cocoa beans or some variation, such as cacao, chocolate liquor or cocoa mass, should be the first ingredient, not sugar. But even if it’s rich in flavonoids, think of chocolate as a treat, not a health food, because of its hefty calories. Fruits and vegetables are a better source of flavonoids on a daily basis—they have fewer calories and an abundance of vitamins and minerals, along with other healthy plant compounds and fiber.

UC Berkeley Wellness Letter, February 2012

In Case You Missed It

BMS-650032 (Asunaprevir)

BMS-790052 (Daclatasvir)

Four-Drug Therapy Wiped Out Hepatitis C Virus in Most Cases

By Gene Emery

NEW YORK (Reuters Health) Jan 18 - Combining the experimental oral drugs asunaprevir and daclatasvir with the established treatment of peginterferon alfa-2a and ribavirin eliminated all traces of hepatitis C virus (HCV) in the blood of every volunteer, even after ribavirin-peginterferon alfa-2a treatment had already failed, in small phase II study released online today by the New England

Journal of Medicine.

The ten patients treated with all four drugs all had undetectable viral levels 12 weeks after treatment stopped, and nine still had undetectable levels after 24 and 48 weeks.

Another 11 patients received only asunaprevir and daclatasvir, and four of them had a sustained virologic response at 12 and 24 weeks after treatment.

"This is a watershed moment in the annals of HCV therapy because it shows that a sustained virologic response can be achieved without interferon," Dr. Raymond T. Chung of Massachusetts General Hospital wrote in an editorial in the January 19 issue.

Dr. Anna Lok of the University of Michigan and chief author of the study told Reuters Health that the cure rate for the peginterferon/ribavirin regime is low. "It's only 36%. But considering that these are difficult patients to treat, 36% is not too bad," she said.

All 21 patients in the current study had genotype 1 HCV, the most common in the U.S., and all had failed to respond to peginterferon plus ribavirin (i.e., they had not had at least a 2 log10 decline in HCV RNA after at least 12 weeks of treatment).

The response was far better when the four drugs were used. By the end of treatment, at week 24, all 10 patients in that group had undetectable levels of HVC RNA. Forty-eight weeks after the end of therapy, only one had any trace of the virus, and the amount was too small to quantify, according to the researchers.

About 4.1 million people in the United States and 180 million worldwide are infected by hepatitis C, with its associated risk of cirrhosis and liver cancer.

In the randomized phase II study, where patients knew what treatment they were getting, everyone received 600 mg of asunaprevir twice daily and 60 mg of daclatasvir once daily for 24 weeks. Both are made by Bristol-Myers Squibb, which paid for the trial.

Ten of the 21 also got 180 mcg of Pegasys brand peginterferon alfa-2a each week and Copegus brand ribavirin, where the daily dose was 1,000 mg for those weighing less than 75kg and 1,200 mg for those weighing more. Both are Roche products.

After 24 weeks of therapy, all 10 patients getting the four-drug regimen and five of the 11 patients receiving the non-interferon regimen had no trace of virus in their blood.

The six patients in the non-interferon group who had viral breakthrough during the treatment period all had HCV genotype 1a. Another patient in that group had viral recurrence after treatment ended.

By 24 weeks after treatment ended, the virus had returned in one of the 10 getting all four drugs. But that one person was retested 13 days after recurrence and levels of HCV RNA were undetectable, a phenomenon that was seen in other patients, said Dr. Lok. "Because it was not persistent, we believe 100% actually maintained virus clearance all the way to week 48."

"To be able to get to 90% or 100% is very remarkable," she said. "On the other hand, we all know that a lot of patients can't handle interferon and ribavirin because of the side effects. What we hear from the patients is that they hate interferon. They prefer not to get treatment. Everyone is looking for when can we have an interferon-free regimen."

In the new study, the side effects were similar in the two experimental groups. The three most common were diarrhea, fatigue and headache, reported by 45% to 73% of patients. Six patients had transient elevations of alanine aminotransferase to more than 3 times the upper limit of normal. Side effect rates were complicated by the fact six of the 11 volunteers randomized to receive only daclatasvir and asunaprevir received rescue therapy with interferon and ribavirin after a viral breakthrough.

None of the 21 dropped out because of the side effects.

Dr. Lok said 48 weeks of peginterferon and ribavirin usually costs about $40,000. Adding a protease inhibitor as a third drug costs another $50,000, and new biologicals often go for a comparable amount.

