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
January 5, 2011
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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27.Bortolotti F, Verucchi G, Cammà C; for the Italian Observatory for HCV Infection and Hepatitis C in Children. Long-term course of chronic hepatitis C in children: from viral clearance to end-stage liver disease. Gastroenterology 134, 1900–1907 (2008).
•• Italian large collaborative report on evolution of children with hepatitis C.
28.Azzari C, Resti M, Bortolotti F et al. Serum levels of HCV RNA in infants and children with chronic hepatitis C. J. Pediatr. Gastroenterol. Nutr. 29, 314–317 (1999).
29.Guido M, Rugge M, Jara P et al. Chronic hepatitis C in children: the pathological and clinical spectrum. Gastroenterology 115, 1525–1529 (1998).
•• Description of histology in pediatric chronic hepatitis C children unaffected by any other disease.
30.Guido M, Bortolotti F, Leandro G et al. Fibrosis in chronic hepatitis C acquired in infancy: is it only a matter of time? Am. J. Gastroenterol. 98, 660–663 (2003).
•• Assessment of factors involved in fibrosis progression in children.
31.Iorio R, Giannattasio A, Sepe A, Terracciano MA, Vecchione R, Vegnente A. Chronic hepatitis C in childhood: a 18-year experience. Clin. Infect. Dis. 41, 1431–1437 (2005).
32.Mohan P, Colvin C, Glymph C et al. Clinical spectrum and histopathologic features of chronic hepatitis C infection in children. J. Pediatr. 150, 168–174 (2007).
33.Harris HE, Mieli-Vergani G, Kelly D, Davison D, Gibb DM, Ramsay ME; The HCV National Register Steering Group. A national sample of individuals who acquired HCV infections in childhood or adolescence: risk factors for advanced disease. J. Pediatr. Gastroenterol. Nutr. 45, 335–341 (2007).
34.Goodman ZD, Makhlouf HR, Liu L et al. Pathology of chronic hepatitis C in children: liver biopsy findings in the Peds-C Trial. Hepatology 47, 836–843 (2008).
•• Details on histology of children included in a large treatment trial.
35.Bortolotti F, Muratori L, Jara P et al. HCV infection associated with LKM1 autoantibodies in children. J. Pediatr. 142, 185–190 (2003).
36.Rumbo C, Fawaz LR, Emre SH et al. Hepatitis C in children: a quaternary referral center perspective. J. Pediatr. Gastroenterol. Nutr. 43, 209–216 (2006).
37.Gonzalez-Peralta RP, Langham MR Jr, Andres JM et al. Hepatocellular carcinoma in 2 young adolescents with chronic hepatitis C. J. Pediatr. Gastroenterol. Nutr. 48, 630–635 (2009).
38.Jonas MM. Children with hepatitis C. Hepatology 36, S173–S178 (2002).
39.Barshes NR, Udell IW, Lee TC et al. The natural history of hepatitis C virus in pediatric liver transplant recipients. Liver Transplant. 12, 1119–1123 (2006).
40.Casiraghi MA, de Paschale M, Romano L et al. Long-term outcome (35 years) of hepatitis C after acquisition of infection through mini-transfusions of blood given at birth. Hepatology 39, 90–96 (2004).
41.Seeff LB. Natural history of chronic hepatitis C. Hepatology 36, S35–S46 (2002).
42.Schneider BL, Gonzalez-Peralta R, Roberts EA. Controversies in the management of pediatric liver disease: Hepatitis B, C and NAFLD: summary of a single topic conference. Hepatology 44, 1344–1354 (2006).
43.Nydegger A, Srivastava A, Wake M et al. Health-related quality of life in children with hepatitis C acquired in the fi rst year of life. J. Gastroenterol. Hepatol. 23, 226–230 (2008).
44.Rodrique JR, Balistreri W, Haber B et al. Impact of hepatitis C virus infection on children and their caregivers: quality of life, cognitive, and emotional outcomes. J. Pediatr. Gastroenterol. Nutr. 48, 341–347 (2009).
45.Barlow CF, Priebe CJ, Mulliken JB et al. Spastic diplegia as a complication of interferon α-2a treatment of hemangiomas of infancy. J. Pediatr. 132, 527–530 (1998).
46.Jacobson KR, Murray K. Zellos A, Schwarz KB. An analysis of published trials of Interferon monotherapy in children with chronic hepatitis C. J. Pediatr. Gastroenterol. Nutr. 34, 52–58 (2002).
