January 7, 2011
There's a fair amount of guesswork to the estimates, but perhaps as many as 20% of American adults have some degree of fatty liver disease, a condition that used to occur almost exclusively in people who drink excessively. The epidemics of obesity and diabetes are to blame. Fatty liver affects between 70% and 90% of people with those conditions, so as obesity and diabetes have become more common, so has fatty liver disease.
Fatty liver disease isn't confined to any one group, and there don't seem to be pronounced gender differences, but studies suggest that Latinos are disproportionately affected. It's primarily a condition of middle age, although children may get it, too. Fatty liver disease is rapidly becoming more common in Asia, and some research suggests that men in India may be especially susceptible.
Plumped-up liver cells
The prevailing theory is that the condition gets started because of insulin resistance, which is, in turn, frequently a consequence of obesity and excess fat tissue in the abdomen. When people are insulin resistant, their muscle, fat, and liver cells don't respond normally to insulin, so levels of the hormone — and the blood sugar it ushers into cells — build up in the blood. As a result, the risk of developing diabetes and heart disease increases. But insulin resistance is a complicated metabolic state that also includes an increase in the amount of free fatty acids circulating in the blood.
Fatty liver disease occurs when some of those fat molecules accumulate inside liver cells. The presence of those fattened cells can then lead to inflammation in the liver and damage to surrounding liver tissue. Once that happens, if excess alcohol is not involved, the condition is called nonalcoholic steatohepatitis (steato- for fat and –hepatitis because the liver is inflamed). Fortunately, that unwieldy name boils down to a handier acronym, NASH. Estimates vary quite a bit, but it seems that 5% to 10% of people with fatty liver disease go on to develop NASH.
NASH is often a relatively stable, low-grade condition that people live with for years, with few if any symptoms. But it can also start a cascade of serious damage to the liver and attempts by the organ to regenerate itself that culminate in an abundance of scar tissue and impaired liver function — a condition called cirrhosis. Cirrhosis is irreversible and can lead to total failure of the liver. It also is associated with an increased risk for developing liver cancer.
Some studies have shown as few as 3% of people with NASH developing cirrhosis, while others have shown as many as 26% doing so. There's no test or risk factor that predicts who will develop cirrhosis and who won't, although one study did find that people who are older or whose initial liver biopsies showed more inflammation were at greater risk. It's clear, though, that the prognosis for NASH is far better than it is for steatohepatitis that's the result of heavy alcohol consumption. Perhaps as many as half of all those with alcoholic steatohepatitis (which lacks a handy acronym) go on to develop cirrhosis.
It's just a theory at this point, but people with fatty liver disease and NASH may need to be more worried about heart disease and stroke than about serious liver problems. An article published in The New England Journal of Medicine in late 2009 argued that the inflammatory and other factors pumped out by a fat-afflicted liver promote the atherosclerotic process that damages the insides of arteries and makes blood more likely to clot, a combination that can lead to heart attack or stroke. The evidence the authors cited is intriguing, if circumstantial. They pointed to a study showing that people with NASH are twice as likely to die from heart attack or stroke as people without it. And NASH seems to add to the risks that come with excess weight. Overweight men with NASH have higher levels of C-reactive protein, an inflammatory factor, and fibrinogen, a clotting factor, than overweight men without NASH. Moreover, the levels of those and other factors go up as NASH gets more severe.
Diagnosis requires a biopsy
Most people with fatty liver disease don't have symptoms, and that's true even if it has developed into NASH. Only occasionally do people feel run-down, or they have an achy feeling in the upper right side of the abdomen, where the liver is located. So, more often than not, fatty liver disease and NASH are discovered incidentally, starting with higher than normal levels of liver enzymes on a routine blood test. Ultrasound imaging, the same technology used to get pictures of developing fetuses, can be informative: the liver looks bright because the fat shows up as white on the image. But neither an ultrasound nor a CT or MRI scan is completely reliable for making a diagnosis. The fat in the liver is visible, but not the NASH-related inflammation. Some researchers have developed formulas that use a simple blood test and measurements of various hormones, inflammatory factors, and liver enzymes to arrive at a diagnosis, but this work is at a preliminary stage.
Currently, a liver biopsy is the only way to make a definitive diagnosis of fatty liver or NASH. Liver biopsies involve inserting a long needle into the right side of the abdomen and extracting a small piece of liver tissue that can be examined under a microscope. Liver biopsies are an invasive procedure, so they aren't entirely free of risk and complications, but they're also fairly routine these days and can be done on an outpatient basis.
Whether a doctor will order a biopsy to nail down a diagnosis depends on many factors, including whether the person is obese or has diabetes or shows other signs of liver trouble.
Weight loss is the treatment
There's been a fair amount of research into using diabetes drugs to treat NASH, even in people who don't have diabetes. Rosiglitazone (sold as Avandia) and pioglitazone (sold as Actos) have been the leading candidates because they reduce insulin resistance, the root cause of fatty livers. They're not looking so promising these days. The FDA has moved to sharply curtail the use of Avandia because it seems to cause heart problems. The results of an important trial published in 2010 in The New England Journal of Medicine showed Actos to be no better than a placebo in improving NASH in people without diabetes.
Another diabetes drug, metformin (Glucophage), might prove to be an effective treatment, but there isn't enough evidence yet. Vitamin E is a possibility: the same trial that showed Actos wasn't effective showed some improvement in the livers of people who took large doses (800 IU daily) of the vitamin. But many doctors are wary about prescribing large doses of vitamin E because they've been associated with an increased risk of bleeding. Besides, the improvements in the liver were limited. Fish oil has produced some favorable results, and clinical trials are under way, but it can't be endorsed yet.
These setbacks and uncertainties have left weight loss (ideally from changes in diet and an increase in physical activity) as the only recommended treatment for most cases of fatty liver disease and NASH. In many cases, weight loss seems to have a very direct effect: as people lose weight, the fatty liver becomes less fatty. Crash dieting is a bad idea, though, because rapid weight loss (losing 4 pounds a week or more) can wind up damaging the liver. Of course, if sustained weight loss were easy, a lot of today's health problems would be solved, not just fatty liver disease and NASH.
In addition to encouraging people to lose weight, doctors will often advise people with diabetes who have fatty liver disease or NASH to be vigilant about controlling their blood sugar.
The bottom line Many parts of the body come to grief once people become obese or develop diabetes. It's not surprising that our livers do too, given how central they are to a whole suite of metabolic processes. There's some evidence that a fatty liver may add to the already high risk of heart disease among people who are obese or have diabetes. Fatty livers can also develop into cirrhotic ones if the inflammatory processes take off.
But there are two bright spots in the take-home message about fatty livers. First, most cases stay relatively stable and don't result in serious liver disease. Second, the treatment is not an expensive drug with side effects, but losing weight — and that will benefit many other parts of the body besides the liver.
Source: Harvard Univ.
Source
January 7, 2011
Natural Compound Blocks Hepatitis C Infection
ScienceDaily (Jan. 6, 2010) — Researchers have identified two cellular proteins that are important factors in hepatitis C virus infection, a finding that may result in the approval of new and less toxic treatments for the disease, which can lead to liver cancer and cirrhosis.
An estimated 270 to 300 million people worldwide are infected with hepatitis C and the conventional treatments -- interferon and ribavirin -- can have significant side effects. A new drug targeting cellular proteins rather than viral proteins would be a valuable addition to the treatment arsenal, said Samuel French, an assistant professor of pathology and senior author of the study.
French and his team set out to identify the cellular factors involved in hepatitis C replication and, using mass spectrometry, found that heat shock proteins (HSPs) 40 and 70 were important for viral infection. HSP 70 was previously known to be involved, but HSP 40 was linked for the first time to hepatitis C infection, French said. They further showed that the natural compound Quercetin, which inhibits the synthesis of these proteins, significantly inhibits viral infection in tissue culture.
"This is an important finding because we can block these proteins with the idea of reducing the level of the virus in people and, ideally, completely eliminate it," said French, who also is a researcher at UCLA's Jonsson Comprehensive Cancer Center.
The study appeared in the most recent issue of the journal Hepatology.
Since Quercetin has been shown to inhibit hepatitis C infection, French said, a Phase I clinical trial will be launched at UCLA to determine if the compound is safe and effective.
Quercetin is a plant-derived bioflavonoid, and is used by some people as a nutritional supplement. Laboratory studies show it may have anti-inflammatory and antioxidant properties, and it is being investigated for a wide range of potential health benefits. Currently, there are early-stage clinical trials testing quercetin for safety and efficacy against sarcoidosis, asthma and glucose absorption in obesity and diabetes.
"Because Quercetin targets cellular proteins rather than viral proteins, there is less likelihood of developing viral resistance," French said. "Cellular proteins cannot change like viral proteins can."
Many patients in the United States have a type of hepatitis C virus that does not respond to the standard treatments. In these cases, if the virus can't be blocked, end-stage liver disease and, ultimately, death may occur. Once HSP 40 and 70 were identified, French and his team used Quercetin in an attempt to block the proteins and found that the compound "reduced infectious particle production at non-toxic concentrations," according to the study.
"Quercetin may allow for the dissection of the viral life cycle and has potential therapeutic use to reduce virus production with low associated toxicity," the study states.
The UCLA clinical trial will most likely target those with type 1 hepatitis C, which is the non-responsive type prevalent in this country. Only about 50 percent of those with type 1 hepatitis C respond to treatment, French said.
Volunteers with type 1 hepatitis C who opt not to undergo conventional therapies would be recruited for the study. In other studies in other diseases, Quercetin has resulted in no significant side effects, French said.
"A non-toxic treatment for chronic hepatitis C would be great because our current therapies have significant side effects and only a certain percentage of the patient population responds," French said.
The three-year study was funded by the National Institutes of Health, the Cure Digestive Diseases Research Center and the Stein Oppenheimer Endowment Award.
Source
An estimated 270 to 300 million people worldwide are infected with hepatitis C and the conventional treatments -- interferon and ribavirin -- can have significant side effects. A new drug targeting cellular proteins rather than viral proteins would be a valuable addition to the treatment arsenal, said Samuel French, an assistant professor of pathology and senior author of the study.
French and his team set out to identify the cellular factors involved in hepatitis C replication and, using mass spectrometry, found that heat shock proteins (HSPs) 40 and 70 were important for viral infection. HSP 70 was previously known to be involved, but HSP 40 was linked for the first time to hepatitis C infection, French said. They further showed that the natural compound Quercetin, which inhibits the synthesis of these proteins, significantly inhibits viral infection in tissue culture.
"This is an important finding because we can block these proteins with the idea of reducing the level of the virus in people and, ideally, completely eliminate it," said French, who also is a researcher at UCLA's Jonsson Comprehensive Cancer Center.
The study appeared in the most recent issue of the journal Hepatology.
Since Quercetin has been shown to inhibit hepatitis C infection, French said, a Phase I clinical trial will be launched at UCLA to determine if the compound is safe and effective.
Quercetin is a plant-derived bioflavonoid, and is used by some people as a nutritional supplement. Laboratory studies show it may have anti-inflammatory and antioxidant properties, and it is being investigated for a wide range of potential health benefits. Currently, there are early-stage clinical trials testing quercetin for safety and efficacy against sarcoidosis, asthma and glucose absorption in obesity and diabetes.
"Because Quercetin targets cellular proteins rather than viral proteins, there is less likelihood of developing viral resistance," French said. "Cellular proteins cannot change like viral proteins can."
Many patients in the United States have a type of hepatitis C virus that does not respond to the standard treatments. In these cases, if the virus can't be blocked, end-stage liver disease and, ultimately, death may occur. Once HSP 40 and 70 were identified, French and his team used Quercetin in an attempt to block the proteins and found that the compound "reduced infectious particle production at non-toxic concentrations," according to the study.
"Quercetin may allow for the dissection of the viral life cycle and has potential therapeutic use to reduce virus production with low associated toxicity," the study states.
The UCLA clinical trial will most likely target those with type 1 hepatitis C, which is the non-responsive type prevalent in this country. Only about 50 percent of those with type 1 hepatitis C respond to treatment, French said.
Volunteers with type 1 hepatitis C who opt not to undergo conventional therapies would be recruited for the study. In other studies in other diseases, Quercetin has resulted in no significant side effects, French said.
"A non-toxic treatment for chronic hepatitis C would be great because our current therapies have significant side effects and only a certain percentage of the patient population responds," French said.
The three-year study was funded by the National Institutes of Health, the Cure Digestive Diseases Research Center and the Stein Oppenheimer Endowment Award.
Source
Nanogen Launches Advanced Hepatitis C Medicine
January 2011
BMI Core View: Drugmakers based in emerging markets will increasingly produce hard-to-manufacture pharmaceuticals. Firms in developing countries enjoy low operating costs, but have traditionally lacked the expertise and equipment to make advanced therapeutics such as biologics. As economies in these non-traditional markets grow, capital will be released for the establishment of modern production facilities, with output destined for both domestic consumption and export.
Ho Chi Minh City-based Nanogen Biopharmaceutical has launched Pegnano (peginterferon alfa-2a) in Vietnam for the treatment of hepatitis C. The complex biologic has Good Manufacturing Practice (GMP) accreditation and is generally used in combination with ribavirin.
However, Swiss multinational Roche has demanded the de-registration of Pegnano because the medicine infringes intellectual property protection for Pegasys (peginterferon alfa-2a), specifically patent No. 2611. Granted in 2002 by the National Office of Intellectual Property of Vietnam, the Pegasys patent is effective until 2017.
Nanogen's Director, Ho Nhan, is assured of Pegnano 's legitimacy. According to the 2009 revision of article 7 of Vietnam's Intellectual Property Law, the government can ban or limit the application of intellectual property rights in cases where such rights harm national defence, the welfare of people or badly affect other crucial national interests.
The company has ...
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Source
BMI Core View: Drugmakers based in emerging markets will increasingly produce hard-to-manufacture pharmaceuticals. Firms in developing countries enjoy low operating costs, but have traditionally lacked the expertise and equipment to make advanced therapeutics such as biologics. As economies in these non-traditional markets grow, capital will be released for the establishment of modern production facilities, with output destined for both domestic consumption and export.
Ho Chi Minh City-based Nanogen Biopharmaceutical has launched Pegnano (peginterferon alfa-2a) in Vietnam for the treatment of hepatitis C. The complex biologic has Good Manufacturing Practice (GMP) accreditation and is generally used in combination with ribavirin.
However, Swiss multinational Roche has demanded the de-registration of Pegnano because the medicine infringes intellectual property protection for Pegasys (peginterferon alfa-2a), specifically patent No. 2611. Granted in 2002 by the National Office of Intellectual Property of Vietnam, the Pegasys patent is effective until 2017.
Nanogen's Director, Ho Nhan, is assured of Pegnano 's legitimacy. According to the 2009 revision of article 7 of Vietnam's Intellectual Property Law, the government can ban or limit the application of intellectual property rights in cases where such rights harm national defence, the welfare of people or badly affect other crucial national interests.
The company has ...
To read the full article, please sign in or take a free trial.
Source
NICUs May Be Source of Donor Organs
By Todd Neale, Staff Writer, MedPage Today
Published: January 06, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Organs from infants who die of cardiac reasons in the neonatal intensive care unit may represent a new donor source for patients awaiting transplantation, a retrospective study showed.
Of 192 infants who died over a three-year period in one of three Boston NICUs, 16 (8%) were deemed candidates for organ donation after cardiac death, according to Anne Hansen, MD, MPH, of Children's Hospital Boston, and colleagues.
Based on warm ischemic time -- the interval between the withdrawal of life support and death -- and other factors, the candidate donors had the potential to provide 18 kidneys, 14 livers, and 10 hearts, the researchers reported in the January issue of the Journal of Pediatrics.
