Young people are given hepatitis C option with NICE guidance

Thu, 28/11/2013 - 13:08

By News team

Peginterferon alfa with ribavirin is the only licensed treatment for young people with chronic hepatitis C

Treatment for children and young people with chronic hepatitis C should include the option of peginterferon alfa in combination with ribavirin, recommends the National Institute for Health and Care Excellence in its 300^th technology appraisal, issued today (27 November).

"Treatment with peginterferon alfa and ribavirin can decrease the hepatitis C virus to undetectable levels, effectively providing a cure for the disease. Early successful treatment is also likely to lessen the social stigma that can be associated with hepatitis C infection later in life," said Carole Longson, director of the NICE health technology evaluation centre.

Peginterferon alfa with ribavirin is currently the only licensed treatment in the UK for children and young people with chronic hepatitis C.

Source

Progression of Liver Disease in Children with Chronic HCV Infection

Provided by NEJM Journal Watch

November 21, 2013

Atif Zaman, MD, MPH reviewing Mohan P et al. Hepatology 2013 Nov.

Histologic changes were slow overall but did include a significant increase in bridging fibrosis or cirrhosis.

The rate of liver disease progression with hepatitis C virus (HCV) infection is well characterized in adults but not in children. Although most study data from Asia and Europe suggest that liver disease progression in children with HCV infection is very slow, data from several U.S. studies indicate that it is still a risk.

In the current retrospective study, investigators compared histologic findings from repeat biopsies in 44 treatment-naive children with HCV infection who were enrolled in a larger randomized treatment trial. Data were from two biopsies taken at least 1 year apart (mean time interval, 5.8±3.5 years). HCV infection was contracted via vertical transmission in 57% of children and via blood transfusion in the rest (except for 2 participants with unknown mode of transmission). The prevalence of genotype 1 infection was 84%.

Analyses of the repeat biopsies showed the following:

• Persistent minimal inflammation in 50% of patients

• Persistent absence of fibrosis in 16% of patients

• An increase in bridging fibrosis or cirrhosis from 11% to 20% (P=0.005)

• No correlation between worsening fibrosis and mode of HCV infection acquisition or demographic, clinical, or laboratory variables

Comment

This is the largest study to date evaluating the histologic progression of hepatitis C virus infection in the pediatric population. In general, histologic progression was quite slow during a 5-year time span in the majority of patients, but, similar to the adult population, a significant minority did have histologic progression. With the advent of more-effective, better-tolerated treatment regimens for HCV infection, considering HCV treatment in the pediatric population will be important, as these patients face many decades of infection and increased risk for histologic progression without treatment.

Disclosures for Atif Zaman, MD, MPH at time of publication Speaker’s bureau Bristol-Myers Squibb; Genentech; Gilead; Kadmon; Merck; Salix; Vertex

Citation(s):

1. Mohan P et al. Evaluating progression of liver disease from repeat liver biopsies in children with chronic hepatitis C: A retrospective study. Hepatology 2013 Nov; 58:1580. (http://dx.doi.org/10.1002/hep.26519)

Source

NICE final draft guidance recommends drugs to treat chronic hepatitis C in children and young people

(Ref: NICE)

October 11th, 2013

In final draft guidance published today NICE has confirmed its earlier draft guidance recommending peginterferon alfa in combination with ribavirin as an option for treating chronic hepatitis C in children and young people.

Hepatitis C is a blood-borne virus that infects the liver. Children and young people get the disease primarily from their mothers at birth. If the virus is not cleared from the body after an acute infection (defined as the first 6 months following initial infection) the condition can progress to chronic hepatitis C (long term infection, lasting more than 6 months). Although hepatitis C rarely causes serous liver damage in children, if left untreated chronic hepatitis C infection increases the risk of scarring of the liver(fibrosis and cirrhosis), liver failure and liver cancer in the future. Peginterferon alfa-2a (Pegasys, Roche Products) and peginterferon alfa-2b (ViraferonPeg, Merck Sharp and Dohme (MSD)), in combination with ribavirin are the only treatments currently licensed in the UK for the treatment of chronic hepatitis C in children and adolescents. They are also licensed for the treatment of chronic hepatitis C in adults.

Professor Carole Longson, NICEHealth Technology Evaluation Centre Director, said: "The independent Appraisal Committee concluded that treatment with peginterferon alfa and ribavirin can decrease the hepatitis C virus to undetectable levels, effectively providing a cure for the disease. Early successful treatment is also likely to lessen the social stigma that can be associated with hepatitis C infection later in life. By widening access to these drugs this guidance will give clinicians and people living with hepatitis C more treatment options."

NICE has not yet issued final guidance to the NHS. Consultees now have the opportunity to appeal the draft guidance. Until NICE issues final guidance, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its guidance on a technology it replaces local recommendations across the country.

Final guidance is likely to be published in November 2013.

Ends

1. The draft guidance will be available from 00:01hrs on Friday 11 October from the NICE website

2. Estimates from the Health Protection Agency in 2011 indicate that 26 people aged 1 year or less and 21 people between the ages of 1 and 14 years were newly diagnosed with HCV in England in 2010. Estimates for chronic infection in children and young people are not available.

3. The Assessment Group calculated that, based on an average age of 11 years, a body weight of 35.5 kg and a body surface area of 1.19 m², a 24-week course of peginterferon alfa-2a and ribavirin costs approximately £3700 while a 48-week course of treatment costs approximately £7400.

4. A 24-week course of peginterferon alfa-2b and ribavirin oral solution costs approximately £4000, while a 48-week course of treatment costs approximately £8100.

5. Ribavirin is manufactured by Roche Products (Copegus) and MSD (Rebetol). Each product is indicated for the treatment of chronic hepatitis C and must only be used as part of a combination regimen with peginterferon alfa or interferon alfa. The marketing authorisation for Copegus does not include specific recommendations for use in children. Copegus should be administered only in combination with the interferon products made by Roche Products (peginterferon alfa-2a or interferon alfa-2a). Rebetol (MSD) is available as an oral solution and 200 mg hard capsules and has a UK marketing authorisation for children and adolescents aged 3 years and older in combination only with MSD products peginterferon alfa-2b or interferon alfa-2b.

6. The cost effectiveness results suggested that peginterferon alfa-2a and peginterferon alfa-2b (each in combination with ribavirin were more effective and less costly than best supportive care.

7. The comparison between peginterferon alfa-2a and peginterferon alfa-2b was not robust enough for the Committee to recommend one treatment over the other.

8. NICE technology appraisals apply across the NHS in England and Wales.

9. The National Institute for Health and Care Excellence (NICE) is the independent body responsible for driving improvement and excellence in the health and social care system. We develop guidance, standards and information on high-quality health and social care. We also advise on ways to promote healthy living and prevent ill health.

Formerly the National Institute for Health and Clinical Excellence, our name changed on 1 April 2013 to reflect our new and additional responsibility to develop guidance and set quality standards for social care, as outlined in the Health and Social Care Act (2012).

Our aim is to help practitioners deliver the best possible care and give people the most effective treatments, which are based on the most up-to-date evidence and provideare value for money, in order to reduce inequalities and variation.

Our products and resources are produced for the NHS, local authorities, care providers, charities, and anyone who has a responsibility for commissioning or providing healthcare, public health or social care services.

To find out more about what we do, visit our website: www.nice.org.uk and follow us on Twitter: @NICEcomms

To read more Press Release articles, click here.

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Noninvasive Imaging Test Detects Liver Disease in Children

Medscape Medical News

Laurie Barclay, MD

Sep 25, 2013

Magnetic resonance elastography (MRE) is a new, noninvasive imaging test that accurately detects fibrosis in children, including those who are severely obese, with nonalcoholic fatty liver disease (NAFLD) and other forms of chronic liver disease, according to a case series. The findings of the case series were published online September 23 in the Journal of Pediatrics.

"Because many pediatrics patients in the United States with NAFLD are severely obese, MRE is likely to be superior to ultrasound-based elastography in this population, as ultrasound-based methods are less reliable in severely obese patients," lead author Stavra Xanthakos, MD, a gastroenterologist at Cincinnati Children's Hospital Medical Center in Ohio, said in a news release.

The increasing prevalence of obesity in the pediatric population has also driven the increasing prevalence of NAFLD, which is now estimated to affect 13% of adolescents, according to the release. Complications of NAFLD include progressive liver disease and liver failure.

In 2011 and 2012, 35 patients aged 4 to 20 years (median, 13 years) with chronic liver disease underwent MRE and liver biopsy. Median body mass index percentile was 99.2.

Compared with liver biopsy as a gold standard, MRE was highly accurate in detecting fibrosis of stage 2 or greater, even in severely obese patients. Using a cutoff of 2.71 kPa, sensitivity for detecting significant fibrosis was 88% and specificity was 85%, with an area-under-the–receiver operating characteristic curve of 0.92 (95% confidence interval, 0.79 - 1.00; P = .02).

MRE Promising, but "Not Yet Ready for Primetime"

MRE, which uses magnetic resonance and low-frequency sound waves to measure tissue stiffness, can be performed in several minutes. At Cincinnati Children's Hospital Medical Center, more than 200 children have undergone liver MRE, with no reported adverse events. In this case series, only 1 patient, aged 4 years, required sedation.

If the findings are confirmed in larger series, use of MRE could reduce the need for liver biopsies to diagnose fibrosis. The latter technique is expensive, invasive, associated with risks, and may be frightening for children and adolescents. Furthermore, biopsy results may be misclassified because of sampling error, insufficient tissue sample size, or fragmentation.

"Having the ability to easily and noninvasively assess the degree of fibrosis in a child's liver could help us identify the issue early and bring the right course of treatment in a timely and effective manner," coauthor Daniel Podberesky, MD, chief of thoracoabdominal imaging at the medical center said in the news release. "An added strength of magnetic resonance technology is the ability to more precisely measure liver fat, which allows us to non-invasively determine changes in liver fat quantity after clinical interventions."

Limitations of this study include its small sample size and case series design.