47.Jara P, Hierro L, Frauca E et al. Interferon a2b treatment in children with chronic HCV hepatitis. J. Pediatr. Gastroenterol. Nutr. 24, 487 (1997).
48.Bortolotti F, Giacchino R, Vajro P et al. Recombinant interferon-α therapy in children with chronic hepatitis C. Hepatology 22, 1623–1627 (1995).
49.Iorio R, Pensati P, Porzio S, Fariello I, Guida S, Vegnente A. Lymphoblastoid interferon a treatment in chronic hepatitis C. Arch. Dis. Child. 74, 152–156 (1996).
50.Bortolotti F, Iorio R, Nebbia G et al. Interferon treatment in children with chronic hepatitis C: long-lasting remission in responders, and risk for disease progression in non-responders. Digest. Liver Dis. 37, 336–341 (2005).
51.Wirth S, Lang T, Gehring S, Gerner P. Recombinant α-interferon plus ribavirin therapy in children and adolescents with chronic hepatitis C. Hepatology 36, 1280–1284 (2002).
52.Gonzalez-Peralta RP, Kelly DA, Haber B et al. Interferon α-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology 42, 1010–1018 (2005).
•• Study on efficacy and toxicity of combined IFN-α plus ribavirin treatment in a large population of children.
53.Schwarz KB, Mohan P, Narkewicz M et al. The safety, efficacy, and pharmacokinetics of peginterferon α-2a (40 kD) in children with chronic hepatitis C. J. Pediatr. Gastroenterol. Nutr. 43, 499–505 (2006).
54.Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401 (2009).
55.Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49, 1335–1374 (2009).
56.Thompson A, Patel K, Tillman H, McHutchison JG. Directly acting antivirals for the treatment of patients with hepatitis C infection: a clinical development update addressing key future challenges. J. Hepatol. 50, 184–194 (2009).
57.Reddy KR, Nelson DR, Zeuzem S. Ribavirin: current role in the optimal clinical management of chronic hepatitis C. J. Hepatol. 50, 402–411 (2009).
58.Wirth S, Ribes-Koninckx C, Bortolotti F et al. Children with HCV infection show high sustained virologic response rates on peginterferon α-2b plus ribavirin treatment. Hepatology 48, 392A (2008).
59.Murray KF, Rodrigue JR, Gonzalez-Peralta RP et al. Design of the PEDS-C trial: pegylated interferon ± ribavirin for children with chronic hepatitis C viral infection. Clin. Trials 4, 661–673 (2007).
60.Schwarz KB, Gonzalez-Peralta, RP, Murray, KF et al. Peginterferon with or without ribavirin for chronic hepatitis C in children and adolescents: final results of the PEDS-C trial. Hepatology48(Suppl. 1),418A (2008).
61.Jara P, Hierro L, de la Vega A et al. Efficacy and safety of PEG-IFNα-2b and ribavirin combination therapy in children with chronic hepatitis C. Pediatr. Infect. Dis. J. 27, 142–148 (2008).
•• Experience of currently recommended therapy in Spanish children.
62.Wirth S, Pieper-Boustani H, Lang T et al. PEG-IFNα plus ribavirin treatment in children and adolescents with chronic hepatitis C. Hepatology 41, 1013–1018 (2005).
•• Experience of currently recommended therapy in German children.
Papers of special note have been highlighted as:
•• of considerable interest
Source
5-year-old's got a whole world in his hands
Elijah Richards, who's being treated for hepatitis C, holds the globe sent to him by supporters from all over the world whom his family came to know through the Internet
Published: 12:00 AM, Sun Dec 19, 2010
Kim Hasty
LAURINBURG - The Richards family is ready for Christmas. The tree and nearly every square foot of visible living space are decorated with some sort of Christmas cheer.
Cheer, in fact, is the general order of the day in this house located a bit off the beaten path of the town's main thoroughfare. The only thing more prevalent than Christmas decorations is the laughter. And in the middle of it all earlier this week was the pint-size source of much of the prevailing sense of happiness.
Sitting cross-legged, with encouragement from not one, but four, older brothers, 5-year-old Elijah was given permission to carefully unwrap the first Christmas present of the season. A little early to start opening presents, perhaps, but this one held an undeniably special significance.
The gift had come from friends. Friends from all over the world. Australia and New Zealand. Italy, France and England. From various parts of the United States, too.
