Paloma Jara

Chronic hepatitis C virus infection in childhood: clinical patterns and evolution in 224 white children.

The characteristics and evolution of hepatitis C virus (HCV) infection were retrospectively investigated in a study of 224 HCV RNA-seropositive white children who were consecutively recruited at 7 European centers in 1980-1998. At presentation, all patients were positive for antibodies to hepatitis C virus, 87% were asymptomatic, and 48% had alanine aminotransferase (ALT) levels that were < or =2 times the upper limit of the range considered to be normal. Of 200 children followed for 1-17.5 years (mean follow-up +/- standard deviation [SD], 6.2+/-4.7 years), only 12 (6%) achieved sustained viremia clearance and normalization of the ALT level. In 92 revised liver biopsy specimen analyses, the mean fibrosis score (+/-SD) was 1.5+/-1.3 for children <15 years of age and 2.3+/-1.2 for children > or =15 years of age (range, 0-6 years; P<.01). Pediatric HCV infection is usually mild, but few patients, especially those who are perinatally infected, clear viremia in the medium-term follow-up. Conversely, the higher rates of fibrosis observed in older patients suggest the possibility of an insidious progression of HCV-associated liver disease.

Chronic Hepatitis C in Children: The Pathological and Clinical Spectrum

BACKGROUND & AIMS Apart from the high-risk groups, the pathology of chronic hepatitis C in children is not well known. The aim of this study was to investigate the morphology of chronic hepatitis C in children without any underlying systemic disease and to evaluate its relationship to clinicovirological factors. METHODS Liver biopsy specimens from 80 children positive for antibody to hepatitis C virus were evaluated using a semiquantitative scoring system. RESULTS Chronic hepatitis was mild in most cases but had high-grade activity in 17 children (21.2%). A significant association was found between the grade of focal necrosis and alanine transaminase levels (P < 0.003). Fibrosis was absent in 22 cases (27.5%), mild in 44 (55%), and moderate in 13 (16.2%). Only 1 patient had cirrhosis. A significant relationship was detected between fibrosis scores and (1) duration of disease (P < 0.03); (2) portal inflammation (P < 0. 002); and (3) interface hepatitis (P < 0.003). CONCLUSIONS In otherwise healthy children, chronic hepatitis C is a morphologically mild disease in most cases. Fibrosis increases with the duration of disease, suggesting that end-stage disease may develop in young adulthood. Alanine transaminase levels correlate with intralobular focal necrosis but not with other lesions. In this respect, liver biopsy retains its importance in the management of chronic hepatitis C in children.

Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period

BACKGROUND/AIMS Chronic hepatitis B virus infection can lead to cirrhosis and hepatocellular carcinoma, particularly in men over 40 years of age and in areas where childhood-onset infection is common. The sequence of events from paediatric infection to severe disease in adults is only partially known. The aim of this study was to evaluate the evolution of chronic hepatitis B acquired in childhood during 20 years of follow-up. PATIENTS One hundred and eighty-five consecutive, otherwise healthy, Caucasian children were enrolled in Padua (Italy) and in Madrid (Spain) between 1975 and 1985, and followed for an average period of 13 years; 168 were hepatitis B e antigen (HBeAg) positive and five had cirrhosis. RESULTS Thirty patients received steroids or levamisole and 21 interferon, but treatment did not significantly influence HBeAg clearance. Overall, two (1.1%) children, with initial cirrhosis, developed hepatocellular carcinoma and the other three (1.6%) cirrhotic patients became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; 14 (7.5%) children maintained HBeAg positive hepatitis; 155 (83.8%) became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; six (3.2%) experienced reactivation of liver disease and viral replication after remission and five (2.7%) maintained biochemical features of liver damage after HBeAg clearance. Only 6% cleared hepatitis B surface antigen. CONCLUSIONS Even considering the bias of treatment, the large majority of Caucasian children with chronic hepatitis B became asymptomatic carriers of infection with normal alanine amino-transferase during the first 20 years of observation. Cirrhosis is an early, rare complication, and a risk factor for hepatocellular carcinoma. A subgroup of patients who experienced reactivation or maintained liver damage after HBeAg clearance seems to be at greater risk for disease progression during adult life.

