A Silent Epidemic: Why Chronic Hepatitis B Matters CME

From Medscape Education Family Medicine

Robert P. Perrillo, MD; John W. Ward, MD

CME Released: 03/14/2012; Valid for credit through 03/14/2013

Slide 1.

Robert Perrillo, MD: Hello. I am Bob Perrillo, Chair of the American Association for the Study of Liver Diseases (AASLD) Hepatitis B Special Interest Group and clinical hepatologist at Baylor University Medical Center in Dallas.

I am pleased to welcome you to this CME-certified activity titled "A Silent Epidemic: Why Chronic Hepatitis B Matters."

I am particularly delighted to be joined today by Dr John Ward, who is the director of the Division of Viral Hepatitis at the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention at the Centers for Disease Control and Prevention (CDC) in Atlanta.

John, why should healthcare providers in the United States be concerned about hepatitis B virus (HBV) infection?

Slide 2.

John Ward, MD: Although HBV infection is a common health problem globally and in the United States, it is known as the silent epidemic because the public and many providers are unaware of its scope. Transmission continues to be a problem here in the United States. Approximately 370 million people worldwide have HBV infection, which causes approximately 660,000 deaths every year. Acute infection may lead to chronic infection that over decades can lead to severe liver disease, liver cirrhosis, and hepatocellular carcinoma (HCC), or primary liver cancer.

Slide 3.

Liver cancer is the second leading cause of cancer deaths worldwide,^[1] and a major cause of those deaths from liver cancer is HBV infection. Hepatitis B is more common in some parts of the world than others; it is a particularly large problem in Asia -- 1 of the most heavily populated areas on the planet -- as well as Sub-Saharan Africa, some areas of South America, and other regions. Persons who migrate from those regions to the United States bring hepatitis B with them. The CDC estimates that up to 1.4 million persons are living with hepatitis B infection in the United States and are at risk for cirrhosis and liver cancer. In addition, approximately 30,000 to 40,000 new infections occur every year in the United States..

Dr Perrillo: It is a worldwide health issue of great importance, and the United States is clearly affected by the effects of immigration from these areas of high endemicity. It is quite clear that clinicians in the United States can benefit from a global perspective of this serious problem. John, what can we do to prevent transmission?

Slide 4.

Dr Ward: The hepatitis B virus that causes hepatitis B disease is transmitted through blood contact in healthcare settings, among injection-drug users, and in the household setting through everyday exposures to small amounts of blood and through sexual contact among adolescents and adults. Importantly, an infected mother can transmit the virus to her infant at birth.

Slide 5.

Fortunately, we have safe and highly effective vaccines to prevent transmission via all of these routes, and our vaccine recommendations are designed to seize those opportunities to prevent transmission. We at the CDC recommend that all newborns in the United States receive the initial birth dose of HBV vaccine before leaving the birthing hospital to prevent acquisition of HBV from the infected mother. We recommend that all children receive the 3-dose vaccine series that begins in the hospital and is completed in the pediatrician's office. [Eds. note: A fourth dose is permissible if a combination vaccine that includes hepatitis B is administered after the birth dose.] The vaccines are highly effective and appear to provide protection for decades. We also recommend vaccination for adults who engage in high-risk sexual behaviors, adults who are current or recent injection-drug users, and men who have sex with men. We also recognize that healthcare workers are at high risk for occupational transmission, and we recommend vaccination for all healthcare workers.

Patients who have only recently been recognized to be at increased risk for hepatitis B transmission are persons with diabetes (in whom transmission can occur when infection control practices are not followed during blood glucose monitoring). The CDC has investigated a number of outbreaks of hepatitis B among persons with diabetes because infection control is not followed in places such as residential care facilities and medical facilities. In November 2011, the CDC recommended that all persons with diabetes younger than 60 years be vaccinated against hepatitis B. Because the vaccine is less effective in persons 60 years and older, it should be given at the discretion of the healthcare provider. I do want to emphasize the new recommendation that persons with diabetes should be offered hepatitis B vaccine. This new recommendation is part of the 2012 Recommended Adult Immunization Schedule.

Dr Perrillo: That is important new information.

One of the major challenges facing healthcare providers, as identified in the 2010 Institute of Medicine (IOM) report,^[2] is the need to more conscientiously screen for hepatitis B infection. John, would you describe for us briefly the CDC screening recommendations?

Slide 6.

Dr Ward: We have an intervention available to us to prevent infection -- vaccination -- and we have interventions to prevent disease progression for persons living with hepatitis B infection -- screening and linkage to care. As treatments have improved over the past 10 to 15 years, the benefits of screening (ie, knowing your status, obtaining timely care) have increased. In 2008, the CDC for the first time issued national recommendations as to who should be screened [for HBV]. The recommendations align with the epidemiology of hepatitis B and the populations that have the highest prevalence of chronic hepatitis B infection. One group includes persons born in countries such as in Asia and Africa that have a high prevalence of hepatitis B and who live in the United States. Some Asian populations in the United States have a staggering 8% to 10% prevalence of chronic hepatitis B infection^[3]; as a result, their liver disease and liver cancer rates are much higher than in other populations.To further compound the issue, many of these Asian and African HBV carriers may be uaware of their HBV status and may not have access to health care, so it is truly a health disparity for those patient populations. Screening is also recommended for men who have sex with men, injection-drug users, and persons who are about to begin immunosuppressive therapy.

One question we are often asked at the CDC is from clinicians who want guidance on how they should interpret results of the various tests for HBV infection. Bob, would you go over the various tests that are available to a clinician to screen someone for hepatitis B, what they measure, and how they should be used?

Slide 7.

Dr Perrillo: Unfortunately, this continues to be an area of confusion for clinicians. Hepatitis B surface antigen (HBsAg) is the basic test that shows whether a patient is infected; notably, HBsAg positive patients may be acutely or chronically infected. Antibody to the hepatitis B core (anti-HBc) can be a marker for ongoing infection as well as an indicator of past infection, and a small percentage of patients with isolated anti-HBc actually have low levels of HBV DNA in their serum; we call this occult infection. Antibody to the surface antigen (anti-HBs) is a neutralizing antibody, and this is the antibody that develops after vaccination and after successful immunologic recovery from either acute or chronic hepatitis B. It is important to note that HBsAg negative individuals who appear to have recovered from infection may continue to have small amounts of HBV DNA in their liver cells and other tissues, perhaps indefinitely, with the lowest amounts of HBV DNA occurring in individuals who have both anti-HBc and anti-HBs.

Many of the HBsAg negative patients we see who have recovered from hepatitis B have both anti-HBc and anti-HBs. This group of patients is at the highest state of immunologic control over future virus replication and accordingly is least susceptible to future reactivation of HBV. The patient who has isolated anti-HBc is a bit more worrisome and controversial because we do not routinely test these people for HBV DNA levels and some may have occult viremia. This factor and absence of the neutralizing antibody (anti-HBs) places them at greater risk for reactivation in the future, particularly during immunosuppressive therapy.

Dr Ward: It suggests that patients who are positive for HBsAg are actively replicating the virus.

Dr Perrillo: It may not be detectable in serum, but it is a protein. It is transcribed from the viral genome, so yes, there has to be some DNA and some replication.

Dr Ward: I have tried to describe the populations that from a public health perspective we feel are important to be screened and linked to care. Perhaps from a clinical perspective, Bob, you can describe the next steps to protect the health of the patient who has been screened and found to have hepatitis B.

Slide 8.

Dr Perrillo: Whenever an HBsAg positive patient comes to our office, we think of a possible need for treatment to forestall disease progression and to prevent the long-term complications of infection. Recently, longitudinal cohort studies have shown that the level of HBV DNA n the blood predicts the relative risk for developing complications, such as cirrhosis and HCC. In addition, data show lower rates of decompensation, liver failure, and HCC in patients with advanced fibrosis who undergo antiviral treatment compared with patients who are not treated or who are treated with placebo.^[34] The data strongly suggest that maintenance treatment to suppress high rates of viral replication in older HBsAg carriers may prevent long-term complications.

Slide 9.