Elijah opened the cushioned box. Inside, of all things, was a globe. A globe small enough that a 5-year-old could lift it out of its box and hold it carefully in his small hands. And one day come to understand its implications.
"It's wonderful they did this for him,'' said his mother, Lana.
The globe, which spins on solar power, sits on a crystal-like pedestal inscribed with these words: "Elijah Richards. Hep C Hero. Christmas 2010.''
Hero is a heavy mantle to hang on a 5-year-old, but this 5-year-old wears it well. A wiggle worm sometimes. A hero all the time.
"They call hepatitis C a dragon,'' Lana Richards said. "But Elijah's gonna beat it because he's a dragon slayer.''
Lana and Shawn Richards knew there was a chance Elijah would be born with hepatitis C because his birth mother had the disease. Hepatitis C is caused by a blood-borne virus that slowly attacks the liver over time. There is no vaccine to prevent the disease and no certain cure. Once a child is infected, the disease has historically lasted a lifetime. In the United States, about 240,000 children have been exposed to the virus.
Undaunted, the Richardses, already the parents of five children, went through with the adoption and accepted Elijah's diagnosis when it came, without flinching.
What they couldn't accept was the fact that the conventional medical practice has historically been to not treat children for hepatitis C until they begin showing symptoms of the disease, which often doesn't happen until they are adults in the prime of life. Part of the reason is that few drugs have been available for treatment in children.
Lana Richards got busy educating herself. She found two websites in particular that offered her the most comfort and the most information - hepcnomads.co.uk and hepatitisckids.freeforums.org. She began online conversations and formed friendships with people who could relate to her struggle to help her son.
Almost exactly a year ago, Elijah began treatment. The Richardses say he is the youngest person undergoing treatment for hepatitis C in North Carolina. While Elijah's treatment originated at UNC Hospitals in Chapel Hill, most of the hands-on efforts come from his mother. Elijah takes antiviral medicines twice a day, and Lana Richards gives her son a once-a-week injection of a chemotherapy medication. Sometimes, she's up all night with him when he's feeling sick.
It is never easy for her, injecting this cheerful little boy with a medication with side effects that sometimes make him very ill.
"I always hesitate,'' she said, "but he always makes me feel better.''
The treatment has taken a toll on Elijah. His blood platelet count is low, and he is battling severe anemia. But if the treatment works - and they won't know that until about six months after his treatment is complete - then Elijah will be considered free of the disease.
That's where the gift of the globe comes in. More than 20 people, most of whom the Richards family knows only from the Internet, banded together and purchased the globe to send to him. A gesture of hope and kindness from all over the world. Elijah can look at those spinning continents and know the locations of all the people who are thinking of him and hoping for the best for him.
They wanted Elijah to know that, all over the world, people are pulling for and praying for this little pioneer. This little hero.
Community news editor Kim Hasty can be reached at hastyk@fayobserver.com or 486-3591.
Source
The Little Dragon Slayer ... Takara's Story
The Little Dragon Slayer
Takara's Story
Takara was daignosed with hepatitis C geno type 1b in June of 2009. Our world as we know it stopped. With the news of Takara having Hep C came the devestating knowledge of how she contracted Hep c, through me, her mother vertical transmission. One may ask why would you have a child knowing you had Hep C? The answer simple. I had just found out I had this virus prior to finding out I was pregnant.
We were informed there was a 3% chance Takara would be infected with the virus. The doctors advised to have her tested at about 2 years of age. We tried several times to have her blood drawn and it wasn't until she was 4 years old before we had a non problematic blood draw which confirmed our worst fear. Takara had Hep C.
Takara's pediatrician reffered us to a infectious disease specialist, who told us he could not treat her. That children are not treated until they are at least 18 years of age. That there was not an approved treatment for children. This answer simply was not acceptable. I began educating myself, searching the internet, making many phone calls and leaving many messages. weeks turned into months. I prayed, searched and prayed some more. I was led to a Pediatric Liver Specialist at UCLA. Dr Susan McDiarmid, 300 miles away and she treated children.
Before Takara could start treatment she needed a liver biopsy. This was to determin the condition of her liver and aid in dosage strength of the medication. Takara started treatment on Feb. 5 2010. It has been almost a year that she has been on treatment. Takara's treatment is over seen by Dr McDiarmid at UCLA, however her medication must be administerd at home. I give her Rebetol (anti viral medication) twice daily and a weekly injection of Pegasys (chemotherapy medication). Takara must also get regular blood draws to monitor her counts. This medicine combination can make, and has made Takara very sick many times. There have been many nights I have been up with her just trying to comfort her. It is not easy to give my little princess medicine, I know will make her sick. Being on treatment for almost a year now has taken a toll on her. Takara has been battling loss of appetite, weight loss, rage, and insomnia to name just a few.