The eventual price of the experimental drugs is not known, assuming they are approved.

Thus, a four-drug regimen would add to the cost, Dr. Lok said, but "if this pans out, it's only 24 weeks of treatment. And if you get a cure once and for all, you don't have to worry about managing the complications of cirrhosis, liver transplant, liver cancer down the road."

SOURCE: http://bit.ly/A5JnBy

N Engl J Med 2012; 366:216-224.

A Phase 3 Study in Combination With BMS-790052 and BMS-650032 in Japanese Hepatitis C Virus (HCV) Patients

This study is not yet open for participant recruitment.

Verified on January 2012 by Bristol-Myers Squibb

First Received on December 2, 2011. Last Updated on January 3, 2012 History of Changes

Hepatitis C-From Clinical Guidelines to Clinical Practice

2012-01-20T12:51:00.000-05:00

From Clinical Guidelines to Clinical Practice
Is Expanding Access to Treatment Cost-effective?

E. Degasperi,
A. Aghemo

Article first published online: 10 JAN 2012

DOI: 10.1111/j.1365-2893.2011.01517.x

Journal of Viral Hepatitis
Special Issue: How to Optimize Treatment of Hepatitis C
Volume 19, Issue Supplement s1, pages 3–6, January 2012

Download PDF

Summary.
Hepatitis C virus (HCV) infection represents a major health problem, being a leading cause of cirrhosis and liver transplantation worldwide. Viral eradication achieved by Peginterferon and Ribavirin therapy is the only therapeutic option that can prevent fibrosis progression in chronic hepatitis and liver-related complications in cirrhotic patients. Unfortunately, the occurrence of potentially serious side effects argues against universal treatment of HCV-infected patients. Indeed most scientific societies suggest that eligibility for therapy be based on baseline factors, the so called clinical drivers for treatment eligibility. Current international guidelines recommend focusing on the severity of liver disease, likelihood of treatment response in terms of chances of sustained virological response (SVR) to antiviral therapy and risk of serious adverse events when making treatment decisions. However, evidence exists that treatment may benefit also patients with mild fibrosis and that baseline predictions of a SVR are inaccurate because of the key role of HCV kinetics while on-therapy. An extended treatment programme is further supported by the fact that an increase in the number of patients treated would ultimately result in a long-term reduction of liver-related deaths.

Abbreviations:
ESRDend-stage renal disease
HCChepatocellular carcinoma
HCVhepatitis C virus
PegIFNPegInterferon
SAEserious adverse events
SVRsustained virological response

Hepatitis C virus (HCV) infection is a major health problem that affects over 170 million people worldwide and represents a leading cause of cirrhosis and liver transplantation. The goal of antiviral therapy is to achieve viral eradication to prevent fibrosis progression in chronic hepatitis [1] and liver-related complications in cirrhotic patients [2]. While a sustained virological response (SVR) can positively impact on the natural history of liver disease, antiviral therapy with PegInterferon (PegIFN) and Ribavirin (Rbv) is associated with many side effects, which in rare cases can be serious and ultimately interfere with treatment outcome because of reduced adherence to therapy. For these reasons, most scientific societies do not currently recommend a broad treatment approach, advocating instead a patient selection process where a multitude of baseline factors are considered as clinical drivers.

From Clinical Guidelines to Clinical Practice

Current international guidelines advise treating those patients who could benefit greatly from therapy, based on liver disease severity and likelihood of treatment response, while minimizing serious adverse events. While this approach seems reasonable from a theoretical point of view, its application in everyday clinical practice is problematic and controversial.

Concerning liver disease severity, the AASLD recommendations suggest that, if a liver biopsy is available, treatment should be started in patients with compensated cirrhosis or bridging fibrosis (Metavir score F > 2) [3].

