Rapid HIV Test Results Better With Blood

By Michael Smith, North American Correspondent, MedPage Today
Published: January 23, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

A rapid HIV test gives slightly less exact results when used with oral samples compared with blood samples, researchers reported.

In pooled results from a systematic review and meta-analysis, the sensitivity of the Oraquick rapid test was 98.03% when oral samples were used, compared with 99.68% using blood, according to Nitika Pant Pai, MD, of McGill University Health Centre in Montreal, and colleagues.

On the other hand, the specificity of the test was similar regardless of the type of samples at 99.74% for oral samples and 99.91% for blood, Pant Pai and colleagues reported online in The Lancet Infectious Diseases.

The Oraquick test, originally approved as a point-of-care HIV test for use with blood, received approval from the FDA in 2004 for use with oral mucosal transudate, the researchers noted. The test has become especially popular in developing countries.

Given the increased emphasis on HIV testing, data on the performance of the Oraquick test using the different sampling approaches will be important to help clinicians and patients interpret results, they argued.

Pant Pai and colleagues analyzed data from 45 studies, including 24 that could be used to understand the comparative accuracy of the test using oral or blood samples, and 21 that could be used to analyze positive predictive values. Because they depend on prevalence, positive and negative predictive values can only be derived from cross-sectional or other population-based studies.

Seven of the 24 accuracy studies contained head-to-head comparisons, while six only gave results for oral samples and 11 only looked at whole blood samples.

Pooling the analyses showed that the sensitivity of the test was about 2% lower when oral samples were used, but specificity was about the same, the researchers reported. In other words, using oral samples was likely to yield more false-positive results.

The researchers calculated positive predictive values using the 21 studies that permitted the analysis. They found that the test's value was similar regardless of sample type in high-prevalence regions, but differed if prevalence was low.

In high-prevalence groups, defined as more than 1% of the population infected with HIV, the positive predictive value of the test was 98.5% using blood samples and 98.65% using oral samples.

But in low-prevalence populations, the value for blood samples was 97.65% compared with 88.55% for oral samples.

Put another way, if the prevalence is low, a positive result using oral samples is less likely to be correct than if blood were used.

The researchers cautioned that although the test's sensitivity seems to be lower with oral versus blood specimens, the estimates "were at the extreme upper end of the range and there is a great deal of overlap" in confidence intervals.

It's possible that the "clinical significance of this difference might also be overshadowed by intrinsic variability in host status and time of testing relative to exposure," they added.

Much of the data comes from high-income settings and the rest from well controlled studies in developing settings, they noted, so the results may not reflect routine testing services in poorer areas.

Finally, the results only apply to the Oraquick test, they wrote.

The Oraquick test is attractive because it is convenient and non-invasive, commented Chi Chiu Leung, MBBS, of the Hong Kong Department of Health, and Shui Shan Lee, MD, of the Chinese University of Hong Kong.

Those characteristics might help increase the rate of HIV testing, they argued in an accompanying comment article, but they appear to come "at the cost of a substantial false-positive rate."

That false-positive rate has to be taken into consideration by clinicians as the rapid test becomes more widely used, they concluded, especially in areas where the prevalence of HIV is low.

Confirmatory testing will remain important, given that the diagnosis of HIV has such profound implications, they wrote.

The study was supported by the Canadian Institutes for Health Research. The authors said they had no conflicts of interest.

The comment authors said they had no conflicts of interest.

Primary source: The Lancet Infectious Diseases
Source reference:

Pant Pai N, et al "Head-to-head comparison of accuracy of a rapid point-of-care HIV test with oral versus whole-blood specimens: a systematic review and meta-analysis" Lancet Infect Dis 2012.

Additional source: The Lancet Infectious Diseases
Source reference:

Leung C, Lee S "Rapid HIV tests: from meta-analysis to field application" Lancet Infect Dis 2012.