"The need to increase the pool of organ donors is clear," they wrote, noting that through the end of October 2009, there were 441 infants added to the waiting list for organs, compared with just 109 donors.
"The discrepancy between the number of possible recipients and donors underscores the importance of understanding the potential role of an infant donation-after-cardiac-death program in maximizing the donor pool for this population," Hansen and her colleagues wrote.
Historically limited to brain-dead patients, organ donation after cardiac death has gained more attention in recent years as a way to expand the donor pool. In 1997, the Institute of Medicine approved the practice as ethically acceptable and medically useful. In 2007, the Joint Commission required all of its accredited hospitals to develop a donation-after-cardiac-death policy.
To see how many deaths in a level III NICU would be theoretically eligible for donation after cardiac death, the researchers performed a retrospective study of all deaths in three Harvard Program in Neonatology NICUs -- at Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, and Children's Hospital Boston -- between 2005 and 2007.
Over the study period, there were 192 deaths in infants who had reached at least 23 weeks of gestation.
Eligibility criteria for donation after cardiac death were developed by transplant surgeons in collaboration with the New England Organ Bank. Exclusion criteria were as follows:
• Postmenstrual age at death of less than 37 weeks
• Weight at death of less than 3 kilograms
• Active infection
• Known HIV-positive status
• Active malignancy, excluding a primary brain tumor
• Encephalopathy of unknown etiology
• Brain death
• No requirement for mechanical ventilation when life support is withdrawn
After those exclusions, 31 infants who died during the study were considered eligible for organ donation. Only 16, however, had a warm ischemic time of less than one hour and were classified as potential donor candidates for kidney and liver transplantation. Of those, 14 had an interval of less than 30 minutes, and also qualified as donors for heart transplantation.
In an accompanying editorial, Lainie Friedman Ross, MD, PhD, of the University of Chicago, and Joel Frader, MD, of Northwestern University in Chicago, wrote that the study raises important clinical controversies, including whether organs can be collected in infants as small as those deemed eligible by the study authors.
Ethical controversies around procuring organs from infants who die of cardiac causes remain as well, they said.
Many pediatricians are not confident that infants who are candidates for organ donation after cardiac death are really dead, "a problem not helped by the variability in practices on how long one waits to certify death after circulatory arrest or subsequently how long surgeons must wait to ensure lack of 'auto-resuscitation' after the pronouncement of death," they wrote.
Also, the editorialists wrote, tension exists between the delivery of optimal end-of-life care and the preparations necessary for efficiently procuring organs.
"Donation after cardiac death almost always challenges standard, even when unproven, end-of-life practices that allow families to have substantial time alone with the patient immediately after death."
Two issues must be addressed before implementing newborn donation-after-cardiac-death programs, Ross and Frader argued.
"First, we need to ensure that donation-after-cardiac-death protocols conform to quality end-of-life care for all concerned: patients, parents, and healthcare professionals," they wrote.
"Second, allocation policies should be designed to promote broader geographic sharing of infant organs so these small-size organs are distributed to children who might otherwise die on the deceased donor wait list."
The study authors reported that they had no conflicts of interest.
Editorialist Ross was funded in part by a grant from the National Library of Medicine on Ethical and Policy Issues in Living Donor Transplantation. Editorialist Frader reported that he had no conflicts of interest.
Primary source: Journal of Pediatrics
Source reference:
Labrecque M, et al "Donation after cardiac death: The potential contribution of an infant organ donor population" J Pediatr 2011; 158: 87-92.
Additional source: Journal of Pediatrics
Source reference:
Ross L, Frader J "Are we ready to expand donation after cardiac death to the newborn population?" J Pediatr 2011; 158: 6-8.
Source
January 6, 2011
Some Emerging HCV Therapies
By Sean R. Hosein
From Canadian AIDS Treatment Information Exchange
December 23, 2010
Underlying some of the research with new anti-HCV agents is the hope that peginterferon, and eventually ribavirin, can eventually be replaced with more tolerable agents. This may not be possible in the immediate future, but some researchers hope that over the next five years perhaps less time spent taking peginterferon and ribavirin may be a possibility for future HCV treatment regimens.
Anti-HCV drugs under development can be divided into several groups, or classes, depending on how they work.
Protease Inhibitors
HCV needs enzymes called NS3/4A proteases that help HCV-infected cells produce new copies of HCV. These enzymes also appear to suppress the ability of infected cells to alert other cells about attack by HCV. So HCV protease inhibitors could have several benefits.
Drug companies often seek to get their drugs first approved by regulatory authorities in the United States, followed by the European Union and then Canada, Australia, Japan and other high-income countries. This is because the U.S. and the EU have large, relatively wealthy populations and present opportunities for sales and profit for drug companies. Also, it is likely that new therapies for HCV will first be approved for use in HCV mono-infection because there are more cases of mono-infection than co-infection and new therapies were initially developed for treating HCV mono-infection.
The two new anti-HCV drugs that are most likely to be approved in the U.S. are the protease inhibitors telaprevir (made by Vertex Pharmaceuticals) and boceprevir (made by Merck).
Both of these drugs have shown powerful anti-HCV activity in clinical trials of HCV mono-infection when taken as part of regimens that contain peginterferon and ribavirin. These protease inhibitors are also useful in people who have previously been treated with standard HCV therapy (peginterferon and ribavirin) but who did not respond.
Boceprevir and telaprevir are expected to be approved in the United States in 2011, with approval in the EU probably occurring in the same year. These drugs are expected to be approved in Canada in 2012.
Both of these protease inhibitors must be taken three times daily and can have side effects such as anemia. Therefore, interest in other HCV protease inhibitors under development -- such as TMC 435350 (made by Tibotec) and GS 9256 (made by Gilead Sciences) -- as well as other drugs by other companies is intense.
Polymerase Inhibitors
These drugs represent another class of anti-HCV agents and interfere with an enzyme called polymerase (hence their name). Examples of polymerase inhibitors include RG7128 and RG1628 (being developed by Hoffmann-La Roche), ABT 072 and ABT 333 (being developed by Abbott) and GS 9190 (being developed by Gilead Sciences).
Cyclophillin Inhibitors
Cyclophillins are receptors for the compound cyclosporine and are found inside of cells. The role of cyclophillins in cells is not fully understood, but these receptors may play a role in infections with viruses such as HIV and HCV. By impairing the activity of these receptors, HCV cyclophillin inhibitors can reduce the ability of HCV-infected cells to produce new viruses. Alisporivir (being developed by Novartis) is an example of a cyclophillin inhibitor.
There are other classes of anti-HCV drugs under development but they are not as far advanced as those previously mentioned.
Future Approaches to Therapy
In the treatment of HIV infection, using a combination of drugs from several classes is now the norm. Combining classes reduces the risk of HIV developing resistance to therapy. The same principle will likely apply to HCV.
Five years from now there should be a full suite of anti-HCV drugs available from different classes. When that happens, combination therapy for HCV might then include drugs from different classes and peginterferon-free regimens might finally be possible.
Reference
Gelman MA, Glenn JS. Mixing the right hepatitis C inhibitor cocktail. Trends in Molecular Medicine. 2010. In press.
Source
From Canadian AIDS Treatment Information Exchange
December 23, 2010
Underlying some of the research with new anti-HCV agents is the hope that peginterferon, and eventually ribavirin, can eventually be replaced with more tolerable agents. This may not be possible in the immediate future, but some researchers hope that over the next five years perhaps less time spent taking peginterferon and ribavirin may be a possibility for future HCV treatment regimens.
Anti-HCV drugs under development can be divided into several groups, or classes, depending on how they work.
Protease Inhibitors
HCV needs enzymes called NS3/4A proteases that help HCV-infected cells produce new copies of HCV. These enzymes also appear to suppress the ability of infected cells to alert other cells about attack by HCV. So HCV protease inhibitors could have several benefits.
Drug companies often seek to get their drugs first approved by regulatory authorities in the United States, followed by the European Union and then Canada, Australia, Japan and other high-income countries. This is because the U.S. and the EU have large, relatively wealthy populations and present opportunities for sales and profit for drug companies. Also, it is likely that new therapies for HCV will first be approved for use in HCV mono-infection because there are more cases of mono-infection than co-infection and new therapies were initially developed for treating HCV mono-infection.
The two new anti-HCV drugs that are most likely to be approved in the U.S. are the protease inhibitors telaprevir (made by Vertex Pharmaceuticals) and boceprevir (made by Merck).
Both of these drugs have shown powerful anti-HCV activity in clinical trials of HCV mono-infection when taken as part of regimens that contain peginterferon and ribavirin. These protease inhibitors are also useful in people who have previously been treated with standard HCV therapy (peginterferon and ribavirin) but who did not respond.
Boceprevir and telaprevir are expected to be approved in the United States in 2011, with approval in the EU probably occurring in the same year. These drugs are expected to be approved in Canada in 2012.
Both of these protease inhibitors must be taken three times daily and can have side effects such as anemia. Therefore, interest in other HCV protease inhibitors under development -- such as TMC 435350 (made by Tibotec) and GS 9256 (made by Gilead Sciences) -- as well as other drugs by other companies is intense.
Polymerase Inhibitors
These drugs represent another class of anti-HCV agents and interfere with an enzyme called polymerase (hence their name). Examples of polymerase inhibitors include RG7128 and RG1628 (being developed by Hoffmann-La Roche), ABT 072 and ABT 333 (being developed by Abbott) and GS 9190 (being developed by Gilead Sciences).
Cyclophillin Inhibitors
Cyclophillins are receptors for the compound cyclosporine and are found inside of cells. The role of cyclophillins in cells is not fully understood, but these receptors may play a role in infections with viruses such as HIV and HCV. By impairing the activity of these receptors, HCV cyclophillin inhibitors can reduce the ability of HCV-infected cells to produce new viruses. Alisporivir (being developed by Novartis) is an example of a cyclophillin inhibitor.
There are other classes of anti-HCV drugs under development but they are not as far advanced as those previously mentioned.
Future Approaches to Therapy
In the treatment of HIV infection, using a combination of drugs from several classes is now the norm. Combining classes reduces the risk of HIV developing resistance to therapy. The same principle will likely apply to HCV.
Five years from now there should be a full suite of anti-HCV drugs available from different classes. When that happens, combination therapy for HCV might then include drugs from different classes and peginterferon-free regimens might finally be possible.
Reference
Gelman MA, Glenn JS. Mixing the right hepatitis C inhibitor cocktail. Trends in Molecular Medicine. 2010. In press.
Source
Reporting could help stop hepatitis C
By Lori Nerbonne / For the Monitor
January 6, 2011
Thank you to Meg Heckman for "My Epidemic," her moving, candid and sobering December series on hepatitis C (concordmonitor.com/hcv). She reminds us that although it is a silent disease in symptoms, it wreaks havoc with victims' lives. Her selflessness in sharing the personal details of her journey is sure to be far-reaching and gives a voice to so many silent victims.
Meg's story reminded me of another hepatitis C victim I had the pleasure of meeting last year at a workshop I attended at the Centers for Disease Control. Dr. Evelyn Mc-Knight, a lovely soft-spoken audiologist from Fremont, Neb., had come to tell about her life-changing diagnosis of hepatitis C that began in 2001.
While undergoing treatment for stage 3 breast cancer at a local oncology clinic, Evelyn's routine blood testing came back positive for Hepatitis C. Knowing she had none of the risk factors caused confusion and alarm. Shortly after, her husband Tom, a local physician, began noticing that some of his patients had an elevated liver enzyme that is sometimes consistent with hepatitis, so he had them tested. All four tested positive for hep C. These same patients were all being treated for cancer at the same oncology clinic as his wife Evelyn.
Eventually the largest outbreak (99 patients) of hepatitis C in a U.S. health care facility was discovered by the determination of a caring husband and physician, and through sheer coincidence. Since then, several other, much larger health care facility outbreaks have been discovered across the country. Inappropriate and dangerous reuse of common medical equipment like syringes and medication vials are the usual culprits.
Evelyn now works as a passionate patient safety advocate and, with the CDC, has launched a national campaign to educate health-care providers and patients about safe injection practices (honoreform.org).
Most of these outbreaks have occurred in outpatient settings, but no health-care facility is immune. But here's the catch: The trigger for an investigation into these outbreaks often occurs when positive hepatitis C blood tests are reported to a centralized lab at the state public health department. Many states require this type of reporting. New Hampshire does not. This means that a cluster of positive tests or a major outbreak in a health-care facility in New Hampshire would likely go unnoticed, putting many unknowing patients at risk for years.
As a recent Monitor editorial underscores, it will take public health, academic, legislative and health-care leaders from across the state to tackle this problem. For many communicable diseases like hepatitis C, a public health model that includes prevention, early detection, tracking and early intervention would not only save billions of our health-care dollars, but human suffering and many precious lives.
(Lori Nerbonne of Bow is the founder of New Hampshire Patient Voices.)
Source
Also See: My Epidemic.....Shared and Written by Meg Heckman of the Concord Monitor
January 6, 2011
Thank you to Meg Heckman for "My Epidemic," her moving, candid and sobering December series on hepatitis C (concordmonitor.com/hcv). She reminds us that although it is a silent disease in symptoms, it wreaks havoc with victims' lives. Her selflessness in sharing the personal details of her journey is sure to be far-reaching and gives a voice to so many silent victims.
Meg's story reminded me of another hepatitis C victim I had the pleasure of meeting last year at a workshop I attended at the Centers for Disease Control. Dr. Evelyn Mc-Knight, a lovely soft-spoken audiologist from Fremont, Neb., had come to tell about her life-changing diagnosis of hepatitis C that began in 2001.
While undergoing treatment for stage 3 breast cancer at a local oncology clinic, Evelyn's routine blood testing came back positive for Hepatitis C. Knowing she had none of the risk factors caused confusion and alarm. Shortly after, her husband Tom, a local physician, began noticing that some of his patients had an elevated liver enzyme that is sometimes consistent with hepatitis, so he had them tested. All four tested positive for hep C. These same patients were all being treated for cancer at the same oncology clinic as his wife Evelyn.
Eventually the largest outbreak (99 patients) of hepatitis C in a U.S. health care facility was discovered by the determination of a caring husband and physician, and through sheer coincidence. Since then, several other, much larger health care facility outbreaks have been discovered across the country. Inappropriate and dangerous reuse of common medical equipment like syringes and medication vials are the usual culprits.
Evelyn now works as a passionate patient safety advocate and, with the CDC, has launched a national campaign to educate health-care providers and patients about safe injection practices (honoreform.org).
Most of these outbreaks have occurred in outpatient settings, but no health-care facility is immune. But here's the catch: The trigger for an investigation into these outbreaks often occurs when positive hepatitis C blood tests are reported to a centralized lab at the state public health department. Many states require this type of reporting. New Hampshire does not. This means that a cluster of positive tests or a major outbreak in a health-care facility in New Hampshire would likely go unnoticed, putting many unknowing patients at risk for years.
As a recent Monitor editorial underscores, it will take public health, academic, legislative and health-care leaders from across the state to tackle this problem. For many communicable diseases like hepatitis C, a public health model that includes prevention, early detection, tracking and early intervention would not only save billions of our health-care dollars, but human suffering and many precious lives.
(Lori Nerbonne of Bow is the founder of New Hampshire Patient Voices.)
Source
Also See: My Epidemic.....Shared and Written by Meg Heckman of the Concord Monitor
Merck Beats Vertex to FDA Hep C Filing
By Adam Feuerstein
01/06/11 - 10:07 AM EST
WHITEHOUSE STATION, NJ (TheStreet) --In the race to market the first next-generation treatment for hepatitis C, Merck(MRK_) is out to an early lead.