High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin

BACKGROUND & AIMS Pegylated interferon (PEG-IFN) alfa-2b plus ribavirin (RBV) is the standard of care for adults with chronic hepatitis C but was not approved for the treatment of children at the time of this study. The aim of this study was to evaluate the efficacy and safety of PEG-IFN alfa-2b plus RBV in children. METHODS Children and adolescents ages 3-17 years were treated with PEG-IFN alfa-2b (60microg/m(2)/week) plus RBV (15mg/kg/day). The duration of therapy was 24 weeks for genotype (G) 2 and G3 patients with low viral load (<600,000IU/ml) and 48 weeks for G1, G4, and G3 with high viral load (>or=600,000IU/ml). The primary end point was sustained virologic response (SVR), defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of therapy. RESULTS SVR was attained by 70 (65%) children. Genotype was the main predictor of response: G1, 53%; G2/3, 93%; G4, 80%. SVRs were similar in younger and older children. Baseline viral load was the main predictor of response in the G1 cohort. No new safety signals were identified, and adverse events (AEs) were generally mild or moderate in severity. Dose was modified because of AEs in 25% of children; 1 child discontinued because of an AE (thrombocytopenia). No serious AEs related to study drugs were reported. CONCLUSION Therapy with PEG-IFN alfa-2b plus RBV in children and adolescents with chronic hepatitis C offers favorable efficacy, reduced injection frequency, and an acceptable safety profile.

Posttransfusion and community-acquired hepatitis C in childhood

Following a longitudinal study of chronic non-A, non-B hepatitis in Italy and Spain, we evaluated the epidemiologic and clinical features of chronic hepatitis C in 77 consecutively observed children (35 male; mean age, 4 years) without underlying systemic diseases. All subjects were positive for antibody to hepatitis C virus in serum by second-generation tests. Forty-six patients had received blood transfusions in the perinatal period; 12 had a mother with antibodies to HCV in serum (five of these mothers were drug users or partners of a drug user); seven had a history of putative percutaneous exposure; and 12 had not been exposed to any risk factors for viral hepatitis. At presentation, only 22% were symptomatic, mean alanine-aminotransferase levels were three times the upper normal value, and liver histology showed active disease in only nine of 28 cases (32%). During a mean observation period of 6 years, only 11 of 57 patients (19%) complained of symptoms and 11 of 40 cases (27%) had histologic features of active hepatitis. Two patients had severe hepatitis with associated cirrhosis. However, only six of 57 cases (10%) achieved sustained biochemical remission. The clinical features and the outcome were similar in both the posttransfusion and the community-acquired cases. These results indicate that transfusions in the perinatal period are the single most important cause of hepatitis C in otherwise healthy children. Community-acquired cases represent an heterogeneous epidemiologic group in which maternal transmission, whether perinatal or postnatal, could be relevant. Histologically severe hepatitis and cirrhosis seem to be an infrequent feature of chronic hepatitis C virus infection in childhood and adolescence, in spite of persistent liver damage.

Tacrolimus and steroids versus ciclosporin microemulsion, steroids, and azathioprine in children undergoing liver transplantation: randomised European multicentre trial.

BACKGROUND Results of studies in adult recipients of liver allograft suggest that tacrolimus is more efficacious than ciclosporin microemulsion in the prevention of acute rejection. We aimed to compare these drugs in children undergoing liver transplantation. METHODS This 12-month multicentre, open-label, parallel-group, randomised study compared a dual tacrolimus regimen (tacrolimus/corticosteroids, n=93) with a triple ciclosporin microemulsion regimen (ciclosporin microemulsion/corticosteroids/azathioprine, n=92) in children who had had liver transplants (age < or =16 years, bodyweight < or =40 kg). Initial oral daily doses were 0.30 mg/kg for tacrolimus and 10 mg/kg for ciclosporin microemulsion. Primary endpoint was the incidence of and time to first histologically proven acute rejection. We excluded patients from analysis if they did not receive the study drug, or were given incorrect medication. Otherwise patients were analysed in accordance with their random treatment allocation, irrespective of whether they switched medication during the trial. FINDINGS Median age was 22 months (IQR 9-56) in the tacrolimus group and 17 months (9-54) in the ciclosporin microemulsion group. We noted no difference between treatment groups with respect to patient survival (93.4% vs 92.2%; p=0.77) or graft survival (92.3% vs 85.4%; p=0.16) at month 12 after transplant. The acute rejection free rate at study end (Kaplan-Meier method) was 55.5% for patients on tacrolimus and 40.2% for patients on ciclosporin microemulsion (p=0.0288). The Kaplan-Meier estimate of patients free from corticosteroid-resistant acute rejection at study end was 94.0% for tacrolimus-treated patients and 70.4% for ciclosporin-microemulsion-treated patients (p<0.0001). Overall, incidence of adverse events did not differ between groups. INTERPRETATION Tacrolimus is a safe and effective treatment for the prevention of rejection after liver transplantation in children.