Additionally, when you see an HBsAg carrier in the office, you can set up surveillance for HCC with a liver ultrasound study and with alpha-fetoprotein testing every 6 months for those over the age of 40 or those with cirrhosis. The AASLD has issued very clear guidelines about providing HCC surveillance in HBsAg carriers.^[4]

I mentioned reactivation due to immunosuppressive therapy, but we can only prevent this complication of immunosuppressive drugs by screening the patient for HBV and evaluating their level of risk. Furthermore, the initial office visit also is the best time to talk about vaccinating household contacts, and to educate the patient about the potential importance of hepatitis B; sadly, the patient may have been told by other providers that HBV infection is not something of great concern. These providers are typically dealing with the patient's other health issues that may appear to have greater priority.

When you see a patient in the clinic who has HBV infection, you should also ask whether other people in the household have been tested. Very often the patient does not know the results of the household contacts' tests or whether the household contacts were tested at all. We should always get this point across that household members need to be tested, particularly if perinatal transmission is suspected in your patient (in which case there might also be an infected sibling who has not yet been tested). The benefits that we just outlined could apply to other household members as well.

Dr Ward: Bob, you mention screening persons who are candidates for immunosuppressive therapy. I wonder if you could explain why it is important to screen that population for hepatitis B infection.

Slide 10.

Dr Perrillo: In our clinic, we see reactivation in patients who have not been screened for HBV and have undergone immunosuppressive therapy, which allows the virus to replicate unimpeded by the host immune response. We see an immunologic reconstitution effect when immunosuppressive therapy is stopped, and that is often followed by a flare of hepatitis because of aggressive cellular immune attack on hepatocytes that have become more heavility infected. What is particularly dramatic is a flare that is superimposed on severe underlying liver disease and advanced fibrosis, because it can lead to liver failure and death.

The population of patients at risk for HBV reactivation due to immunosuppressive therapy stretches far beyond those undergoing cancer chemotherapy; there are many thousands of patients on other, seemingly more benign immunosuppressive agents, such as tumor necrosis factor-alpha inhibitors, which have also been linked to reactivation. Again, the message is to screen patients before exposure to such drugs and then, if the patient is positive for HBsAg or isolated anti-HBc, you can refer the patient to a specialist who can initiate prophylactic antiviral therapy. The good news is that antiviral therapy, given for a few days to weeks prior to the initiation of immunosuppressive therapy, can prevent the vast majority of these reactivation events from occurring; that is really important to keep in mind.

Dr Ward: Yes, it is an important opportunity to intervene.

Dr Perrillo: John, we have indicated today that hepatitis B is a potentially serious disease both globally and in the United States that is best dealt with by conscientious attention to vaccination, screening those at risk, and linking patients who are HBsAg positive to care. John, can you tell me the health priority plan for hepatitis B, and how are we going to deal with this in the United States in the future?

Slide 11.

Dr Ward: I am happy to report that there has been a lot of attention paid to hepatitis B over the past several years at the policy level here in the United States. In 2010, the IOM released a report calling attention to hepatitis B and to C; the IOM recognized them as underappreciated health problems with missed opportunities of prevention, care, and treatment that resulted in unnecessary loss of life and quality of life.^[2] In its report, the IOM issued several recommendations that the US government could take to improve hepatitis prevention, care, and treatment; this led the Department of Health and Human Services (DHHS) to release a plan for viral hepatitis in May 2011. The plan includes a number of activities that the agencies within that department -- including the National Institutes of Health, Food and Drug Administration, and CDC -- could initiate to improve education for providers as well as communities (particularly those experiencing health disparities) in order to improve the opportunities for testing and linkage to care and treatment. Other activities include strengthening surveillance, so that we can better grasp the transmission and burden of disease, and identifying individuals who are not getting preventive services and care services. We have set a goal of eliminating transmission through vaccination, and the plan outlines opportunities to realize that goal, while recognizing particular groups at risk for multiple forms of hepatitis. The plan also recognizes the problem of patient safety and transmission in the healthcare setting. I am happy to report that the plan is available from the DHHS. It is very dynamic, and it really sets hepatitis as a new health priority for the nation.

Slide 12.

Dr Perrillo: It is resoundingly clear, then, that although hepatitis B is a serious clinical and public health issue, it is also something that we can prevent and treat. Treatments have advanced markedly over the past 10 to 15 years, and we now have oral antiviral agents that are very safe and can be given long-term to suppress viral replication. I believe these agents are going to lower the frequency of the complications associated with HBV. It is a very important message, but you can only identify the patients who will benefit most from these therapies through diligent HBV screening.

Dr Ward: Right.

Dr Perrillo: Our message today is that we need to vaccinate patients at risk for HBV, we need to screen those people that we think might be HBV-positive, and we need to link the HBV-positive patients to care. We have to be more active in our surveillance, per the IOM report. The future sounds a bit better because we are beginning to recognize hepatitis B as a serious health priority in this nation and identify where the gaps have been in our surveillance and linkage to care. It is imperative to appreciate the deficiencies in dealing with this serious health issue in order to devise practical and meaningful solutions, wouldn't you agree?

Dr Ward: I could not agree more. We have a good vaccine. We can prevent transmission. We have screening tests and guidelines for direct screening to the populations most in need. People can only benefit from these advances in treatment if we get them screened and into quality care. Both in public health and in clinical medicine, we should realize these opportunities can translate into health benefits for the people in the United States.

Slide 13.

Dr Perrillo: Thank you, John, for your interesting comments and in-depth discussion today, and I want to thank you all for participating in this activity.

To proceed to the CME post-test, please click on the Earn CME Credit link on this page. Also please be sure to complete the program evaluation that follows. Once again, thank you very much.

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Source

GPs urged to investigate raised ALT levels for hepatitis C

By David Swan | 15 Mar 2012

GPs should follow up all patients with a mildly raised alanine aminotransferase level to rule out hidden hepatitis C infection, say researchers.

The Dutch study looked at the prevalence of hidden hepatitis C infection in primary care patients and a cut-off for investigating raised ALT levels.

The researchers identified patients referred by their GP for liver enzyme testing with a mildly elevated ALT test result (30-100 IU/l) and grouped them by the different ranges of ALT elevation – 30-50 IU/l, 50-70 IU/l and 70-100 IU/l. Each group contained 250 samples, and each patient was tested for hepatitis C and hepatitis B.

They found prevalence of hepatitis C was not elevated in patients with an ALT level of 30-50 IU/l, but the prevalence of positive anti-hepatitis C test results was 2.0% in the 50-70 IU/l ALT level group and 1.2% in those with an ALT level of 70-100 IU/l.

They concluded that in primary care patients with an ALT elevation between 50 IU/l and 100 IU/l the risk of hepatitis C infection was substantially elevated.

Study lead Professor Charles Helsper, assistant professor and lecturer for GP-specialty training at Utrecht University, said: ‘It is recommended that in all patients with an ALT elevation of 50 UI/l-100 UI/l, particularly those for whom no clear explanation for the ALT elevation is found, diagnostic follow-up for hepatitis C is performed.'

British Journal of General Practice 2012; 62: e212-e216

Source

EASL-EORTC publish joint clinical practice guidelines on hepatocellular carcinoma management

Public release date: 15-Mar-2012

Contact: Travis Taylor
travis.taylor@cohnwolfe.com
0044-207-331-5472
European Association for the Study of the Liver

The European Association for the Study of the Liver (EASL) and the European Organisation for Research and Treatment of Cancer (EORTC) today publish their first joint Clinical Practice Guidelines (CPGs) on the management of hepatocellular carcinoma (HCC).(1) The EASL-EORTC guidelines define the use of surveillance, diagnosis and therapeutic strategies recommended for patients with HCC.

HCC is the most common form of liver cancer, representing more than 90% of primary liver cancers and an increasing global health burden. It is estimated that, by 2020, the number of cases will reach 78,000 in Europe (up from 65,000 in 2008) and 27,000 in the US (up from 21,000 in 2008). Affecting 2.4 times more men than women, approximately 90% of HCCs are associated with a known underlying risk factor -- the most frequent including chronic viral hepatitis (types B and C), alcohol intake and aflatoxin(2) exposure.

Lead author Professor Josep M Llovet said: "Despite the availability of effective surveillance and treatment strategies for HCC, the proportion of patients currently receiving these interventions is suboptimal. When considered in light of HCC's growing European and global incidence, it is critical that measures are implemented to increase access to surveillance, early diagnosis and effective treatment."