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Teens Lacking in Protection Against Hepatitis A

By Todd Neale, Senior Staff Writer, MedPage Today
Published: January 23, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Most adolescents have not been vaccinated against hepatitis A virus, leaving them vulnerable to serious disease as they move into adulthood, a cross-sectional study showed.
In 2009, only 42% of U.S. teens ages 13 to 17 had received at least one dose of the vaccine and only 29.5% had received two doses, according to Christina Dorell, MD, MPH, of the CDC's National Center for Immunization and Respiratory Diseases in Atlanta, and colleagues.
Rates were highest in states that had been covered by recommendations for routine hepatitis A vaccination the longest, the researchers reported in the February issue of Pediatrics.

Finally, in 2006, ACIP recommended routine vaccination for all U.S. children starting at age 1, bringing the remaining 33 states and the District of Columbia into the fold.

Gradual implementation of the recommendations has been associated with a dramatic drop in rates of hepatitis A infection in the U.S. The virus likely will persist, however, because of introductions through contaminated food, international travel, and international adoption, placing unvaccinated individuals at risk.

To assess vaccine coverage in U.S. adolescents, Dorell and colleagues turned to the 2009 National Immunization Survey-Teen, which collected information through landline telephone surveys of parents and guardians and mailed surveys of vaccination providers.

Most of the 20,066 teens, ages 13 to 17, included in the current analysis had not received any doses of vaccine by 2009.

One-dose coverage was 74.3% among the states covered by a routine vaccination recommendation since 1999; 54% among those covered by a recommendation for consideration of the vaccine since 1999; and 27.8% for the remaining states not covered by a recommendation until 2006.

The most consistent predictor of having been vaccinated was receipt of a recommendation from a healthcare professional. That was associated with a 30% to 160% relative increase and 21% to 34% absolute increase in coverage rates among the three groups of states.

"Recommendations from healthcare providers increase parental acceptance of vaccination, and parents change their minds about delaying and refusing vaccines because of information or assurances from healthcare providers," according to Dorrell and colleagues.

Only one-quarter of the teens in the study received such a recommendation, however.

"Provider concerns about vaccine reimbursement and insurance coverage and some physicians' perception that hepatitis A is not a significant health problem have been identified as barriers to recommending [the vaccine]," the authors wrote.

"As a result, it may be useful to continue educating vaccination providers about the severity of hepatitis A infection among adolescents and adults and the safety and high efficacy of [the vaccine], which can be given to anyone needing or wishing protection."

Aside from provider input, other factors that were tied to vaccination rates were presence of a state requirement, racial and ethnic background, type of living area (urban, suburban, or rural), household income, and geographic region.

The researchers acknowledged some limitations of the study, including the possibility that it may not be representative of households without landline telephones. Also, they relied on parental report to determine whether a healthcare provider gave a recommendation about the vaccine. There was the possibility of nonresponse bias and the potential for incomplete information from the provider regarding vaccination.

The authors reported that they had no conflicts of interest.

Primary source: Pediatrics
Source reference:
Dorell C, et al "Hepatitis A vaccination coverage among adolescents in the United States" Pediatrics 2012; 129: 213-221.

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FDA Warnings Not Heeded Equally

By Kristina Fiore, Staff Writer, MedPage Today
Published: January 23, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

The attention paid to FDA notices about drug risks appears to be highly variable, with some notices having a wide impact and others garnering a delayed response or none at all, researchers found.

In a review of the literature, serious adverse event warnings appeared to be most heeded of all FDA communications, but response still varied depending on the drug, Caleb Alexander, MD, of the University of Chicago, and colleagues reported in Medical Care.

For instance, use of rosiglitazone (Avandia) fell tremendously after an FDA warning about cardiovascular events associated with use of the drug

On the other hand, cautioning against the use of long-acting beta-agonists (LABAs) without inhaled controller medications didn't impact the use of those drugs in asthma, the researchers found.

"We will need a better understanding of how to make [FDA risk communications] work, and where they can go wrong," Alexander said in a statement. "And we will need more and better studies of the successes and failures of this process."

To assess the full impact of FDA risk communications on the use of drugs and other outcomes, the researchers looked at 49 studies, published between 1990 and 2010, that evaluated the success of these notices.

They divided the notices into four categories:

• Warnings about serious adverse events
• Recommendations against use in specific subpopulations
• Prevention of drug-drug interactions
• Calls for increased lab or clinical monitoring

Warnings about potential serious adverse events with specific drugs were associated with large drops in use of those agents, but the impact varied by drug, as seen with rosiglitazone versus LABAs, the researchers found.