On top of all this Takara tries to carry on her daily routine. She attends all day kindergarten, which she looks forward to and enjoys greatly- most days.
I have met families from all over the world online in my search for knowledge, on how to battle and cope with these dangerous side effects. Families that have supported Takara in her fight against Hep C, some by purchasing from her website I set up for her, and others by praying and sharing valuable information.
It is for this reason, on Takara's last day of treatment in Feb., we are going to present Takara with a Mova Globe. We will show to Takara, all the locations of the families who have been, and still are supporting and praying for her.
Even though Takara's treatment will officially end this Feb. It will be a new begining for her. They call Hep C the "Dragon" and even as her fight with the dragon comes to an end, it will be another 6 months before we will know if treatment was a success for our little Dragon Slayer.
Jenell Chow
Direct Antiviral Agents for Hepatitis C – New Developments
Lange Christian Markus, Sarrazin Christoph, Zeuzem Stefan
European Gastroenterology & Hepatology Review, 2010;6(1):70–7
PDF download article
Abstract
Numerous directly acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection are currently under development. The final results of phase II clinical trials that evaluated the most advanced compounds – telaprevir and boceprevir – indicate that the addition of these NS3/4A protease inhibitors to pegylated interferon-alpha (pegIFN-α) and ribavirin strongly improves the chances of achieving a sustained virological response (SVR) in treatment-naïve HCV genotype 1 patients and in prior non-responders and relapsers. However, monotherapy with DAAs frequently results in the selection of resistant quasi-species and viral breakthrough and is therefore not suitable. Generally, NS5B polymerase inhibitors have a lower antiviral efficacy than protease inhibitors, and their ability to improve SVR rates remains to be established. Future research should elaborate on whether an SVR can be achieved with combination therapies of DAA agents without IFN-α; in addition, DAAs targeting genotypes other than HCV genotype 1 should be evaluated.
Keywords
Directly acting antiviral agents (DAAs), specifically targeted antiviral therapy for hepatitis c (STAT-C), protease inhibitor, polymerase inhibitor, hepatitis C, antiviral therapy, viral resistance, drug resistance
Disclosure: Christian Markus Lange has no conflicts of interest to declare. Christoph Sarrazin is a clinical investigator, consultant and/or a member of the speaker’s bureau of Abbott, BMS, Boehringer Ingelheim, Falk, Gilead, Merck, Novartis, Roche, Siemens, Tibotec and Vertex. Stefan Zeuzum is a clinical investigator, consultant and/or a member of the speaker’s bureau of Abbott, Anadys, BMS, Boehringer Ingelheim, Gilead, HGS, Merck, Novartis, Roche, Tibotec and Vertex.
Received: 7 May 2010 Accepted: 29 June 2010 Citation: European Gastroenterology & Hepatology Review, 2010;6(1):70–6
Correspondence: Stefan Zeuzem, Klinikum der JW Goethe-Universität Frankfurt am Main Medizinische Klinik I, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. E: zeuzem@em.uni-frankfurt.de
The odds of achieving a sustained virological response (SVR) in patients with chronic hepatitis C with a therapy of pegylated interferon-alpha (pegIFN-α) and ribavirin are still too low, particularly in patients infected with hepatitis C virus (HCV) genotypes 1 or 4.1–4 Therefore, intensive efforts have been made to develop directly acting antiviral agents (DAAs) against HCV.5–12 Many of these DAAs are currently in phase I–III development and will significantly change treatment options for HCV infection in the near future. The most advanced compounds are telaprevir and boceprevir, which are both inhibitors of the HCV NS3 protease and have been shown to significantly enhance SVR rates in HCV genotype 1 patients when applied in addition to pegIFN-α and ribavirin.13–15
NS3/4A Protease Inhibitors
NS3/4A protease inhibitors can be divided into two chemical classes: macrocyclic inhibitors and linear tetra-peptide α-ketoamid derivatives. Ciluprevir has a macrocyclic structure and was the first protease inhibitor evaluated in patients with chronic hepatitis C. Ciluprevir, as well as subsequently developed NS3/4A protease inhibitors of both molecular classes, strongly inhibited HCV replication during monotherapy, but also frequently caused the selection of resistant mutants, which may be followed by viral breakthrough.12,16–18 Although the development of ciluprevir was stopped because of serious cardiotoxicity observed in an animal model, the proof of principle was provided for successful suppression of HCV replication by NS3/4A inhibitors in patients with chronic hepatitis C. Subsequent studies have shown that the frequency of resistance development against protease inhibitors can be vastly reduced by the additional administration of pegIFN and ribavirin. Telaprevir and boceprevir are the most advanced NS3/4A protease inhibitors, and are currently in phase III evaluation.