Based on a systematic review of existing literature, the CPGs provide best practice recommendations on a number of key areas:

• Epidemiology, risk factors and prevention
• Surveillance, including target populations
• Diagnosis, including non-invasive diagnosis, pathological diagnosis, molecular diagnosis and assessment of disease extension
• Staging systems, including the Barcelona-Clinic Liver Cancer (BCLC) classification (outcome prediction and treatment allocation) and molecular classification of HCC
• Surgical, loco-regional and medical treatment update, including latest advances and methods, and the endorsement of treatment stage migration
• Clinical trial design
• Assessment of response, and recommendation of the modified RECIST (mRECIST) criteria

The guidelines also identify major unmet needs for advancing HCC research and, ultimately, contributing to improved patient care, recommending physicians, investigators, health policy agencies, the pharmaceutical industry and care providers prioritise devoting future resources to:

• Evaluating adjuvant therapies after resection/local ablation and the benefits of combining molecular therapies with local ablation and loco-regional treatments
• Exploring downstaging(3) strategies to rescue patients with HCCs beyond conventional Milan criteria
• Developing effective treatment packages for advanced tumours and second-line therapies
• Robust cost-benefit and health-economic analysis/studies to facilitate clinical decision-making
• Providing adequate quality of life assessment tools, as quality of life is a relevant end-point for research studies

Professor Llovet said: "The HCC CPGs outline a clear need for investment in research, through which it will be possible to address important future clinical goals and advances, such as biobanking (the considered collection of tissue and serum samples in research studies) and personalised medicine."

Commenting on the CPGs, EASL Secretary General Professor Mark Thursz said: "EASL is dedicated to promoting hepatology research and education to improve the worldwide treatment of liver disease. As there have been several key clinical and scientific advances over the past decade, these guidelines update the recommendations reported by the EASL HCC panel of experts in 2001. EASL hopes these new HCC guidelines provide clinicians with the most up-to-date, evidence based methods for the management of affected patients."

###

To be simultaneously published in the Journal of Hepatology (Vol. 56 No. 4 April, 2012) and the European Journal of Cancer (Vol. 48 No. 5 March, 2012), the EASL-EORTC joint CPGs on the management of HCC will also be presented during a session of the International Liver CongressTM 2012 in Barcelona (1530, Saturday, April 21st).

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL's main focus on education and research is delivered through numerous events and initiatives, including:

• The International Liver CongressTM (http://www.easl.eu/_the-international-liver-congress/general-information) which is the main scientific and professional event in hepatology worldwide
• Meetings including Monothematic and Special conferences, Post Graduate Courses and other endorsed meetings that take place throughout the year (http://www.easl.eu/_events)
• Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology (http://www.easl.eu/_education)
• Journal of Hepatology, published monthly (http://www.easl.eu/members/journal-of-hepatology)
• Participation in a number of policy initiatives at European level

About the EORTC

The EORTC is a unique organization – a vibrant example of the fact that science and research know no national boundaries. Established in 1962, the EORTC is a non-profit research organization operating as an international association under Belgian law.

The EORTC currently links a network of more than 2,500 pre-clinical scientists and oncologists in more than 300 hospitals in over 30 countries. It encompasses all aspects of cancer research, from translational research and new drug development to large phase III clinical trials and meta-analyses.

The 170 members of the EORTC Headquarters staff handle some 6,000 new patients enrolled each year in cancer clinical trials, approximately 30 protocols that are permanently open to patient entry, over 50,000 patients who are in follow-up, and a database of more than 180,000 patients.

The ultimate goal of the EORTC is to improve the future of cancer therapy by developing new agents and innovative approaches and to test more effective treatment strategies using commercially available drugs, or surgery and radiotherapy.

http://www.eortc.org/

1. Llovet, J.M. et al (2012) EASL-EORTC Clinical Practice Guidelines: Management of Hepatocellular Carcinoma. Available at http://www.easl.eu/_clinical-practice-guideline

2. Aflatoxins are naturally occurring toxins produced by many species of the fungus Aspergillus and are among the most carcinogenic substances known. Dietary exposure to aflatoxin B1, derived from the fungi Aspergillus flavus and Aspergillus parasiticus, is an important co-factor for HCC development in parts of Africa and Asia. These moulds are ubiquitous in nature and contaminate a number of staple foodstuffs in tropical and subtropical regions.

3. Downstaging is a situation in which a patient with a previously unresectable tumour or large number of tumours becomes eligible for surgery (resection) or transplant after treatment.

Source

Liver Transplant Program at Methodist Specialty and Transplant Hospital Recognized as Best in the Nation

PRESS RE:EASE

March 14, 2012, 6:37 p.m. EDT

SAN ANTONIO, March 14, 2012 /PRNewswire via COMTEX/ -- Success at Texas Hospital Offers Hope for Millions Affected by Liver-Destroying Hepatitis C

Liver transplant surgeons at a San Antonio hospital are poised to save hundreds of lives as deaths from liver-destroying hepatitis C increase, with recent reports indicating baby boomers are highest risk.

The Liver Transplant Program at Methodist Specialty and Transplant Hospital (MSTH), a campus of Methodist Hospital, has been recognized as the best liver transplant program in the country, based on data recently released by the Scientific Registry for Transplant Patients.

The MSTH program has the best one-year patient survival rate in the United States among patients with the most seriously advanced liver disease, according to data from the Organ Procurement and Transplant Network (OPTN)/SRTS Annual Data Report. The ranking is based on comparisons of programs performing 10 or more transplants annually.

"Key to becoming the top program in the country is having a hospital and staff devoted to abdominal transplant surgeries with both outpatient and inpatient services," said Preston Foster, M.D., FACS, Surgical Director, Liver Disease and Transplant Program, Texas Transplant Institute, a department of Methodist Hospital. "Our highly experienced and devoted team of physician specialists, nurses and care coordinators consider each patient's individual needs. We provide a continuum of care from diagnosis of liver disease, evaluation for transplant, transplant surgery and recovery, including continued monitoring in our outpatient clinic."

Philip Ostrander, 54, benefited from the outstanding program in San Antonio, surviving more than eight years with his new liver. Ostrander developed liver disease as the result of hepatitis C and cirrhosis of the liver. Just before Thanksgiving in 2003, his condition began to deteriorate. "By January 8, one of the doctors advised my wife to make funeral arrangements," said Ostrander. "Luckily, Dr. Foster said to wait. I was placed on the liver transplant wait list and on January 23 I had my transplant. My transplant gave me a whole new lease on life," Ostrander said.

The MSTH Liver Transplant Program began in 2001 and has performed 290 transplants since that time. Liver transplant procedures can be especially complex because many patients are at life-threatening stages of liver disease and prone to complications. The San Antonio team has implemented several techniques that have resulted in more successful outcomes:

Preservation techniques used during transplantation of the donor liver

Revascularization techniques of the donor liver

Venous bypass machine used to prevent low-blood pressure and low-body temperature during the transplant

Techniques to reduce the number of immunosuppressive drugs post transplant

Multi-disciplinary care of patients throughout transplant process

Aggressive treatment to protect donor liver from hepatitis C

According to the CDC, an estimated 3.2 million Americans have chronic hepatitis C, the leading cause of liver transplants. To read more about the nation's leading liver transplant program and view additional patient profiles, visit bit.ly/y5fLx2.

SOURCE Methodist Healthcare

Source

Mayo Clinic Health Letter Highlights, March 2012: Nonalcoholic Fatty Liver Disease on the Rise; Potentially Risky Supplements; Short-Term Loss of Memory Could be Temporary Amnesia

PRESS RELEASE

March 14, 2012, 1:38 p.m. EDT

ROCHESTER, Minn., Mar 14, 2012 (BUSINESS WIRE) -- Here are highlights from the March issue of Mayo Clinic Health Letter. You may cite this publication as often as you wish. Reprinting is allowed for a fee. Mayo Clinic Health Letter attribution is required. Include the following subscription information as your editorial policies permit: Visit www.HealthLetter.MayoClinic.com or call toll-free for subscription information, 1-800-333-9037, extension 9771.

Rise in Nonalcoholic Fatty Liver Disease Linked to Obesity

ROCHESTER, Minn. -- Nonalcoholic fatty liver disease (NAFLD) is on the rise in the United States, according to the March issue of Mayo Clinic Health Letter.

NAFLD causes excess fat to accumulate in the liver. As the fat builds, some patients experience fatigue, weight loss and pain in the upper right abdomen. A buildup of fat in the liver can result in inflammation and scarring (fibrosis). The more serious form of this illness can cause severe liver damage and eventually lead to liver failure or liver cancer in about 5 percent of those with the illness.