"Our results show the exciting potential of MRE to improve clinical care and reduce dependence on liver biopsies, but it is not yet ready for primetime clinical use," Dr. Xanthakos concludes in the news release. "In addition to validation in larger pediatric cohorts, we still need to determine whether MRE can predict changes in liver disease over time. We hope to study MRE in patients to test how well changes in imaging correlate with changes in liver stiffness after treatment or lifestyle changes."

The National Institutes of Health, the National Center for Research Resources, and the National Center for Advancing Translational Sciences supported this study. Dr. Podberesky received travel reimbursement from GE Healthcare. The other authors have disclosed no relevant financial relationships.

J Pediatr. Published online September 23, 2013. Full text

Source

Kids Have Hep C Too

September 5, 2013

Adults are not the only ones who are infected with the Hepatitis C virus. Research shows that a majority of childhood cases are missed.

By Nicole Cutler L.Ac.

After decades of the Hepatitis C virus (HCV) going unnoticed by mainstream institutions, this illness is finally being recognized as a major health problem. An estimated five times more Americans are infected with Hepatitis C than HIV – the virus that causes AIDS, yet HCV is not routinely screened for. This is unfortunate, because the earlier Hepatitis C treatment commences the better chance there is of eliminating the virus. While prevention, detection and treatment of Hepatitis C are just now gaining momentum, these efforts primarily target adults. Hopefully, research released will encourage the medical community to expand Hepatitis C education and awareness to include children.

Continue reading this entire article …..

Fatty Liver Disease: More Prevalent in Children

Cleveland Clinic

The Cleveland Clinic's Pediatric Preventive Cardiology and Metabolic Clinic treats and studies nonalcoholic steatohepatitis (NASH).

IN THE LAB Updated September 9, 2013, 7:27 p.m. ET

A type of liver disease once thought to afflict primarily adult alcoholics appears to be rampant in children.

Some 1 in 10 children in the U.S., or more than 7 million, are thought to have the disease, according to recent studies.

The condition, in which the normally rust-colored organ becomes bloated and discolored by yellowish fat cells, has become so common in non-drinkers that it has been dubbed nonalcoholic fatty liver disease.

The disease's prevalence is alarming doctors who worry about its progression to nonalcoholic steatohepatitis, or NASH, when the fatty liver becomes inflamed and cells are damaged. That leads to the end stage of cirrhosis, when the liver forms scar tissue and ultimately stops working.

The condition's rise is tied to the obesity epidemic—about 40% of obese children have it—but isn't caused solely by being overweight. The disease appears to be growing among normal-weight children too, experts say.

And even though obesity rates are starting to level off, the prevalence of fatty liver disease continues to rise, they say.

It also has no symptoms, which means a person could have it for decades without knowing.

"The disease is very silent," said Naim Alkhouri, director of the Pediatric Preventive Cardiology and Metabolic Clinic at the Cleveland Clinic.

Because fatty liver disease has been recognized only fairly recently in children, it's unclear how the disease progresses into adulthood. Roughly 10% of people with fatty liver disease will develop NASH; another 15% to 20% of those will get cirrhosis. While the early stages of fatty liver disease and NASH are reversible, cirrhosis is not.

"This is just really worrisome to have this number of children who have a disease this severe," said Miriam Vos, a pediatrics professor at Emory University School of Medicine who studies and treats kids with fatty liver disease.

In a study published this year, Dr. Vos and her colleagues looked at data from a national health study for elevated liver enzymes, a sign of fatty liver disease. The percentage of children in the sample suspected of having the disease grew to 10.7% between 2007 and 2010, from about 4% between 1988 and 1994.

In the last decade, more scientists have started studying fatty liver disease and NASH, trying to figure out who gets them and why. Last week, the U.S. Food and Drug Administration held a two-day meeting to discuss with industry and other stakeholders the best way to study new treatments and speed up clinical trials.

NASH, the inflamed fatty liver condition, is currently the third-most-common reason for liver transplants, behind alcoholism and hepatitis C. Experts expect it will eclipse the other two by 2030. The liver helps digest food, absorb nutrients and expel toxins from the body.

It's likely there are multiple factors that worsen fatty liver disease. Early research shows that the disease is partly genetic but likely needs to be triggered by environmental conditions, like obesity or insulin resistance. Much of the current research has focused on genes and specific nutrients in the diet that might cause the disease. One culprit is fructose, a type of sugar found in corn syrup and fruit juice, which are widely consumed in western diets, according to Dr. Vos's research.

Some imaging studies of children born from obese women show that even the infants have more fat on their liver.

Also, certain ethnic groups, including Mexican-Americans, appear to be particularly susceptible, whereas African-Americans appear more protected against fatty liver disease, even though rates of obesity are high in the U.S. population. Scientists have discovered several genes linked to the disease. At least one, PNPLA3, appears more often in the Mexican-American population, according to Dr. Vos.

Usually fatty liver disease is detected when other health problems arise. Obesity, insulin resistance or diabetes may prompt a doctor to order blood work to determine how the liver is functioning.

Sherry Waskowski's son Gregory was 12 when he was diagnosed with fatty liver disease two years ago. He had gone to see a doctor for his long-standing acid reflux, but because he was overweight, the physician checked his cholesterol levels, blood sugar, and—unbeknown to Ms. Waskowski—his liver enzymes, his mother says. His liver enzymes came back elevated and the ultrasound that followed glowed bright, indicating an accumulation of fat.

"It was very frightening and I felt so totally responsible," Ms. Waskowski says.

The medical team educated the Waskowskis, who live in Cleveland, about the condition and what Gregory needed to do to reduce his weight, which is the primary recommendation for treatment. He now exercises five hours a week, mostly by walking on the treadmill, and eats more fruits and vegetables. The Cleveland Clinic's Dr. Alkhouri, one of his doctors, wrote a note to his school advising against excess snacking there for Gregory.

Gregory's weight is now in the normal range and his last ultrasound, in March, showed his liver had much less fat, according to Ms. Waskowski.

There's a debate in the field about whether kids should be routinely screened for the condition and, if so, the best way to do it, Dr. Alkhouri says.

While elevated liver enzymes can be a sign of the disease, hepatitis C and other metabolic liver diseases must be ruled out first. Ultrasound helps detect the presence of fat on the liver, but is expensive. The best way of diagnosing a fatty liver is to take a sample of the liver with a biopsy, but this procedure can be painful and has side effects.

Researchers are trying to identify biomarkers detectable through breath or blood samples instead. At a major conference in the field called Digestive Disease Week, Dr. Alkhouri and his colleagues presented the results of a pilot study. It showed that different concentrations of chemicals were found in the breath of obese kids with fatty liver disease compared with those without. If the test is validated upon further study, it may be useful clinically in several years, he says.

Treatments for fatty liver disease are limited. They include weight loss through diet and exercise. Another way to battle the condition is vitamin E, an antioxidant found in supplements and foods including eggs and some leafy vegetables like spinach, that helps to reduce inflammation in adults and children with NASH, according to Joel Lavine, chief of Gastroenterology, Hepatology and Nutrition at Columbia University.

Several trials are under way for treatments for pediatric NASH. The National Institute of Diabetes and Digestive and Kidney Diseases is sponsoring one study and co-sponsoring another.

Bariatric surgery is also being studied as a possible treatment, though it's controversial because no randomized studies exist looking at NASH. Preliminary data from the Cincinnati Children's Hospital Medical Center—not yet published—suggest the procedure is very effective in adolescents with NASH, according to Stavra Xanthakos, medical director of the Surgical Weight Loss Program for Teens there, who collected data.

"If you could mimic the effect of surgery without going through the surgery, that's where a lot of interest is," said Dr. Xanthakos.

Write to Shirley S. Wang at Shirley.Wang@wsj.com

Organ Damage

Some facts about nonalcoholic fatty liver disease:

About 10% of children in the U.S. are thought to have the condition.

Several factors likely contribute, including genetics, obesity, diet and insulin resistance.

It has no detectable symptoms.

Weight loss is the standard treatment for earlier stages of liver disease.

—Source: Miriam Vos, Emory University

Source

NICE draft guidance recommends drugs to treat chronic hepatitis C in children and young people

In draft guidance published today NICE recommends peginterferon alfa in combination with ribavirin as an option for treating chronic hepatitis C in children and young people.

Hepatitis C is a blood-borne virus that infects the liver. Children and young people get the disease primarily from their mothers at birth. If the virus is not cleared from the body, either naturally or through drugs to treat it, an acute infection (defined as the first six months following initial infection) can progress to chronic hepatitis C (long term infection, lasting more than six months). Chronic hepatitis C infection increases the risk of scarring of the liver (fibrosis and cirrhosis), liver failure and liver cancer. Peginterferon alfa-2a (Pegasys, Roche Products) and peginterferon alfa-2b (ViraferonPeg, Merck Sharp and Dohme (MSD)), in combination with ribavirin are the only treatments currently licensed in the UK for the treatment of chronic hepatitis C in children and adolescents.

Professor Carole Longson, NICE Health Technology Evaluation Centre Director, said: “Hepatitis C is a potentially debilitating condition, and although it rarely causes serious liver damage in children, if left untreated there is a high risk that it will cause liver cirrhosis and eventual liver failure many years down the line. The independent Appraisal Committee concluded that treatment with peginterferon alfa and ribavirin can decrease the hepatitis C virus to undetectable levels, effectively providing the equivalent of a cure for the disease. By widening access to these drugs this guidance will give clinicians and people living with hepatitis C more treatment options. Early successful treatment is also likely to lessen the social stigma that can be associated with hepatitis C infection later in life.”

Until final guidance is issued to the NHS, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations across the country.