Or, as my kids would so delicately put it: "Vertex Pharmaceuticals(VRTX_), you just got burned!!!"
The U.S. Food and Drug Administration accepted Merck's approval filing for its hepatitis C drug boceprevir, the company said Thursday. The news from Merck is a bit of a surprise since the company hadn't previously announced or confirmed that boceprevir had been filed with U.S. regulators.
It's also a tad embarrassing for Vertex, which is still waiting to hear back from FDA about the acceptance of the approval filing for telaprevir, its competing hepatitis C drug. That news should come by Jan. 24, based on Vertex's previous announcement that it filed the drug's application on Nov. 23.
Still, it seems as if Merck beat Vertex to the FDA by at least two weeks.
Merck's boceprevir, therefore, has a chance to grab bragging rights as the first, next-generation hepatitis C drug approved by FDA.
If both drugs are approved, boceprevir could be on the market by the second week of May, or approximately two to three weeks before Vertex has a chance to do the same with telaprevir.
In the grand scheme of things, a two-week head start is trivial. But given Vertex's reputation for supreme confidence (some would say cockiness), the fact that slothy Big Pharma giant Merck has taken the early lead in the hepatitis C drug race is a surprising comeuppance.
Vertex shares were down 19 cents to $36.68 in early Thursday trading.
A Merck spokesman would not confirm the exact FDA filing date for boceprevir. A Vertex spokesman said, "We expect to hear from the FDA this month regarding our request for priority review."
Cheer up, Vertex. The race to approval for a new hepatitis C drug is really just the starting point. What really matters is how each drug fares in the commercial market. Merck's early lead now may not matter much once doctors and patients have a choice of which drug to use.
Source
Also See:
-- Merck scoots past Vertex in blockbuster race for hep C drug approval
-- Boceprevir, Merck’s Investigational Oral Hepatitis C Protease Inhibitor, Receives FDA Priority Review and EMA Accelerated Assessment
01/06/11 - 10:07 AM EST
WHITEHOUSE STATION, NJ (TheStreet) --In the race to market the first next-generation treatment for hepatitis C, Merck(MRK_) is out to an early lead.
Or, as my kids would so delicately put it: "Vertex Pharmaceuticals(VRTX_), you just got burned!!!"
The U.S. Food and Drug Administration accepted Merck's approval filing for its hepatitis C drug boceprevir, the company said Thursday. The news from Merck is a bit of a surprise since the company hadn't previously announced or confirmed that boceprevir had been filed with U.S. regulators.
It's also a tad embarrassing for Vertex, which is still waiting to hear back from FDA about the acceptance of the approval filing for telaprevir, its competing hepatitis C drug. That news should come by Jan. 24, based on Vertex's previous announcement that it filed the drug's application on Nov. 23.
Still, it seems as if Merck beat Vertex to the FDA by at least two weeks.
Merck's boceprevir, therefore, has a chance to grab bragging rights as the first, next-generation hepatitis C drug approved by FDA.
If both drugs are approved, boceprevir could be on the market by the second week of May, or approximately two to three weeks before Vertex has a chance to do the same with telaprevir.
In the grand scheme of things, a two-week head start is trivial. But given Vertex's reputation for supreme confidence (some would say cockiness), the fact that slothy Big Pharma giant Merck has taken the early lead in the hepatitis C drug race is a surprising comeuppance.
Vertex shares were down 19 cents to $36.68 in early Thursday trading.
A Merck spokesman would not confirm the exact FDA filing date for boceprevir. A Vertex spokesman said, "We expect to hear from the FDA this month regarding our request for priority review."
Cheer up, Vertex. The race to approval for a new hepatitis C drug is really just the starting point. What really matters is how each drug fares in the commercial market. Merck's early lead now may not matter much once doctors and patients have a choice of which drug to use.
Source
Also See:
-- Merck scoots past Vertex in blockbuster race for hep C drug approval
-- Boceprevir, Merck’s Investigational Oral Hepatitis C Protease Inhibitor, Receives FDA Priority Review and EMA Accelerated Assessment
Merck scoots past Vertex in blockbuster race for hep C drug approval
January 6, 2011 — 12:23pm ET
By John Carroll
Merck ($MRK) has stolen a small lead in its hot race with Vertex ($VRTX) for regulatory approval of a new hepatitis C treatment. The pharma giant says that regulators in the U.S. as well as Europe have accepted its applications for boceprevir. And the FDA plans on an expedited, six month review.
Vertex, meanwhile, is still waiting for confirmation from the FDA on its closely-watched application for telaprevir, which it confidently expects will win approval this year after presenting a mountain of promising late-stage data on its behalf. Word should arrive in the next couple of weeks, though, which will help the market handicappers estimate where these two drug prospects are likely to land later in 2011.
"We are pleased that the FDA and EMA have accepted boceprevir for expedited review. Our goal is to be able to bring forward a new treatment option for patients living with chronic hepatitis C, and we are now closer to that goal," said Dr. Peter Kim, president, Merck Research Laboratories.
There's no such thing as a sure thing in drug development, but both drugs are considered odds-on favorites for an approval. And they promise to shake up the hep C treatment field in short order.
Source
Also See: Boceprevir, Merck’s Investigational Oral Hepatitis C Protease Inhibitor, Receives FDA Priority Review and EMA Accelerated Assessment
By John Carroll
Merck ($MRK) has stolen a small lead in its hot race with Vertex ($VRTX) for regulatory approval of a new hepatitis C treatment. The pharma giant says that regulators in the U.S. as well as Europe have accepted its applications for boceprevir. And the FDA plans on an expedited, six month review.
Vertex, meanwhile, is still waiting for confirmation from the FDA on its closely-watched application for telaprevir, which it confidently expects will win approval this year after presenting a mountain of promising late-stage data on its behalf. Word should arrive in the next couple of weeks, though, which will help the market handicappers estimate where these two drug prospects are likely to land later in 2011.
"We are pleased that the FDA and EMA have accepted boceprevir for expedited review. Our goal is to be able to bring forward a new treatment option for patients living with chronic hepatitis C, and we are now closer to that goal," said Dr. Peter Kim, president, Merck Research Laboratories.
There's no such thing as a sure thing in drug development, but both drugs are considered odds-on favorites for an approval. And they promise to shake up the hep C treatment field in short order.
Source
Also See: Boceprevir, Merck’s Investigational Oral Hepatitis C Protease Inhibitor, Receives FDA Priority Review and EMA Accelerated Assessment
Pharmasset says HCV drugs show promise
Thu Jan 6, 2011 7:48am EST
* PSI-7977 shows rapid viral suppression
* PSI-938 found to be well tolerated
Jan 6 (Reuters) - Pharmasset Inc (VRUS.O) said interim analyses of clinical studies of its two drugs for chronic hepatitis C showed promise.
A mid-stage study of the drug, codenamed PSI-7977, showed rapid viral suppression with all patients remaining below limit of detection at the end of treatment. No serious adverse events were reported.
The drug was granted "fast track" designation in August. Fast-track status is designed to expedite the review of drugs to treat serious diseases and fill unmet medical needs. [id:nSGE67B0JZ]
The company said it expects to start a 24-week mid-stage study of the drug in the second quarter of 2011.
An early-stage study of the drug, codenamed PSI-938, as a monotherapy was found to be safe and well-tolerated, Pharmasset said.
The Princeton, New Jersey-based company's shares, which have risen 50 percent in the last three months, closed at $46.59 on Wednesday on Nasdaq. (Reporting by Shravya Jain in Bangalore; Editing by Sriraj Kalluvila)
Source
Thursday, January 06, 2011
Pharmasset Reports Interim Study Results For Its Hepatitis C Drugs
Pharmasset (NASDAQ:VRUS) announced today interim results for the Phase 2b study for its PSI-7977 drug and the Phase 1 study for its PSI-938 drug. Both drugs are designed to treat Hepatitis C.
The Phase 2b study consisted of evaluating the effects of various PSI-7977 dosages in patients with Hepatitis C genotype 1, 2 or 3. The patients also received antiviral drugs commonly used to fight Hepatitis C.
Hepatitis genotype 1 patients received dosages of PSI-7977 and antiviral drugs over a 12-week period followed by 12 or 36 weeks of just antiviral drugs. Heptatitis genotype 2 and 3 patients received dosages of PSI-7977 and antiviral drugs over 12 weeks with no therapy afterward.
For the patients with Hepatitis C genotype 2 or 3, the data shows no serious adverse events and no discontinuations due to adverse events, the New Jersey-based company said. All patients showed viral suppression.
Results for the patients with Hepatitis C genotype 1 will be released in the second quarter of 2011, the company said.
During the second quarter of 2011, the company also expect to initiate a 24-week Phase 2b study of PSI-7977 with pegylated interferon and ribavirin.
In a separate Phase 1 study, the company also tested the PSI-938, a Hepatitis drug in a different chemical form than the PSI-7977.
Over a period of 14 days, patients were given dosages of only PSI-938 and showed no serious adverse events as well as no dose modifications or discontinuations, the company said. Also, the patients did not see an increase in the severity of viral infection while on therapy.
PSI-938 will also be tested in combination with PSI-7977, with the results scheduled to be reported sometime this quarter.
Source
* PSI-7977 shows rapid viral suppression
* PSI-938 found to be well tolerated
Jan 6 (Reuters) - Pharmasset Inc (VRUS.O) said interim analyses of clinical studies of its two drugs for chronic hepatitis C showed promise.
A mid-stage study of the drug, codenamed PSI-7977, showed rapid viral suppression with all patients remaining below limit of detection at the end of treatment. No serious adverse events were reported.
The drug was granted "fast track" designation in August. Fast-track status is designed to expedite the review of drugs to treat serious diseases and fill unmet medical needs. [id:nSGE67B0JZ]
The company said it expects to start a 24-week mid-stage study of the drug in the second quarter of 2011.
An early-stage study of the drug, codenamed PSI-938, as a monotherapy was found to be safe and well-tolerated, Pharmasset said.
The Princeton, New Jersey-based company's shares, which have risen 50 percent in the last three months, closed at $46.59 on Wednesday on Nasdaq. (Reporting by Shravya Jain in Bangalore; Editing by Sriraj Kalluvila)
Source
Thursday, January 06, 2011
Pharmasset Reports Interim Study Results For Its Hepatitis C Drugs
Pharmasset (NASDAQ:VRUS) announced today interim results for the Phase 2b study for its PSI-7977 drug and the Phase 1 study for its PSI-938 drug. Both drugs are designed to treat Hepatitis C.
The Phase 2b study consisted of evaluating the effects of various PSI-7977 dosages in patients with Hepatitis C genotype 1, 2 or 3. The patients also received antiviral drugs commonly used to fight Hepatitis C.
Hepatitis genotype 1 patients received dosages of PSI-7977 and antiviral drugs over a 12-week period followed by 12 or 36 weeks of just antiviral drugs. Heptatitis genotype 2 and 3 patients received dosages of PSI-7977 and antiviral drugs over 12 weeks with no therapy afterward.
For the patients with Hepatitis C genotype 2 or 3, the data shows no serious adverse events and no discontinuations due to adverse events, the New Jersey-based company said. All patients showed viral suppression.
Results for the patients with Hepatitis C genotype 1 will be released in the second quarter of 2011, the company said.
During the second quarter of 2011, the company also expect to initiate a 24-week Phase 2b study of PSI-7977 with pegylated interferon and ribavirin.
In a separate Phase 1 study, the company also tested the PSI-938, a Hepatitis drug in a different chemical form than the PSI-7977.
Over a period of 14 days, patients were given dosages of only PSI-938 and showed no serious adverse events as well as no dose modifications or discontinuations, the company said. Also, the patients did not see an increase in the severity of viral infection while on therapy.
PSI-938 will also be tested in combination with PSI-7977, with the results scheduled to be reported sometime this quarter.
Source
Boceprevir, Merck’s Investigational Oral Hepatitis C Protease Inhibitor, Receives FDA Priority Review and EMA Accelerated Assessment
January 06, 2011 08:00 AM Eastern Time
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck, known as MSD outside the United States and Canada, announced today that regulatory applications for boceprevir, Merck's investigational oral hepatitis C virus (HCV) protease inhibitor, were submitted in 2010 and have been accepted for expedited review in both the U.S. and the European Union.
The U.S. Food and Drug Administration (FDA) granted the New Drug Application (NDA) for boceprevir Priority Review status, a designation given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. FDA's goal for completing a Priority Review is six months.
Additionally, the European Medicines Agency (EMA) accepted the Marketing Authorization Application (MAA) for boceprevir for accelerated assessment. Accelerated assessment is available for products that respond to unmet medical needs or represent a significant improvement over current treatment options within a major public health interest such as treatment of hepatitis C virus infection.
Data in the NDA and MAA have been provided in support of the proposed use of boceprevir for the treatment of chronic HCV genotype 1 infection, in combination with standard therapy, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.
"We are pleased that the FDA and EMA have accepted boceprevir for expedited review. Our goal is to be able to bring forward a new treatment option for patients living with chronic hepatitis C, and we are now closer to that goal,” said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories.
Merck's global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. Extensive research efforts are underway to develop differentiated oral therapies that bring innovation to viral hepatitis care.
About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit http://www.merck.com/.
Forward-Looking Statement
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.
The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.
Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2009 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (http://www.sec.gov/).
Contacts
Merck
Media:
Ian McConnell, 908-423-3046
Robert Consalvo, 908-295-0928
or
Investors:
Joe Romanelli, 908-423-5088
Source
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck, known as MSD outside the United States and Canada, announced today that regulatory applications for boceprevir, Merck's investigational oral hepatitis C virus (HCV) protease inhibitor, were submitted in 2010 and have been accepted for expedited review in both the U.S. and the European Union.
The U.S. Food and Drug Administration (FDA) granted the New Drug Application (NDA) for boceprevir Priority Review status, a designation given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. FDA's goal for completing a Priority Review is six months.
Additionally, the European Medicines Agency (EMA) accepted the Marketing Authorization Application (MAA) for boceprevir for accelerated assessment. Accelerated assessment is available for products that respond to unmet medical needs or represent a significant improvement over current treatment options within a major public health interest such as treatment of hepatitis C virus infection.
Data in the NDA and MAA have been provided in support of the proposed use of boceprevir for the treatment of chronic HCV genotype 1 infection, in combination with standard therapy, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.
"We are pleased that the FDA and EMA have accepted boceprevir for expedited review. Our goal is to be able to bring forward a new treatment option for patients living with chronic hepatitis C, and we are now closer to that goal,” said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories.
Merck's global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. Extensive research efforts are underway to develop differentiated oral therapies that bring innovation to viral hepatitis care.
About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit http://www.merck.com/.
Forward-Looking Statement
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.
The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.
Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2009 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (http://www.sec.gov/).
Contacts
Merck
Media:
Ian McConnell, 908-423-3046
Robert Consalvo, 908-295-0928
or
Investors:
Joe Romanelli, 908-423-5088
Source
January 5, 2011
National Patient Advocate Foundation Calls on Arizona Leadership to Reinstate Medicaid Benefits for State's Patients Awaiting Transplant
Nation's Leading Patient Advocacy Policy Organization Calls on Governor Brewer, State Leaders to Restore Access to Life-Saving Transplants for Arizona's Nearly 100 Patients in Need
WASHINGTON, Jan. 5, 2011 /PRNewswire-USNewswire/ -- The National Patient Advocate Foundation (NPAF) – a national, non-profit organization dedicated to the mission of creating avenues of improved patient access to healthcare through public policy reform at the state and federal levels – called on Arizona's key lawmakers today to reinstate benefits for the state's adult Medicaid patients awaiting certain types of organ and bone marrow transplants, thereby reversing the state legislature's recent decision to deny coverage for these types of services.