In the early stages, NAFLD doesn't cause signs or symptoms. The disease is often discovered during routine blood tests that show that certain liver enzymes are elevated. Additional blood tests and imaging may confirm the diagnosis.

Researchers believe the increasing incidence of NAFLD is associated with rising rates of obesity. Experts estimate that about two-thirds of obese adults and half of obese children may have fatty livers.

There are no specific therapies for the disease. Instead, doctors focus on treating risk factors. Recommendations include:

Weight loss: Losing excess weight can improve and possibly even reverse fatty liver disease to some degree.

Healthy diet: Many people who have the disease also have increased levels of fat (lipids) in their blood, including low-density lipoprotein (LDL) cholesterol and triglycerides. Doctors recommend a diet rich in fruits, vegetables and whole grains with limited amounts of cholesterol and saturated fats. Cutting out fast food may be particularly helpful as this food is associated with progressive inflammation and scarring in people with NAFLD.

Physical activity: A recent study of adults with NAFLD suggests that vigorous physical activity may help reduce damage from fatty liver disease.

Liver protection: People with the disease should avoid drinking alcohol and any unnecessary use of medication that can put the liver at risk. For example, high doses of acetaminophen, a pain reliever found in many prescription and over-the-counter drugs, can cause liver damage.

A Vitamin a Day Might not Keep the Doctor Away

ROCHESTER, Minn. -- Over the past few years, studies have found that vitamins previously considered beneficial may not be helping -- and may be causing harm. The March issue of Mayo Clinic Health Letter provides an overview on the latest advice about taking vitamins.

The newest research is from the Iowa Women's Health Study. This 20-year study of 38,000 women age 55 and older showed that taking a multivitamin appears to increase the risk of premature death. Evidence from this study and others suggest there is no need to take most supplements for general health or disease prevention. Exceptions appear to be calcium supplements and vitamin D for bone health.

The Mayo Clinic Health Letter highlights some potentially risky supplements:

Vitamin E: A 2005 review of research found that taking daily vitamin E supplements of 400 international units (IU) or more and possibly as low as 150 IU a day may pose health risks, including increased risk of premature death.

Vitamin A: A large study of postmenopausal women found that long-term intake of at least 6,660 IU of vitamin A acetate or palmitate may increase the risk of hip fractures. However, other research hasn't come to the same conclusion.

Folate and folic acid (vitamin B-9): Supplementation helps prevent birth defects, but evidence of other benefits has been elusive. The Iowa Women's Health Study suggests that folic acid supplements might increase the risk of premature death by 5.9 percent. Other studies have linked folic acid supplements with an increased risk of colorectal cancer.

Vitamin B-6: Large daily doses -- more than 100 milligrams (mg) -- can cause nerve damage over time. In the Iowa study, vitamin B-6 appeared to increase the risk of premature death by 4.1 percent.

Vitamin B-3 (niacin): High doses can help lower high cholesterol levels. This treatment should be done under a doctor's supervision because side effects can include severe liver disease.

Trace minerals: Copper, chromium, magnesium, selenium and zinc are among the essential trace minerals. There is no solid evidence that trace mineral supplements have any benefit in the absence of deficiencies -- which are rare. The Iowa Women's Health Study indicated that the risk of premature death increased 3.6 percent in those taking magnesium, 3 percent in those taking zinc, and 18 percent in those taking copper supplements.

It's always wise to consult with a doctor about any diet supplements. There are situations where supplements are beneficial to health. But healthy individuals who take supplements as an "insurance policy" against inadequate nutrition may in fact be increasing their health risks.

Transient Global Amnesia: Memory Temporarily Interrupted

ROCHESTER, Minn. -- A one-time memory loss -- for up to 24 hours -- might not be a sign of a brain injury or dementia. Instead, it could be transient global amnesia. The March issue of Mayo Clinic Health Letter covers this uncommon and puzzling form of amnesia

People with transient global amnesia experience sudden loss of recent memory and can't form new memories. The episode usually lasts six to 12 hours but may last up to 24 hours. During that time, people know who they are and recognize family and friends. Complex tasks, such as driving, are still possible. In the midst of transient global amnesia, those affected don't know where they are or how they got there. They would likely ask the same questions repeatedly. Once the episode is over, life returns to normal -- absent any memories from that short time.

This form of amnesia is most common in adults age 50 and older and usually occurs only once. The underlying cause is unknown. There's debate about what triggers an episode. Reported events have been linked to sudden immersion in cold or hot water, strenuous physical activities, emotional or psychological stress, and pain. Some have found an association with migraines.

Although temporary, transient global amnesia warrants immediate medical attention. Diagnosis is based on excluding more serious neurological conditions such as stroke, seizure or head injury. Transient global amnesia is not a predictor of future memory loss or a risk factor for other more serious conditions.

Mayo Clinic Health Letter is an eight-page monthly newsletter of reliable, accurate and practical information on today's health and medical news. To subscribe, please call 1-800-333-9037 (toll-free), extension 9771, or visit www.HealthLetter.MayoClinic.com .

About Mayo Clinic Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit http://www.mayoclinic.org and www.mayoclinic.org/news .

SOURCE: Mayo Clinic

Source

Okairos Announces Initiation of Phase I/II Clinical Trial for Potential First-in-Class Hepatitis C Vaccine

PRESS RELEASE

March 14, 2012, 4:00 a.m. EDT

BASEL, Switzerland, Mar 14, 2012 (BUSINESS WIRE) -- Okairos today announced the initiation of a Phase I/II clinical trial evaluating its vaccine against the hepatitis C virus (HCV). This is the first multi-center, double blinded, randomized, placebo-controlled trial of a vaccine to prevent HCV infection, and represents a major milestone in the collaboration between Okairos and the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the US National Institutes of Health (NIH). The NIH-funded trial will be conducted by co-principal investigators from Johns Hopkins University and the University of California San Francisco (UCSF).

The trial follows promising Phase I results that were recently published in Science Translational Medicine, showing that the vaccine had a good safety profile, was well tolerated, and that it stimulated a highly potent T-cell response in healthy volunteers. This Phase I/II trial will provide the opportunity to demonstrate the potential effectiveness of such an approach in protecting against chronic HCV infection, the leading cause of liver cancer.i

Dr Riccardo Cortese, Chief Executive Officer of Okairos, said: "This news represents many years of work in developing our technology platform and proving its utility in early clinical studies in HCV and other areas. We are very pleased to be part of this productive collaboration and look forward to initiating additional clinical programs from our platform in the near future."

The trial will enroll 350 subjects and will begin with an interim Phase I analysis of safety and immunogenicity data in a subset of them. The primary endpoints of the overall study will measure the incidence of chronic HCV infection, as well as the safety and tolerability of the vaccine.

Dr Alfredo Nicosia, Chief Scientific Officer of Okairos, explained: "The history of vaccine research has primarily focused on stimulating antibody responses. We've unlocked the door to stimulating robust T-cell responses and will leverage this technology to combat important diseases such as HCV, respiratory syncytial virus (RSV) and influenza."

About hepatitis C virus (HCV)

Three per cent of the global population carries HCV, which affects the liver cells and is the leading cause of liver transplants in the US. Around 170 million people have the chronic form of the disease, which may lead to cirrhosis, liver failure, hepatocellular carcinoma and ultimately death. In the US and Western Europe around 150,000 new cases occur annually.ii Extensive variations of the virus present major challenges to the development of a vaccine - there is currently no vaccine for the prevention (prophylactic vaccine) of HCV infection.

About Okairos' HCV vaccine

Extensive preclinical experiments and studies of the interaction of the virus with the human immune system have highlighted the importance of T-cells in counteracting HCV. Okairos' HCV vaccine is based on a technology platform that uses proprietary, chimpanzee-derived adenovirus vectors to stimulate a robust T-cell response against selected antigens. Okairos' research has shown that it is able to stimulate robust T-cell responses that provide strong protection in preclinical non-human primate challenge models.

About Okairos

Okairos is a clinical-stage biopharmaceutical company, developing genetic vaccines for major infectious diseases - including malaria, hepatitis C, influenza, respiratory syncytial virus and cancer - using a novel proprietary technology. The company is headquartered in Basel, Switzerland and has laboratories in Rome and Naples, Italy.