Ends

Notes to Editors

About the draft guidance

1. The draft guidance will be available from 00:01hrs on Thursday 18 June
2. Estimates from the Health Protection Agency in 2011 indicate that 26 people aged 1 year or less and 21 people between the ages of 1 and 14 years were newly diagnosed with HCV in England in 2010. Estimates for chronic infection in children and young people are not available.
3. The Assessment Group calculated that, based on an average age of 11 years, a body weight of 35.5 kg and a body surface area of 1.19 m², a 24-week course of peginterferon alfa-2a and ribavirin costs approximately £3700 while a 48-week course of treatment costs approximately £7400.
4. A 24-week course of peginterferon alfa-2b and ribavirin oral solution costs approximately £4000, while a 48-week course of treatment costs approximately £8100.
5. Ribavirin is manufactured by Roche Products (Copegus) and MSD (Rebetol). Each product is indicated for the treatment of chronic hepatitis C and must only be used as part of a combination regimen with peginterferon alfa or interferon alfa. The marketing authorisation for Copegus does not include specific recommendations for use in children. Copegus should be administered only in combination with the interferon products made by Roche Products (peginterferon alfa-2a or interferon alfa-2a). Rebetol (MSD) is available as an oral solution and 200 mg hard capsules and has a UK marketing authorisation for children and adolescents aged 3 years and older in combination only with MSD products peginterferon alfa-2b or interferon alfa-2b.
6. The cost effectiveness results suggested that peginterferon alfa-2a and peginterferon alfa-2b (each in combination with ribavirin were more effective and less costly than best supportive care.
7. The comparison between peginterferon alfa-2a and peginterferon alfa-2b was not robust enough for the Committee to recommend one treatment over the other.
8. NICE technology appraisals apply across the NHS in England and Wales.

About NICE

The National Institute for Health and Care Excellence (NICE) is the independent body responsible for driving improvement and excellence in the health and social care system. We develop guidance, standards and information on high-quality health and social care. We also advise on ways to promote healthy living and prevent ill health. Formerly the National Institute for Health and Clinical Excellence, our name changed on 1 April 2013 to reflect our new and additional responsibility to develop guidance and set quality standards for social care, as outlined in the Health and Social Care Act (2012). Our aim is to help practitioners deliver the best possible care and give people the most effective treatments, which are based on the most up-to-date evidence and provideare value for money, in order to reduce inequalities and variation. Our products and resources are produced for the NHS, local authorities, care providers, charities, and anyone who has a responsibility for commissioning or providing healthcare, public health or social care services. Follow us on Twitter: @NICEcomms

This page was last updated: 17 July 2013

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Poor treatment outcomes common among children with HIV/HCV coinfection

Provided by Healio

July 8, 2013

European children with HIV/HCV coinfection often have poor outcomes from HCV therapy, according to results presented at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

In a retrospective case note review, researchers identified 10 patients collected from four of 10 evaluated cohorts containing one or more patients coinfected with hepatitis C and HIV aged younger than 25 years. All patients had perinatal or early childhood HIV acquisition and had received HCV therapy with either pegylated interferon alfa-2a or alfa-2b (n=5 each) with ribavirin for a median duration of 48 weeks.

“Little is known about anti-HCV therapy and its outcomes in HIV/HCV coinfected children,” the researchers wrote. “Our aim was to document use and effectiveness of HCV treatment in HIV/HCV coinfected children and young people in Europe.”

The cohort included six females and four males, with eight cases of HCV genotype 1, one genotype 4 and one with an unknown genotype. The patients (median age at treatment initiation, 17.1 years) had a median HCV infection duration of 13.4 years. Among seven cases with evaluable fibrosis, stage F2 was observed in two cases, F3 in three and F4 in two cases.

One participant experienced early response, defined as undetectable HCV RNA at 12 weeks, and later achieved sustained virological response. No other participants experienced early or sustained response to therapy. No patients discontinued treatment due to adverse events, though investigators noted two cases of decreased neutrophil counts during treatment. One patient, who required retreatment 2 years after the treatment included in this study, died after liver transplantation.

“There is a very limited experience of treating HCV in HIV/HCV coinfected children,” the researchers concluded. “Our results show poor treatment outcomes in these cases, most of whom had advanced fibrosis and [genotype 1].”

For more information:

Turkova A. WEPE484: HCV Treatment in Children and Young Adults with HIV/HCV Coinfection in Europe. Presented at: IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 03, 2013; Kuala Lumpur, Malaysia.

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Hep C knowledge gap endangering children

Gastroenterology Update 11 JUNE 2013

Hugo Wilcken

People at high risk of hepatitis C infection have a poor knowledge of the disease which is putting their children in danger, an Australian survey has found.

Less than half of those attending NSW methadone clinics admitted to being positive for the hepatitis C virus (HCV), a survey of 330 people found, although actual exposure rates in high-risk populations are generally double that.

Around half said their children had been tested for HCV but almost all believed their children’s status was negative, the authors from the University of Sydney said.

This clearly reflected a lack of understanding of the risk of vertical transmission from mother to child, as well as poor compliance with current guidelines which recommend the children of all high-risk people be tested, the authors said.

But when offered free testing for themselves and their children, only one participant accepted.

Writing in the Journal of Paediatrics and Child Health the authors said children of high-risk populations “remain an unrecognised cohort of HCV carriers and are particularly at risk of spreading and developing the infection in later life”.

The findings suggested “a striking non-adherence to best practice, a lack of awareness of HCV...and that many children in this high-risk population are lost to follow-up,” the authors said.

They underlined the need to screen children born to HCVpositive mothers and also to screen high-risk populations at least every one to two years.

The authors recommended active case monitoring through a HCV registry for high-risk people and their children, as well as further initiatives to raise awareness in the general population.

Journal of Paediatrics and Child Health 2013; online

%2012/06/2013%209:40:13%20AM&utm_content=" target=_blank>Source

Partial Livers from Deceased Donors Saving the Lives of Infants

Press Release

June 10, 2013

New research reveals that transplantation of partial livers from deceased adult and teen donors has become less risky for infants and young children, helping to save these young lives. Findings published online in Liver Transplantation, a journal of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, indicate that risk of organ failure and mortality from partial or split liver transplant was comparable to whole organ transplant in this pediatric population.

Available livers for transplantation are in short supply, particularly size-matched organs for the youngest patient on the waitlist. While there is evidence that partial organs donated from living donors are superior to those from deceased donors, they accounted for less than 11% of pediatric liver transplants in 2010. Since 2002, studies show an eight-fold increase in the use of partial grafts from deceased donors, accounting for up to 32% of liver transplants in children.

“Infants and young children have the highest waitlist mortality rates among all candidates for liver transplant,” explains senior author Dr. Heung Bae Kim, Director of the Pediatric Transplant Center at Boston Children’s Hospital in Massachusetts. “Extended time on the liver transplant waitlist also places children at greater risk for long-term health issues and growth delays, which is why it is so important to look for methods that shorten the waitlist time to reduce mortality and improve quality of life for pediatric patients.”

To further understand outcomes of using deceased donor partial livers in infants, the team identified 2,679 liver transplant recipients under the age of two in the United Network of Organ Sharing (UNOS) database from 1995-2010. There were 1,114 partial livers and 1,565 whole organs from deceased donors that were used in the transplants analyzed. They examined mortality and graft survival over time.

Graft survival between partial and whole grafts were significantly different in 1995-2000, but comparable in 2001-2005 and 2006-2010, suggesting that transplants using partial livers became less risky over time. Adjusted risk of graft failure and mortality was similar for partial and whole organs in 2006-2010.

“Infants continue to have twice the mortality rate of adult candidates on the waitlist,” concludes Dr. Kim. “Our study confirms that organ failure and mortality risk in the very young was similar for partial and whole organs from deceased donors. The transplant community must continue to look for ways to reduce mortality rates in pediatric patients and using partial livers from deceased, as well as living donors, may hold the key.”

Full citation: “Deceased Donor Liver Transplantation in Infants and Small Children: Are Partial Grafts Riskier Than Whole Organs?” Ryan P. Cauley, Khashayar Vakili, Kristina Potanos, Nora Fullington, Dionne A. Graham, Jonathan A. Finkelstein and Heung Bae Kim. Liver Transplantation; (DOI: 10.1002/lt.23667) Online Publication: May 21, 2013.
URL: http://doi.wiley.com/10.1022/lt.23667

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Pegylated Interferon Therapy May Slow Growth in Children

From Medscape Medical News

Joe Barber Jr, PhD

August 13, 2012 — Pegylated interferon alpha-2 (Peg-IFN-α2a) treatment appeared to change body weight, linear growth, and body composition in children with chronic hepatitis C virus (HCV) infection, although many of these changes returned to baseline after treatment cessation, according to the findings of a prospective study by Maureen M. Jonas, MD, from Children's Hospital Boston, Massachusetts, and colleagues, who published their findings in the August issue of Hepatology.

Despite previous findings of changes in the height and weight of children treated with IFN-α for hepatitis B or HCV, many questions remain to be answered. "In particular, the question of whether and how changes in weight represent changes in body composition has never been studied," the authors write. "In addition, the long-term effects, especially on linear growth, have not been fully elucidated."

The authors included 5- to 17-year-old children with chronic HCV infection who had not received previous treatment and assigned them to receive Peg-IFN-α2a (180 μg/1.73 m² body surface area) plus either ribavirin (15 mg/kg/day; n = 55) or placebo (15 mg/kg/day; n = 59) for 24, 48, or 72 weeks, depending on treatment response.

Among the 106 children included in the analysis, changes in weight (changes in the weight-for-age z score [WAZ] of −0.31 ± 0.03, −0.43 ± 0.04, and −0.50 ± 0.13 after 24, 48, and 72 weeks of treatment, respectively; all P < .0001), height (changes in the height-for-age z score [HAZ] of −0.14 ± 0.02, −0.28 ± 0.02, and −0.50 ± 0.07 after 24, 48, and 72 weeks of treatment, respectively; all P < .0001), and body mass index (BMI; changes in the BMI z score [BMIZ] of −0.33 ± 0.04 [P < .0001], α0.40 ± 0.04 [P < .0001], and −0.35 ± 0.14 [P = .01] after 24, 48, and 72 weeks of treatment, respectively) were seen.