Following a budget-cutting decision which became effective in October 2010, Arizona no longer funds certain types of transplants for adults under the state's Medicaid program, the Arizona Health Care Cost Containment System (AHCCCS). These types of transplants include lung transplants, liver transplants for hepatitis C patients, and some bone marrow and pancreas transplants, which at times can be the only option for survival for patients facing certain types of cancer and other serious illnesses. In letters sent to Governor Jan Brewer, Speaker of the House Kirk Adams, President of the Senate Robert Burns and AHCCCS Director Thomas Betlach, NPAF urged the state's policymakers to reverse this decision in order to make certain that all Arizona's patients in need have access to medically necessary transplants.
"As an organization dedicated to helping ensure all critically ill patients are able to access the life-saving care they need, we felt it necessary to speak out on behalf of Arizona's Medicaid patients who are now unable to receive essential transplants as a result of the state's recent budget decision," said Nancy Davenport-Ennis, Founder and CEO of NPAF. "Though we appreciate states' severe funding shortfalls, we must join the growing chorus of leading medical centers, experts and physicians, and patients themselves in urging Governor Brewer and the state's leadership to reverse this dangerous position that could be truly devastating for AHCCCS patients awaiting transplant."
In voting to cut funds for covering these types of transplants, state lawmakers relied upon data provided by the AHCCCS showing a limited success rate for the procedures. However, many experts and advocates – including AHCCCS patients who have had successful organ transplants prior to this decision – have questioned the accuracy of this data.
As stated in its letter, NPAF is pleased that the new coverage guidelines exempt pediatric patients, but remains seriously concerned about the denial of benefits for transplants which remain the standard of care for adult patients. For example, allogeneic hematopoietic cell transplant (a type of transplant involving bone marrow, peripheral blood or cord blood), which is no longer covered for adult patients on AHCCCS, remains the standard of care for patients suffering from several types of leukemia, multiple myeloma and non-Hodgkin lymphoma, among other serious conditions.
"According to national data, there are over 2,000 patients on transplant waiting lists in Arizona, and of these, 97 are AHCCCS patients who are affected by the reduction in state benefits. These are 97 lives that are now without hope of getting coverage for their transplants without a reversal in this policy," added Davenport-Ennis. "We must speak up on these patients' behalf, and we sincerely hope to work with Arizona's lawmakers to ensure that all patients in need of transplants, regardless of reimbursement model, have access to these life-saving procedures."
NPAF and its companion organization, the Patient Advocate Foundation (PAF), were established in 1996 on the principle that health care is a basic human need and shared social responsibility. NPAF is dedicated to working with Congress and all levels of government to overcome challenges and create solutions that will allow for high-quality, affordable health care for all. In 2009, PAF case managers assisted 55,384 patients, each with chronic, life-threatening or debilitating conditions struggling to access health care. Additionally, PAF responds to millions of online requests for information or chat line support. For more information see www.npaf.org.
SOURCE National Patient Advocate Foundation
RELATED LINKS
http://www.npaf.org/
Source
Also See:
-- NVHR Blasts Arizona Medicaid's 'Inhumane' Policy Depriving Hepatitis C Patients Liver Transplant Coverage
-- Budget cuts stop Phoenix man from getting new liver
-- Arizona Cuts Financing for Transplant Patients
WASHINGTON, Jan. 5, 2011 /PRNewswire-USNewswire/ -- The National Patient Advocate Foundation (NPAF) – a national, non-profit organization dedicated to the mission of creating avenues of improved patient access to healthcare through public policy reform at the state and federal levels – called on Arizona's key lawmakers today to reinstate benefits for the state's adult Medicaid patients awaiting certain types of organ and bone marrow transplants, thereby reversing the state legislature's recent decision to deny coverage for these types of services.
Following a budget-cutting decision which became effective in October 2010, Arizona no longer funds certain types of transplants for adults under the state's Medicaid program, the Arizona Health Care Cost Containment System (AHCCCS). These types of transplants include lung transplants, liver transplants for hepatitis C patients, and some bone marrow and pancreas transplants, which at times can be the only option for survival for patients facing certain types of cancer and other serious illnesses. In letters sent to Governor Jan Brewer, Speaker of the House Kirk Adams, President of the Senate Robert Burns and AHCCCS Director Thomas Betlach, NPAF urged the state's policymakers to reverse this decision in order to make certain that all Arizona's patients in need have access to medically necessary transplants.
"As an organization dedicated to helping ensure all critically ill patients are able to access the life-saving care they need, we felt it necessary to speak out on behalf of Arizona's Medicaid patients who are now unable to receive essential transplants as a result of the state's recent budget decision," said Nancy Davenport-Ennis, Founder and CEO of NPAF. "Though we appreciate states' severe funding shortfalls, we must join the growing chorus of leading medical centers, experts and physicians, and patients themselves in urging Governor Brewer and the state's leadership to reverse this dangerous position that could be truly devastating for AHCCCS patients awaiting transplant."
In voting to cut funds for covering these types of transplants, state lawmakers relied upon data provided by the AHCCCS showing a limited success rate for the procedures. However, many experts and advocates – including AHCCCS patients who have had successful organ transplants prior to this decision – have questioned the accuracy of this data.
As stated in its letter, NPAF is pleased that the new coverage guidelines exempt pediatric patients, but remains seriously concerned about the denial of benefits for transplants which remain the standard of care for adult patients. For example, allogeneic hematopoietic cell transplant (a type of transplant involving bone marrow, peripheral blood or cord blood), which is no longer covered for adult patients on AHCCCS, remains the standard of care for patients suffering from several types of leukemia, multiple myeloma and non-Hodgkin lymphoma, among other serious conditions.
"According to national data, there are over 2,000 patients on transplant waiting lists in Arizona, and of these, 97 are AHCCCS patients who are affected by the reduction in state benefits. These are 97 lives that are now without hope of getting coverage for their transplants without a reversal in this policy," added Davenport-Ennis. "We must speak up on these patients' behalf, and we sincerely hope to work with Arizona's lawmakers to ensure that all patients in need of transplants, regardless of reimbursement model, have access to these life-saving procedures."
NPAF and its companion organization, the Patient Advocate Foundation (PAF), were established in 1996 on the principle that health care is a basic human need and shared social responsibility. NPAF is dedicated to working with Congress and all levels of government to overcome challenges and create solutions that will allow for high-quality, affordable health care for all. In 2009, PAF case managers assisted 55,384 patients, each with chronic, life-threatening or debilitating conditions struggling to access health care. Additionally, PAF responds to millions of online requests for information or chat line support. For more information see www.npaf.org.
SOURCE National Patient Advocate Foundation
RELATED LINKS
http://www.npaf.org/
Source
Also See:
-- NVHR Blasts Arizona Medicaid's 'Inhumane' Policy Depriving Hepatitis C Patients Liver Transplant Coverage
-- Budget cuts stop Phoenix man from getting new liver
-- Arizona Cuts Financing for Transplant Patients
Budesonide for Autoimmune Hepatitis
Budesonide was superior to prednisone at inducing remission with fewer steroid-specific adverse effects.
Autoimmune hepatitis (AIH) is a chronic liver disease associated with excess morbidity and mortality. The mainstay of AIH therapy is prednisone plus azathioprine. However, both short-term and long-term use of prednisone can cause adverse effects. A potential alternate AIH treatment is budesonide, a steroid with high liver exposure but low systemic exposure that proved in a pilot study to be effective in previously untreated AIH patients.
Now, researchers have conducted an industry-supported, double-blind, randomized, controlled, multicenter, phase IIb trial of budesonide involving 203 noncirrhotic patients with AIH. In part one of the study, patients received azathioprine (1–2 mg/kg/day) plus either prednisone (40 mg daily, tapering to 10 mg) or budesonide (3 mg, 2–3 times daily) for 6 months. Patients who achieved complete biochemical response by 3 months — and, at the investigator's discretion, those not in remission by 6 months — could proceed to part two of the study, a 6-month, open-label segment in which all patients received azathioprine and budesonide.
At 6 months, more patients in the budesonide group than in the prednisone group achieved the primary endpoint: complete biochemical response (normalization of liver enzymes) and the absence of steroid-specific adverse effects, such as moon face, acne, buffalo hump, diabetes, and striae (47.0% vs. 18.4%; P<0.001); more patients in the budesonide group achieved complete biochemical response (60.0% vs. 38.8%; P=0.001), and fewer experienced steroid-specific adverse effects (28.0% vs. 53.4%; P<0.001). At 12 months, 95 (54.8%) of 173 patients who completed part two of the study achieved complete response; rates of complete response were similar between patients originally randomized to budesonide or prednisone.
Comment: This study of well-characterized AIH showed that budesonide plus azathioprine was superior to prednisone plus azathioprine at inducing and maintaining remission with fewer steroid-specific adverse effects. Because the primary efficacy endpoint was determined at 6 months, the study did not address whether remission was maintained long term with budesonide. In addition, budesonide is considerably more expensive than prednisone and thus might not be cost-effective if needed long term. These issues aside, clinicians should consider budesonide plus azathioprine as another treatment option for AIH.
— Atif Zaman, MD, MPH
Published in Journal Watch Gastroenterology December 17, 2010
Citation(s):
Manns MP et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 2010 Oct; 139:1198.
Medline abstract (Free)
Source
Autoimmune hepatitis (AIH) is a chronic liver disease associated with excess morbidity and mortality. The mainstay of AIH therapy is prednisone plus azathioprine. However, both short-term and long-term use of prednisone can cause adverse effects. A potential alternate AIH treatment is budesonide, a steroid with high liver exposure but low systemic exposure that proved in a pilot study to be effective in previously untreated AIH patients.
Now, researchers have conducted an industry-supported, double-blind, randomized, controlled, multicenter, phase IIb trial of budesonide involving 203 noncirrhotic patients with AIH. In part one of the study, patients received azathioprine (1–2 mg/kg/day) plus either prednisone (40 mg daily, tapering to 10 mg) or budesonide (3 mg, 2–3 times daily) for 6 months. Patients who achieved complete biochemical response by 3 months — and, at the investigator's discretion, those not in remission by 6 months — could proceed to part two of the study, a 6-month, open-label segment in which all patients received azathioprine and budesonide.
At 6 months, more patients in the budesonide group than in the prednisone group achieved the primary endpoint: complete biochemical response (normalization of liver enzymes) and the absence of steroid-specific adverse effects, such as moon face, acne, buffalo hump, diabetes, and striae (47.0% vs. 18.4%; P<0.001); more patients in the budesonide group achieved complete biochemical response (60.0% vs. 38.8%; P=0.001), and fewer experienced steroid-specific adverse effects (28.0% vs. 53.4%; P<0.001). At 12 months, 95 (54.8%) of 173 patients who completed part two of the study achieved complete response; rates of complete response were similar between patients originally randomized to budesonide or prednisone.
Comment: This study of well-characterized AIH showed that budesonide plus azathioprine was superior to prednisone plus azathioprine at inducing and maintaining remission with fewer steroid-specific adverse effects. Because the primary efficacy endpoint was determined at 6 months, the study did not address whether remission was maintained long term with budesonide. In addition, budesonide is considerably more expensive than prednisone and thus might not be cost-effective if needed long term. These issues aside, clinicians should consider budesonide plus azathioprine as another treatment option for AIH.
— Atif Zaman, MD, MPH
Published in Journal Watch Gastroenterology December 17, 2010
Citation(s):
Manns MP et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 2010 Oct; 139:1198.
Medline abstract (Free)
Source
Treatment of Hepatitis C in children
Paloma Jara; Loreto Hierro
Posted: 03/02/2010;
Expert Rev Gastroenterol Hepatol. 2010;4(1):51-61.
© 2010 Expert Reviews Ltd.
Abstract and Introduction
Abstract
Hepatitis C affects 4–10% of children born to infected mothers, and 80% of them develop chronic infection. Most patients with chronic hepatitis C virus infection are asymptomatic, with persistent or intermittent biochemical abnormalities. Severe liver disease may develop 10 years after onset of infection, with a less than 2% overall risk during the pediatric age. Available therapies have no contraindication in children if otherwise healthy. The US FDA and EMEA have recently approved combined pegylated-IFN-α2b plus ribavirin treatment for children, who should be over 3 years of age in order to avoid severe side effects. Experiences in pilot trials and international studies indicate a response rate of 50% in genotype 1 patients, and more than 90% in genotype 2 or 3 patients, indicating resolution of chronic disease.
Introduction
The possibility of curing chronic hepatitis C virus (HCV) infection by means of PEG-IFN plus ribavirin – the currently recommended treatment – has raised controversy about the convenience of treating pediatric patients. As children with chronic HCV infection are usually asymptomatic and rarely develop severe liver damage, the possibility of eliciting adverse effects from current therapies must be appropriately balanced against the benefits. Characteristics of HCV infection in children and the results of treatment are reviewed here in order to substantiate decisions.
The discovery of HCV and the use of anti-HCV levels as a marker of exposure was available in the early 1990s to exclude infected blood and organ donors. Before this, most HCV infections were acquired by transfusions or inadequately sterilized needles or instruments. Pediatric populations heavily affected in the past due to repeated administration of blood derivatives for hemoglobinopathies, hemophilia or cancer treatment are now young adults, and therefore beyond the scope of this revision. In certain areas of the world, post-transfusional hepatitis C remains a hazard. Cumulative information on superimposed HCV infection to some underlying diseases of children indicates similar chronicization rates, deleterious effects of iron overload added to viral-induced liver damage and evidence of difficult-to-treat patients because of conditions that affect the tolerability of drugs, such as anemia or renal insufficiency.
The effectiveness of excluding parenteral routes of HCV is demonstrated in young populations of industrialized countries.[1] Perinatal mother-to-child transmission accounts for 95% of all cases of hepatitis C in children born after 1990. In addition, over the years there has been a reduction in the number of pediatric cases of vertical transmission because the anti-HCV-positive rate has decreased in younger women as a result of lesser transfusional transmission of the disease, and due to changes in illicit drug abuse with a shift towards nonintravenous forms of administration.[2]
In the current setting, most affected children are otherwise healthy. The applicability of treatment is the rule. Combined treatment offers a 50–90% chance (according to HCV genotype) of clearing HCV infection, thus avoiding the progression of liver disease. This review will focus on the benefits of current therapy, mostly evident in the long term, and also on drug toxicity.
Origin of HCV Infection in Children: Mother-to-child Transmission
Hepatitis C is an asymptomatic disease in infants. The only efficient method for its detection is the investigation of children at risk. Infants of women with hepatitis C should be tested for HCV RNA on two occasions, between the ages of 2 and 6 months, and again at 18 to 24 months, along with serum anti-HCV.[3–5] Variants to this schedule are also employed. Tests performed in umbilical cord or before 1 month of age give a high rate of false-negative and false-positive results and are not recommended.
The offspring of anti-HCV-positive mothers have anti-HCV antibodies in their blood as a result of passive transplacental transfer. These antibodies remain detectable in the infant for the first 12–15 months of life. The definition of mother-to-child transmission of HCV includes: the detection of anti-HCV antibodies in a child over 18 months of age, or the detection of HCV RNA in a child over 2 months of age, preferably confirmed in two different samples.[3]
Children born to anti-HCV-positive and HCV RNA-positive mothers have an infection risk of 4–10%, with no differences between caesarean or vaginal delivery, or between children who are breastfed or receive infant formulas.[3,6] Once pre- or peri-natal transmission has been discarded, cohabitation of the child with the mother entails no appreciable risk.