Notices about use of drugs for certain populations tended to spill over into others, they reported. For instance, a warning about antidepressant use in children and adolescents led to declines in their use among adults as well.

"As with other public policies, FDA communications have the potential for unintended consequences," they wrote.

They also found that warnings about drug-drug interactions appeared to take a long time to be put into practice. Several studies found the largest declines in cisapride (Propulsid) co-prescribing happened only after a third FDA warning, and the greatest drop in terfenadine (Seldane) co-prescribing didn't occur until 18 months after the initial notice.

Finally, there was no evidence that practitioners heeded recommendations about increased monitoring, though some may have done so transiently, Alexander and colleagues found.

Rates of glucose testing for patients on antipsychotics, for example, went unchanged after the FDA advised keeping watch for hyperlipidemia and diabetes, while rates of liver enzyme monitoring after a black box warning for troglitazone (Rezulin) increased slightly after FDA warnings, but waned again over time.

Studies that assessed provider attitudes about FDA communications generally found high levels of clinician awareness of warnings and label changes.

The researchers concluded that based on settings where incident and prevalent use were examined, notices are adopted more quickly for new patients rather than those continuing on their medication.

They also said the findings suggest that "warnings will be most effective in cases where they are specific, where acceptable alternatives are available, and where the messaging is reinforced over time."

They called for more research on factors associated with fast and sustained responses to risk communications, and continued work on characterizing the effects of advisories and warnings on a variety of behaviors "to enhance the science of risk communication regarding prescription drugs."

The study was limited by the heterogeneity of the included analyses and because regulatory advisories have a level of complexity that may not be fully captured by the studies.

The researchers reported no conflicts of interest.

Primary source: Medical Care
Source reference:
Dusetzina SB, et al "Impact of FDA drug risk communications on healthcare utilization and health behaviors: A systematic review" Med Care 2011.

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Experimental hepatitis C vaccine tested

Published on Monday 23 January 2012 23:44

“An early clinical trial of a hepatitis C vaccine has shown ‘promising’ results,” BBC News has today reported.

This story is based on a clinical trial that tested the dosage and safety of a newly developed vaccine against the hepatitis C virus. Researchers developed a vaccine by inserting small pieces of DNA from a hepatitis C virus into a rare form of the virus that causes the common cold. When faced with a vaccine like this, the body should mount an immune response and ‘remember’ the virus so that it can respond swiftly to any potential infections in the future. The researchers found that cells indicating immunity to the virus were present for a year in 41 healthy people who were vaccinated. This suggests that the immune system was prepared to respond if faced with the virus. None of the people involved with the study experienced significant side effects.

This was an early-stage clinical trial designed to test the safety of the vaccine rather than whether it could prevent infections. Extensive further research will now be needed to determine effectiveness, particularly whether or not it can prevent hepatitis C infections in real-life settings. Given the complexities of testing and development, it is likely to take many years before any such vaccine could enter clinical use.

Where did the story come from?

The study was carried out by researchers from the Universities of Oxford and Birmingham, and from institutions throughout Italy. The research was funded by the European Union, the UK Medical Research Council, the Wellcome Trust, the UK National Institute for Health Research and the US National Institutes of Health.

The study was published in the journal Science Translational Medicine.

The media reported on this study appropriately, with both the BBC and the Daily Mirror emphasising the early nature of the research and the fact that the possibility of a working vaccine is still several years away.

What kind of research was this?

This was a phase I clinical trial that tested the safety and tolerability of a new vaccine intended to prevent infection with the hepatitis C virus. The virus primarily affects the liver, causing inflammation and damage to the organ. It can lead to severe liver scarring (cirrhosis) and liver cancer. There are currently no vaccines available to protect against infection with hepatitis C, and treatments vary in effectiveness depending upon the specific strain of the virus causing the infection.

The Health Protection Agency estimates that more than 200,000 people have the disease in the UK, and that many carry the virus without knowing it. Approximately 20% of people infected with the virus have a natural immunity to it and will clear the virus within the first six months after infection, before the disease is considered to be chronic. Among those who develop chronic hepatitis C, most can clear the infection with the help of drugs, although not all respond to treatment and some remain chronically infected. As a blood-borne virus, it is particularly common among intravenous (IV) drug users.