WAZ and BMIZ tended to return to baseline levels by 96 weeks after treatment discontinuation, irrespective of the duration of treatment, as the group treated for 72 weeks had changes in WAZ and BMIZ of 0.01 ± 0.14 and 0.13 ± 0.09 at 96 weeks after treatment cessation, respectively. However, HAZ remained significantly below baseline at this same time (change in HAZ, α0.41 ± 0.19; P < .03).

Changes in body fat composition were also observed after Peg-IFN-α2a (changes in the percentage body fat z score of −0.12 ± 0.05 and −0.14 ± 0.06 after 24 and 48 weeks of treatment, respectively, both P = .02; changes in the free fat mass z score [FFMZ] of −0.33 ± 0.05 and −0.37 ± 0.05 after 24 and 48 weeks of treatment, respectively; both P < .0001). Of note, these particular body composition changes were not significant for those receiving 72 weeks of treatment. In addition, these values again generally returned to baseline by 96 weeks after treatment cessation, excluding FFMZ at 96 weeks after the cessation of 24-week treatment (change in FFMZ, −0.28 ± 0.08; P = .0003).

No differences in dietary habits, physical activity, or sleeping patterns were observed among the children during the study, and no abnormalities in weight, height, BMI, or body composition were observed before the start of treatment.

Despite the findings that most changes appeared to be reversible, the authors stressed the need for additional data. "It is critical that longer term growth and metabolic data are gathered to determine the ultimate effect of this therapy, so that informed decisions can be made about optimal timing of treatment in this vulnerable population," the authors write.

This work was supported by a cooperative agreement between the National Institute of Diabetes and Digestive and Kidney Diseases and the US Food and Drug Administration and, in part, by a National Institutes of Health/National Center for Research Resources Colorado CTSI grant and the following study sites: Children’s Hospital Colorado, Aurora; Children’s Hospital Boston; University of California, San Francisco; Children’s National Medical Center, Washington, DC; Columbia University Medical Center, New York City; University of Florida, Gainesville; University of Washington, Seattle; Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia; Johns Hopkins Medical Center, Baltimore, Maryland; University of Cincinnati, Ohio; and Indiana University, Indianapolis. Additional support was provided by Hoffmann-La Roche for study medications, the data coordinating center, and central laboratory costs. The authors have disclosed no relevant financial relationships.

Hepatology. 2012;56:523-531. Abstract

Source

Acetaminophen overdoses common cause of kids' liver failure

Acetaminophen which is an ingredient in a variety of over-the-counter and prescription medications, is also one of the leading causes of acute liver failure. (Scott Olson/Getty )

Dosing misunderstanding common among adults

CBC News Posted: Jun 4, 2012 2:11 PM ET Last Updated: Jun 4, 2012 3:17 PM ET

Acetaminophen painkiller overdoses can cause life-threatening liver failure in children but the problem is avoidable, Canadian doctors say.

"Acetaminophen overdose is a major cause of acute liver failure and is the most common identifiable cause of acute liver failure in children," Dr. Rod Lim of the Children's Hospital at London Health Sciences Centre and his co-authors wrote in Monday's issue of the Canadian Medical Association Journal.

Spoons are often used by parents but are inaccurate, as are liquid droppers, the pediatricians said.

They suggested:

• Better packaging to make it easier for parents to calculate and give an appropriate dose.
• Keeping children's acetaminophen behind the counter so a pharmacist can give parents written information on what dose and volume to use based on the child's weight.
• Doctors should keep in mind that infants' livers metabolize acetaminophen differently than adults, which can influence the risk of liver damage in young patients.

The team reported on a 22-day-old boy they successfully treated in the emergency department at a community hospital after an accidental overdose.

A doctor told the newborn's parents to give him 40 milligrams of acetaminophen before bringing him in for a circumcision.

The boy weighed 4.1 kilograms so the intended dose was 10 milligrams per kilogram.

The bottle showed a concentration of acetaminophen of 80 milligrams per millilitre, which the parents misinterpreted as meaning the bottle contained 80 milligrams of acetaminophen in total. They gave him 10 millilitres, or about half the bottle.

The error was discovered during the circumcision.

He recovered after intravenous treatment and showed no evidence of any long-term consequences of the accidental overdose, the doctors said.

Substantial potential for errors

The boy's case illustrates how well-educated parents miscalculated the dose of acetaminophen.

The weight-based dosing and conversion from milligrams of weight to millilitres of volume for many liquid preparations of children's medications can pose challenges, doctors say.

Between 2000 and 2004 in the U.S., 24 deaths were reported to poison control centres, and one third were due to acetaminophen overdose, the researchers said in noted comparable Canadian data have not yet been compiled.

In 2009, Health Canada revised its labelling standards for products containing acetaminophen and mandated that weight-based dosing charts be included with the products.

Heavy users of acetaminophen

Despite regulatory moves in Canada and the U.S., the authors said there's still room to improve.

Last week, U.S. researchers concluded many adults are also at risk of overdosing from over-the-counter pain relievers containing acetaminophen, like Tylenol.

The researchers interviewed 500 adults patients at outpatient general medicine clinics in Atlanta and Chicago. More than half had used acetaminophen in the past six months and 19 per cent said they were heavy users who took acetaminophen every day or a couple of times a week.

Nearly a quarter, or 23.8 per cent, of the participants showed they would overdose on a single over-the-counter acetaminophen product by exceeding a dose of four grams in a 24-hour period.

About five per cent made serious errors by taking more than six grams over 24 hours.

And 45.6 per cent of the adults demonstrated they would overdose by 'double-dipping' with two acetaminophen-containing products.

"Misunderstanding of the active ingredient and proper instructions for over-the-counter medications containing acetaminophen is common," Dr. Michael Wolf, an associate professor of medicine at Northwestern University in Chicago and his co-authors wrote in the Journal of General Internal Medicine.

"The potential for errors and adverse events associated with unintentional misuse of these products is substantial, particularly among heavy users of acetaminophen and those with limited literacy."

Source

Durability of Sustained Response Shown in Paediatric Patients With Chronic Hepatitis C Who Were Treated With Interferon Alfa-2b Plus Ribavirin

From Journal of Viral Hepatitis

D. A. Kelly; B. Haber; R. P. González-Peralta; K. F. Murray; M. M. Jonas; J. P. Molleston; M. R. Narkewicz; F. R. Sinatra; T. Lang; A. Lachaux; S. Wirth; M. Shelton; H. S. Te; H. Pollack; W. Deng; S. Noviello; J. K. Albrecht

Posted: 05/07/2012; J Viral Hepat. 2012;19(4):263-270. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Summary. Long-term studies in adults indicate that sustained virologic response (SVR) after combination treatment for chronic hepatitis C (CHC) predicts long-term clearance. Although peginterferon plus ribavirin is now standard care for children with CHC, long-term follow-up studies are not yet available. This study evaluated durability of virologic response over 5 years in children previously treated with interferon alfa-2b plus ribavirin (IFN/R). Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed the 6-month follow-up in two previous clinical trials, participated in this long-term follow-up study. All were assessed annually for up to 5 years; patients with SVR were assessed for durability of virologic response. Children with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA 24-week post-treatment (n = 41) were followed for a median of 284 weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with the same genotype. Kaplan–Meier estimate for sustained response at 5 years was 98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels (n = 4) or missing HCV RNA at the 24-week follow-up visit (n = 2) in the initial treatment studies had virologic response during this long-term follow-up study. Linear growth rate was impaired during treatment with rapid increases in the immediate 6 months post-treatment. Mean height percentile at the end of the 5-year follow-up was slightly less than the mean pretreatment height percentile. Five patients experienced serious adverse events; none related to study drug exposure. SVR after IFN/R predicts long-term clearance of HCV in paediatric patients; growth normalized in the majority of children during the long-term follow-up. Similar long-term results could be expected after peginterferon alfa-2b plus ribavirin treatment.

Introduction

The World Health Organization estimates the prevalence of hepatitis C virus (HCV) infection between 1.3% and 1.7% in Europe and the Americas.^[1] Seroprevalence of HCV among children is lower than in adults, with estimated rates of 0.1–0.4% in developed countries.^[2,3] Although chronic hepatitis C (CHC) is often benign in young children, the occurrence of fibrosis increases with age and duration of the disease.^[4] Thus, effective treatment of children with CHC may reduce the progression of liver disease in young adulthood.^[5] Studies using interferon (both nonpegylated and pegylated) plus ribavirin for 48 or 52 weeks in children and adolescents with CHC have yielded sustained virologic response (SVR) rates of 46–65%.^[6–11] However, the long-term safety of interferon (both nonpegylated and pegylated) plus ribavirin and durability of the virologic response in children are unknown and are essential outcome measures.

In a long-term follow-up study of adults with CHC who attained SVR after treatment with interferon alfa-2b with or without ribavirin, 99% remained virus free during the subsequent 5-year period.^[12] Similar findings were seen in adults previously treated with peginterferon alfa-2b plus ribavirin.^[13] These findings indicate that sustained loss of serum HCV RNA for 6 months after the end of treatment is an excellent predictor of long-term viral clearance in adult patients with CHC.

The durability of response has not been formally studied in the paediatric population. Although peginterferon plus ribavirin is currently the standard of care for the treatment of paediatric patients with CHC, there are no long-term data on safety or durability of virologic response. Thus, long-term data on children treated with interferon alfa-2b plus ribavirin are uniquely relevant. This study was designed to confirm long-term safety and durability of virologic response in paediatric patients with CHC who were previously treated with interferon alfa-2b plus ribavirin for 48 weeks.^[8]

Materials and Methods

Study Design

A phase 3b, multicentre, long-term, follow-up study of paediatric patients with CHC who were previously treated with interferon alfa-2b (Intron A®; Schering-Plough Corporation, now Merck & Co., Whitehouse Station, NJ, USA) 3 MIU/m² three times per week plus ribavirin (Rebetol®; Schering-Plough Corporation, now Merck & Co.) 8, 12, or 15 mg/kg/day for 48 weeks in two international clinical trials was conducted.^[8] The initial treatment studies allowed patients who had detectable HCV RNA levels at treatment week 24 to discontinue as treatment failures at the discretion of individual investigators. Patients who completed 24 weeks of follow-up after the end of treatment in the two clinical trials were eligible for enrolment. No study medications were administered to patients during the 5-year follow-up study.