Excellent reviews on HCV vertical transmission are available.[3,6,7] Some risk factors have been clearly identified, such as maternal viremia[4,8] or maternal co-infection with HIV-1.[3] Maternal intravenous drug use, the presence of HCV RNA in maternal peripheral blood mononuclear cells and genetic factors (HLA-DRB1*10 in children) could also facilitate transmission.[9–11]
However, discordance exists between studies. Viral load in the mother is a rational risk factor involved in transmission to the child, but was found to be either high or not significantly different between transmitting and nontransmitting mothers.[8,12] Other risk factors are linked to abnormal labor, as published data support facilitated transmission by a prolonged time from rupture of membranes to birth.[6,13,14] Antiretroviral treatment of HIV-infected mothers decreases the risk of HCV transmission to levels similar to HIV-negative mothers.[6]
Mother-to-child transmission theoretically can occur in utero, at the end of pregnancy or at delivery. Among 54 infected infants tested within 3 days of birth, 31% displayed HCV viremia, suggesting that intrauterine infection could have occurred.[15]
There are currently no established interventions to prevent infection of the child born to an infected mother. In particular, there is no evidence to suggest that women should be offered an elective caesarean delivery or be advised to avoid breastfeeding.[4]
Course of HCV Infection in Children
In order to know the characteristics of HCV infection in children from the onset, many studies aimed at the surveillance of children born to HCV-positive mothers. HCV screening is not mandatory in pregnant women, as no intervention can be carried out to prevent transmission. In large hospital series, the rate of anti-HCV-positive women is approximately 0.6%, of whom 60% are viremic. The reduced number of infected children (4–10% of those born from viremic mothers) requires collaborative studies, with an extended time for recruitment of children from several centers.
No symptoms are observed at the beginning of hepatitis C. In a series of 70 children with vertical transmission, the majority (93%) developed aminotransferase elevations 1.2- to 21-times the normal values in the first year of life, with maximum values occurring either in the first or second semester.[16] None developed hepatitis with jaundice. Overall, 62 out of 70 children could be followed up to 24 months of age or more. The cumulative probability of HCV RNA persistence was 90% at 2 years, 81% by the end of the third year of life and 81% at the fifth year. A sustained alanine aminotransferase (ALT) normalization with clearance of HCV RNA was observed in 12 out of 62 (19%) patients starting from the second year of life or the beginning of the third year. All those cured children remained anti-HCV positive.[16]
According to the European Pediatric Hepatitis Network (EPHN) the estimated proportion of children with clearance of viremia, out of 155 children with HCV infection observed from birth, was 17% by 2 years of age, 24% by 3 years and 30% by 5 years.[17] No patient cleared infection beyond the fifth year. The tendency towards chronicity showed no gender-based difference. In contrast to the aforementioned study, many of the children with a resolved infection evolved to a negative anti-HCV status in this study.
A retrospective Canadian study on 39 children with neonatal infection found a 25% probability of clearing infection by 7 years of age. Clearance occurred in 30% of nontransfusional and 16% transfusion-associated hepatitis C. No further clearance was observed beyond 7 years.[18]
Genotype influences clearance rates. Children with genotype 3 infection had the highest ALT levels and the highest rate of spontaneous viremia clearance.[16] In a series of 119 Italian cases diagnosed within the first 3 years of life, clearance rates were 5, 2.5, 7, 32 and 6% for genotypes 1a, 1b, 2, 3 and 4, respectively.[19]
Overall, prospective studies show that 80% of children develop chronic infection, the diagnosis being established in those who remain HCV RNA-positive at 3 years of age. Spontaneous clearance after that time is unlikely.
The chronicity rate of HCV in children infected at birth does not differ from that of adults or children infected at older ages. Nearly 70% of children with inherited bleeding disorders or leukemia develop chronic infections.[20,21] Serologic cross-sectional surveys show that 75–85% of anti-HCV-positive adults display positive HCV RNA. However, some series of children infected during cardiac surgery and two cohorts of young women infected by contaminated immune globulin had a chronic infection rate of 55%.[22–24]
Liver Damage in Pediatric Chronic HCV Infection
Data are derived from vertically infected children identified in prospective studies and series of children who were found to have HCV chronic infection at varying times of life, when screened because of risk exposures or asymptomatic aminotransferase elevation. Provided the children are otherwise healthy and not affected by chronic illnesses, the characteristics of chronic HCV infection are not related to the mode of infection acquisition (parenteral or vertical route).[25]
Chronic HCV infection is usually an asymptomatic disease. Nearly 15% of children present nonspecific, mild and transient symptoms at the time of initial diagnosis, probably related to intercurrent illness that leads to HCV detection. Hepatomegaly is noted in 10% of infants. HCV-associated cryoglobulinemia, vasculitis and porphyria cutanea tarda are not reported.
During chronic infection, different patterns of biochemical abnormalities are observed. In two large series of 194 and 332 children, respectively, ALT levels were persistently abnormal in 42–45% of patients, normal or normalized in 8–23% and intermittently elevated in 35–41%.[26,27]
The predominant genotypes in European and American children are 1a and 1b (70%), although in recent years, and considering children with vertical transmission, the proportion of genotype 1 infections has decreased to 54%, with a rise in genotypes 3 (23%) and 4 (7%).[19] The viral load does not appear to be correlated to ALT levels or the histologic lesions.[28]
A biopsy is needed for accurate assessment of lesions produced by chronic hepatitis. Although not performed in every affected child, it usually reveals mild lesions. Noninvasive biochemical tests (Fibro-Test and Acti-Test) are being evaluated in children with hepatitis C for their correlation with histology.
In a study of Italian and Spanish children, the histologic activity index (HAI) was found to be low in most patients, with a mean value of 3.6 (range 0–11). The final diagnoses were normal liver histology or with minimal and nonspecific lesions in 17.5% of the cases, chronic hepatitis with a low activity in 60% and high activity in 21%. Those patients with a definitive diagnosis of highly active chronic hepatitis were significantly older on average (12 years) than children with low-activity chronic hepatitis or minimal liver lesions (8 years). Fibrosis was absent in 27.5% of cases, mild in 55% and moderate in 16.2%. Only 1.3% (one of the 80 children) had cirrhosis. A significant relationship was detected between fibrosis scores and duration of disease, portal inflammation and interface hepatitis.[29]
In a later report with additional children (total of 112 cases) fibrosis was assessed by the METAVIR scale.[30] Age of patients at biopsy and duration of infection strongly correlated with fibrosis stage. A strong difference was observed between patients whose infection lasted less and more than 10 years. The mean rate of 'estimated' fibrosis progression in a linear progression model was 0.227 ± 0.372 METAVIR units per year, with a median of 0.142. Theoretically, cirrhosis could develop after a mean time of 28 years. However, the rate of 'observed' fibrosis progression per year in the 13 subjects who underwent paired biopsies was variable among them (seven had increased and six unchanged scores), averaging 0.112 ± 0.14. The progression of fibrosis seems to be a function of the duration of the infection, when no other risk factors for liver damage are present.
Similar histologic findings have been reported in several series, some of which included patients affected by other superimposed conditions to HCV (Table 1).[26,31–34]
A recent report on 121 children without decompensated disease and recruited in several American centers for a therapeutic trial[34] has shown that children with normal ALT were as likely to have significant inflammation as those with elevated ALT levels. Five patients (4.2%) had bridging fibrosis and two (1.7%) had cirrhosis. There was a highly significant correlation of inflammation with fibrosis. In the subset of 94 children with perinatal transmission, there was a weak correlation of estimated duration of disease with inflammation that approached statistical significance. The two children with cirrhosis were both 14 years old, whereas the five with bridging fibrosis were 11–16 years old. The lack of correlation of age or duration of infection with fibrosis might have been due to the small number of patients with advanced fibrosis.
Other authors found the severity of liver disease did not seem to depend on the duration of infection.[31
Severe Liver Disease in Children
In a series of 332 persistently viremic Italian children, who were otherwise healthy, six patients (1.8%) with high ALT levels developed signs and symptoms of advanced liver disease (asthenia, epistaxis, pruritus, ascites and gastrointestinal bleeding). Two patients developed decompensated liver disease at a very young age (2 and 5 years, respectively); however, most cases of advanced disease were older (age 11–15 years).[27] Genotype 1a was involved in five cases. None of these children had a history of drug or alcohol abuse, nor were they obese.
Decompensated liver disease was observed in one out of 194 (0.5%) children included in a multicenter European study.[26] This patient had a history of blood transfusions for hemolytic–uremic syndrome at the age of 3 years. Liver transplantation was needed when he was 19 years of age. The infection was due to HCV genotype 1a, and liver–kidney microsomal antibody type 1 (LKM1) was found to be positive.[35]
LKM1 antibodies are detected in 6–10% of children with chronic HCV infection. Overall, features of these patients help to differentiate them from those with autoimmune hepatitis. Coexistence of LKM markers was associated with a higher than expected rate of significant fibrosis (Ishak score >3 in 27%) in a series comprising 21 patients.[35]
Other cases of severe liver disease in childhood have been reported occasionally. A quaternary referral center in the USA described seven cases (7.7% of 91 referred patients) aged 4–18 years old (mean 11 years).[36] Other authors reported two 14-year-old adolescents, one of them without comorbid conditions, with cirrhosis and hepatocellular carcinoma.[37]
The small proportion of children with chronic hepatitis C leading to liver failure is confirmed in liver transplantation registries, as HCV comprises less than 1% of the indications in children.[38] Among 63 cumulative pediatric cases (1988–2005) undergoing transplantation for HCV end-stage disease in the USA, 88% were over 10 years old.[39]
Outcomes in Adult Age
An assessment of the characteristics of liver disease in adults who acquired HCV infection in childhood is available for certain populations of patients. Overall, patients who acquired HCV by parenteral routes predominate, and many were affected by transient or persistent conditions that may influence outcome. A report on 11 patients infected at birth by the same blood donor found, by the age of 35 years, nine cases with no fibrosis or mild fibrosis and one each with discrete (Ishak 3) or marked (Ishak 4) fibrosis.[40] Similar findings were obtained in children who acquired HCV infection after cardiac surgery, and in a series of leukemia survivors.[21]
Since there are no prospective studies on the course of the infection from infancy to adulthood, the data provided by studies in adult patients are of interest. In these studies, infections beginning before 40 years of age presented a severe liver disease rate of only 2–8% after 20 years, while infections developing after age 40 years yielded a 20% cirrhosis rate after 20 years. The estimation of the percentage of patients that develop severe disease in the course of a lifetime varies according to the different studies. In the period of 20 years after first infection, 20% of the patients seen in referral centers developed cirrhosis, although in the case of patients identified through screening of the general population or blood donors, only 4–7% were found to have cirrhosis.[41]
Treatment
There are different approaches to the treatment of children with chronic hepatitis C.[42] The main characteristic of chronic hepatitis C is its persistence over time with slow progression to fibrosis. Severe disease is rare in children, and therefore follow-up without treatment until adult life is a valid option for most pediatric patients. Treatment during childhood does not achieve increased rates of response compared with adult patients and adverse effects are frequent and, even in some cases, may be severe. Conversely, treatment may be justified, since it allows definitive resolution in a subgroup of patients. Quality of life is not affected in children with HCV infection, but parents are worried about the outcome and perceive the difficulties of social life, even when there is a negligible risk of horizontal transmission.[43,44] Adolescence and young adulthood are associated with high scholar or work demands, and more difficult compliance with medical visits. All those factors may lead to postponed treatment.
The decision to treat should consider several aspects in the individual patient: age, severity of disease, efficacy of the chosen therapy, its adverse effects, compliance to treatment and willingness. Children under 3 years old are not eligible for treatment (and treatment is not approved), as HCV infection may still spontaneously resolve and spastic diplegia has been reported in infants treated with IFN-α for hemangiomas.[45]
Over time, and in parallel with the results obtained in adults, experience has been gained in children with IFN-α monotherapy,[46–50] the combined use of IFN-α and ribavirin,[51,52] pegylated IFN (PEG-IFN) monotherapy[53] and, at present, the use of PEG-IFN with ribavirin, which was approved by the US FDA (in December 2008) and the EMEA (in December 2009) for children older than 3 years of age.
Baseline Patient Evaluation
Patients are excluded if they have comorbid medical conditions (i.e., moderate or severe depression, psychiatric conditions, seizures and renal insufficiency) that could compromise the tolerability of the drugs. Patients testing positive for autoimmunity markers – antinuclear antibody, smooth muscle antibody and LKM1 – are enrolled if other features do not suggest autoimmune hepatitis. Adolescents should be instructed in birth control during antiviral therapy and for 6 months after treatment cessation. Routine pregnancy testing is advised in girls of child-bearing potential.
The viral genotype involved must be known in order to assess the probability of response and to design the duration of therapy. Viral load must be quantified since the decision to maintain therapy will depend on the course of viraemia at week 12 of treatment in the case of genotypes other than 2 and 3. A biopsy is recommended before starting treatment. According to several studies performed on pediatric chronic HCV infection histology, showing mild lesions in most, the need for a biopsy to assess the disease is controversial, although it is the only method to identify severe cases. However, treatment decisions should not rely on histological findings.
Further workout should be carried out, especially in line with recent observations of genetic polymorphisms linked to response to treatment, which can be of value for treatment decisions in the future. Candidate studies are polymorphisms near the IL28B gene, encoding IFN-λ-3, which has been associated with an approximately twofold change in response to treatment.[54]
Treatment Design
Common terminology refers to 'rapid viral response' when viremia turns undetectable in week 4 of treatment, 'early viral response' when HCV RNA is negative in week 12 and 'end of treatment response' when viremia proves negative at the end of treatment. Sustained virologic response (SVR) is defined as undetectable serum HCV RNA 24 weeks after treatment cessation and is equivalent to resolution of infection.
In treatment-naive patients, the likelihood of achieving a SVR is best predicted by a more than 2 log10 unit decrease in HCV RNA by 12 weeks of therapy. Among naive populations, less than 2% of patients who fail to achieve an early virological response ultimately achieve a SVR.
Therapy aims to achieve negative conversion of HCV viremia to below the detection limit of the qualitative PCR technique employed (30–50 IU/ml). Once negativity has been achieved, treatment must continue long enough to ensure eradication of the infection in the liver. Different HCV genotypes exhibit different sensitivities to treatment. Genotypes 2 and 3 are more sensitive, with healing rates of 83–100% of all patients treated for 24 weeks. In the case of genotypes 1 and 4, the overall SVR rate is 50%, and 48 weeks of therapy are required. The high probability of a favorable response in the case of a sensitive genotype means all patients need treatment for 24 weeks. In the case of less-sensitive genotypes, re-evaluation is carried out after 12 weeks. If at this point there has been a decrease in viral load of at least 2 log10, treatment is continued up to 48 weeks. However, if such a decrease in viral load is not found, treatment is withdrawn, since healing is not likely to occur even if the full treatment course is administered.
Guidelines of treatment are well established in adults.[55] In these patients current studies aim to shorten the duration of therapy (to 16 weeks in the case of a sensitive or favorable genotype, and to 24 weeks in the case of genotype 1) for those subjects with rapid viral response, and to prolong therapy (48 weeks for genotype 3 and 72 weeks for genotype 1) for those subjects showing a drop in viremia, but with persistent positive HCV RNA at week 12. Other ongoing investigations aim to increase efficacy by adding antiviral agents, such as telaprevir or boceprevir, to the conventional PEG-IFN plus ribavirin treatment.[56]
Drugs
Pegylated IFN-α Pegylated IFN-α is created by covalently linking a polyethylene glycol moiety to the IFN-α protein. The addition of this moiety to IFN-α confers an extended serum half-life compared with native IFN-α, allows once-weekly dosing and significantly improves SVR rates. Two forms of PEG-IFN have been developed, PEG-IFN-α-2b and PEG-IFN-α-2a. PEG-IFN-α-2a uses a large (40 kD) branched polyethylene glycol molecule, while PEG-IFN-α-2b uses a smaller (12 kD) linear molecule. The overall results from controlled trials in adults suggest that they achieve a similar rate of SVR.