The development of an effective vaccine would be invaluable, as the World Health Organization estimates that around 130-170 million people around the world have chronic hepatitis C, and therefore could pass the infection on. Certain countries are also reported to have very high rates of hepatitis C, with around 22% of the Egyptian population having a chronic infection.

Phase I clinical trials are conducted in small groups of healthy individuals, and are designed to test the safety and tolerability of new drugs and therapies. They are not designed to test the effectiveness of new treatments, although the results are used to determine the dosing regimen that should be used in future studies. Such small, early studies are required before larger, longer-term research can be conducted to assess the effectiveness of the therapy.

What did the research involve?

The researchers made the vaccine by inserting small pieces of DNA from the hepatitis C virus into a rare form of the virus that causes the common cold. They injected 41 healthy volunteers with the vaccine, and collected data on any side effects, as well as the scale and duration of the immune response. Two rounds of the vaccine were given – an initial priming dose and a subsequent boosting dose four weeks later.

They first conducted ‘dose-escalation’ studies to determine the size of vaccine dose that produced an optimal immune response. The researchers divided the volunteers into groups of four or five people, with each group being given a different dose of the vaccine. They assessed the immune response and tolerability of the vaccine at each of these increasing doses.

The researchers also assessed, in laboratory experiments, whether the immune responses would hold against different strains of the hepatitis C virus, including the strain most commonly affecting European IV drug users (a group that is at highest risk of hepatitis C infection in the UK). To do this they took a blood sample from the study participants, challenged the blood cells with proteins found in different strains of the virus, and analysed the immune response. This was done using laboratory tests. No participants were exposed to these viruses.

What were the basic results?

The researchers found that there were no serious side effects associated with the vaccine. They observed mild side effects that increased at higher doses, but they were short lived.

The researchers determined an optimal dose for the vaccine, and found that the immune response elicited by this dose was similar to that seen in people who have a natural immunity to the hepatitis C virus. They were able to detect this immune response up to a year after vaccination.

They found that the vaccine elicited an immune system response to multiple hepatitis C strains, including the strain that is most common to European IV drug users. The immune response to this strain was, however, approximately only 20% of the response seen to the strain used in the vaccine. Despite this lower response level, this was still higher than the response seen in control subjects not given the vaccine. This indicates that the vaccine did in fact produce some immune response against a common European strain of the virus.

How did the researchers interpret the results?

The researchers say that this study indicates that the vaccine can induce a sustained immune response to the hepatitis C virus, and that further clinical studies into its use as a preventative and therapeutic agent are needed. The next step, they say, is to test it in a setting where exposure to the hepatitis C virus is common, such as in IV drug users, which could help test whether the immunisation is an effective vaccine.

Conclusion

This was a small, early-stage human study into a new vaccine against the hepatitis C virus. While such research is required to determine the safety profile of a new therapy, little information on the effectiveness of the vaccine can be gleaned from the study.

Phase I clinical trials are designed to determine the optimal dose of a new therapy, and to assess the safety and tolerability of treatments. This study shows that the developed vaccine is well tolerated and safe to use, and the preliminary results indicate that the immune response may be similar to that of people with a natural immunity to the virus.

In addition to the small study size and the focus on safety and not effectiveness, there are other practical limitations to the study that should be considered before it is concluded that a preventative vaccine against hepatitis C will be available, even in the next several years:

• Further research is needed to determine whether the vaccine will be effective over a longer period than a year.
• The researchers say that the specific strain of the hepatitis C virus used in the vaccine is common in the US, but that it is not the most common strain in the UK. This may limit how useful any future vaccine is in this country.
• The researchers point out that there are difficulties surrounding the design and execution of future trials, as the virus is common to specific subgroups of people. Future trials will need to be conducted in high-risk groups in whom the predominant virus strain is the same as the strain used to develop the vaccine.

All in all, this was an important initial study into the development of a vaccine against a virus that is difficult to detect and treat. As this was an early-stage study, it will be several years before it could potentially result in an available vaccine.