Baseline data, including gastrointestinal/liver examinations, weight and height measurements, haematology, blood chemistry, and HCV RNA, were obtained from the 24-week follow-up visit in the initial treatment studies. Annual assessments for clinical evidence of liver disease progression and safety in all patients as well as virologic relapse in those who attained SVR in the initial treatment studies were performed for up to 5 years. A patient was considered to have an enduring SVR at a given time point if serum HCV RNA [by quantitative polymerase chain reaction (PCR)] was undetectable at that time point. A patient was considered to have relapsed if a single serum sample had detectable HCV RNA.

Polymerase chain reaction testing for HCV RNA was performed by Schering-Plough Research Institute using a proprietary TaqMan reverse transcriptase–PCR assay (lower limit of detection, <125 IU/mL) and by Quest Diagnostics, Nichols Institute, using the Roche COBAS TaqMan assay (lower limit of quantitation, <50 IU/mL).

The study was conducted in accordance with Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies.

Study Population

Paediatric patients (3–16 years of age) from 24 study sites (17 in the United States and seven international) who participated in one of two clinical trials were invited to enrol in the long-term, follow-up study.^[8] Patients who completed 24 weeks of follow-up in the initial treatment studies and whose parents or legal guardians provided informed consent prior to any study-related procedures were included. Patients were excluded if they were currently participating in any other clinical trial for treatment of CHC, if they had received antiviral retreatment for CHC after completing 24 weeks of follow-up in the initial treatment studies or if the investigator determined that the patient had any condition which would make him or her unsuitable for participation in the study. Patients were discontinued from the study if antiviral retreatment for CHC was administered, if the investigator determined that it was in the best interest of the patient or if the patient wished to withdraw.

Efficacy End Point

The primary efficacy end point was the assessment of the durability of SVR in paediatric patients with CHC who were previously treated with interferon alfa-2b plus ribavirin. Durability of SVR was assessed at 1 year after the week-24 follow-up visit of the initial treatment studies and then annually for the next 4 years.

Safety Assessments

Signs of clinical disease progression and safety were assessed for patients at 1 year after the week-24 follow-up visit of the initial treatment studies and then annually for the next 4 years. To assess for clinical disease progression, investigators examined patients for ascites, hepatomegaly, splenomegaly and liver tenderness. In addition to the physical exams and laboratory evaluations, height and weight measurements were collected. Growth measurements were converted electronically to an age- and gender-specific percentile according to the method developed by the Centers for Disease Control and Prevention.^[14] Growth velocities during the different study periods were compared with age- and gender-standardized norms for the US population. Growth velocity was calculated by regressing assessed height during the period over the day of assessed height from randomization. At least two height assessments at least 90 days apart were required in any period to calculate growth velocity. Growth velocity percentiles relative to those norms were determined to assess the impact of treatment on growth.^[14,15]

Results

Patient Disposition

Of the 166 patients who received interferon alfa-2b plus ribavirin in the two initial treatment studies, 147 (78 sustained responders and 69 treatment failures) completed 24 weeks of follow-up and were eligible for enrolment in the long-term follow-up study (Fig. 1). Enrolled patients (N = 97) had been treated with interferon alfa-2b (3 MIU/m²) three times per week plus ribavirin 8 mg/kg/day (n = 11), 12 mg/kg/day (n = 10) or 15 mg/kg/day (n = 76) at 16 study centres. Owing to the timing of the initial treatment studies and long-term study enrolment, the majority of the enrolled patients (54%, 52/97) were initially treated in the second study, the phase 3 trial.^[8] Of those enrolled in this long-term follow-up study, 58% (56/97) had attained SVR and 42% (41/97) of them had not attained SVR (Table 1). Therefore, 72% of sustained responders and 59% of treatment failures from the initial treatment studies entered this long-term follow-up study. In genotype 1, infected patients were 77% (75/97) of the study population, of whom 47% (35/75) had achieved SVR.

Figure 1. Patient disposition. Study 1, a phase 1 trial, includes patients who were treated with IFN alfa-2b plus RBV 8, 12 or 15 mg/kg/day and Study 2, a phase 3 trial, includes patients treated with IFN alfa-2b plus RBV 15 mg/kg/day.⁸

Duration of Long-term Follow-up

Overall, 70% (68/97) of patients completed the 5 years of long-term follow-up (Table 2). More patients who attained SVR (75%, 42/56) than those who did not attain SVR (63%, 26/41) in the initial treatment studies completed the long-term follow-up. One patient with detectable HCV RNA at the end of the initial treatment study was subsequently retreated with peginterferon alfa-2b and ribavirin and was therefore withdrawn from the long-term follow-up study.

Efficacy Evaluation

Durability of Response Of 56 patients who attained SVR, only one had virologic relapse during long-term follow-up, with detectable serum HCV RNA level of 3.6 million copies/mL at the year-1 annual evaluation. HCV genotype was 1a at initial infection and at relapse. This patient had received interferon alfa-2b plus ribavirin (15 mg/kg/day) and completed 48 weeks of treatment without any known dose reductions. The Kaplan–Meier point estimate (95% confidence intervals) for the likelihood of maintaining SVR at 5 years after the initial treatment studies was 98% (95%, 100%).

Alanine Aminotransferase Levels The majority (98%, 51/52) of patients who attained SVR and had normal alanine aminotransferase (ALT) levels at the 24-week follow-up of the initial treatment studies maintained normal ALT levels throughout their long-term follow-up visits. The remaining patient with SVR had an elevated ALT level during long-term follow-up (67 U/L at the year-5 visit) with hepatomegaly, possibly caused by obesity (body mass index of 37.1 kg/m²). The investigator did not consider this finding to be clinically significant. In addition, three patients who attained SVR but had abnormal ALT levels at week-24 follow-up visit had normalized ALT levels at their last long-term follow-up evaluation. ALT values in the long-term follow-up period were missing for one patient.

Treatment Failures Of the 41 patients who did not respond to therapy and who had detectable HCV RNA levels at the 24-week follow-up in the initial treatment studies, 26 (63%) completed the 5-year follow-up study. Among these 41 patients with treatment failure, 33 (80%) had ALT levels <2 times their baseline ALT level throughout the study; 7 (17%) had elevated ALT levels of at least two times their baseline level within the last 3 years of long-term follow-up, despite having ALT levels <2 times their baseline level at the 24-week follow-up visit in the initial treatment studies; and one had missing ALT levels.

Six patients who enrolled in the long-term follow-up study had been treated with interferon alfa-2b (3 MIU/m²) three times/week plus ribavirin 15 mg/kg/day in the initial treatment studies and were classified as treatment failures. Four of these patients had low detectable serum HCV RNA (125–250 copies/mL) at week-24 follow-up in the initial treatment studies although they had undetectable HCV RNA levels at week 24 during treatment and three of the four patients had undetectable HCV RNA levels at week 12 as well. These patients had undetectable serum HCV RNA and normal ALT values throughout the long-term follow-up study (4–5 years after completing treatment). The two remaining patients were defined as not having responded to therapy when they entered the long-term follow-up study because, although they had undetectable serum HCV RNA at their last visit in the initial treatment protocol, they did not have HCV RNA results available for the 24-week follow-up visit. However, their serum HCV RNA remained undetectable throughout the 5 years of long-term follow-up.

Safety Evaluation

In this long-term follow-up study, 5% (5/97) of patients reported a serious adverse event, all of which were considered unlikely to be related to previous treatment with interferon alfa-2b and ribavirin. The serious adverse events included a cardiac catheterization in a patient with a history of congenital heart disease, injury with loss of consciousness after tipping an all-terrain vehicle, contrast media reaction during magnetic resonance imaging, tooth abscess and depression with self-injurious ideation and drug abuse after an alleged sexual assault. No patients died during the study. During the initial treatment studies, 23 of the 118 patients reported severe adverse events, which included mainly neutropenia as well as more significant events of suicidal ideation (n = 3), attempted suicide (n = 1) and hypothyroidism requiring treatment (n = 3); one patient with hypothyroidism also developed diabetes mellitus.^[8] Of these seven patients with more significant events, five patients were followed for up to 5 years in this long-term follow-up study without further serious adverse events reported. Mean changes in haematologic parameters (haemoglobin, platelet and white blood cell counts) during treatment returned to normal levels at the end of the 24-week follow-up period and remained stable during the long-term follow-up study. No patient showed signs of clinical progression of hepatic disease.

Body Weight and Height During the initial treatment studies, weight loss occurred during treatment with compensatory weight gain during the 24-week follow-up and long-term follow-up (Table 3). The mean weight percentile, 60th percentile, for all patients at the end of the long-term follow-up was above their mean baseline weight percentile, 54th percentile, as well as the median for the US population.^[14]

The mean height percentile, 44th percentile, for all patients at the end of the long-term follow-up was slightly below the patients' mean pretreatment baseline height percentile, 48th percentile, and below the median for the US population (Table 3). Twenty (21%) patients had >15 height percentiles decrease from baseline to their last visit in the long-term follow-up period. Of these 20 patients, 10 patients had >30 percentiles decreases. Decreases in height of >15 percentiles were most common in patients treated with interferon alfa-2b plus ribavirin during their estimated period of peak growth velocity based on age [girls 9–12 years old (6/15, 40%) vs girls 3–8 and 13–16 years old (1/31, 3%); P = 0.001 and boys 11–14 years old (9/19, 47%) vs boys 3–10 and 15–16 years old (4/32, 13%); P = 0.006]. In contrast, 15 (15%) patients (girls 4–12 years old and boys 5–16 years old) had increases in height of >15 percentiles from baseline to their last visit in the long-term follow-up study.