Adverse events of PEG-IFN occur in the same proportion of patients and are of the same quality as observed with IFN-α. PEG-IFN is more convenient because of the weekly administration and influenza-like symptoms being limited to one versus three doses per week with conventional IFN.
Dosing in Children A once-weekly dose of PEG-IFN-α-2a is calculated from each patient's body surface area according to the formula BSA (m2)/(1.73 m2) × 180 µg. This dosing achieves adequate therapeutic concentrations.[53]
PEG-IFN-α-2a 1–1.5 µg/kg once a week has been given to children after approval in adults. Another approach is to adjust the adult dosing of 1.5 µg/kg to the body surface of the child, so dosing for children results in 60 µg/m2 per week.
The PEG-IFN-α dose is transiently decreased in patients with a neutrophil count of less than 1–1.25 × 109 cells/ml to avoid significant neutropenia. PEG-IFN-α is temporarily discontinued if the neutrophil counts fall below 0.75–1.00 × 109 cells/ml; and it is resumed once the neutrophil counts recover.
Ribavirin Ribavirin is a guanosine analog. Ribavirin alone has a relatively minor antiviral effect in HCV-infected patients, but in combination with PEG-IFN-α it appears to enhance the second and third phases of viral decay, thereby reducing the chance of relapse.[57] Its suggested mechanisms of action include error catastrophe resulting from mutagenesis via incorporation of ribavirin into HCV RNA during replication, direct inhibition of HCV RNA replication, inosine-monophospatedehydrogenase inhibition and immunomodulation. A relationship between ribavirin dose and response to therapy with both IFN-α-2a and -α-2b has been established, especially in patients with HCV genotype 1.
Ribavirin is cleared by the kidneys, so it should be reduced in patients with decreased creatinine clearance and completely avoided in renal insufficiency. Its main toxicity is hemolytic anemia, directly related to the concentration of ribavirin in erythrocytes. Anemia is the most common reason for ribavirin dose reduction or treatment discontinuation.
Dosing in Children A study in children receiving IFN-α-2b plus ribavirin 8, 12 or 15 mg/kg/day demonstrated that those on 15 mg/kg had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12, with an acceptable safety profile.[52]
On-therapy Assessments in Children
For assessment of efficacy, HCV RNA titers are measured at weeks 4, 12, 24 and 36, at the end of treatment, and every 12 weeks for another 6 months after the end of treatment. The assessment of safety should be planned in order to promptly detect adverse effects that require dose adjustment. Drugs cause influenza-like symptoms, neutropenia, anemia and weight loss especially during the first month of treatment. Clinical and analytical follow-up is performed every 2 weeks in the first phase of therapy. Monthly visits are advisable up to the sixth month, and scheduled every 3 months for the remaining period of treatment and for another 6 months after the end of treatment. Depression, thyroid disorders and growth velocity should be assessed. The long-term effects on thyroid function (if disturbed during treatment) and on growth would require an extended time (i.e., 2 years) of follow-up.
Efficacy of PEG-IFN Plus Ribavirin Treatment in Children
Combined therapy with PEG-IFN and ribavirin has improved sustained response rates compared with other treatments and currently represents the standard therapy in adult patients.
There are two ongoing trials in children with almost finished efficacy reports.[58–60] One international study investigates the pharmacokinetics, efficacy and safety of PEG-IFN-α-2b 60 µg/m2/week combined with ribavirin 15 mg/kg/day in 107 children. Another multicenter North American trial investigates PEG-IFN-α-2a plus ribavirin (55 children) compared with PEG-IFN-α-2a monotherapy (59 children) (Table 2).
Two European studies have been published with the data on the efficacy and adverse effects of the PEG-IFN plus ribavirin combination in children. One was conducted in a center in Spain; 30 children (24 naive) were enrolled to receive PEG-IFN-α-2a 1 µg/kg/week with ribavirin 15 mg/kg/day.[61] The other trial was carried out in several centers in Germany, and 61 children (51 naive) were given PEG-IFN-α-2a 1.5 µg/kg/week plus ribavirin 15 mg/kg/day.[62] In both studies the duration of treatment was 24 or 48 weeks in genotype 2/3 infections, and for 48 weeks in the case of genotype 1 or 4. The results were similar in both (Table 2), and showed a response equal to or slightly greater than that reported in children on conventional IFN-α given three-times per week plus ribavirin.
In the Spanish study, involving strict chronic infection inclusion criteria (over 3 years from infection), and with a patient age of 3.5–16 years, 69% of the cases were due to mother-to-child transmission, 86.6% corresponded to genotype 1, and baseline viral load was >5 log10 IU/ml in 66.6% of cases. SVR was achieved in 15 (50%) of 30 patients: in three (100%) out of three patients with HCV genotype 3, and in 12 (44%) out of 27 with HCV genotype 1. One patient with HCV genotype 4 did not respond. All patients who attained SVR remained HCV RNA-negative at further follow-up visits (up to 36 months) and had normal liver function.[61]
In the German study, the patients were between 2–17 years of age; 40.3% of the infections were the result of vertical transmission and 75.8% presented genotype 1. Of 46 patients with genotype 1, 22 (47.8%) showed SVR. All individuals with genotype 2 or 3 (n = 13) responded permanently, irrespective of the duration of treatment (i.e., 24 or 48 weeks) (p < 0.0003). One of two patients with genotype 4 had SVR.[62]
Predictors of Response
The study of baseline characteristics of treated patients may help to identify predictors for response, in order to select the candidates for therapy. Among adult patients, those aged less than 40 years without advanced disease show better response rates. However, overall results of treatment during childhood do not clearly offer significantly better results compared with adults.
The most important determinants of response in children are the viral genotype and viremia levels among those with genotype-1 infection. No baseline characteristic excludes response to therapy among those with genotype 1. On the other hand, the evolution of viremia after 12 weeks of therapy is of much help to identify future responders. In practical terms, all children may be eligible for treatment and early stopping rules according to week 12 viremia should be applied.
The HCV genotype is the main baseline predictor of response. Recent unpublished pediatric trials obtained a response in 93% of genotype 2 or 3, 80% of genotype 4 and 53% of genotype 1 HCV infections, and 47% of genotype 1 compared with 80% of genotype non-1, respectively.[58,60] In the international PEG-IFN-α-2a plus ribavirin study, response in genotype 1 was influenced by baseline viral load, as those showing HCV-RNA over 6 × 105IU/ml had 29% SVR compared with 72% SVR in genotype 1 with lower titers.[58]
Patient age does not seem to influence response (SVR: age < 12 years versus older children: 54.8 vs 63.3% in the German study and 45 vs 60% in the Spanish study). Responders show similar baseline ALT levels compared with nonresponders, and children with normal aminotransferase values display the same SVR rate as those with abnormal biochemistry prior to therapy. The baseline viral load and Knodell index did not influence the response in the Spanish study. However, in both experiences, the response in those children who developed the infection as a result of blood transfusions tended to be higher than in those with mother-to-child transmission (German children: 70.4 vs 48%; p = 0.087; Spanish children: 78 vs 38%; p = 0.1).[61,62]
Virological surveillance while on therapy appears to be the best predictor of response. In the Spanish study, only one patient showed negative HCV RNA at week 4. At week 12 of treatment, 51.7% showed undetectable HCV RNA, while 72% presented a greater than 2 log10 decrease compared with baseline viral load. A SVR was elicited in 87 and 71% of those presenting the above characteristics, respectively, at week 12. No cases with less than 2 log10 reduction at week 12 achieved sustained response. Continued therapy for 48 weeks in six children with positive HCV RNA at week 24 was ineffective in all cases.[61]
The German study reported that 62.3% of the treated children achieved negative HCV RNA at week 12. In turn, 91% of the patients with genotype 1 and 92.3% of those with genotypes 2/3 who showed a sustained response presented undetectable viremia at week 12 of therapy.[62]
Nonresponders to Therapy
Circumstances associated with a lack of response in children have not yet been elucidated.
Children with genotype 1 infection with mother-to-child transmission, currently representing the most numerous group, have shown SVR rates of 37.5 and 35% in the Spanish and German studies, respectively.[61,62] Thus, for many patients current therapy is inefficient.
Nonresponders can be retreated, but there is a very limited experience in children. According to studies in adults, the likelihood of response to retreatment depends on the type of response to prior therapy (relapsers achieve near 40% of SVR compared with 10% in nonresponders) and the differences in efficacy between the initial and the retreatment regimens. Very few children who failed to respond with IFN-α monotherapy were retreated with IFN-α plus ribavirin,[51] or PEG-IFN-α-2a plus ribavirin.[61,62] Using the highest efficacy PEG-IFN plus ribavirin, a sustained response was achieved in three out of 11 cases.
Adverse Effects
The adverse effects of PEG-IFN plus ribavirin are similar to those associated with conventional IFN, involving fewer injections and immediate injection reactions. Other adverse effects were of the same nature and intensity.
The toxicity of PEG-IFN plus ribavirin treatment must be carefully evaluated. It has been assessed in only two studies.[61,62]
In almost all children and adolescents, transient flu-like symptoms with variable intensity, including moderate fever, are observed during the first weeks of treatment. In most of them, the symptoms resolved or were of minor intensity during the second 6 months. Febrile convulsions are a hazard in younger children, but the problem did not occur in available series. Dose reduction by 20–30% of PEG-IFN was carried out because of considerable leukopenia in 5% of patients in the German series. Prolonged (>1 month) or permanent reductions in PEG-IFN-α-2b doses were required in 23% of Spanish children (Table 3).[61,62]
Owing to hemolysis induced by ribavirin, mean hemoglobin levels decrease within the first week of therapy, reaching a mean maximal decrease of 1.4 g/dl by week 12. Hemoglobin values are stable during the remaining period and return to normal when therapy is discontinued or completed. No reduction in ribavirin dose was required. Reticulocyte levels increased during therapy but returned to normal thereafter.
School performance is not grossly affected. Transient changes in character or mood have been recorded in 15–30% of the children, but severe psychological impairment was not observed.[61,62] Depression is a concern and should be looked for in adolescents, as suicidal ideation and even suicidal attempts have been reported during treatment with conventional IFN-α plus ribavirin.[52]
Patients with detectable LKM1 antibodies at baseline have shown either stable or varying titers during therapy. No patient developed LKM1 antibodies, although previous experiences have shown that LKM1 appear in 5% of children treated with IFN-α.[35] No specific liver function events occurred in antinuclear antibody-positive or LKM1 antibody-positive patients during or after therapy. Regarding the possibility of IFN facilitating autoimmune disease, one girl was reported to have developed diabetes mellitus after 9 months of treatment; therapy was continued without changing dosage and the patient showed SVR.[62]
The emergence of thyroid antibodies and thyroid-stimulating hormone elevation during treatment is significant. In the German study, five individuals received a weight-adjusted dose of l-thyroxine until the end of treatment. In three of these, l-thyroxine could be stopped during follow-up, and in two patients thyroid hormone supplementation was maintained 12 months after discontinuation of ribavirin and PEG-IFN.[62]
According to the Spanish study, four patients developed antithyroid antibodies. Two patients showed sudden decreases in thyroid-stimulating hormone values during therapy, accompanied by high T4 values and weight loss. Treatment was discontinued immediately in both patients. Anti-thyroid antibodies appeared in successive checkups. No specific therapy for hyperthyroidism was required and thyroid-stimulating hormone and T4 values returned to normal. The remaining two patients developed antithyroid antibodies during therapy and the condition persisted when off therapy. Mild elevation of thyroid-stimulating hormone or T4 values was observed in another additional six patients.[61]
Growth during the 48-week treatment period has been shown to be reduced in most patients by a mean of 1.6 cm compared with the average growth for age and gender. Growth velocity was normal in the 6-month period after the end of treatment; however, the modest decrease in height percentile observed during therapy was not recovered in the short term.[61]
Conclusion
In conclusion, the efficacy of combined therapy in children warrants its application. A response rate of 50% in genotype 1 patients and more than 90% in genotype 2 or 3 patients is achieved, which means cure of a chronic disease. However, more in-depth studies are needed, with further investigation of the factors implicated in the development of thyroid alterations in some children.
Expert Commentary
Current treatment (PEG-IFN-α plus ribavirin) in children with chronic hepatitis C should be managed by pediatric specialists. Many individual and family variables determine the appropriate time to initiate treatment. Mid-childhood age before adolescence is preferable. Side effects are usually well tolerated, but severe adverse events may occur in a low number of children. The near complete efficacy in favorable genotypes, and the early stopping rules for genotype 1 cases shifts the balance toward applying treatment to children, although new drug investigation is needed. The mild disease that children usually present makes safer the initiation of studies once efficacy and toxicity profiles of new drugs have been assessed in adult patients.
Five-year View
New lines of research in children are necessary to assess long-term clinical outcomes, to develop noninvasive methods for detecting fibrosis, to establish gene polymorphisms related to disease progression and response to therapy and to identify individuals at risk for significant side effects before treatment initiation. Trials with combined therapy plus antivirals should begin as soon as safety profiles have been established in adult patients.
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Papers of special note have been highlighted as:
•• of considerable interest
Source
Posted: 03/02/2010;
Expert Rev Gastroenterol Hepatol. 2010;4(1):51-61.
© 2010 Expert Reviews Ltd.
Abstract and Introduction
Abstract
Hepatitis C affects 4–10% of children born to infected mothers, and 80% of them develop chronic infection. Most patients with chronic hepatitis C virus infection are asymptomatic, with persistent or intermittent biochemical abnormalities. Severe liver disease may develop 10 years after onset of infection, with a less than 2% overall risk during the pediatric age. Available therapies have no contraindication in children if otherwise healthy. The US FDA and EMEA have recently approved combined pegylated-IFN-α2b plus ribavirin treatment for children, who should be over 3 years of age in order to avoid severe side effects. Experiences in pilot trials and international studies indicate a response rate of 50% in genotype 1 patients, and more than 90% in genotype 2 or 3 patients, indicating resolution of chronic disease.
Introduction
The possibility of curing chronic hepatitis C virus (HCV) infection by means of PEG-IFN plus ribavirin – the currently recommended treatment – has raised controversy about the convenience of treating pediatric patients. As children with chronic HCV infection are usually asymptomatic and rarely develop severe liver damage, the possibility of eliciting adverse effects from current therapies must be appropriately balanced against the benefits. Characteristics of HCV infection in children and the results of treatment are reviewed here in order to substantiate decisions.
The discovery of HCV and the use of anti-HCV levels as a marker of exposure was available in the early 1990s to exclude infected blood and organ donors. Before this, most HCV infections were acquired by transfusions or inadequately sterilized needles or instruments. Pediatric populations heavily affected in the past due to repeated administration of blood derivatives for hemoglobinopathies, hemophilia or cancer treatment are now young adults, and therefore beyond the scope of this revision. In certain areas of the world, post-transfusional hepatitis C remains a hazard. Cumulative information on superimposed HCV infection to some underlying diseases of children indicates similar chronicization rates, deleterious effects of iron overload added to viral-induced liver damage and evidence of difficult-to-treat patients because of conditions that affect the tolerability of drugs, such as anemia or renal insufficiency.