Okairos' technology platform is centered on the development of new, potent adenovirus vectors to generate a pipeline of T-cell vaccines against a range of infectious diseases for which there is currently no effective vaccine. The company is also pursuing therapeutic vaccines to treat cancer.

The company's investors include BioMedInvest, Boehringer Ingelheim Venture Fund, LSP, Novartis Venture Funds and Versant Ventures.

For more information, visit www.okairos.com 

References

i www.cdc.gov/hepatitis/C/cFAQ.htm 

ii www.who.int/csr/disease/hepatitis/Hepc.pdf 

SOURCE: Okairos

Source

‘Faster, cheaper’ hepatitis C test designed

14 March 2012

CAIRO — The American University in Cairo said Wednesday that a team of its researchers has designed a faster and cheaper test for all types of hepatitis C, which it says affects about 10 million Egyptians.

The development “reduces the two-step testing proccet carried out over a number of days to a one-step process that takes less than an hour... at a fraction of the cost of traditional diagnostic protocols,” the university said.

The liquid chemistry test can diagnose hepatitis C using gold nanoparticles, it said.

“Our test is sensitive and inexpensive, and it does not need sophisticated equipment,” said Hassan Azzazy, professor of chemistry and head of the research team.

“Detecting HCV during the first six months raises the recovery rate to 90 percent. Little is done on the national level to combat the alarming prevalence of hepatitis C in Egypt,” said Azzazy.

The AUC said Egypt has about 10 million people who suffer from the hepatitis C virus (HCV), with the blood-borne pathogen infecting almost 500,000 in the country each year.

Worldwide, around 170 million people are estimated to be living with the chronic disease caused by the virus.

Unlike hepatitis A or B, most people infected with HCV cannot shake off the virus on their own because, when under attack by the immune system, it morphs into stronger variants.

The World Health Organisation estimates that three to four million people are newly infected with HCV each year.

The WHO says Egypt has one of the highest rates of hepatitis C prevalence in the world, putting the rate of infection in the country at 22 percent.

Source

New compound discovered that rapidly kills liver cancer

March 14, 2012

Scientists have identified a new compound that rapidly kills hepatocellular carcinoma (HCC) cells, the most common form of liver cancer and fifth most common cancer worldwide, while sparing healthy tissue. The compound, Factor Qunolinone Inhibitor 1 (FQI1), works by inhibiting an oncogene originally discovered by a team of researchers led by Devanand Sarkar, M.B.B.S., Ph.D., Harrison Scholar at Virginia Commonwealth University (VCU) Massey Cancer Center, Blick Scholar and assistant professor in the Department of Human and Molecular Genetics and member of the VCU Institute of Molecular Medicine at the VCU School of Medicine.

Recently published in the journal Proceedings of the National Academy of Sciences, the study demonstrates that HCC cells have what is known as an "oncogene addiction" to the transcription factor Late SV40 Factor (LSF). Oncogene addiction is a term used when a cancer cell is found to be dependent on a single gene to survive. Using the compound Factor Quinolinone Inhibitor 1 (FQI1), the scientists prevented LSF from binding to HCC DNA during the transcription process, which is the first step in a series of actions that lead to cell division and duplication. This action caused rapid HCC cell death in laboratory experiments and a dramatic reduction in tumor growth in mouse models with no observable toxicity to normal liver cells.

"We may be on the verge of developing a new, effective drug for liver cancer," said Sarkar. "In the last 2 to 3 years, we demonstrated the role of LSF in liver cancer and have been screening over 110,000 compounds to identify the ones that inhibit LSF function. We identified FQI1 as one of a class of effective compounds, but we never anticipated it would work this well."

Sarkar discovered LSF's role in liver cancer in 2010 when he demonstrated significantly higher LSF levels in HCC patients in comparison to healthy individuals, and showed that inhibition of LSF reduced the progression of HCC in laboratory experiments. This finding led to the collaboration between VCU and Boston University that resulted in the discovery of FQI1.

Now that FQI1 has been identified, pharmacokinetic studies are being conducted to determine how the drug behaves in the human body. Once the scientists have determined how the drug is absorbed, distributed, metabolized and eliminated from the body, they will work with clinicians to translate their findings into phase I clinical trials in patients with liver cancer.

"We have proven this compound is effective and nontoxic in living animals," said Sarkar. "While we won't know how FQI1 reacts in humans until the first clinical trial, we are very excited by our findings and hope they lead to a new drug for a disease that is currently very difficult to treat."

More information: http://www.pnas.or … ull.pdf+html

Provided by Virginia Commonwealth University (news : web)

Source

Hundreds Of New Yorkers Attend Annual Hepatitis C Legislative Awareness Day To Request State Plan For 2013

Status C Unknown Urges Lawmakers to Address Growing Impact of Virus That Has Surpassed HIV as a Cause of Death -- Approximately 300,000 residents of New York State are infected with the hepatitis C virus, but up to 70% don't know. U.S. deaths associated with hepatitis C have surpassed those from HIV according to a new report from the CDC, and up to 1 in 33 baby boomers may be infected.

Albany, NY (PRWEB) March 14, 2012

Status C Unknown, a non-profit 501(c)3 today led hundreds of patients and advocates from around New York State to Albany for the sixth annual Hepatitis C Legislative Awareness Day, urging lawmakers to adopt a plan for 2013 to combat the increasing incidence of hepatitis C infection in New York State with education, testing and treatment programs. The request comes just weeks after the U.S. Centers for Disease Control & Prevention (CDC) reported that more Americans died from hepatitis C than from HIV in 2010 and that 1 in 33 baby boomers are likely infected.

Hepatitis C, which can be detected by a simple blood test, is a chronic viral infection that causes liver disease and affects approximately 300,000 New York State residents (CDC, NYS Department of Health). Because it is often asymptomatic or “silent,” most people don’t know they’re infected until they have serious liver damage. With early detection and new treatments, up to 75% of people with hepatitis C can now be cured.

“It is unconscionable that thousands of NYS residents are sick and dying every year because they don’t know they have hepatitis C when it can be identified by a simple blood test and treated,” said Shari Foster, founder of Status C Unknown and a Long Island, NY resident, who was unaware she had hepatitis C until she went into liver failure and nearly died from internal bleeding. “We know that budgets are tight, but hepatitis C is taking a personal and financial toll on our state, and evidence shows that intervention not only reduces suffering but is also cost-effective. We need to have a comprehensive plan in place.”

Advocates also urged lawmakers to maintain the current budget for hepatitis C education, testing and treatment and to approve additional funds being proposed by the Health Disparities Work Group of the New York State Medicaid Redesign Team (MRT).

Assemblyman Kenneth Zebrowski (D – New City) spoke to a group of the advocates, patients and fellow legislators about how his father, Assemblyman Kenneth P. Zebrowski, died from liver disease resulting from hepatitis C in 2007 at the age of 61 – he had been infected for 23 years before being diagnosed. Since being elected to his father’s seat, Zebrowski has worked to increase state initiatives to help detect, treat and prevent hepatitis C and requested renewed support from fellow lawmakers.

“It is so important that we have advocacy, awareness and support each and every year to assist families in dealing with this disease,” said Zebrowski. “We need to help ensure that at-risk New Yorkers get tested for hepatitis C so they can benefit from available and effective treatment.”

“I applaud the Governor’s proposed funding increase through the MRT to promote hepatitis C care and treatment and help bring this disease out of the shadows,” he added. “Our work is not done -- I will continue to advocate for increased funding for treatment and research, more available testing and improved awareness of this little-known disease.”

About Hepatitis C
According to the CDC, an estimated 3.2 million Americans have chronic hepatitis C virus infection. Most people do not know they are infected because they don’t look or feel sick. There are about 17,000 new cases of infection each year. Chronic hepatitis C can result in long-term health problems, including liver damage, liver failure, liver cancer, or even death. It is the leading cause of cirrhosis and liver cancer and the most common reason for liver transplantation in the U.S. Approximately 8,000–10,000 people die every year from hepatitis C-related liver disease.