Source

New Hepatitis C Regimen Stimulates Changes in Therapy Management

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.

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.

Source

Study finds the love of a dog or cat helps women cope with HIV/AIDS

January 23, 2012

A spoonful of medicine goes down a lot easier if there is a dog or cat around. Having pets is helpful for women living with HIV/AIDS and managing their chronic illness, according to a new study from the Frances Payne Bolton School of Nursing at Case Western Reserve University.

"We think this finding about pets can apply to women managing other chronic illnesses," said Allison R. Webel, instructor of nursing and lead author of the article, "The Relationship Between Social Roles and Self-Management Behavior in Women Living with HIV/AIDS," which appears in the online journal Women's Health Issues.

Webel set out to better understand how women manage their HIV/AIDS and stay on track to take their medications, follow doctors' orders and live healthy lifestyles. She conducted 12 focus groups with 48 women to find out what they did to stay healthy. The women had an average age of 42, about 90 percent had children, and more than half were single.

During the focus groups, six predominant social roles emerged that helped and hindered these women in managing their illness: pet owner, mother/grandmother, faith believer, advocate, stigmatized patient, and employee. All roles had a positive impact except stigmatized patient, which prevented women from revealing their illness and seeking out appropriate supports.

"Much information is available about the impact of work and family roles, but little is known about other social roles that women assume," Webel said.

Being a pet owner was an important surprise, added Webel, who collaborated with co-author Patricia Higgins, a professor of nursing at Case Western Reserve University.

"Pets—primarily dogs—gave these women a sense of support and pleasure," Webel said.

When discussing the effect their pets have on their lives, the women weighed in. "She's going to be right there when I'm hurting," a cat owner said. Another said: "Dogs know when you're in a bad mood…she knows that I'm sick, and everywhere I go, she goes. She wants to protect me."

The human and animal bond in healing and therapy is being recognized, Webel said, as more animals are visiting nursing homes to connect to people with dementia or hospitals to visit children with long hospital stays.

Being a pet owner is just one social aspect of these women's lives. "We found the social context in which this self-management happens is important," Webel said.

Another strong role to emerge was advocate. Participants wanted to give back and help stop others from engaging in activities that might make them sick, the researchers report.

While roles as mothers and workers are well documented, "less-defined social roles also have a positive impact on self-management of their chronic illness," Webel said.

Provided by Case Western Reserve University (news : web)

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High Prevalence of Hep B in Cambodia: Doctor

Monday, 23 January 2012

Soeung Sophat, VOA Khmer | Washington, DC

Hepatitis B, a disease that attacks the liver, has high prevalence in Cambodia, but there are now a number of drugs to treat it, a US doctor said Thursday.

Taing Tek Hong, a Florida-based physician, told “Hello VOA” that the US Food and Drug Administration has approved the following drugs to treat hepatitis B: Interferon alpha-2b, Peg Interferon alfa-2a, Lamivudine (Epivir-HBV), Adefovir (Hepsera), Entecavir (Baraclude), Telbivudine (Tyzeka), Tenofovir (Viread).

In 2002, as many as 13 percent of Cambodian blood donors tested positive for the antigen of the Hepatitis-B virus, he said. Another study showed prevalence of around 12 percent for people aged 20 to 35.

Chronic infection affects most infants, around a third of infected children below age five and around 6 percent of anyone affected age six and above, he said. Chronic infection leads to death in around 15 percent to 25 percent of patients, he said.

“Hepatitis B can be transmitted by sexual contact, sharing of needles and syringes contaminated with infected blood, accidental needle sticks, or mother to child,” Taing Tek Hong said. “Risk factors include unprotected sex with more than one partner, unprotected sex with someone who’s infected with HBV, having a sexually transmitted infection, such as gonorrhea or chlamydia, men who have sexual contact with other men, and sharing needles during IV-drug use.”

Other risks include living in a household with someone with a chronic infection, working where exposure to blood is common, receiving dialysis or traveling to regions like Africa, Central and Southeast Asia and Eastern Europe, he said.

Source

Your liver is for life - so treat it well

Vicky Fenton and Dr Alexander Grimson

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%.

