Population pharmacokinetics of peginterferon alfa-2b in pediatric patients with chronic hepatitis C.

PURPOSE: The aim of this study was to characterize the population pharmacokinetics of peginterferon (PEG-IFN) alfa-2b in pediatric patients with chronic hepatitis C and to identify covariates influencing PEG-IFN alfa-2b disposition. METHODS: Pharmacokinetic data from a multicenter open-label study of subcutaneously administered peginterferon alfa-2b (60 µg/m(2)/wk) plus oral ribavirin (15 mg/kg/day) in patients with chronic hepatitis C aged 3-17 years old was used to develop a population pharmacokinetic nonlinear mixed-effects model. RESULTS: The final population pharmacokinetic analysis was conducted with the pooled data from 107 pediatric patients. A one-compartment model with first-order absorption, first-order elimination, exponential inter-individual variability on clearance, and a combination additive and proportional residual error model adequately described the PEG-IFN alfa-2b pharmacokinetic profile. Age (apparent clearance and apparent volume of distribution) and sex (apparent clearance) were significant covariates. The mean body surface area normalized apparent clearance of PEG-IFN alfa-2b was 0.56 L/h/m(2), and was similar when evaluated across the pediatric age groups. CONCLUSION: The final population model suggests age-dependent increases in clearance and volume of distribution of PEG-IFN alfa-2b in pediatric patients with chronic hepatitis C. The apparent clearance normalized to body surface area was similar across pediatric age groups, supporting the use of body size-adjusted dosing in pediatric subjects.

Liver infiltrating mononuclear cells in children with type 1 autoimmune hepatitis.

OBJECTIVE: To investigate infiltrating cells in the liver of children with type 1 autoimmune hepatitis (AH-1). METHODS: liver biopsies from 24 untreated AH-1 patients (14 children, 10 adults), five patients with hepatitis C virus related chronic hepatitis (HCV), and 10 control liver specimens (CL) were processed for immunohistochemical cell characterisation. RESULTS: Two different cell distribution patterns were detected in the liver of patients with AH-1: (1) CD4(+) and CD20(+) cells were found in the central areas of the portal tracts (portal distribution); (2) CD8(+) cells were observed at the periphery of the portal space (periportal distribution). Some cell subsets, like CD56, CD57, Fas-L, and Bak, showed a non-defined distribution pattern. The presence of two well defined patterns of cell distribution was not observed in HCV and CL (CD4(+), CD20(+), and CD8(+) cells were uniformly distributed in the portal space). In AH-1 and CL, the NK markers CD56 and CD57 were found scattered throughout the liver parenchyma. However, in HCV biopsies, CD56(+) cells were also clearly increased in both the portal and the periportal areas. Biopsies of AH-1 and HCV patients showed a uniform distribution of Fas-L and Bak in the portal and periportal areas, with Bak staining also detected in the hepatic parenchyma. CONCLUSIONS: Despite clinical and genetic differences, there was a similar distribution of liver infiltrating mononuclear cells in children and adults with AH-1. These results raise the possibility of reclassifying cryptogenic chronic hepatitis by immunohistochemical analysis of infiltrating liver cells.

Chronic active autoimmune hepatitis in children. Strong association with a particular HLA-DR6 (DRB1*1301) haplotype.

The association of HLA antigens and type I or "lupoid" CAH-C was investigated in a population of 52 Argentinian Caucasoid patients. When compared with a population of normal individuals of the same ethnic group (n = 197), a significant increase of HLA-DR6 was observed (68.6% in patients vs 17.3% in controls; RR = 12.3, chi 2 = 52.4, pc = 0.00001). DNA typing showed that the HLA-DRB1*1301 allele was present in 32 out of 33 HLA-DR6 patients (66.6% of all the C-CAH patients vs 10.5% in controls; RR = 16.2, chi 2 = 111.3, pc = 0.00001). Analysis of HLA-DQB1 alleles also showed a significant increase of DQB1*0603 (RR = 15.4, chi 2 = 106.5, pc = 0.00001), an allele found in strong linkage disequilibrium with DRB1*1301. The association of CAH-C with this particular HLA-DR6 haplotype has not been previously described for the adult onset CAH. This different HLA predisposition, together with the fact that extrahepatic autoimmune diseases occur frequently only in the adult form of the disease, suggest that the immunopathogenic mechanisms involved in the development of these diseases may be different.

[Genotype characterization of hepatitis C virus infection in children]. / Caracterización genotipica de la infección por el virus de hepatitis C en niños.

Hepatitis C virus (HCV) infection in children was assessed by RT-nested PCR of the 5'untranslated region (5'UTR) of the viral genome combined with virus genotyping, performed by restriction fragment length polymorphism (RFLP). We analysed HCV infection in 64 children and in 9 HCV chronically infected mothers corresponding to 10 of them. Thirty two children were positive for serum HCV RNA as determined by RT-nested PCR. The viremia was analysed in consecutive samples of 25 children. Nine children (36%) were always positive for HCV RNA, in 5 (20%) a positive RT-nested PCR turned negative in subsequent samples, other 9 (36%) showed alternating RT-nested PCR results and in 2 (8%) the RT-nested PCR turned positive after an initial negative result. The HCV genotype distribution was studied in 27/32 children and in 9 mothers, and it was similar to that reported in the literature for adult and pediatric patients in our country. Genotype 1 was predominant in our population. HCV genotype did not change in the same patient during the time of this study. HCV genotype was the same in mother-infant pairs. We could not establish a correlation between HCV genotype and vertical transmission of HCV. This study will be helpful to further analyze HCV behavior during pediatric infection and the host's response in the initial stages of it.