There is no vaccine to prevent hepatitis C, which is spread primarily through infected blood. It can be detected with a blood test, and an FDA-approved rapid fingerstick test can detect antibodies to the virus. Treatments are available and new therapies are actively being developed. More information: http://www.cdc.gov/hepatitis/C/cFAQ.htm

In 2010, the NYS Department of Health (DOH) issued “NYS Viral Hepatitis Strategic Plan 2010 – 2015,” which includes a strategic framework for prevention, education, surveillance/research and treatment of hepatitis C. http://www.health.ny.gov/diseases/communicable/hepatitis/strategic/background_rationale_hepatitis_c.htm

About Status C Unknown
Status C Unknown is a non-profit 501 c 3 that was founded by Long Island resident Shari Foster, who was successfully treated for hepatitis C in 2005. The mission of the organization is to raise awareness about hepatitis C to help reduce transmission and increase testing and provide patient support. More information at http://www.statuscunknown.org

Source

Broader screening for hepatitis C would be cost effective, study suggests

Public release date: 14-Mar-2012

Contact: Laurel White
lwhite@pcipr.com
312-558-1770
Infectious Diseases Society of America

Linking those infected with care is key to reducing related mortality and morbidity

Broader screening to identify people infected with hepatitis C virus (HCV) would likely be cost effective, according to a new report published in Clinical Infectious Diseases and available online. Significantly reducing HCV-related mortality and morbidity, however, will require a coordinated effort that emphasizes not only increased testing but also linking those infected with the treatment they need.

The HCV epidemic peaked many years ago, but roughly 4 million U.S. residents still suffer the consequences of chronic hepatitis C. A growing proportion of those infected now has advanced disease, including cirrhosis of the liver and liver cancer. Deaths from chronic infection have doubled over the last decade and are expected to more than double again by 2030.

The current "risk factor-based approach to screening has failed to identify at least half of those infected, leading to a situation in which a quarter of those newly diagnosed already suffer from cirrhosis of the liver," said Dr. Phillip O. Coffin, who led a team of researchers, including Drs. John D. Scott, Matthew R. Golden, and Sean D. Sullivan, at the University of Washington in Seattle who estimated the cost-effectiveness and impact of HCV screening.

Adding a one-time screening for all adults between the ages of 20 and 69 and factoring in the costs of managing late-stage liver fibrosis versus the costs of attempting to cure patients of hepatitis C, Dr. Coffin's team used statistical modeling techniques to analyze the benefit of broadening screening guidelines. They found that screening all adults was cost effective across a wide range of assumptions related to the costs and effects of screening and treatment. At the same time, the proportion of deaths averted by screening is likely to be relatively small, unless testing efforts are accompanied by substantial increases in successful referral of infected persons for treatment.

"The stealth epidemic of hepatitis C has finally matured, leaving a narrow window of opportunity to find those with advancing disease, connect them with care, and prevent the tragic and costly consequences of liver cancer and end-stage liver disease," Dr. Coffin said. Doctors are hampered by current overly narrow screening guidelines, and managing chronic HCV infection becomes increasingly expensive as it progresses.

"We need to screen the population, but that won't be enough to make a big difference," Dr. Coffin said. "Hepatitis C is a lot like HIV. The U.S. took a long time to come to the conclusion that we needed to really emphasize testing and efforts to link people to care. Hepatitis C is the same. We need a large scale, coordinated effort to identify people with this infection and make sure they get the care they need."

###

Clinical Infectious Diseases is a leading journal in the field of infectious disease with a broad international readership. The journal publishes articles on a variety of subjects of interest to practitioners and researchers. Topics range from clinical descriptions of infections, public health, microbiology, and immunology to the prevention of infection, the evaluation of current and novel treatments, and the promotion of optimal practices for diagnosis and treatment. The journal publishes original research, editorial commentaries, review articles, and practice guidelines and is among the most highly cited journals in the field of infectious diseases. Clinical Infectious Diseases is an official publication of the Infectious Diseases Society of America (IDSA). Based in Arlington, Va., IDSA is a professional society representing nearly 10,000 physicians and scientists who specialize in infectious diseases. For more information, visit www.idsociety.org.

Source

Economic Burden of Hepatitis C-associated Diseases in the United States

From Journal of Viral Hepatitis

A. C. El Khoury; W. K. Klimack; C. Wallace; H. Razavi

Posted: 03/14/2012; J Viral Hepat. 2012;19(3):153-160. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Summary. There are approximately 100 drugs in development to treat hepatitis C. Over the next decade, a number of new therapies will become available. A good understanding of the cost of hepatitis C sequelae is important for assessing the value of new treatments. The objective of this study was to assess the economic burden data sources for hepatitis C in the United States. A systematic literature search was conducted to identify studies reporting the costs of hepatitis C sequelae in the United States. Over 400 references were identified, of which 50 were pertinent. The costs were compiled and adjusted to 2010 constant US dollars using the medical component of the consumer price index (CPI). The cost of liver transplants was estimated at $201 110 ($178 760–$223 460), hepatocellular carcinoma (HCC) at $23 755–$44 200, variceal haemorrhage at $25 595, compensated cirrhosis at $585–$1110, refractory ascites at $24 755, hepatic encephalopathy at $16 430, sensitive ascites at $2450, moderate chronic hepatitis C at $155, and mild chronic hepatitis C at $145 per year per person. All studies were traced back to a handful of publications in the 1990s, which have provided the basis for all sequelae-based cost estimates to date. Hepatitis C imposes a high economic burden. Most cost analysis is more than 10 years old, and more research is required to update the sequelae costs associated with HCV infection.

Introduction

Chronic hepatitis C is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) and a major indication for liver transplantation.^[1] The burden of the disease is expected to increase in the United States as the hepatitis C virus (HCV)-infected population ages.^[2]

There are approximately 3.9 million (MM) HCV-infected persons in the United States and 12 000 die annually from HCV-related liver disease.^[3] A high proportion of US patients became infected in the 1960s and 1970s as injection recreational drug users. Now approaching or older than 60 years of age, they represent a cohort that is expected to develop significant liver disease.^[4] It is projected that compensated cirrhosis and HCC will increase by over 80 per cent from the year 2000 to the year 2020. Over the same period, it is estimated that decompensated cirrhosis would increase over 100 per cent and that liver-related deaths would increase by 181 per cent.^[5]

Understanding the economic burden of diseases relating to HCV infection has value in itself. It is also important as a baseline for policy and resource allocation decisions as well as determining the cost effectiveness of new therapies. Given the wide selection of sources available on this topic, the focus of this study was to systematically review published literature and develop baseline costs for future work on this topic in the United States.

Methodology

To investigate the costs associated with HCV infection sequelae, the progression of the disease was researched (Fig. 1). Then, a systematic review of the literature was conducted to identify studies reporting the cost of HCV infection sequelae. Indexed articles were identified by searching in PubMed using the following terms: '(liver transplantation OR chronic hepatitis C OR HCC OR HCC OR chronic liver disease OR cirrhosis OR ascites OR variceal haemorrhage OR hepatic encephalopathy OR fulminant hepatitis) AND (cost OR treatment cost OR economic burden)' OR 'hepatitis C AND (cost of illness OR economic burden OR markov OR (disease progression AND model)'. In addition, the HCV database at the Center for Disease Analysis,^[6] which contains over 2700 indexed and nonindexed sources from 1985 to 2010, was searched using the same terms. Furthermore, references cited within the articles were reviewed. This last step proved to be important as it not only provided new references, but also identified all studies that relied on the previous work. The scope of the search was global to identify ex-US studies that also analysed US-based data.

Figure 1. Simplified hepatitis C sequelae progression.

Cost data were categorized annually and were converted to 2010 US dollars using the medical component of the consumer price index which captured the change in prices and inflation over time.^[7] The service component of the index was used for adjusting the liver transplantation cost while the commodity component was used for all other costs such as chronic hepatitis C, ascites, and cirrhosis. The top-down costs were not adjusted to 2010 US dollars. These estimates incorporated two components: incremental medical cost and number of visits and/or hospital days. The latter depended on the number of cases in a year, which could not be adjusted to 2010 values.

Given that most cost studies were traced back to a single source, a weighted average mean approach was not applied here. Instead, the 2010 adjusted cost for the original study was reported along with minimum and maximum values for other published data that significantly differed.

Results

Over 400 references were identified, of which 50 were pertinent to this work. Of the original 400, approximately 50% did not contain specific cost data. Another 12.5% were specific to the treated population on the current standard of care (interferon or pegylated interferon plus ribavirin) and did not examine the costs of sequelae. Another 12.5% of the articles were too broad (e.g., all liver diseases) or too specific (e.g., HIV co-infected population). Of the remaining 25%, half, or 50 articles, were applicable to the US population, and the rest were specific to other countries.