Source

Community Health Center launches new video conferencing technology

Published: Sunday, January 22, 2012; Last Updated: Monday, January 23, 2012 12:43 AM EST

By JIM SALEMI
Press Staff

MIDDLETOWN — Community Health Center unveiled a new tool Friday that will allow it to lend the expertise of CHC HIV specialist to other CHC clinics that do not have such specialists.

Called Project ECHO Hepatitis C/HIV, is a state of the art video conferencing system that allows for multiple clinics in the CHC system to link together to share expertise and information to treat HIV and Hepatitis C patients.

The purpose of the project, according to Eliza Cole, spokeswoman for CHC, is to provide specialist support and education to help primary care teams manage cases that would otherwise be referred out to specialists.

“This system will allow us to offer specialized treatment to patients across the state, many of whom do not have access to such treatment otherwise. In many communities there are few specialists willing to accept patients without insurance or with Medicaid insurance,” Dr. Marwan Haddad, Medical Director of HIV, HCV, and Buprenorphine Services for CHC.

The system was developed by the University of Mexico originally to allow for treatment of Hepatitis C and HIV in rural areas via video-conference with a specialists. With the new video conferencing technology, CHC will be able to extend treatment to six clinics in the CHC system that do not have HIV care specialists. Those clinics include Bristol, Norwalk, Waterbury, Enfield, Clinton, and New London.

CHC offers HIV and Hepatitis C treatment at its New Britain, Meriden, and Middletown clinics.

Five of those clinics without a HIV hepatitis C specialist were linked up with a five member panel of medical, behavioral and pharmaceutical experts in Middletown in a conference room at the organization’s offices on Main Street.

A large panel, flat screen monitor hung on the wall with its screen divided into six parts. A large camera on a table under the monitor was aimed at the table where the CHC staff were seated. A microphone was at the center of the table. The staff looked at patient information on their laptops as they asked questions of health care experts at CHC locations in Waterbury, New London Clinton, Norwalk and Bristol and offered advice or asked for additional information about the patient's history, medications, psychiatric conditions, if any, and their medication regimens.

For some of the cases, financial counseling and keeping the patient on their regimens and scheduled visits seemed to be discussed as much as medical conditions.

“Some patients have a hard time following up because of costs and transportation issues,” Haddad told a physician in New London via the ECHO system while discussing a patient who skipped follow up visits.

“We need to try and correct that. The first barrier to treatment is cost or lack of insurance and transportation issues,” he told his colleague.

The program will eventually allow CHC to expand access to care for other conditions, such as diabetes, asthma and chronic pain management, Cole said.

The CHC Project ECHO Hepatitis C/HIV program is funded in part by a grant from The Mayday Fund and Vertex Pharmaceuticals Inc., in support of the ‘Hep-C Circle of Care’ program.

Source

Gender differences in liver cancer risk explained by small changes in genome

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

Public release date: 19-Jan-2012

Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine

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).

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4 billion enterprise.

Penn's Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools and among the top 10 schools for primary care. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $507.6 million awarded in the 2010 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital – the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2010, Penn Medicine provided $788 million to benefit our community.

Source

Many U.S. Adults Not Vaccinated for Hepatitis B

Missed opportunities lead to many new infections each year, study found

Last Updated: January 20, 2012.

Missed opportunities lead to many new infections each year, study found.

FRIDAY, Jan. 20 (HealthDay News) -- More than half (51.4 percent) of American adults at risk for hepatitis B infection have not been vaccinated, a new study says.

People at risk for hepatitis B infection, which can lead to liver disease, include those who share needles when using injectable drugs and those who engage in certain risky sexual practices. Previous research shows that 95 percent of new hepatitis B infections occur among people with these types of behavioral risk factors.

The finding about vaccination rates comes from researchers at Brown University in Providence, R.I., who analyzed data from 15,000 adults who took part in the 2007 U.S. Behavioral Risk Factor Surveillance Survey.

The study also found that more than half of those who weren't vaccinated had the potential to receive the vaccine. These missed opportunities are a reason why hepatitis B infections persist, the researchers said.