Mean growth velocity (2.46 ± 2.48 cm/year) and mean growth velocity percentile (11 ± 22) were at their lowest during treatment (Table 3). During the 24-week follow-up period of the initial studies, both growth velocity and growth velocity percentile increased to levels above the median for the US population. Mean growth velocity during this period was 5.40 ± 4.13 cm/year, and mean growth velocity percentile increased to 62 ± 40. During the long-term follow-up period, mean growth velocity was 3.29 ± 2.74 cm/year, and mean growth velocity percentile was 36.7 ± 37.6.

Discussion

Chronic hepatitis C is a significant cause of liver disease and a frequent indication for liver transplantation in adults.^[16] Long-term follow-up studies in adult patients with CHC have shown that attainment of SVR (defined as undetectable HCV RNA at 24 weeks after the end of therapy) following treatment with interferon (nonpegylated and pegylated) with or without ribavirin therapy is durable and predictive of long-term clinical benefit.^[12,17–26] Results of this 5-year follow-up study confirm that the long-term outcome for children who achieved SVR with interferon alfa-2b and ribavirin treatment for CHC is consistent with that observed in adults. Overall, 98% (55/56) of paediatric patients who attained SVR maintained undetectable HCV RNA levels during the long-term follow-up period. In addition to maintaining undetectable HCV RNA levels, 98% of paediatric patients who attained SVR and had normal ALT levels following treatment maintained normal ALT levels at their last long-term follow-up visit. The high percentage of patients who maintained long-term undetectable HCV RNA levels and normalization of ALT confirm the durability of virologic response in this population of paediatric patients, highlighting the success of this therapy in children.

Although nonpegylated interferon plus ribavirin is no longer the standard of care treatment for CHC in children, long-term data on safety and durability of response of any interferon in this population are not yet available. This study of long-term response in children treated with interferon alfa-2b plus ribavirin demonstrates similar durability to that reported in adults and suggests that similar outcomes are likely in children treated with peginterferon plus ribavirin. In addition, this study provides data on decreases in growth during combination therapy and recovery post-treatment, which is of value in selecting children for CHC therapy.

The initial treatment studies indicated that 8% and 20% of patients had haemoglobin level <10 g/dL and/or neutropenia (<1000 cells/L), respectively, while on treatment they recovered to pretreatment levels after therapy.^[8] No evidence of latent effects of treatment with interferon alfa-2b and ribavirin on haematologic parameters was apparent. Additionally, no delayed serious adverse events related to previous interferon alfa-2b and ribavirin treatment during the 5-year follow-up period were reported.

Treatment with interferon alfa-2b has been shown to cause a temporary slowing of growth in paediatric patients.^[27] Growth analyses of the initial and long-term follow-up studies showed that treatment with interferon alfa-2b and ribavirin slowed patients' growth during treatment and that some patients did not return to their baseline height percentile when treatment was completed. The mean height percentile observed during the 5 years of follow-up was slightly below the mean pretreatment height percentile and the median for the US population, but the mean last weight percentile was above the median for the US population and mean pretreatment weight percentile. Although the largest decreases in height percentiles were mainly seen in patients treated during their estimated peak height velocity based on age, there is much variability in the timing and rate of growth during puberty between individuals, and growth charts only capture a certain standard. In addition, a major limitation of our observations regarding growth is the absence of parental height data that would provide perspective on the patients' estimated final target heights.

Observations regarding a temporary reduction in growth velocity have also been made in paediatric patients receiving peginterferon alfa-2b plus ribavirin. Jara et al. reported a reduction in growth of 1.6 cm compared with the growth velocity 50th percentile for age and sex in 22 of 26 paediatric patients receiving peginterferon alfa-2b plus ribavirin. Despite a return to normal growth velocity after the end of treatment, the authors reported that the modest decrease in height percentile that occurred during treatment was not regained during the 6-month follow-up period.^[9] In addition, Wirth et al.^[10] reported that the mean height percentile after the 24-week post-treatment follow-up period for 107 paediatric patients treated with peginterferon alfa-2b plus ribavirin was slightly lower than the median of the US population and below the mean pretreatment height percentile. The 5-year long-term follow-up of this study is ongoing. However, Sokal et al.^[28] reported no influence of peginterferon alfa-2a plus ribavirin therapy on height in 65 paediatric patients. The trends seen in growth after interferon and ribavirin therapy are not consistent.

The risk/benefit ratio between the possible slowing of growth in paediatric patients receiving interferon products and the clinical consequences if treatment is withheld or delayed must be considered when treating a child with CHC with these agents. Much variability in growth was seen in this population, but supporting data including parental heights, nutritional status, concurrent disease status and medications were not available to firmly assess the impact of treatment on growth in this population. The long-term effect on growth is being further studied in patients who underwent treatment with peginterferon alfa-2b and ribavirin, and will be available in coming years.

Spontaneous resolution of chronic HCV infection is rare in untreated children, whereas persistent viremia after infection is almost universal.^[5] The disease course varies, but most children show at least mild or moderate hepatic inflammation and a small proportion have steatosis.^[29] Rare cases of children with hepatitis C-related bridging fibrosis, decompensated cirrhosis and hepatocellular carcinoma have been reported.^[4,30–33] Delaying therapy until early adulthood may have less impact on growth but increases the risk of liver disease progression or the need for liver transplantation in the interim, which may impede attainment of SVR in later years. In contrast, early treatment with interferon alfa-2b plus ribavirin results in an enduring clinical cure in almost half of all treated paediatric patients. The possibility of successful viral clearance needs to be weighed against the reported adverse events in children, which are largely consistent with the well-described tolerability profile among adult patients with hepatitis C receiving interferon alfa-2b (nonpegylated or pegylated) plus ribavirin.^[8] Thus, the arguments for withholding therapy from paediatric patients may be outweighed by the benefits of early viral eradication and the potential difficulties that may be incurred if treatment is delayed until the course of disease is further advanced. In addition, peginterferon alfa plus ribavirin treatment has shown improvement in therapeutic outcome among paediatric patients with CHC and is likely to demonstrate similar durability.^[10,11]

In conclusion, results of this 5-year follow-up study confirm that sustained loss of serum HCV RNA 24 weeks after the end of treatment with interferon alfa-2b plus ribavirin is predictive of long-term virologic response in paediatric patients. Most children had normalized (within 15 percentiles of pretreatment height) or improved growth during this 5-year long-term follow-up, although their mean height percentile at their last long-term follow-up visit was slightly below their mean pretreatment height. The findings of this study support the future treatment of paediatric patients with hepatitis C to prevent progression of liver disease.

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16. Gordon FD, Kwo P, Vargas HE. Treatment of hepatitis C in liver transplant recipients. Liver Transpl 2009; 15: 126–135.
17. Veldt BJ, Saracco G, Boyer N et al. Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy. Gut 2004; 53: 1504–1508.
18. Lau DT, Kleiner DE, Ghany MG, Park Y, Schmid P, Hoofnagle JH. 10-Year follow-up after interferon-alpha therapy for chronic hepatitis C. Hepatology 1998; 28: 1121–1127.
19. Marcellin P, Boyer N, Gervais A et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997; 127: 875–881.
20. Chemello L, Cavalletto L, Casarin C et al. Persistent hepatitis C viremia predicts late relapse after sustained response to interferon-alpha in chronic hepatitis C. TriVeneto Viral Hepatitis Group. Ann Intern Med 1996; 124: 1058–1060.
21. Manesis EK, Papaioannou C, Gioustozi A, Kafiri G, Koskinas J, Hadziyannis SJ. Biochemical and virological outcome of patients with chronic hepatitis C treated with interferon alfa-2b for 6 or 12 months: a 4-year follow-up of 211 patients. Hepatology 1997; 26: 734–739.
22. Fontaine H, Chaix ML, Lagneau JL, Brechot C, Pol S. Recovery from chronic hepatitis C in long-term responders to ribavirin plus interferon alfa. Lancet 2000; 356: 41.
23. Sim H, Yim C, Krajden M, Heathcote J. Durability of serological remission in chronic hepatitis C treated with interferon-alpha-2B. Am J Gastroenterol 1998; 93: 39–43.
24. Collier JD, Adams PA, Feinman V et al. Long term follow-up of patients with chronic hepatitis C treated with interferon alpha. Can J Gastroenterol 2000; 14: 77B–80B.
25. Reichard O, Glaumann H, Fryden A, Norkrans G, Wejstal R, Weiland O. Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon. J Hepatol 1999; 30: 783–787.
26. Camma C, Di Marco V, Lo Iacono O et al. Long-term course of interferontreated chronic hepatitis C. J Hepatol 1998; 28: 531–537.
27. Comanor L, Minor J, Conjeevaram HS et al. Impact of chronic hepatitis B and interferon-alpha therapy on growth of children. J Viral Hepat 2001; 8: 139–147.
28. Sokal EM, Bourgois A, Stephenne X et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents. J Hepatol 2010; 53: 170–178.
29. Goodman ZD, Makhlouf HR, Liu L et al. Pathology of chronic hepatitis C in children: liver biopsy findings in the Peds-C Trial. Hepatology 2008; 47: 836–843.
30. Badizadegan K, Jonas MM, Ott MJ, Nelson SP, Perez-Atayde AR. Histopathology of the liver in children with chronic hepatitis C viral infection. Hepatology 1998; 28: 1416– 1423.
31. Rumbo C, Fawaz RL, Emre SH et al. Hepatitis C in children: a quaternary referral center perspective. J Pediatr Gastroenterol Nutr 2006; 43: 209– 216.
32. Strickland DK, Jenkins JJ, Hudson MM. Hepatitis C infection and hepatocellular carcinoma after treatment of childhood cancer. J Pediatr Hematol Oncol 2001; 23: 527–529.
33. Gonzalez-Peralta RP, Langham MR, Andres JM et al. Hepatocellular carcinoma in 2 young adolescents with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2009; 48: 630–635.