Disease Progression

A number of studies reported the disease progression for HCV infection summarized in Fig. 1.^[8–14]

After infection with HCV, the acute phase lasts for 6 months, when roughly 15–45% per cent will spontaneously clear the infection.^[13,15] A very small proportion will develop fulminant hepatitis, which may rapidly lead to death.^[13] Acute infections will transition from mild to moderate chronic hepatitis C.^[11–14] Fibrosis develops and when severe enough, the patient becomes cirrhotic. Initially, the cirrhosis is restricted sufficiently that the liver is able to compensate for the damage and provide normal functioning. Decompensated cirrhosis arises when conditions secondary to liver failure develop.

Individuals with compensated cirrhosis can develop ascites, which is the accumulation of fluid in the abdomen owing to high portal venous pressure. Initially, the condition responds to diuretic medications. For some patients, the condition becomes unresponsive, resulting in diuretic refractory ascites. Other cirrhotics can develop variceal haemorrhage, which is bleeding from enlarged veins in the oesophagus caused by high portal venous pressure. Hepatic encephalopathy, which is loss of cognitive function owing to rising toxin levels in the bloodstream, is another sequela. Persons with chronic hepatitis C can also develop HCC, the primary cancer of the liver.

Liver transplantation is a well-accepted treatment for end-stage liver disease as well as for HCC in some cases. The procedure is expensive for several reasons. Extensive patient diagnostics are required. Donor liver procurement requires deployment of surgical teams. The surgery is interdisciplinary, complex, and long. Need for surgical reintervention and use of medication are high. Readmission is often required. Use of live donors has increased the number of available donor organs, but it has also increased patient costs.^[8,16–18]

Economic Burden

Two approaches were reported for estimating the economic burden of hepatitis C: top-down and bottom-up. In the top-down approach (Table 1), the national estimates for medical spending were used to calculate the total cost.^[19–23] The National Hospital Discharge Survey (NHDS), National Ambulatory Medical Care Survey (NAMCS), and National Hospital Ambulatory Medical Care Survey (NHAMCS) data sets were used to estimate inpatient hospital stays, physician office visits, emergency room visits, and hospital outpatient visits, respectively. The average length of stay and total days of care by disease were obtained from these databases, which were used in calculating indirect costs. Direct cost associated with hepatitis C was estimated at $694–$1660 million per year, HCC (all causes) at $261–$978 million per year, HCC (hepatitis C only) at $140 million per year, and chronic liver diseases and cirrhosis at $1421 million per year. These cost estimates were in different years, as shown in Table 1, making direct comparison difficult.

The indirect costs, defined as the cost of forgone earnings or production because of hospitalization, ambulatory care, premature death, and work loss because of acute or chronic infection, were often higher than the direct costs. In a 2010 study, the indirect cost associated with hepatitis C was estimated at $490 per year per diagnosed individual.^[24] In the 2008 report by the National Institute of Health (NIH),^[19] the indirect cost ($1.78 billion in 2004) for hepatitis C was 67% higher than estimated direct costs ($1.1 billion in 2004).

In the bottom-up approach, a patient cohort model was used to estimate the total cost using the cost and transition probability for each sequela.^{[8,9,12,25–29]} In the latter approach, the disease progression analysis used Markov models and updated transition probabilities, but the disease cost component in all studies was traced back to a handful of publications as shown in Table 2.^[8,26,29] The most frequently used study was by Bennett et al.^[8] where the incremental cost (cost for one additional patient) was assessed in a study of 126 hospital patients at the University of Florida. Outpatient costs were estimated by applying an assumed cost/charge ratio to fee schedules and wholesale medication costs. A panel provided frequency estimates for services and medications. The study by Younossi et al.^[26] used Medicare fee schedules and physician assessment of cost frequency to estimate the cost of chronic hepatitis C and cirrhosis.

A considerable number of studies were published on liver transplantation cost,^[16,30–43] which were consolidated and analysed by a recent meta-analysis.^[16] The mean cost of liver transplantation was estimated at $201 110 (2010 US dollar) with a 95% confidence interval of $178 60–$223 460. Subsequent years' cost was estimated at $37 535 with a range of $30 550–$46 750 in 2010 dollars.^[8,44]

Discussion

According to a database of drugs in development by Thomson Pharma,^[45] there are approximately 100 drugs in development to treat hepatitis C. Over the next decade, a number of new therapies will become available. A good understanding of the cost of hepatitis C sequelae is important to assess the value of the new treatments.

Top-down studies use national survey results to estimate the total cost attributed to chronic liver diseases, hepatitis C, and HCC. The NHDS is an annual survey conducted by the Center for Disease Control and Prevention that collects data on the characteristics of inpatients discharged from non-Federal short-stay (<30 days) hospitals in the United States.^[46] Data are collected from 239 hospitals and include demographic information and length of stay, as well as patients' diagnoses and procedures coded to International Classifications of Diseases (ICD). The NAMCS collects demographic data, reason for the visit, services provided, diagnostic procedures, diagnosis by ICD code, drugs prescribed, patient management, and planned future treatment from office based physicians.^[47] The survey includes results from 1600 responding physicians and about 42 000 patient visits. The NHAMCS gathers data from hospital emergency and outpatient departments as well as ambulatory surgery centres.^[47] All of the above surveys exclude Federal, military, and Veteran's administration hospitals. These surveys do have limitations. Extrapolation is carried out from a small sample. One case may be reported multiple times if it involves multiple visits, and they under-report cases that do not involve visits to hospitals, outpatient centres, or physician offices (e.g., veterans who have a higher prevalence of hepatitis C).^[48] However, despite these limitations, they have been used to estimate the number of cases and duration of treatment by disease.

The studies took different approaches for estimating the associated cost. Work by Leigh et al.^[20] started with the total national expenditure of $1035 billion on medical care in 1996, portioned it to hepatitis C based on hospital days, and adjusted it by including assumptions for outpatient visits. The NIH report relied on nationally reported costs, Medicare costs, and audit sales data for prescription drugs.^[19] Hospital costs were estimated from the Healthcare Cost and Utilization Project (HCUP NIS), which collects data on hospital inpatient stays.^[49] It includes data from 37 states reporting approximately 8 million hospital stays each year. The data collected include demographic, admission and discharge status, length of stay, total charges and payment source as well as diagnosis using ICD codes. In the top-down approach, billed charges were used as a surrogate for the total cost of patient services. For hospital charges, cost-to-charge ratio from the Center for Medicare & Medicaid Services^[50] was used to calculate total cost. Medicare reimbursement rates were used to estimate physician charges. Prescription drug costs were estimated from audited data provided by Verispan.^[19] The American Gastroenterological Association (AGA) also published a study reporting the cost burden of digestive diseases, but their study was later updated by the NIH report.^[19,21]

All top-down studies relied on the same data set, and yet, there was considerable variability in the projected cost (e.g., $694–$1660 million for chronic hepatitis C as shown in Table 1). The large difference in the forecast was because of two factors: methodology and number of cases over time. Not all studies used the same methodology to estimate total number of cases or cost. For example, the study by Leigh et al. used the ICD code for liver diseases (and adjusted for percentage that can be attributed to hepatitis C) rather than the code for hepatitis C because they felt that hepatitis C cases were under-recorded by the hospitals. In their cost estimates, they also included health care expenditure cost such as construction of new hospitals, arguing that without hepatitis C, some portion of these new expenses would not be necessary. Overall, their estimated direct cost attributed to chronic hepatitis C ($1660) in 1997 was substantially higher than estimates by the NIH ($1065) in 2004.^[19,20] Top-down studies captured costs at a particular point in time. Comparison across years and studies is feasible for diseases whose population is steady over time. However, this was not the case with HCV infection and its sequelae. As an example, HCC cases doubled between 1985 and 1998, making comparison across years difficult.^[23]

Comparison across top-down studies was not possible. There were too many variables changing across studies to allow direct comparison. That said, the NIH report was the gold standard in this group of studies. It was the most recent analysis, the editor was involved in the earlier AGA study and would have adjusted for the shortcoming of the earlier study, and it provided the most robust methodology. It should be noted that top-down analyses captured total costs including prescription drugs. In the NIH report, 47% of the annual cost associated with chronic hepatitis C was attributed to drug costs.^[19] Top-down studies are based on a set number of cases at a point in time. Coupled with an epidemiology study, the bottom-up analysis lends itself more readily for estimating the cost of the disease burden in the absence of treatment or the economic benefits of new treatment.