"This is a really simple thing that we could do, and if somebody ends up getting the disease because we didn't make the effort, then I think that's really a shame," study senior author Brian Montague, an assistant professor of medicine in the Warren Alpert Medical School of Brown University and a physician at the Miriam Hospital in Providence, said in a university news release.

The likelihood of vaccination was lower among people older than 33, those with less access to health insurance and those who are also unvaccinated against other diseases, such as the flu.

But even among those with access to health care, thousands of people had not been vaccinated against hepatitis B infection, the study found.

The researchers identified some locations where improved rates of hepatitis B vaccination would make a substantial difference. For example, hepatitis B vaccinations could be given when people are tested for HIV at the doctor's office, hospital, clinic or jail.

The study was published online Jan. 12 in the journal Infection.

More information

The U.S. National Institute of Diabetes and Digestive and Kidney Diseases has more about hepatitis B.

SOURCE: Brown University, news release, Jan. 19, 2012

Source

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

From Reuters Health Information

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.

Source

Also See:

1. First Hepatitis C Treatment Data Demonstrating Proof of Principle with Direct-Acting Antiviral-only Therapy Published
2. Hepatitis C treatment with antivirals is effective: study
3. Bristol-Myers Hepatitis C Pills Clear Virus Without Interferon
4. New Combo KOs HCV Without Interferon, Ribavirin
5. Combination of oral drugs suppresses common type of hepatitis C

Hepatitis C infection identified as leading risk factor for HCC

Posted on HemOncToday.com January 19, 2012

Yang JD. Mayo Clin Proc. 2012;87:9-16.

Liver-scarring diseases such as cirrhosis from alcohol consumption continue to present a high risk for the development hepatocellular carcinoma, but hepatitis C infection has been identified as the leading risk factor, according study results published in Mayo Clinic Proceedings.

Researchers analyzed trends in incidence, etiology and treatment of liver cancer among residents in Olmsted County, Minn. Using medical records from a community-wide medical record linkage system, they identified 104 residents aged older than 20 years diagnosed with hepatocellular carcinoma (HCC) from 1976 to 2008.

Divided into three eras based on time of diagnosis, the analysis demonstrated that the age- and sex-adjusted incidence rate for HCC in Olmsted County was 3.5/100,000 person-years for the first era (1976-1990), 3.8/100,000 for the second era (1991-2000) and 6.9/100,000 for the third era (2001-2008).

In the first era, alcohol use was identified as the most common cause of HCC, with no diagnoses of hepatitis C virus (HCV). In the second era, however, the percentage of HCCs attributable to HCV had risen to 25%, including 7.1% who were observed to have joint HCV and alcohol use as causes of HCC. In the third era, 21 of 47 patients diagnosed with HCC had evidence of chronic HCV infection.

The increase in the proportion of HCV most significantly affected patients aged 50 to 59 years — seven of eight exhibited HCV in the most recent era. Additionally, coexisting alcoholic liver disease was common in HCV patients who developed HCC at an age younger than 60 years: Six of eight HCV patients aged younger than 60 years had coexisting alcoholic liver disease, whereas only one (6.3%) of 16 patients aged 60 years or older had this coexisting disease (P,.01).

“The liver scarring from hepatitis C can take 20 to 30 years to develop into cancer,” W. Ray Kim, MD, principal investigator in the study, said in a press release. “We’re now seeing cancer patients in their 50s and 60s who contracted hepatitis C 30 years ago and didn’t even know they were infected.”

Disclosure: Study researcher Lewis R. Roberts, MBChB, PhD, reports receiving research grants from Bristol-Myers Squibb and MDS Nordion.

Source

American Red Cross Fined Millions for “Shoddy” Blood Collection—Again

January 20, 2012
Ruth McCambridge

January 19, 2012; Source: Care2 | The American Red Cross has been fined $9.6 million after the U.S. Food and Drug Administration (FDA) found hundreds of violations in its blood collection procedures. The fines have been levied against half of the blood collection centers nationwide. The violations—which include having donated blood infected with HIV, Hepatitis C and the West Nile Virus—were detailed in a 32-page Adverse Determination Letter (ADL) written by Evelyn Bonnin, the FDA Director of the Baltimore District and issued by the FDA. The letter details problems including poorly trained staff and inadequate record keeping where donated blood was mishandled or misplaced. In some cases, potentially infected blood was transfused into patients.