To register to view full article click here
Keywords:
Directly acting antiviral agents (DAAs), specifically targeted antiviral therapy for hepatitis c (STAT-C), protease inhibitor, polymerase inhibitor, hepatitis C, antiviral therapy, viral resistance, drug resistance
Source
European Gastroenterology & Hepatology Review, 2010;6(1):70–7
PDF download article
Abstract
Numerous directly acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection are currently under development. The final results of phase II clinical trials that evaluated the most advanced compounds – telaprevir and boceprevir – indicate that the addition of these NS3/4A protease inhibitors to pegylated interferon-alpha (pegIFN-α) and ribavirin strongly improves the chances of achieving a sustained virological response (SVR) in treatment-naïve HCV genotype 1 patients and in prior non-responders and relapsers. However, monotherapy with DAAs frequently results in the selection of resistant quasi-species and viral breakthrough and is therefore not suitable. Generally, NS5B polymerase inhibitors have a lower antiviral efficacy than protease inhibitors, and their ability to improve SVR rates remains to be established. Future research should elaborate on whether an SVR can be achieved with combination therapies of DAA agents without IFN-α; in addition, DAAs targeting genotypes other than HCV genotype 1 should be evaluated.
Keywords
Directly acting antiviral agents (DAAs), specifically targeted antiviral therapy for hepatitis c (STAT-C), protease inhibitor, polymerase inhibitor, hepatitis C, antiviral therapy, viral resistance, drug resistance
Disclosure: Christian Markus Lange has no conflicts of interest to declare. Christoph Sarrazin is a clinical investigator, consultant and/or a member of the speaker’s bureau of Abbott, BMS, Boehringer Ingelheim, Falk, Gilead, Merck, Novartis, Roche, Siemens, Tibotec and Vertex. Stefan Zeuzum is a clinical investigator, consultant and/or a member of the speaker’s bureau of Abbott, Anadys, BMS, Boehringer Ingelheim, Gilead, HGS, Merck, Novartis, Roche, Tibotec and Vertex.
Received: 7 May 2010 Accepted: 29 June 2010 Citation: European Gastroenterology & Hepatology Review, 2010;6(1):70–6
Correspondence: Stefan Zeuzem, Klinikum der JW Goethe-Universität Frankfurt am Main Medizinische Klinik I, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. E: zeuzem@em.uni-frankfurt.de
The odds of achieving a sustained virological response (SVR) in patients with chronic hepatitis C with a therapy of pegylated interferon-alpha (pegIFN-α) and ribavirin are still too low, particularly in patients infected with hepatitis C virus (HCV) genotypes 1 or 4.1–4 Therefore, intensive efforts have been made to develop directly acting antiviral agents (DAAs) against HCV.5–12 Many of these DAAs are currently in phase I–III development and will significantly change treatment options for HCV infection in the near future. The most advanced compounds are telaprevir and boceprevir, which are both inhibitors of the HCV NS3 protease and have been shown to significantly enhance SVR rates in HCV genotype 1 patients when applied in addition to pegIFN-α and ribavirin.13–15
NS3/4A Protease Inhibitors
NS3/4A protease inhibitors can be divided into two chemical classes: macrocyclic inhibitors and linear tetra-peptide α-ketoamid derivatives. Ciluprevir has a macrocyclic structure and was the first protease inhibitor evaluated in patients with chronic hepatitis C. Ciluprevir, as well as subsequently developed NS3/4A protease inhibitors of both molecular classes, strongly inhibited HCV replication during monotherapy, but also frequently caused the selection of resistant mutants, which may be followed by viral breakthrough.12,16–18 Although the development of ciluprevir was stopped because of serious cardiotoxicity observed in an animal model, the proof of principle was provided for successful suppression of HCV replication by NS3/4A inhibitors in patients with chronic hepatitis C. Subsequent studies have shown that the frequency of resistance development against protease inhibitors can be vastly reduced by the additional administration of pegIFN and ribavirin. Telaprevir and boceprevir are the most advanced NS3/4A protease inhibitors, and are currently in phase III evaluation.