In fact the outcome of compensated HCV cirrhosis is influenced by complications such as hepatocellular carcinoma (HCC), ascites, variceal bleeding, portosystemic encephalopathy and jaundice, which have an annual incidence estimated between 0.5% and 3.5%, and which eventually lead to liver transplantation or death [4]. The beneficial impact of antiviral therapy is well established: SVR to PegIFN and Rbv improves survival in patients with advanced fibrosis or cirrhosis by reducing liver-related complications and liver-related death [5]. However, although treating advanced liver disease is clearly indicated, it is difficult to define a cut-off for mild-moderate disease to identify the best candidates for treatment. Liver biopsy, the current gold standard for assessing fibrosis stage, may underscore fibrosis by one point in at least 30% of patients because of sampling problems or heterogeneous liver architecture [6]; moreover, fibrosis progression does not follow a linear pattern during the natural history of chronic hepatitis C infection. Some authors have hypothesized that patients can be categorized as slow, intermediate, or rapid progressors, based on a time to cirrhosis of <20, 20–50, and >50 years [7]. Others have elaborated models where fibrosis progression is a linear process with an abrupt acceleration during the natural course of liver disease [8]. A number of factors have been identified as accelerators of fibrosis progression, including male sex, co-infections (e.g., HBV, HIV), comorbidities, and even genetic factors; however, prediction of fibrosis progression at the individual level is not currently possible.

Moreover, the many extrahepatic manifestations of HCV infection have led some to consider it a systemic disease [9]. Indeed a pathogenic role for HCV has been established in mixed cryoglobulinemia, a disease that can lead to impaired kidney function and polyneuropathy. Moreover, higher prevalences of B-cell non-Hodgkin lymphoma, monoclonal gammopathies and dermatological diseases (lichen planus) have been observed in HCV patients. While anecdotal reports of other associations, for example, with autoimmune thyroiditis, sicca syndrome, diabetes, non-cryoglobulinemic nephritis, psoriasis, neuropathies, arthritis, dermatomyositis, vitiligo, and cardiopathies require confirmation [9].

Recently, Tsui et al. [10] reported that HCV infection increased the risk of developing end-stage renal disease (ESRD) in a cohort of 52 874 patients infected with HCV compared with 421 495 uninfected patients, with a median follow-up of 3.6 years. A decline of estimated glomerular filtration rate >10 mL/min was observed in 14% of HCV+ patients, compared with 9% of HCV− patients (P < 0.01), indicating that HCV is associated with progressive impairment of renal function (OR for ESRD 1.68).

Hepatitis C virus (HCV) has long been assumed to play a pathogenic role in the development of B-cell lymphomas through polyclonal immune stimulation that eventually leads to monoclonal proliferation. Results from a murine model expressing the full genome of HCV in B-cells have recently suggested a direct role for HCV in the pathogenesis of B-cell lymphomas: Kasama et al. [11] observed a significant increase in spontaneous B-cell lymphomas in rzCD19Cre mice, in which the CD19 gene drives constitutive B-cell-specific expression of the full HCV genome. No significant increases were noted when the HCV genome was integrated but not expressed.

These results have two important implications: first, they demonstrate that HCV infection can lead to B-cell lymphoma in a murine model; secondly, lymphoma is a direct consequence of the presence of the virus and not purely an effect of immune stimulation, because expression of HCV genes at an early embryonic stage results in immunological tolerance to virus. This reinforces the concept that HCV eradication may prevent B-cell lymphomas. This hypothesis is supported by the findings of Kawamura et al.[12], who reported a lower cumulative incidence of malignant lymphoma after 15 years in patients achieving HCV eradication compared with patients who did not (0% for SVR vs 2.6% for persistent infection; Log-rank test P = 0.0159).

Therefore, treating HCV infection and eradicating the virus would impact not only on liver disease, but also on extrahepatic complications, suggesting that treatment decisions should also consider the risk of developing HCV-related diseases during the course of the infection.

According to the AASLD guidelines, eligibility for antiviral therapy should depend also on the likelihood of achieving an SVR to antiviral therapy. Unfortunately, this recommendation has several weak points: not only does it partially contradict the concept of treating only patients with advanced fibrosis, because liver fibrosis is a strong negative predictor of success in antiviral therapy, with SVR decreasing from 70% in patients with a baseline staging of F0 to 10% in stage F4 [13] but also most of the other predictors of treatment failure in chronic hepatitis C, such as genotype 1 or 4, age, race and genetic polymorphisms, are nonmodifiable factors. The matter is further complicated by the fact that the factors considered modifiable, such as obesity, steatosis, insulin-resistance, are either very hard to modify (obesity and steatosis) or their modification has not been shown to improve SVR rates. Attempts to combine baseline moderators of treatment outcome have also been quite disappointing: SVR is estimated at 97% in young, noncirrhotic, normal weight patients with low viral loads, and at 7% in 60-year-old, cirrhotic patients with BMI > 30 kg/m2 and high viral loads [14], demonstrating again that the patients most in-need (i.e. cirrhotic) are also the most difficult to cure, because of unfavourable predictors deriving from liver stage, age and comorbidities that enhance disease progression. Further doubt is cast on the value of baseline predictors by the fact that, independent of negative baseline factors, the probability of achieving SVR soars to roughly 80% in patients who attain undetectable HCV-RNA levels at week 4 [15].