The Red Cross has responded that they are disappointed in the FDA for relying on the results of an inspection carried out 15 months ago. They say that they have cleaned up their procedures in the meantime and that their blood supply is “safer than ever.” But this argument may be difficult to sell since this is not the first time the Red Cross has been fined for such infractions. In fact, they have apparently been fined $47 million for similar violations since 2003. The FDA letter states, “many of the violations recounted in this letter are virtually identical to violations charged in previous ADLs. [The Red Cross] has known of these continuing problems and has failed to take adequate steps to correct them.” –Ruth McCambridge

Source

Surveillance for Hepatocellular Carcinoma in Patients With Cirrhosis

From Clinical Gastroenterology and Hepatology

Ju Dong Yang; W. Ray Kim

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).

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.

Management Strategies and Supporting Evidence

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). 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).

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.

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). 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. 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

1. 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.
2. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236.
3. 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.
4. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417–422.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.

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GAO asked to review VA quality-of-care policies

By Patricia Kime - Staff writer
Posted : Thursday Jan 19, 2012 17:57:33 EST

The top Democrats on the House and Senate Veterans’ Affairs committees are seeking an investigation of the Veterans Affairs Department’s handling of several incidents involving improper sterilization of reusable medical equipment.

The lawmakers say those problems could be an indication that VA leaders are not following their own guidelines for investigating such incidents or disciplining those responsible.

In a Jan. 19 letter to Government Accountability Office Comptroller Gene Dodaro, Sen. Patty Murray, D-Wash., and Rep. Bob Filner, D-Calif., asked for a GAO review of VA’s procedures and policies.

“We continue to hear about the same types of quality-of-care incidents at VA medical facilities and we are concerned this is an indication that VA is not effectively learning from these incidents and subsequently translating these lessons into system-wide improvements,” Murray and Filner wrote.

In the past seven years, more than 13,000 veterans treated at VA health facilities have been placed at risk for exposure to infectious disease such as hepatitis and HIV after undergoing procedures with improperly sterilized equipment.

From 2004 to 2009, 11,000 veterans at the Murfreesboro, Tenn., Augusta, Ga., and Miami VA medical centers were notified of their risk after they underwent colonoscopies with improperly prepared endoscopes.

At least 25 veterans contracted Hepatitis C, eight developed Hepatitis B and five tested positive for HIV.

In January 2011, surgeries at the St. Louis VA Medical Center were halted after VA found 1,812 vets were placed at risk from improperly sterilized surgical equipment.

And in Dayton, Ohio, VA offered to test 500 veterans for possible exposure after leaders determined a dentist didn’t change his latex gloves between patients.

“On numerous occasions, VA has reported to Congress about the various investigations it has conducted and the problems these investigations have identified, which they claim to have led to the development of new processes and procedures to reduce risk,” the lawmakers wrote.

In October, members of the House Veterans’ Affairs Committee were surprised to learn that Miami VA Medical Center Chief Mary Berrocal still had her job.

Berrocal received a letter of admonition in 2009 after the colonoscopy scandal surfaced but remained as chief until November, roughly a month after she testified that conditions at the facility were improving.

Her testimony came a week after a Miami VA employee was arrested for selling the names and personal information of 18 patients and compromising the personal data of 3,000 veterans, and three months after a veteran was allowed to leave the medical center when she should have been placed on suicide watch.

Veteran Catawba Howard was shot by police just hours after she left the medical center.

“This raises concerns as to whether VA’s leadership is taking appropriate actions, including appropriate disciplinary actions, to effectively address the problems across the system,” the lawmakers wrote.

VA spokesman Josh Taylor said Thursday that the department is committed to providing safe, high-quality care.

He said VA agrees with Murray and Filner that “every health care provider must ensure they follow good infection-control practices and that they send equipment for proper reprocessing. Failure to do so is unacceptable.”

Taylor added that VA has been recognized by the New England Journal of Medicine for its patient disclosure policy, what he called a “reflection of VA’s commitment to transparency.”

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