To register to view full article click here
Keywords:
Directly acting antiviral agents (DAAs), specifically targeted antiviral therapy for hepatitis c (STAT-C), protease inhibitor, polymerase inhibitor, hepatitis C, antiviral therapy, viral resistance, drug resistance
Source
Hepatitis C: In 2011, a predictive marker for response to therapy
Public release date: 5-Jan-2011
Contact: Matthew Albert
albertm@pasteur.fr
33-670-010-396
INSERM (Institut national de la santé et de la recherche médicale)
Scientists at Inserm and Institut Pasteur have performed biomarker discovery on patients being treated for chronic hepatitis C infection. Their work, published in The Journal of Clinical Investigation, demonstrates that the plasma levels of the protein IP-10 predict, prior to treatment initiation, the efficacy of treatment with pegylated-interferon and ribavirin. Based on these results, the scientists have developed a prognostic test. Commercialization is anticipated in 2011, and will help inform physicians of the chances that patients will respond to standard treatment or if instead they will require new therapeutic cocktails (e.g., inclusion of protease inhibitors).
Importantly, hepatitis C is the leading cause of primary liver cancer (hepatocellular carcinoma) and it remains an important cause of liver failure due to fibrosis and cirrhosis. This infectious disease represents a major public health problem, with greater than 170 million cases worldwide. The World Health Organization estimates 3 to 4 million new cases per year and considers the virus a " viral time bomb" due to the long term sequella of infection.
Currently, there is no approved vaccine available and approximately 80% of individuals infected by the virus develop chronic disease, a risk factor for cirrhosis, liver failure, liver cancer as well as other medical complications (e.g., diabetes).
For the past ten years, treatment has been based on the use of type I interferon given in combination with the anti-viral ribavirin. While effective, it results in a cure for only 50% of patients. Moreover, treatment is long (24 – 48 weeks), and it results in severe side effects (e.g., depression, anemia).
It is in this context that the Inserm and Institut Pasteur sponsored research lab of Dr. Matthew Albert, in close collaboration with the Liver Disease Unit headed by Prof. Stanislas Pol, evaluated plasma biomarkers to define predictors for patients' response to treatment.
With the help of the Centre for Human Immunology at Institut Pasteur, the investigators involved have performed a prospective study. They identified the protein IP-10 as a prognostic biomarker – elevated in those patients for whom treatment was ineffective. This observation was paradoxical as IP-10 is considered a pro-inflammatory molecule, which should have facilitated migration of activated T cells to the liver, the exact cell types responsible for viral immunity. In fact, what was discovered is that the IP-10 had been catabolized and it was a truncated form present in the HCV patients. Strikingly, the short form of IP-10 is an antagonist and inhibits T cell recruitment. Thus, it is suggested that the antagonist form of IP-10 is responsible for the failure to respond to treatment in the 50% of patients who do not benefit from pegylated-interferon / ribavirin treatment.
The investigators worked in close collaboration with an American company, Rules Based Medicine, Inc., who will develop a diagnostic test to distinguish the different forms of IP-10 as a simple blood test. This test will be a significant step towards the improved management of patients with HCV as well as other chronic inflammatory diseases.
###
This scientific work was conducted under the direction of Matthew L. Albert, MD PhD, Mixed Institut Pasteur / Inserm Research Unit; and Stanislas Pol, MD PhD, Univerisity of Paris, Descartes and Institut Cochin. Financial support was provided by the ANRS and promotion of the study was taken by Inserm Medical.
To know more:
Source
Evidence for chemokine antagonisms in human infected chronically with Hepatitis C Virus.
Armanda Casrouge, Jérémie Decalf, Mina Ahloulay, Cyril Lababidi, Hala Mansour, Anaïs Vallet-Pichard, Vincent Mallet, Estelle Mottez, James Mapes, Arnaud Fontanet, Stanislas Pol and Matthew L. Albert.
Journal of Clinical Investigation.
and the related news article
Chemokine antagonism in chronic hepatitis C virus infection.
Edgar D. Charles and Lynn B. Dustin
Journal of Clinical Investigation.