The effectiveness of excluding parenteral routes of HCV is demonstrated in young populations of industrialized countries.[1] Perinatal mother-to-child transmission accounts for 95% of all cases of hepatitis C in children born after 1990. In addition, over the years there has been a reduction in the number of pediatric cases of vertical transmission because the anti-HCV-positive rate has decreased in younger women as a result of lesser transfusional transmission of the disease, and due to changes in illicit drug abuse with a shift towards nonintravenous forms of administration.[2]
In the current setting, most affected children are otherwise healthy. The applicability of treatment is the rule. Combined treatment offers a 50–90% chance (according to HCV genotype) of clearing HCV infection, thus avoiding the progression of liver disease. This review will focus on the benefits of current therapy, mostly evident in the long term, and also on drug toxicity.
Origin of HCV Infection in Children: Mother-to-child Transmission
Hepatitis C is an asymptomatic disease in infants. The only efficient method for its detection is the investigation of children at risk. Infants of women with hepatitis C should be tested for HCV RNA on two occasions, between the ages of 2 and 6 months, and again at 18 to 24 months, along with serum anti-HCV.[3–5] Variants to this schedule are also employed. Tests performed in umbilical cord or before 1 month of age give a high rate of false-negative and false-positive results and are not recommended.
The offspring of anti-HCV-positive mothers have anti-HCV antibodies in their blood as a result of passive transplacental transfer. These antibodies remain detectable in the infant for the first 12–15 months of life. The definition of mother-to-child transmission of HCV includes: the detection of anti-HCV antibodies in a child over 18 months of age, or the detection of HCV RNA in a child over 2 months of age, preferably confirmed in two different samples.[3]
Children born to anti-HCV-positive and HCV RNA-positive mothers have an infection risk of 4–10%, with no differences between caesarean or vaginal delivery, or between children who are breastfed or receive infant formulas.[3,6] Once pre- or peri-natal transmission has been discarded, cohabitation of the child with the mother entails no appreciable risk.
Excellent reviews on HCV vertical transmission are available.[3,6,7] Some risk factors have been clearly identified, such as maternal viremia[4,8] or maternal co-infection with HIV-1.[3] Maternal intravenous drug use, the presence of HCV RNA in maternal peripheral blood mononuclear cells and genetic factors (HLA-DRB1*10 in children) could also facilitate transmission.[9–11]
However, discordance exists between studies. Viral load in the mother is a rational risk factor involved in transmission to the child, but was found to be either high or not significantly different between transmitting and nontransmitting mothers.[8,12] Other risk factors are linked to abnormal labor, as published data support facilitated transmission by a prolonged time from rupture of membranes to birth.[6,13,14] Antiretroviral treatment of HIV-infected mothers decreases the risk of HCV transmission to levels similar to HIV-negative mothers.[6]
Mother-to-child transmission theoretically can occur in utero, at the end of pregnancy or at delivery. Among 54 infected infants tested within 3 days of birth, 31% displayed HCV viremia, suggesting that intrauterine infection could have occurred.[15]
There are currently no established interventions to prevent infection of the child born to an infected mother. In particular, there is no evidence to suggest that women should be offered an elective caesarean delivery or be advised to avoid breastfeeding.[4]
Course of HCV Infection in Children
In order to know the characteristics of HCV infection in children from the onset, many studies aimed at the surveillance of children born to HCV-positive mothers. HCV screening is not mandatory in pregnant women, as no intervention can be carried out to prevent transmission. In large hospital series, the rate of anti-HCV-positive women is approximately 0.6%, of whom 60% are viremic. The reduced number of infected children (4–10% of those born from viremic mothers) requires collaborative studies, with an extended time for recruitment of children from several centers.
No symptoms are observed at the beginning of hepatitis C. In a series of 70 children with vertical transmission, the majority (93%) developed aminotransferase elevations 1.2- to 21-times the normal values in the first year of life, with maximum values occurring either in the first or second semester.[16] None developed hepatitis with jaundice. Overall, 62 out of 70 children could be followed up to 24 months of age or more. The cumulative probability of HCV RNA persistence was 90% at 2 years, 81% by the end of the third year of life and 81% at the fifth year. A sustained alanine aminotransferase (ALT) normalization with clearance of HCV RNA was observed in 12 out of 62 (19%) patients starting from the second year of life or the beginning of the third year. All those cured children remained anti-HCV positive.[16]
According to the European Pediatric Hepatitis Network (EPHN) the estimated proportion of children with clearance of viremia, out of 155 children with HCV infection observed from birth, was 17% by 2 years of age, 24% by 3 years and 30% by 5 years.[17] No patient cleared infection beyond the fifth year. The tendency towards chronicity showed no gender-based difference. In contrast to the aforementioned study, many of the children with a resolved infection evolved to a negative anti-HCV status in this study.
A retrospective Canadian study on 39 children with neonatal infection found a 25% probability of clearing infection by 7 years of age. Clearance occurred in 30% of nontransfusional and 16% transfusion-associated hepatitis C. No further clearance was observed beyond 7 years.[18]
Genotype influences clearance rates. Children with genotype 3 infection had the highest ALT levels and the highest rate of spontaneous viremia clearance.[16] In a series of 119 Italian cases diagnosed within the first 3 years of life, clearance rates were 5, 2.5, 7, 32 and 6% for genotypes 1a, 1b, 2, 3 and 4, respectively.[19]
Overall, prospective studies show that 80% of children develop chronic infection, the diagnosis being established in those who remain HCV RNA-positive at 3 years of age. Spontaneous clearance after that time is unlikely.
The chronicity rate of HCV in children infected at birth does not differ from that of adults or children infected at older ages. Nearly 70% of children with inherited bleeding disorders or leukemia develop chronic infections.[20,21] Serologic cross-sectional surveys show that 75–85% of anti-HCV-positive adults display positive HCV RNA. However, some series of children infected during cardiac surgery and two cohorts of young women infected by contaminated immune globulin had a chronic infection rate of 55%.[22–24]
Liver Damage in Pediatric Chronic HCV Infection
Data are derived from vertically infected children identified in prospective studies and series of children who were found to have HCV chronic infection at varying times of life, when screened because of risk exposures or asymptomatic aminotransferase elevation. Provided the children are otherwise healthy and not affected by chronic illnesses, the characteristics of chronic HCV infection are not related to the mode of infection acquisition (parenteral or vertical route).[25]
Chronic HCV infection is usually an asymptomatic disease. Nearly 15% of children present nonspecific, mild and transient symptoms at the time of initial diagnosis, probably related to intercurrent illness that leads to HCV detection. Hepatomegaly is noted in 10% of infants. HCV-associated cryoglobulinemia, vasculitis and porphyria cutanea tarda are not reported.
During chronic infection, different patterns of biochemical abnormalities are observed. In two large series of 194 and 332 children, respectively, ALT levels were persistently abnormal in 42–45% of patients, normal or normalized in 8–23% and intermittently elevated in 35–41%.[26,27]
The predominant genotypes in European and American children are 1a and 1b (70%), although in recent years, and considering children with vertical transmission, the proportion of genotype 1 infections has decreased to 54%, with a rise in genotypes 3 (23%) and 4 (7%).[19] The viral load does not appear to be correlated to ALT levels or the histologic lesions.[28]
A biopsy is needed for accurate assessment of lesions produced by chronic hepatitis. Although not performed in every affected child, it usually reveals mild lesions. Noninvasive biochemical tests (Fibro-Test and Acti-Test) are being evaluated in children with hepatitis C for their correlation with histology.
In a study of Italian and Spanish children, the histologic activity index (HAI) was found to be low in most patients, with a mean value of 3.6 (range 0–11). The final diagnoses were normal liver histology or with minimal and nonspecific lesions in 17.5% of the cases, chronic hepatitis with a low activity in 60% and high activity in 21%. Those patients with a definitive diagnosis of highly active chronic hepatitis were significantly older on average (12 years) than children with low-activity chronic hepatitis or minimal liver lesions (8 years). Fibrosis was absent in 27.5% of cases, mild in 55% and moderate in 16.2%. Only 1.3% (one of the 80 children) had cirrhosis. A significant relationship was detected between fibrosis scores and duration of disease, portal inflammation and interface hepatitis.[29]
In a later report with additional children (total of 112 cases) fibrosis was assessed by the METAVIR scale.[30] Age of patients at biopsy and duration of infection strongly correlated with fibrosis stage. A strong difference was observed between patients whose infection lasted less and more than 10 years. The mean rate of 'estimated' fibrosis progression in a linear progression model was 0.227 ± 0.372 METAVIR units per year, with a median of 0.142. Theoretically, cirrhosis could develop after a mean time of 28 years. However, the rate of 'observed' fibrosis progression per year in the 13 subjects who underwent paired biopsies was variable among them (seven had increased and six unchanged scores), averaging 0.112 ± 0.14. The progression of fibrosis seems to be a function of the duration of the infection, when no other risk factors for liver damage are present.
Similar histologic findings have been reported in several series, some of which included patients affected by other superimposed conditions to HCV (Table 1).[26,31–34]
A recent report on 121 children without decompensated disease and recruited in several American centers for a therapeutic trial[34] has shown that children with normal ALT were as likely to have significant inflammation as those with elevated ALT levels. Five patients (4.2%) had bridging fibrosis and two (1.7%) had cirrhosis. There was a highly significant correlation of inflammation with fibrosis. In the subset of 94 children with perinatal transmission, there was a weak correlation of estimated duration of disease with inflammation that approached statistical significance. The two children with cirrhosis were both 14 years old, whereas the five with bridging fibrosis were 11–16 years old. The lack of correlation of age or duration of infection with fibrosis might have been due to the small number of patients with advanced fibrosis.
Other authors found the severity of liver disease did not seem to depend on the duration of infection.[31
Severe Liver Disease in Children
In a series of 332 persistently viremic Italian children, who were otherwise healthy, six patients (1.8%) with high ALT levels developed signs and symptoms of advanced liver disease (asthenia, epistaxis, pruritus, ascites and gastrointestinal bleeding). Two patients developed decompensated liver disease at a very young age (2 and 5 years, respectively); however, most cases of advanced disease were older (age 11–15 years).[27] Genotype 1a was involved in five cases. None of these children had a history of drug or alcohol abuse, nor were they obese.
Decompensated liver disease was observed in one out of 194 (0.5%) children included in a multicenter European study.[26] This patient had a history of blood transfusions for hemolytic–uremic syndrome at the age of 3 years. Liver transplantation was needed when he was 19 years of age. The infection was due to HCV genotype 1a, and liver–kidney microsomal antibody type 1 (LKM1) was found to be positive.[35]
LKM1 antibodies are detected in 6–10% of children with chronic HCV infection. Overall, features of these patients help to differentiate them from those with autoimmune hepatitis. Coexistence of LKM markers was associated with a higher than expected rate of significant fibrosis (Ishak score >3 in 27%) in a series comprising 21 patients.[35]
Other cases of severe liver disease in childhood have been reported occasionally. A quaternary referral center in the USA described seven cases (7.7% of 91 referred patients) aged 4–18 years old (mean 11 years).[36] Other authors reported two 14-year-old adolescents, one of them without comorbid conditions, with cirrhosis and hepatocellular carcinoma.[37]
The small proportion of children with chronic hepatitis C leading to liver failure is confirmed in liver transplantation registries, as HCV comprises less than 1% of the indications in children.[38] Among 63 cumulative pediatric cases (1988–2005) undergoing transplantation for HCV end-stage disease in the USA, 88% were over 10 years old.[39]
Outcomes in Adult Age
An assessment of the characteristics of liver disease in adults who acquired HCV infection in childhood is available for certain populations of patients. Overall, patients who acquired HCV by parenteral routes predominate, and many were affected by transient or persistent conditions that may influence outcome. A report on 11 patients infected at birth by the same blood donor found, by the age of 35 years, nine cases with no fibrosis or mild fibrosis and one each with discrete (Ishak 3) or marked (Ishak 4) fibrosis.[40] Similar findings were obtained in children who acquired HCV infection after cardiac surgery, and in a series of leukemia survivors.[21]
Since there are no prospective studies on the course of the infection from infancy to adulthood, the data provided by studies in adult patients are of interest. In these studies, infections beginning before 40 years of age presented a severe liver disease rate of only 2–8% after 20 years, while infections developing after age 40 years yielded a 20% cirrhosis rate after 20 years. The estimation of the percentage of patients that develop severe disease in the course of a lifetime varies according to the different studies. In the period of 20 years after first infection, 20% of the patients seen in referral centers developed cirrhosis, although in the case of patients identified through screening of the general population or blood donors, only 4–7% were found to have cirrhosis.[41]
Treatment
There are different approaches to the treatment of children with chronic hepatitis C.[42] The main characteristic of chronic hepatitis C is its persistence over time with slow progression to fibrosis. Severe disease is rare in children, and therefore follow-up without treatment until adult life is a valid option for most pediatric patients. Treatment during childhood does not achieve increased rates of response compared with adult patients and adverse effects are frequent and, even in some cases, may be severe. Conversely, treatment may be justified, since it allows definitive resolution in a subgroup of patients. Quality of life is not affected in children with HCV infection, but parents are worried about the outcome and perceive the difficulties of social life, even when there is a negligible risk of horizontal transmission.[43,44] Adolescence and young adulthood are associated with high scholar or work demands, and more difficult compliance with medical visits. All those factors may lead to postponed treatment.
The decision to treat should consider several aspects in the individual patient: age, severity of disease, efficacy of the chosen therapy, its adverse effects, compliance to treatment and willingness. Children under 3 years old are not eligible for treatment (and treatment is not approved), as HCV infection may still spontaneously resolve and spastic diplegia has been reported in infants treated with IFN-α for hemangiomas.[45]
Over time, and in parallel with the results obtained in adults, experience has been gained in children with IFN-α monotherapy,[46–50] the combined use of IFN-α and ribavirin,[51,52] pegylated IFN (PEG-IFN) monotherapy[53] and, at present, the use of PEG-IFN with ribavirin, which was approved by the US FDA (in December 2008) and the EMEA (in December 2009) for children older than 3 years of age.
Baseline Patient Evaluation
Patients are excluded if they have comorbid medical conditions (i.e., moderate or severe depression, psychiatric conditions, seizures and renal insufficiency) that could compromise the tolerability of the drugs. Patients testing positive for autoimmunity markers – antinuclear antibody, smooth muscle antibody and LKM1 – are enrolled if other features do not suggest autoimmune hepatitis. Adolescents should be instructed in birth control during antiviral therapy and for 6 months after treatment cessation. Routine pregnancy testing is advised in girls of child-bearing potential.
The viral genotype involved must be known in order to assess the probability of response and to design the duration of therapy. Viral load must be quantified since the decision to maintain therapy will depend on the course of viraemia at week 12 of treatment in the case of genotypes other than 2 and 3. A biopsy is recommended before starting treatment. According to several studies performed on pediatric chronic HCV infection histology, showing mild lesions in most, the need for a biopsy to assess the disease is controversial, although it is the only method to identify severe cases. However, treatment decisions should not rely on histological findings.
Further workout should be carried out, especially in line with recent observations of genetic polymorphisms linked to response to treatment, which can be of value for treatment decisions in the future. Candidate studies are polymorphisms near the IL28B gene, encoding IFN-λ-3, which has been associated with an approximately twofold change in response to treatment.[54]
Treatment Design
Common terminology refers to 'rapid viral response' when viremia turns undetectable in week 4 of treatment, 'early viral response' when HCV RNA is negative in week 12 and 'end of treatment response' when viremia proves negative at the end of treatment. Sustained virologic response (SVR) is defined as undetectable serum HCV RNA 24 weeks after treatment cessation and is equivalent to resolution of infection.