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Hepatitis B program helps cut infant infections

Genevra Pittman

Reuters

4:16 p.m. CDT, March 27, 2012

NEW YORK (Reuters Health) - A program to prevent chronic hepatitis B infection in newborns seems to be working, according to a new study from researchers at the Centers for Disease Control and Prevention.

They found that more babies exposed to hepatitis B through their moms have gotten vaccinated right away, and fewer have ended up with chronic infections, since the program started in 1990.

That's important because the virus can be passed between mother and child during birth, and over the long run chronic infection increases the risk of liver failure and cancer.

"The findings were very encouraging -- they showed that most infants completed the (vaccination) series," said Emily Smith, the lead researcher on the study.
"For the infants that were followed... they had great results and outcomes," she told Reuters Health.

Still, Smith emphasized that there's work to be done in making sure all new moms with hepatitis B are reported to the CDC's program so that babies can receive the proper care to prevent infection.

40,000 NEW INFECTIONS PER YEAR

About one million people living in the United States have chronic hepatitis B infection, and an additional 40,000 are infected every year though bodily fluids such as blood and semen -- as well as during birth.

The CDC's vaccine program calls for screening all pregnant women for hepatitis B and giving exposed babies antibodies and a vaccine against the virus within 12 hours of birth, followed by an additional two or three vaccine doses over the next year or so. Individual cities and states submit reports to the CDC on the number of hepatitis B cases identified in women and how their infants were managed, and those numbers are used to make nationwide estimates.

Based on those reports, the researchers calculated that from 1994 to 2008, the number of women who screened positive for hepatitis B each year increased from about 19,000 to close to 26,000. And health care workers seemed to get better at making sure their babies were protect against the virus.

Over the study period, the number of exposed babies who got both hepatitis B antibodies and a vaccine within a day of birth increased from 92 percent to almost 97 percent.

Along with that, tracked infants who ended up with chronic hepatitis B infection fell from two percent to less than one percent by 2008, the researchers reported in Pediatrics.

LONGER FOLLOW-UP NEEDED

Still, they were only able to follow about half of babies out to one year. And the number of infants who'd had all of their hepatitis B vaccines by that point actually decreased during the study period -- from 86 percent to 78 percent -- with at least some of that due to more families refusing vaccines.

"The program is certainly working -- they're vaccinating more infants successfully," said Dr. Maya Gambarin-Gelwan, who has studied hepatitis B at Weill Cornell Medical College in New York but wasn't involved in the new research.

"But half of the infants who are born to those mothers are slipping through the system essentially," she told Reuters Health. "It's also bothersome that there's this growing percentage of infants who are not completing vaccination or that we don't have a follow-up on."

Smith agreed that not being able to follow infants over time is a problem.

"Women need to receive hepatitis B screening and positive results need to be reported to (the program), to make sure that the infants receive vaccination and care and testing," she said.

Gambarin-Gelwan added that it's important to get the message out that hepatitis B programs really do work when babies get all of their recommended vaccines, especially to communities with high virus rates, such as among Asian-Americans.

Dr. Tram Tran from Cedars-Sinai Medical Center in Los Angeles told Reuters Health that while doctors are really good at screening women early in pregnancy when they're already in the health care system, there's still a big gap for other women, such immigrants and illicit drug users.

And even if those women do get screened, she said, they may not have the resources to bring their babies back for the multiple hepatitis B shots necessary for protection.

"It's a completely preventable disease, that's the thing that's frustrating," said Tran, a hepatitis researcher who wasn't part of the study team.

"We have a vaccine that works really well. It's just getting to these high-risk pockets and these high-risk groups where there's still a lot of opportunity."

SOURCE: http://bit.ly/GRqwAP Pediatrics, online March 26, 2012.

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Also See: Hepatitis B Vaccinations Increasing for At-Risk Infants

Hepatitis B Vaccinations Increasing for At-Risk Infants

From Medscape Medical News

Jenni Laidman

March 26, 2012 — A greater percentage of infants at risk for hepatitis B are being successfully vaccinated against the virus, but almost half of all at-risk infants slip through the healthcare system unnoticed. This puts them at risk for chronic liver disease and premature death, according to an article published online March 26 in Pediatrics.

Despite a 33% increase in the number of infants at risk for hepatitis B (from 19,208 in 1994 to 25,600 in 2008; P < .001) the percentage of infants managed for hepatitis B risk increased even more (from 40.8% to 50.5%; P < .001) in those years.

Emily A. Smith, MPH, from the Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, and colleagues examined data from 1994 to 2008 to determine the success of the National Perinatal Hepatitis B Prevention Program (PHBPP), established in 1990 by the CDC to decrease perinatal hepatitis B virus (HBV) transmission.

Although CDC guidelines call for hepatitis B (HepB) vaccination before hospital discharge for all newborns, infants born to mothers who test positive for the hepatitis B surface antigen (HBsAG) are to receive HepB, as well as hepatitis B immune globulin (HBIG), within 12 hours of birth, followed by 2 to 3 more HepB doses during infancy, with a goal of 90% series completion by 6 to 8 months of age. PHBPP protocol calls for these at-risk infants to be tested for the infection after the vaccination series is complete.

At-risk infants who fail to complete the vaccine series or who delay completion have a significantly higher risk for chronic HBV. In a study of 426 children at risk for HBV, incomplete vaccination increased risk for chronic infection almost 8-fold. Another study showed that receiving HBIG more than 12 hours after birth was associated with increased risk for HBV infection among at-risk infants.

The new analysis covered 49 states (excluding Alaska), as well as Chicago, Illinois; Houston, Texas; New York City; Philadelphia, Pennsylvania; San Antonio, Texas; and Washington, DC. "The PHBPP achieved substantial progress in preventing perinatal hepatitis B virus infection in the United States," the authors note.

Among the case-managed infants, 94.4% received HepB and HBIG within a day of birth, and a smaller proportion of children completed the vaccine series within a year, falling from 86.0% to 77.7% (P = .004). However, testing for HBV increased among children who completed the vaccination series, rising from 25.1% to 56.0% (P < .001). This testing showed a decline in chronic HBV infections, from 2.1% in 1999 to 0.8% in 2008 (P = .001).

However, the authors acknowledge, "Significant gaps remain in identifying HBsAG-positive pregnant women, and completing management and assessment of their infants to ensure prevention of perinatal hepatitis B virus transformation."

Children born to mothers with the hepatitis B surface antigen have a 90% risk of developing chronic hepatitis, which could lead to liver failure or liver cancer. However, proper prophylaxis prevents 85% to 95% of infections.

Although fewer infants were lost to follow-up in 2008 (13.0%) than in 2004 (26.4%), the difference was not significant (P = .126) The most common reason for lack of follow-up was failure to locate the child, at 33.1%, followed by "moved out of country," at 24.4%. Family refusal was a growing reason children did not complete testing, rising from 10.8% in 2005 to 17.9% in 2008 (P = .020). The authors termed this "problematic."

Even with timely vaccines, risks remain for some portion of at-risk children. An estimated 1% to 10% of infants born to hepatitis-positive mothers develop chronic or breakthrough hepatitis infection. Breakthrough infection is strongly associated with the mother's viral load, with transmission rates as high as 32% for mothers with HBV DNA concentrations greater than 10⁸ copies/mL.

The authors have disclosed no relevant financial relationships.

Pediatrics. 2012;129:609-616.

Source

Researchers unravel genetic mechanism of fatty liver disease in obese children

Public release date: 26-Mar-2012

Contact: Karen N. Peart
karen.peart@yale.edu
203-432-1326
Yale University

Obese youths with particular genetic variants may be more prone to fatty liver disease, a leading cause of chronic liver disease in children and adolescents in industrialized countries, according to new findings by Yale School of Medicine researchers.

The study, which focused on three ethnic groups, is published in the March issue of the journal Hepatology.

Led by Nicola Santoro, M.D., associate research scientist in the Department of Pediatrics at Yale School of Medicine, the authors measured the hepatic, or liver, fat content of children using magnetic resonance imaging. The study included 181 Caucasian, 139 African-American and 135 Hispanic children who were, on average, age 13.

"We observed that a common genetic variant known as Patatin-like phospholipase domain containing protein-3 (PNPLA3) working with a regulatory protein called glucokinase (GCKR), was associated with increased triglycerides, very low-density lipoproteins levels, and fatty liver," said Santoro.

Santoro explained that his observations could help unravel the genetic mechanisms that contribute to liver fat metabolism. "This may drive the decisions about future drug targets to treat hypertriglyceridemia and non-alcoholic fatty liver disease," he said.

Childhood obesity is a global health concern. Experts say nonalcoholic fatty liver disease is now the leading cause of chronic liver disease in children and adolescents in industrialized countries.

"Our findings confirm that obese youths with genetic variants in the GCKR and PNPLA3 genes may be more susceptible to fatty liver disease," said Santoro, who is cautious about automatically extending this observation to the overall population.

"Our data refer to a population of obese children and adolescents," he said. "I think that further studies in a larger sample size involving lean subjects and adults may help to further define in more details these associations."

###

Other authors on the study included Clarence K. Zhang, Hongyu Zhao, Andrew J. Pakstis, Grace Kim, Romy Kursawe, Daniel J. Dykas, Allen E. Bale, Cosimo Giannini, Bridget Pierpont, Melissa M. Shaw, Leif Groop, and Sonia Caprio.

The work was also funded, in part, by the Yale Clinical and Translational Science Award grant from the National Center for Research Resources at the National Institutes of Health.

Citation: Hepatology Vol. 55, No. 3 (March 2012)
http://onlinelibrary.wiley.com/doi/10.1002/hep.24806/abstract.

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The long-term horizon: Patients who will remain untreated in the era of triple therapy

Clinical Liver Disease

Volume 1, Issue 1, pages 20–23, February 2012

Andrew Aronsohn M.D., Donald Jensen M.D.^‡,*

Article first published online: 6 MAR 2012

DOI: 10.1002/cld.5

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

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The direct-acting antivirals (DAAs) telaprevir and boceprevir have revolutionized hepatitis C virus (HCV) therapy by improving therapeutic outcomes for many patients. Although DAA-based therapy is a great leap forward, it is not a panacea, and many patients will not be appropriate candidates for this treatment. This review defines the patients who will remain untreated and explores emerging challenges in the era of triple therapy.