Contact information
Matthew Albert
Unité mixte Institut Pasteur / Inserm
Email : albertm@pasteur.fr
Tel : +33 6 7001 0396
Stanislas Pol
Unité 1016 « Institut Cochin »
Service Hépatologie, Hôpital Cochin
Email : stanislas.pol@cch.aphp.fr
Source
Contact: Matthew Albert
albertm@pasteur.fr
33-670-010-396
INSERM (Institut national de la santé et de la recherche médicale)
Scientists at Inserm and Institut Pasteur have performed biomarker discovery on patients being treated for chronic hepatitis C infection. Their work, published in The Journal of Clinical Investigation, demonstrates that the plasma levels of the protein IP-10 predict, prior to treatment initiation, the efficacy of treatment with pegylated-interferon and ribavirin. Based on these results, the scientists have developed a prognostic test. Commercialization is anticipated in 2011, and will help inform physicians of the chances that patients will respond to standard treatment or if instead they will require new therapeutic cocktails (e.g., inclusion of protease inhibitors).
Importantly, hepatitis C is the leading cause of primary liver cancer (hepatocellular carcinoma) and it remains an important cause of liver failure due to fibrosis and cirrhosis. This infectious disease represents a major public health problem, with greater than 170 million cases worldwide. The World Health Organization estimates 3 to 4 million new cases per year and considers the virus a " viral time bomb" due to the long term sequella of infection.
Currently, there is no approved vaccine available and approximately 80% of individuals infected by the virus develop chronic disease, a risk factor for cirrhosis, liver failure, liver cancer as well as other medical complications (e.g., diabetes).
For the past ten years, treatment has been based on the use of type I interferon given in combination with the anti-viral ribavirin. While effective, it results in a cure for only 50% of patients. Moreover, treatment is long (24 – 48 weeks), and it results in severe side effects (e.g., depression, anemia).
It is in this context that the Inserm and Institut Pasteur sponsored research lab of Dr. Matthew Albert, in close collaboration with the Liver Disease Unit headed by Prof. Stanislas Pol, evaluated plasma biomarkers to define predictors for patients' response to treatment.
With the help of the Centre for Human Immunology at Institut Pasteur, the investigators involved have performed a prospective study. They identified the protein IP-10 as a prognostic biomarker – elevated in those patients for whom treatment was ineffective. This observation was paradoxical as IP-10 is considered a pro-inflammatory molecule, which should have facilitated migration of activated T cells to the liver, the exact cell types responsible for viral immunity. In fact, what was discovered is that the IP-10 had been catabolized and it was a truncated form present in the HCV patients. Strikingly, the short form of IP-10 is an antagonist and inhibits T cell recruitment. Thus, it is suggested that the antagonist form of IP-10 is responsible for the failure to respond to treatment in the 50% of patients who do not benefit from pegylated-interferon / ribavirin treatment.
The investigators worked in close collaboration with an American company, Rules Based Medicine, Inc., who will develop a diagnostic test to distinguish the different forms of IP-10 as a simple blood test. This test will be a significant step towards the improved management of patients with HCV as well as other chronic inflammatory diseases.
###
This scientific work was conducted under the direction of Matthew L. Albert, MD PhD, Mixed Institut Pasteur / Inserm Research Unit; and Stanislas Pol, MD PhD, Univerisity of Paris, Descartes and Institut Cochin. Financial support was provided by the ANRS and promotion of the study was taken by Inserm Medical.
To know more:
Source
Evidence for chemokine antagonisms in human infected chronically with Hepatitis C Virus.
Armanda Casrouge, Jérémie Decalf, Mina Ahloulay, Cyril Lababidi, Hala Mansour, Anaïs Vallet-Pichard, Vincent Mallet, Estelle Mottez, James Mapes, Arnaud Fontanet, Stanislas Pol and Matthew L. Albert.
Journal of Clinical Investigation.
and the related news article
Chemokine antagonism in chronic hepatitis C virus infection.
Edgar D. Charles and Lynn B. Dustin
Journal of Clinical Investigation.
Contact information
Matthew Albert
Unité mixte Institut Pasteur / Inserm
Email : albertm@pasteur.fr
Tel : +33 6 7001 0396
Stanislas Pol
Unité 1016 « Institut Cochin »
Service Hépatologie, Hôpital Cochin
Email : stanislas.pol@cch.aphp.fr
Source
LSM detects undiagnosed chronic liver disease
Published date :24-Dec-2010
MedWire News: Study findings show that liver stiffness measurement (LSM) can detect undiagnosed chronic liver disease in apparently healthy individuals, with the added benefit of a 100% positive predictive value for cirrhosis screening.