Efficacy and Safety of Peginterferon-α2b and Ribavirin Combination Therapy in Children With Chronic Hepatitis C Infection

Background: Interferon (IFN)-&agr;2b plus ribavirin is approved for treatment of hepatitis C in children; however, little is known about efficacy and tolerability of pegylated IFN (PEG-IFN)-&agr;2b in this population. The objective of this study was to test the efficacy and safety of PEG-IFN-&agr;2b plus ribavirin in children with chronic hepatitis C. Methods: Thirty children 3–16 years of age who had detectable hepatitis C virus (HCV) RNA for ≥3 years after exposure and elevated alanine aminotransferase values received PEG-IFN-&agr;2b 1.0 &mgr;g/kg/wk plus ribavirin 15 mg/kg/d for 24 weeks (genotype 2/3) or 48 weeks (genotype 1/4). The primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<50 IU/mL) at week 24 of follow-up. Results: SVR was achieved in 50% of patients (3/3 genotype 3; 12/27 genotype 1/4). At week 12, 52% of patients were HCV RNA negative and 72% had a >2 log10 decrease in viral load, compared with baseline; 87% and 71% of these patients, respectively, attained an SVR. Therapy was discontinued in 3 patients as a result of adverse events. No patient required ribavirin dose reduction; PEG-IFN-&agr;2b dose was reduced in 23% of patients to manage neutropenia. Conclusions: Combination therapy with PEG-IFN-&agr;2b and ribavirin treatment was effective in children with chronic hepatitis C. Virologic status at week 12 identified future responders and nonresponders. PEG-IFN-&agr;2b and ribavirin were reasonably well tolerated, with no unexpected or permanent adverse effects. Further studies are needed to identify the optimum treatment regimen for this patient population.

Fibrosis in chronic hepatitis C acquired in infancy: is it only a matter of time?

Abstract Objective The natural history of chronic hepatitis C acquired in infancy is not well understood. The progression of fibrosis was analyzed in untreated children with chronic hepatitis C virus infection and no other hepatotoxic cofactors. Methods A total of 112 pediatric patients (13 with paired liver biopsies) were considered. Fibrosis was assessed by METAVIR score (i.e., stage F1 to F4). The ratio between the stage of fibrosis (METAVIR units) and the presumed duration of infection represented the “estimated” rate of fibrosis progression per year. In patients with paired biopsies, the “observed” rate of fibrosis progression was defined as the difference between the stage of fibrosis in the two biopsies divided by the time interval between them. Results Both age of patients at biopsy and duration of infection correlated with stage of fibrosis (p Conclusions Chronic hepatitis C acquired in childhood is a progressive, slow-moving, fibrotic disease. Fibrosis progression inferred on the basis of linear mathematical models should be critically evaluated in the clinical practice.

Recurrence of Bile Salt Export Pump Deficiency after Liver Transplantation

Severe bile salt export pump (BSEP) deficiency is a hereditary cholestatic condition that starts in infancy and leads to end-stage liver disease. Three children who underwent orthotopic liver transplantation for severe BSEP deficiency had post-transplantation episodes of cholestatic dysfunction that mimicked the original disease. Remission of all episodes was achieved by intensifying the immunosuppressive regimen. The phenotypic recurrence of the disease correlated with the presence of circulating high-titer antibodies against BSEP that inhibit transport by BSEP in vitro. When administered to rats, these antibodies targeted the bile canaliculi and impaired bile acid secretion.

Interferon-α treatment of chronic hepatitis B in childhood : A consensus advice based on experience in European children

BACKGROUND The efficacy of interferon (IFN) in children with chronic hepatitis B has been evaluated in randomized controlled trials over the past decade, but recommendations for treatment based on this experience have not been published yet. The purpose of this workshop, held in Madrid in October 1997, was to provide pediatricians with guidelines for practical use of IFN in hepatitis B. METHODS Eighteen European pediatricians and hepatologists agreed to report and discuss their experience on 1,122 treated children, 40% of whom were considered responders. RESULTS Agreement was obtained on the following main items: 1) rationale for treatment is to accelerate hepatitis B early antigen (HBeAg) clearance in a subgroup of patients; 2) candidates for treatment are children with HBeAg and HBV DNA positivity, with low-intermediate HBV DNA levels and abnormal alanine aminotransferase values, aged 2 years or more; 3) IFN is contraindicated in children with decompensated liver disease, cytopenia, severe renal or cardiac disorders, and autoimmune disease; 4) the standard treatment regimen is 5 mU/m2 thrice weekly for 6 months. Retreatment in nonresponders is not indicated. CONCLUSIONS A consensus was obtained on the use of IFN in children with hepatitis B, based on its short-term efficacy. The long-term clinical and virological effects of the drug, however, remain to be evaluated.