The last key guidance issue when selecting patients for anti-HCV treatment is the risk of side effects. Indeed, therapy must not be administered to certain categories of patients at high risk for serious adverse events, such as those with major uncontrolled depressive illness, autoimmune hepatitis, pregnancy, severe concurrent diseases, solid organ transplant (kidney, lung and heart) or known hypersensitivity to PegIFN or Ribavirin.

Moreover, some categories of patients are potentially exposed to many side effects, such as those with kidney failure, on haemodialysis or with decompensated liver disease. In these patients, treatment is not contraindicated but requires expert clinical management (Table 1). In all other patients, therapy may be complicated by side effects such as flu-like syndrome, anaemia and mood alteration, but these are usually mild. The rate of discontinuation for adverse events is generally between 10% and 15%, while serious adverse events (SAE) are observed in 3–4% of patients [16–18]. Although these numbers are low, it is important to note that most SAEs require expert and multidisciplinary management. For example in the IDEAL study, the most common SAEs were neuro-psychiatric symptoms (28%), infections (22%) and gastro-intestinal disorders (21%) [18]. Therefore, the availability of support from experienced colleagues is critical, especially in case of psychiatric symptoms, suggesting that the evaluation of eligibility for treatment should consider also the local potential for managing side effects and the availability of professional advice in other clinical fields, factors that can reduce discontinuation rates and optimize treatment outcomes.

Table 1. Patients contraindicated for antiviral therapy according to AASLD guidelines and categories of patients in whom therapy should be managed in expert centres ESRD, end-stage renal disease; OLT, orthotopic liver transplantation.

Contraindications to antiviral treatment
Major uncontrolled depressive illness
Solid organ transplant (heart, lung and kidney)
Autoimmune hepatitis
Pregnancy or unwilling to comply with contraception
Severe concurrent medical diseases
Age <2 years
Known hypersensitivity to drugs used in antiviral therapy
Patients requiring expert clinical management
ESRD
Patients on haemodialysis
Decompensated liver disease
Post-OLT patients

Is Expanding Access to Treatment Cost-effective?

For the above reasons, it seems appropriate that all motivated patients not presenting contraindications be considered for antiviral therapy, provided that the clinical centre can manage rare potential SAEs. However, such an aggressive treatment algorithm could lead to over-treatment and potentially have a negative impact on healthcare costs. Surprisingly, in contrast to this, European data on treatment for HCV reveal a general under-treatment of patients, with 1–16 patients treated with PegIFN per 100 prevalent cases [19]. The same is true also in the USA, where only 22% of patients diagnosed with HCV infection are given therapy.

Concerning costs, Volk et al. [20] have assessed public health impact of antiviral therapy in the United States, comparing costs deriving from management of treated or untreated patients: an estimated 50% increase in the number of treated patients could prevent 30% of liver-related deaths from HCV by 2030; the percentage of deaths prevented over that period would increase to 50% with a 75% increase in treated patients and a modest increase in the rate of SVR.

In conclusion, treating more HCV-infected patients could positively impact on public health in terms of deaths prevented, reducing also social costs derived from the management of chronically infected patients (follow-up, surveillance and hospitalization) thus optimizing public expenditures.

Patient eligibility for antiviral therapy requires a complex and extended evaluation, which should consider not only liver staging, but also patient characteristics, baseline predictors of disease progression and the probability of treatment success. Treating chronic hepatitis C could prevent extrahepatic HCV-related manifestations, thus reducing also non-liver-related complications. However, management of treatment requires clinical experience in dealing with side effects, and, for some cases, therapy can be administered only in expert centres. Although treating more patients increases costs, viral eradication is cost-effective in terms of reducing public expenses deriving from the care of chronically infected patients.

Disclosures

Alessio Aghemo participated in Advisory Committees supported by Roche and received travel support from Bristol-Myers Squibb, Roche, Glaxo-Smith-Kline. Elisabetta Degasperi has no financial disclosure to declare.

References