There was considerably more consistency among the bottom-up analyses. However, further research into the origins of the assumptions found that nearly all studies were using data reported by Bennett et al. in 1997.^[8] In this original study, the incremental cost (cost for one additional patient) was assessed in a study of 126 hospital patients at the University of Florida. Outpatient costs were estimated by applying an assumed cost/charge ratio to fee schedules and wholesale medication costs. A panel provided frequency estimates for services and medications. The fixed costs (cost of purchasing new building, equipment, etc.) were not considered. On an individual patient level, this is a safe assumption. However, at an infected population level, this approach will underestimate the total cost as the incidence of morbidities increases. Finally, this study reported the variable cost and diagnosis-related group cost. Nearly all subsequent reports used the variable cost only, which again underestimated the total cost associated with the sequelae. A couple of investigators did develop independent cost analyses, which were substantially different. A study by Younossi et al.^[26] used Medicare fee schedules and physician assessment of cost frequency to estimate the cost of decompensated cirrhosis ($585 per year in 2010 US dollars vs$1110 from Bennett et al.). However, the same study used cost estimates from the Bennett study for HCC and liver transplantation. Kim et al.^[29] used HCC annual costs from a 1994 NIH report based on a top-down approach. The top-down cost was $23 755 per year in 2010 US dollars vs$44 200 from Bennett et al. The cost of liver transplantation was studied by many authors.^[16,30–43] A recent meta-analysis by van der Hilst et al. consolidated all previous work to report a total cost of $201 110 (2010 US dollar) per liver transplant with a 95% confidence interval of $178 60–$223 460 (2010 US dollar). They showed that the cost of liver transplantation was 57% higher in the United States as compared to the Organization for Economic Cooperation and Development (OECD) countries. This analysis is considered the gold standard owing to its wide scope and the robustness of the methodology. It excluded the work by Bennett et al., which estimated at $174 935 (2010 dollar), lower than the range provided by the meta-analysis. The cost in subsequent years was reported by two studies:^[8,44] mean of $37 535 per year in 2010 dollars with range of $30 550–$46 750. Again, the cost estimate by Bennett et al. ($30 550 per year) was at the lower end of the range. The higher end of the range was defined by change in cost liver transplantation over the years.

Our analysis highlights the need for more updated cost studies. The historical cost burden analyses relied on data that were over 10 years old, and may not reflect the current clinical practice. The old data most likely underestimate the current costs even after adjustment for inflation. As an example, the variable cost associated with mild chronic hepatitis was estimated at $146 per patient per year in 2010 dollars.^[8] A more recent study reported that, excluding the outpatient visit, the cost of HCV antibody testing and HCV RNA PCR testing was $107 and $300, respectively, in 2006.^[51] Future studies could leverage insurance claim data, which have been shown to be an important source to reflect current standard practices.^[52,53]

Finally, the cost burden of hepatitis C also has an indirect cost component. A number of studies estimated the indirect cost defined as the cost of forgone earnings or production owing to hospitalization, ambulatory care, work loss owing to acute or chronic infection, and premature death.^{[19–21,24,29]} In most cases, the indirect cost was higher than the projected direct expenses. The total annual indirect cost was estimated at $51–$3370 million in the reported year (see Table 1). At the lower end of the range, only productivity loss owing to time away from paid labour was considered.^[21,29] At the high end of the range, production loss owing to early death was added. The most recent study for indirect cost was published by the NIH, which estimated the indirect cost at $2847 in 2004.^[19] Hospital and ambulatory data were used to estimate foregone earnings. Loss owing to early death was estimated using forgone lifetime earnings to age 75. Overall, hospital stays, ambulatory care, and mortality accounted for $46.6, $51.2, and $1685.7 million respectively in 2004. However, this technique underestimated the cost associated with work and leisure loss that did not result in hospitalization or physician visits. Using a completely different approach, Su et al.^[24] estimated the indirect cost associated with disease-related absence using data from multiple large employers in the United States by comparing record of employees with and without HCV. They attributed an increase of $490 (2007 dollar) per person per year in indirect costs to HCV infection.

Over the next decade, a number of new therapies will become available to treat hepatitis C. The debate over the cost effectiveness of these new therapies will depend on the comparison of no treatment, treatment with pegylated interferon and ribavirin, and treatment with new therapies/combinations. This review reported all relevant cost studies in the United States by different categories: top-down, bottom-up, direct, and indirect. The top-down analyses could not be compared directly with bottom-up estimates, as the former represented the cost and duration and number of hospital and physician visits in a particular year while the latter focused on cost per year for each sequelae. The indirect cost, cost associated with loss of productivity and early death, can be substantially higher than direct costs—cost of physician visits, hospitalization, diagnosis, and treatment. Although bottom-up estimates are more appropriate for scenario-based cost burden analysis, most sequelae costs date back to analyses in the 1990s. Updated cost analyses would help stakeholders make informed decisions when choosing among future therapeutic alternatives.

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CROI 2012: Prometheus Index Predicts Hepatitis C Treatment Response

Jim Kling

March 14, 2012 (Seattle, Washington) — In patients monoinfected with hepatitis C virus (HCV), a modification of the Prometheus index reliably estimates the probability of achieving a sustained virologic response with pegylated interferon plus ribavirin therapy, according to research presented here at the 19th Conference on Retroviruses and Opportunistic Infections.

This finding, presented at a poster session by José Medrano, MD, a clinical investigator at Hospital Carlos III in Madrid, Spain, could help patients and physicians decide whether to proceed with currently available therapies or to wait for novel therapies that are in development and will likely be available in the near future.

The Prometheus index — which incorporates interleukin (IL)28B variants, HCV RNA level, HCV genotype, and liver fibrosis — has been used to successfully predict sustained virologic response in patients coinfected with HIV and HCV.

To determine the ability of the index to predict response to treatment in HCV-infected patients, Dr. Medrano and colleagues conducted a multicohort study at clinics in France and Spain. The study involved 422 interferon-naïve patients who had undergone elastometry in the previous 12 months to assess liver fibrosis, serum HCV RNA measurement, HCV genotyping, and IL28B testing. The team excluded patients who had discontinued therapy because of adverse effects or who had poor drug compliance.

Of the 422 patients, 245 were coinfected with HIV and HCV and 177 were monoinfected with HCV.

The team found that the Prometheus index was worse at predicting treatment outcome in HCV monoinfected patients (area under the receiver operating characteristic [AUROC], 0.77; 95% confidence interval [CI], 0.70 to 0.84) than in HIV/HCV coinfected patients (AUROC, 0.87; 95% CI 0.83 to 0.92; P = .01).

The team then developed a new index that incorporated HIV status and HCV-1 subtype. They confirmed that a number of variables were independently associated with a failure to achieve sustained virologic response in HCV monoinfected patients: liver stiffness; HCV RNA level; IL28B favorable allelic variants (CT/TT; odds ratio [OR] 5.241; 95% CI, 3.097 to 8.870; P < .01); HCV genotypes 1 to 4 (OR, 9.128; 95% CI, 4.156 to 20.047; P < .01); and HIV-positive status (OR, 1.554; 95% CI, 0.929 to 2.599; P = .09).

The Prometheus index can be used in its current form to predict responses in HCV monoinfected patients, but clinicians "must know that prediction will be less accurate than in HIV/HCV coinfected patients," Dr. Medrano told Medscape Medical News.

The results might find application in settings with limited resources. "You could limit antivirals, which are very expensive, to patients with a lower probability of a virologic response," Dr. Medrano said.

The Prometheus index is available for the iPhone, iPad, and Android phones, but the modified Prometheus index is still being developed and will require further validation, he explained.

The index could help physicians and patients decide whether to pursue antiviral therapy now or to wait for new drugs on the horizon, according to Dawn Fishbein, MD, medical director of SAIC-Frederick's Partnership for HIV/AIDS Progress in Washington, DC, who attended the session.

"The side-effect profile [of currently available drugs] is enormous. It's important when we talk to a patient to say: 'This is the prediction of how you're going to respond now, so perhaps you should wait for newer treatments or you should do treatment now'," Dr. Fishbein told Medscape Medical News.

Dr. Medrano and Dr. Fishbein have disclosed no relevant financial relationships.

19th Conference on Retroviruses and Opportunistic Infections (CROI): Abstract 761. Presented March 7, 2012.

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