In treatment-naive patients, the likelihood of achieving a SVR is best predicted by a more than 2 log10 unit decrease in HCV RNA by 12 weeks of therapy. Among naive populations, less than 2% of patients who fail to achieve an early virological response ultimately achieve a SVR.
Therapy aims to achieve negative conversion of HCV viremia to below the detection limit of the qualitative PCR technique employed (30–50 IU/ml). Once negativity has been achieved, treatment must continue long enough to ensure eradication of the infection in the liver. Different HCV genotypes exhibit different sensitivities to treatment. Genotypes 2 and 3 are more sensitive, with healing rates of 83–100% of all patients treated for 24 weeks. In the case of genotypes 1 and 4, the overall SVR rate is 50%, and 48 weeks of therapy are required. The high probability of a favorable response in the case of a sensitive genotype means all patients need treatment for 24 weeks. In the case of less-sensitive genotypes, re-evaluation is carried out after 12 weeks. If at this point there has been a decrease in viral load of at least 2 log10, treatment is continued up to 48 weeks. However, if such a decrease in viral load is not found, treatment is withdrawn, since healing is not likely to occur even if the full treatment course is administered.
Guidelines of treatment are well established in adults.[55] In these patients current studies aim to shorten the duration of therapy (to 16 weeks in the case of a sensitive or favorable genotype, and to 24 weeks in the case of genotype 1) for those subjects with rapid viral response, and to prolong therapy (48 weeks for genotype 3 and 72 weeks for genotype 1) for those subjects showing a drop in viremia, but with persistent positive HCV RNA at week 12. Other ongoing investigations aim to increase efficacy by adding antiviral agents, such as telaprevir or boceprevir, to the conventional PEG-IFN plus ribavirin treatment.[56]
Drugs
Pegylated IFN-α Pegylated IFN-α is created by covalently linking a polyethylene glycol moiety to the IFN-α protein. The addition of this moiety to IFN-α confers an extended serum half-life compared with native IFN-α, allows once-weekly dosing and significantly improves SVR rates. Two forms of PEG-IFN have been developed, PEG-IFN-α-2b and PEG-IFN-α-2a. PEG-IFN-α-2a uses a large (40 kD) branched polyethylene glycol molecule, while PEG-IFN-α-2b uses a smaller (12 kD) linear molecule. The overall results from controlled trials in adults suggest that they achieve a similar rate of SVR.
Adverse events of PEG-IFN occur in the same proportion of patients and are of the same quality as observed with IFN-α. PEG-IFN is more convenient because of the weekly administration and influenza-like symptoms being limited to one versus three doses per week with conventional IFN.
Dosing in Children A once-weekly dose of PEG-IFN-α-2a is calculated from each patient's body surface area according to the formula BSA (m2)/(1.73 m2) × 180 µg. This dosing achieves adequate therapeutic concentrations.[53]
PEG-IFN-α-2a 1–1.5 µg/kg once a week has been given to children after approval in adults. Another approach is to adjust the adult dosing of 1.5 µg/kg to the body surface of the child, so dosing for children results in 60 µg/m2 per week.
The PEG-IFN-α dose is transiently decreased in patients with a neutrophil count of less than 1–1.25 × 109 cells/ml to avoid significant neutropenia. PEG-IFN-α is temporarily discontinued if the neutrophil counts fall below 0.75–1.00 × 109 cells/ml; and it is resumed once the neutrophil counts recover.
Ribavirin Ribavirin is a guanosine analog. Ribavirin alone has a relatively minor antiviral effect in HCV-infected patients, but in combination with PEG-IFN-α it appears to enhance the second and third phases of viral decay, thereby reducing the chance of relapse.[57] Its suggested mechanisms of action include error catastrophe resulting from mutagenesis via incorporation of ribavirin into HCV RNA during replication, direct inhibition of HCV RNA replication, inosine-monophospatedehydrogenase inhibition and immunomodulation. A relationship between ribavirin dose and response to therapy with both IFN-α-2a and -α-2b has been established, especially in patients with HCV genotype 1.
Ribavirin is cleared by the kidneys, so it should be reduced in patients with decreased creatinine clearance and completely avoided in renal insufficiency. Its main toxicity is hemolytic anemia, directly related to the concentration of ribavirin in erythrocytes. Anemia is the most common reason for ribavirin dose reduction or treatment discontinuation.
Dosing in Children A study in children receiving IFN-α-2b plus ribavirin 8, 12 or 15 mg/kg/day demonstrated that those on 15 mg/kg had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12, with an acceptable safety profile.[52]
On-therapy Assessments in Children
For assessment of efficacy, HCV RNA titers are measured at weeks 4, 12, 24 and 36, at the end of treatment, and every 12 weeks for another 6 months after the end of treatment. The assessment of safety should be planned in order to promptly detect adverse effects that require dose adjustment. Drugs cause influenza-like symptoms, neutropenia, anemia and weight loss especially during the first month of treatment. Clinical and analytical follow-up is performed every 2 weeks in the first phase of therapy. Monthly visits are advisable up to the sixth month, and scheduled every 3 months for the remaining period of treatment and for another 6 months after the end of treatment. Depression, thyroid disorders and growth velocity should be assessed. The long-term effects on thyroid function (if disturbed during treatment) and on growth would require an extended time (i.e., 2 years) of follow-up.
Efficacy of PEG-IFN Plus Ribavirin Treatment in Children
Combined therapy with PEG-IFN and ribavirin has improved sustained response rates compared with other treatments and currently represents the standard therapy in adult patients.
There are two ongoing trials in children with almost finished efficacy reports.[58–60] One international study investigates the pharmacokinetics, efficacy and safety of PEG-IFN-α-2b 60 µg/m2/week combined with ribavirin 15 mg/kg/day in 107 children. Another multicenter North American trial investigates PEG-IFN-α-2a plus ribavirin (55 children) compared with PEG-IFN-α-2a monotherapy (59 children) (Table 2).
Two European studies have been published with the data on the efficacy and adverse effects of the PEG-IFN plus ribavirin combination in children. One was conducted in a center in Spain; 30 children (24 naive) were enrolled to receive PEG-IFN-α-2a 1 µg/kg/week with ribavirin 15 mg/kg/day.[61] The other trial was carried out in several centers in Germany, and 61 children (51 naive) were given PEG-IFN-α-2a 1.5 µg/kg/week plus ribavirin 15 mg/kg/day.[62] In both studies the duration of treatment was 24 or 48 weeks in genotype 2/3 infections, and for 48 weeks in the case of genotype 1 or 4. The results were similar in both (Table 2), and showed a response equal to or slightly greater than that reported in children on conventional IFN-α given three-times per week plus ribavirin.
In the Spanish study, involving strict chronic infection inclusion criteria (over 3 years from infection), and with a patient age of 3.5–16 years, 69% of the cases were due to mother-to-child transmission, 86.6% corresponded to genotype 1, and baseline viral load was >5 log10 IU/ml in 66.6% of cases. SVR was achieved in 15 (50%) of 30 patients: in three (100%) out of three patients with HCV genotype 3, and in 12 (44%) out of 27 with HCV genotype 1. One patient with HCV genotype 4 did not respond. All patients who attained SVR remained HCV RNA-negative at further follow-up visits (up to 36 months) and had normal liver function.[61]
In the German study, the patients were between 2–17 years of age; 40.3% of the infections were the result of vertical transmission and 75.8% presented genotype 1. Of 46 patients with genotype 1, 22 (47.8%) showed SVR. All individuals with genotype 2 or 3 (n = 13) responded permanently, irrespective of the duration of treatment (i.e., 24 or 48 weeks) (p < 0.0003). One of two patients with genotype 4 had SVR.[62]
Predictors of Response
The study of baseline characteristics of treated patients may help to identify predictors for response, in order to select the candidates for therapy. Among adult patients, those aged less than 40 years without advanced disease show better response rates. However, overall results of treatment during childhood do not clearly offer significantly better results compared with adults.
The most important determinants of response in children are the viral genotype and viremia levels among those with genotype-1 infection. No baseline characteristic excludes response to therapy among those with genotype 1. On the other hand, the evolution of viremia after 12 weeks of therapy is of much help to identify future responders. In practical terms, all children may be eligible for treatment and early stopping rules according to week 12 viremia should be applied.
The HCV genotype is the main baseline predictor of response. Recent unpublished pediatric trials obtained a response in 93% of genotype 2 or 3, 80% of genotype 4 and 53% of genotype 1 HCV infections, and 47% of genotype 1 compared with 80% of genotype non-1, respectively.[58,60] In the international PEG-IFN-α-2a plus ribavirin study, response in genotype 1 was influenced by baseline viral load, as those showing HCV-RNA over 6 × 105IU/ml had 29% SVR compared with 72% SVR in genotype 1 with lower titers.[58]
Patient age does not seem to influence response (SVR: age < 12 years versus older children: 54.8 vs 63.3% in the German study and 45 vs 60% in the Spanish study). Responders show similar baseline ALT levels compared with nonresponders, and children with normal aminotransferase values display the same SVR rate as those with abnormal biochemistry prior to therapy. The baseline viral load and Knodell index did not influence the response in the Spanish study. However, in both experiences, the response in those children who developed the infection as a result of blood transfusions tended to be higher than in those with mother-to-child transmission (German children: 70.4 vs 48%; p = 0.087; Spanish children: 78 vs 38%; p = 0.1).[61,62]
Virological surveillance while on therapy appears to be the best predictor of response. In the Spanish study, only one patient showed negative HCV RNA at week 4. At week 12 of treatment, 51.7% showed undetectable HCV RNA, while 72% presented a greater than 2 log10 decrease compared with baseline viral load. A SVR was elicited in 87 and 71% of those presenting the above characteristics, respectively, at week 12. No cases with less than 2 log10 reduction at week 12 achieved sustained response. Continued therapy for 48 weeks in six children with positive HCV RNA at week 24 was ineffective in all cases.[61]
The German study reported that 62.3% of the treated children achieved negative HCV RNA at week 12. In turn, 91% of the patients with genotype 1 and 92.3% of those with genotypes 2/3 who showed a sustained response presented undetectable viremia at week 12 of therapy.[62]
Nonresponders to Therapy
Circumstances associated with a lack of response in children have not yet been elucidated.
Children with genotype 1 infection with mother-to-child transmission, currently representing the most numerous group, have shown SVR rates of 37.5 and 35% in the Spanish and German studies, respectively.[61,62] Thus, for many patients current therapy is inefficient.
Nonresponders can be retreated, but there is a very limited experience in children. According to studies in adults, the likelihood of response to retreatment depends on the type of response to prior therapy (relapsers achieve near 40% of SVR compared with 10% in nonresponders) and the differences in efficacy between the initial and the retreatment regimens. Very few children who failed to respond with IFN-α monotherapy were retreated with IFN-α plus ribavirin,[51] or PEG-IFN-α-2a plus ribavirin.[61,62] Using the highest efficacy PEG-IFN plus ribavirin, a sustained response was achieved in three out of 11 cases.
Adverse Effects
The adverse effects of PEG-IFN plus ribavirin are similar to those associated with conventional IFN, involving fewer injections and immediate injection reactions. Other adverse effects were of the same nature and intensity.
The toxicity of PEG-IFN plus ribavirin treatment must be carefully evaluated. It has been assessed in only two studies.[61,62]
In almost all children and adolescents, transient flu-like symptoms with variable intensity, including moderate fever, are observed during the first weeks of treatment. In most of them, the symptoms resolved or were of minor intensity during the second 6 months. Febrile convulsions are a hazard in younger children, but the problem did not occur in available series. Dose reduction by 20–30% of PEG-IFN was carried out because of considerable leukopenia in 5% of patients in the German series. Prolonged (>1 month) or permanent reductions in PEG-IFN-α-2b doses were required in 23% of Spanish children (Table 3).[61,62]
Owing to hemolysis induced by ribavirin, mean hemoglobin levels decrease within the first week of therapy, reaching a mean maximal decrease of 1.4 g/dl by week 12. Hemoglobin values are stable during the remaining period and return to normal when therapy is discontinued or completed. No reduction in ribavirin dose was required. Reticulocyte levels increased during therapy but returned to normal thereafter.
School performance is not grossly affected. Transient changes in character or mood have been recorded in 15–30% of the children, but severe psychological impairment was not observed.[61,62] Depression is a concern and should be looked for in adolescents, as suicidal ideation and even suicidal attempts have been reported during treatment with conventional IFN-α plus ribavirin.[52]
Patients with detectable LKM1 antibodies at baseline have shown either stable or varying titers during therapy. No patient developed LKM1 antibodies, although previous experiences have shown that LKM1 appear in 5% of children treated with IFN-α.[35] No specific liver function events occurred in antinuclear antibody-positive or LKM1 antibody-positive patients during or after therapy. Regarding the possibility of IFN facilitating autoimmune disease, one girl was reported to have developed diabetes mellitus after 9 months of treatment; therapy was continued without changing dosage and the patient showed SVR.[62]
The emergence of thyroid antibodies and thyroid-stimulating hormone elevation during treatment is significant. In the German study, five individuals received a weight-adjusted dose of l-thyroxine until the end of treatment. In three of these, l-thyroxine could be stopped during follow-up, and in two patients thyroid hormone supplementation was maintained 12 months after discontinuation of ribavirin and PEG-IFN.[62]
According to the Spanish study, four patients developed antithyroid antibodies. Two patients showed sudden decreases in thyroid-stimulating hormone values during therapy, accompanied by high T4 values and weight loss. Treatment was discontinued immediately in both patients. Anti-thyroid antibodies appeared in successive checkups. No specific therapy for hyperthyroidism was required and thyroid-stimulating hormone and T4 values returned to normal. The remaining two patients developed antithyroid antibodies during therapy and the condition persisted when off therapy. Mild elevation of thyroid-stimulating hormone or T4 values was observed in another additional six patients.[61]
Growth during the 48-week treatment period has been shown to be reduced in most patients by a mean of 1.6 cm compared with the average growth for age and gender. Growth velocity was normal in the 6-month period after the end of treatment; however, the modest decrease in height percentile observed during therapy was not recovered in the short term.[61]
Conclusion
In conclusion, the efficacy of combined therapy in children warrants its application. A response rate of 50% in genotype 1 patients and more than 90% in genotype 2 or 3 patients is achieved, which means cure of a chronic disease. However, more in-depth studies are needed, with further investigation of the factors implicated in the development of thyroid alterations in some children.
Expert Commentary
Current treatment (PEG-IFN-α plus ribavirin) in children with chronic hepatitis C should be managed by pediatric specialists. Many individual and family variables determine the appropriate time to initiate treatment. Mid-childhood age before adolescence is preferable. Side effects are usually well tolerated, but severe adverse events may occur in a low number of children. The near complete efficacy in favorable genotypes, and the early stopping rules for genotype 1 cases shifts the balance toward applying treatment to children, although new drug investigation is needed. The mild disease that children usually present makes safer the initiation of studies once efficacy and toxicity profiles of new drugs have been assessed in adult patients.
Five-year View
New lines of research in children are necessary to assess long-term clinical outcomes, to develop noninvasive methods for detecting fibrosis, to establish gene polymorphisms related to disease progression and response to therapy and to identify individuals at risk for significant side effects before treatment initiation. Trials with combined therapy plus antivirals should begin as soon as safety profiles have been established in adult patients.
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•• Experience of currently recommended therapy in Spanish children.
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•• Experience of currently recommended therapy in German children.
Papers of special note have been highlighted as:
•• of considerable interest
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