Patients with Contraindications to Pegylated Interferon (PEG) and Ribavirin (RBV)

PEG and RBV remain part of the current DAA-based therapy; therefore, patients with contraindications to the previous standard-of-care treatment are unlikely to be candidates for triple therapy (Table 1). This includes patients with previous adverse reactions to PEG or RBV and patients with uncontrolled autoimmune disease.1 In addition, interferon-induced bone marrow suppression, in combination with the hemolytic effects of RBV, can result in significant anemia and pancytopenia, and this makes patients with preexisting cytopenias, severe peripheral vascular disease, pulmonary disease, or coronary artery disease potentially unsuitable candidates for treatment.1 Finally, depression has been reported to occur in 23.2% of patients undergoing interferon therapy.2 Although patients tend to respond well to antidepressants during HCV therapy, severe uncontrolled depression remains a contraindication to treatment.1

DAA, direct-acting antivirals; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PEG, pegylated interferon; RBV, ribavirin; SVR, sustained virological response.

Patients with Contraindications or Limited Responses to DAA Therapy

Boceprevir and telaprevir have significant interactions with both cytochrome P450 3A and p-glycoprotein, and these result in significant drug-drug interactions (Table 2).3, 4 A thorough medication history should be taken before treatment, and it is possible in many cases to substitute or hold a contraindicated drug during HCV therapy. However, in rare instances, patients who are taking a contraindicated medication that cannot be modified may not be candidates for current DAA-based therapy.

Although triple therapy is highly effective in most patients, response rates among patients with cirrhosis (especially previous null responders) remain relatively low. In the Sprint (Serine Protease Inhibitor Therapy) 2 study, cirrhosis was a significantly negative predictor of sustained virological response (SVR) in patients treated with boceprevir [odds ratio = 2.5 (1.4–4.6), P = 0.003].5 Furthermore, in the REALIZE study, investigators performed a subgroup analysis of patients with cirrhosis who were treated with telaprevir-based therapy and were previous null responders, and they found an SVR rate of only 29%.6 Clearly, many patients with HCV-related cirrhosis (especially previous nonresponders) will have limited success with the current therapy and will require treatment beyond what is currently available.

Understudied Populations

HCV affects many patients who have unique characteristics that are beyond the scope of currently published phase 3 registration trials of DAAs. These patients may benefit from DAA therapy but will pose a significant challenge to clinicians because there are limited data (if any) for guiding their care (Table 3).

Patients Coinfected With Human Immunodeficiency Virus (HIV)

At least 17% of patients with HIV are coinfected with HCV.7 Progression to cirrhosis is more rapid in coinfected patients, and hepatic failure is an increasingly common cause of death in this patient population.8 The treatment of HCV in the setting of HIV is a longstanding clinical challenge because previous standard-of-care therapy with PEG/RBV has resulted in suboptimal SVR rates. In 2004, the AIDS Pegasys Ribavirin International Co-Infection Trial study group performed a multicenter, international study of HCV therapy in 868 patients coinfected with HIV. In genotype 1 patients, the SVR rate was 29%, which is lower than the published rates for PEG/RBV-based therapy in the non–HIV-infected population.9, 10 Currently, there are no available data describing DAA-based therapy in the HIV/HCV-coinfected population, and although improved treatment outcomes are anticipated, safety concerns (primarily involving drug-drug interactions) must first be addressed.

Liver Transplant Recipients

Patients with chronic HCV who undergo liver transplantation universally experience HCV recurrence in the transplanted liver. This leads to inferior posttransplant patient and graft survival in comparison with many other indications for liver transplantation.11 HCV therapy with PEG/RBV after liver transplantation has been largely unsuccessful because of poor SVR rates and significant adverse events, which include acute rejection.12, 13 Theoretically, direct-acting agents should be ideal in an immunocompromised host because there is less reliance on the host immune system for antiviral activity. Telaprevir and boceprevir are strong inhibitors of the enzyme cytochrome P450, which also plays a key role in the metabolism of the immunosuppressants commonly used in liver transplantation: cyclosporine and tacrolimus. Pharmacokinetic studies investigating the interaction between telaprevir and cyclosporine yielded extremely high drug concentrations of immunosuppressants when they were tested in healthy controls (a 70-fold increase in the tacrolimus concentration and a 4.6-fold increase in the cyclosporine concentration).14 Further prospective studies will be needed to determine safe and efficacious dosing strategies when these medications are used together.

Patients With Decompensated Cirrhosis

Successful HCV treatment in patients with cirrhosis has been shown to increase survival and decrease the development of ascites, esophageal varices, and hepatic encepaholpathy.15 Unfortunately, few decompensated patients with genotype 1 or 4 who undergo HCV treatment with PEG/RBV will achieve SVR (7%); therapy is often poorly tolerated, and frequent dose reductions and discontinuations are required.16 Current guidelines from the American Association for the Study of Liver Diseases recommend that for patients with decompensated cirrhosis, attempts at treatment should be “administered by experienced clinicians with vigilant monitoring for adverse events preferably in patients who have already been accepted as candidates for liver transplantation.”1 The risk of further decompensation along with the low SVR rates means that the previous standard-of-care treatment with PEG/RBV is rarely a viable option. With the use of more potent antiviral agents, SVR rates may increase; however, DAA metabolism appears to be different in patients with advanced cirrhosis versus patients with earlier stages of disease, and the tolerability and safety in this population remain largely unknown. Decisions to treat these patients with triple therapy rely solely on anecdotal accounts, and they should be made with extreme caution and should be based on physician experience and unique patient characteristics.

Pediatric and Elderly Populations

Recent National Health and Nutrition Examination Survey data suggest that approximately 0.2% to 0.4% of children up to 14 years old are infected with HCV.17 The majority of pediatric HCV infections occur as a result of maternal-fetal transmission. Because of the shorter period of chronic infection, pediatric patients usually have earlier stage disease at the time of diagnosis in comparison with adults; however, progression to cirrhosis and hepatocellular carcinoma has been reported.18, 19 In a pilot study of 62 patients between the ages of 2 and 17 years who were treated with PEG and RBV, 48% of the patients with genotype 1 achieved SVR.20 Although the results are based on limited data, the treatment outcomes appear to be similar to those of the adult population, and so are the adverse events during therapy, with the exception of spastic diplegia, which is a severe form of neurotoxicity seen in infants treated with interferon-α.17 The pediatric population would very likely tolerate and benefit from more potent agents; however, to date, there are no data on the use of telaprevir, boceprevir, or other new HCV therapies in this population. The current Food and Drug Administration treatment for patients who are 18 or less years old remains interferon plus RBV three times a week (3–18 years old) or PEG plus RBV once a week (5–18 years old).

In upcoming years, the highest prevalence of HCV infection will be seen in patients who are 65 years old or older.21 Older patients with HCV have a faster rate of progression to cirrhosis and have a higher incidence of hepatocellular carcinoma; this indicates a significant therapeutic need in this understudied population.22, 23 Patients more than 65 years old are more likely to be cirrhotic and have comorbidities that make treatment with PEG/RBV less effective. This was shown by Huang et al.24 in a study of 70 HCV patients older than 65 years who were treated with PEG/RBV. In comparison with younger cohorts, older patients had significantly inferior SVR rates and higher rates of dose reduction and therapy discontinuation. DAAs may improve response rates; however, there are significant concerns about the tolerability of triple therapy in this population and especially in patients who have been unable to tolerate PEG/RBV in the past. The consideration of alternate dosing schedules and treatment algorithms may be key to the use of DAA-based therapy in this population.

Patients With Previous DAA Exposure

Unlike dual-therapy treatment with PEG/RBV, treatment failure with DAAs is complicated by the emergence of resistant variants. Pawlotsky25 defined three major factors that influence the clinical ramifications of resistance: the genetic barrier to resistance, the fitness of the resistant variant, and the attainable drug exposure. First-generation protease inhibitors such as telaprevir and boceprevir have a low genetic barrier to resistance; however, after the discontinuation of therapy, the wild-type virus typically regains dominance, possibly to the point of the complete eradication of the resistant variants over time. Patients who develop resistant variants while they are being treated with one protease inhibitor will not likely be candidates for treatment with the other available protease inhibitor because boceprevir and telaprevir have been shown to share cross resistance in vitro. In addition, the emergence of resistance is also related to interferon insensitivity, which would hinder successful therapy with any DAA that requires interferon as part of the therapeutic regimen. As more DAAs become available, the treatment of patients who develop resistant variants may become similar to HIV treatment, in which combinations of agents are selected on the basis of viral resistance profiles.

Overcoming Current Challenges with DAA Therapy

This review describes many groups of patients who are underserved by currently available DAA therapy (Fig. 1). Fortunately, there are robust basic, translational, and clinical investigations aimed specifically at addressing these shortcomings. For those with limited responses or contraindications to telaprevir- or boceprevir-based treatment, ongoing clinical trials are evaluating the safety and efficacy of the next generation of protease inhibitors, polymerase inhibitors, and other novel agents such as cyclophilin inhibitors and short interfering RNA. In addition, many new agents are being investigated in interferon-free combinations that are targeted at patients who have deferred interferon-based treatment because of their own preference or medical contraindications. Finally, active research is taking place through both sponsored trials and investigator-initiated studies evaluating current DAA-based therapy in many of the understudied populations mentioned in this review.

Figure 1. Treatment algorithm for difficult-to-treat patients.

Chronic HCV progresses slowly, and most patients do not develop advanced liver disease until at least 2 to 3 decades after the time of infection. Within understudied and difficult-to-treat populations, patients with early-stage disease will have the luxury of waiting for safer or more effective therapies; however, patients who already have advanced disease will have limited options and will remain a challenge, even in the era of DAA therapy.

References

Source