"So far, liver biopsy has been the gold standard for the assessment of fibrosis in patients with chronic liver disease," say Dominique Roulot (Avicenne Hospital, Bobigny, France) and co-authors.
"However, in cases of suspicion of non-alcoholic fatty liver disease (NAFLD), liver biopsy is difficult to recommend for apparently healthy patients with normal liver tests, because of its possible complications," they add.
A total of 1190 individuals from the general population, aged 45 years or older, attending for a medical check-up participated in the current study. All patients received LSM, in addition to laboratory tests and medical examinations. Those who scored over 8 kPa on the LSM were referred to a liver unit for further investigations.
Overall, 94 (8.5%) patients had a LSM >8 kPa, including nine patients with a LSM >13 kPa. The researchers note that although LSM values were normal in 4% of patients with perturbed liver tests, these tests came back as normal in 43% of patients with LSM >8 kPa.
NAFLD and alcoholic liver disease (ALD) were diagnosed as the likely causes of chronic liver disease in 52 and 20 patients, respectively. Hepatitis B and C were diagnosed in nine patients, and primary biliary cirrhosis in one patient.
Liver biopsy results confirmed that all of the nine patients with LSM >13 kPa had liver cirrhosis due to ALD or chronic hepatitis B/C. The remaining 18 biopsies showed liver fibrosis in all patients except one who presented with isolated steatosis.
Factors significantly associated with a LSM >8 kPa included being aged 57 years or older, having a body mass index ≥30 kg/m2, elevated waist circumference, diabetes, alanine aminotransferase ≥40 UI/l, and γ-glutamyltranspeptidase ≥45 UI/l.
The researchers say the findings suggest that "a relatively high percentage of liver diseases remain undiagnosed in apparently healthy individuals, and that LSM might contribute to referring these patients to hepatologists."
They conclude in the journal Gut: "If future studies determine that the superior positive predictive value of LSM can be achieved at an acceptable cost, compared with common screening methods, LSM might represent a first-line procedure for the mass screening of liver disease in the general population."
MedWire (http://www.medwire-news.md/) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010
Source
MedWire News: Study findings show that liver stiffness measurement (LSM) can detect undiagnosed chronic liver disease in apparently healthy individuals, with the added benefit of a 100% positive predictive value for cirrhosis screening.
"So far, liver biopsy has been the gold standard for the assessment of fibrosis in patients with chronic liver disease," say Dominique Roulot (Avicenne Hospital, Bobigny, France) and co-authors.
"However, in cases of suspicion of non-alcoholic fatty liver disease (NAFLD), liver biopsy is difficult to recommend for apparently healthy patients with normal liver tests, because of its possible complications," they add.
A total of 1190 individuals from the general population, aged 45 years or older, attending for a medical check-up participated in the current study. All patients received LSM, in addition to laboratory tests and medical examinations. Those who scored over 8 kPa on the LSM were referred to a liver unit for further investigations.
Overall, 94 (8.5%) patients had a LSM >8 kPa, including nine patients with a LSM >13 kPa. The researchers note that although LSM values were normal in 4% of patients with perturbed liver tests, these tests came back as normal in 43% of patients with LSM >8 kPa.
NAFLD and alcoholic liver disease (ALD) were diagnosed as the likely causes of chronic liver disease in 52 and 20 patients, respectively. Hepatitis B and C were diagnosed in nine patients, and primary biliary cirrhosis in one patient.
Liver biopsy results confirmed that all of the nine patients with LSM >13 kPa had liver cirrhosis due to ALD or chronic hepatitis B/C. The remaining 18 biopsies showed liver fibrosis in all patients except one who presented with isolated steatosis.
Factors significantly associated with a LSM >8 kPa included being aged 57 years or older, having a body mass index ≥30 kg/m2, elevated waist circumference, diabetes, alanine aminotransferase ≥40 UI/l, and γ-glutamyltranspeptidase ≥45 UI/l.
The researchers say the findings suggest that "a relatively high percentage of liver diseases remain undiagnosed in apparently healthy individuals, and that LSM might contribute to referring these patients to hepatologists."
They conclude in the journal Gut: "If future studies determine that the superior positive predictive value of LSM can be achieved at an acceptable cost, compared with common screening methods, LSM might represent a first-line procedure for the mass screening of liver disease in the general population."
MedWire (http://www.medwire-news.md/) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010
Source
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