Genomic and phylogenetic analysis of hepatitis C virus strains from Argentina.

HCV genomic characterization was performed by nucleotide sequence analysis (n=50) combined with restriction fragment length polymorphism (RFLP) of the 5' UTR region in 82 isolates corresponding to different Argentine groups. Genotype 1 was detected in 70.7% of the samples (58 out of 82), genotype 2 in 21.9% (18 of 82) and genotype 3 in the remaining 6 sera (7.3%). HCV 1b subtype contributed with 35.3% to the whole population studied (29 to 82) and was detected in 6 out of 21 sporadic cases. Besides their epidemiological significance, these results should be taken into account when future vaccines are considered on the basis of geographical HCV genotypic prevalence.

A patient with Simpson-Golabi-Behmel syndrome and hepatocellular carcinoma.

Simpson-Golabi-Behmel syndrome (SGBS) is an X linked disorder characterised by pre- and postnatal overgrowth, coarse facial features, and visceral and skeletal abnormalities. Like other overgrowth syndromes, in the SGBS there is an increased risk for developing neoplasia, mainly embryonic, such as Wilms tumour. We report a 3 year old male patient with SGBS and hepatocellular carcinoma, a previously undescribed tumour associated with the syndrome.

Distribution of hepatitis B virus genotypes in two different pediatric populations from Argentina.

Differences in pathogenesis and the probability of becoming a chronic carrier depend on the age at which hepatitis B virus (HBV) infection is acquired, ranging from 82% in infants less than 6 months of age to 15 to 30% in older children. HBV genotypes from 22 pediatric patients from two areas that differ in prevalence have been determined. Phylogenetic analysis shows a clear difference between the genotype distribution in Buenos Aires, a low-prevalence area, and that found in Gualeguay, Entre Ríos, a high-prevalence area. While the analysis allocated the sequences in the Buenos Aires group to genotypes A (36%), D (9%), and F (55%), the Gualeguay group presented exclusively genotype A isolates with very low nucleotide divergence, which suggests a strong founder viral population. The high prevalence of genotype F in the Buenos Aires group and its high intragroup heterogeneity agree with the American origin of this genotype.

Caracterización genotipica de la infección por el virus de hepatitis C en niños. / [Genotype characterization of hepatitis C virus infection in children]

Hepatitis C virus (HCV) infection in children was assessed by RT-nested PCR of the 5untranslated region (5UTR) of the viral genome combined with virus genotyping, performed by restriction fragment length polymorphism (RFLP). We analysed HCV infection in 64 children and in 9 HCV chronically infected mothers corresponding to 10 of them. Thirty two children were positive for serum HCV RNA as determined by RT-nested PCR. The viremia was analysed in consecutive samples of 25 children. Nine children (36

) were always positive for HCV RNA, in 5 (20

) a positive RT-nested PCR turned negative in subsequent samples, other 9 (36

) showed alternating RT-nested PCR results and in 2 (8

) the RT-nested PCR turned positive after an initial negative result. The HCV genotype distribution was studied in 27/32 children and in 9 mothers, and it was similar to that reported in the literature for adult and pediatric patients in our country. Genotype 1 was predominant in our population. HCV genotype did not change in the same patient during the time of this study. HCV genotype was the same in mother-infant pairs. We could not establish a correlation between HCV genotype and vertical transmission of HCV. This study will be helpful to further analyze HCV behavior during pediatric infection and the hosts response in the initial stages of it.

Indicaciones y resultados del trasplante hepático con donante vivo relacionado en el tratamiento de la insuficiencia hepática aguda / Indications and results of hepatic transplatation using living-related donor in the treatment of acute hepatic insufficiency

La técnica de trasplante hepático(TH)con donante vivo relacionado(DVR)es un recurso valioso para resolver la escacez de donantes y la aplicabilidad del TH en niños con insuficiencia hepática aguda(IHA)Se analizan las indicaciones y resultados del TH con DVR en niñops con IHA y hepatopatía crónica severa(HCS)Entre junio de 1995 y Junio de 1998 se realizaron en nuestro centro 107 TH en 104 pacientes(77 adultos y 27 niños)De los 27 pacientes pediátricos 13(48 por ciento)fueron transplantados con DVR.La edad media fue de 38 meses con un rango de 7 meses a 9 años.De los 13 pacientes transplantados con DVR,4 presentaron complicaciones postrasplante:trombosis arterial que requirió postrsplante en un caso,fístula biliar y absceso abdominal que requirió reexploración en otro y estenosis de la anstomosis billiar tratados con dilatación percutánea en dos casos.Dos pacientes fallecieron,uno de ellos a los 18 meses del trasplante.La curva de sobrevida actuarial al año de todos los niños trasplantados con DVR(Kaplan-Meier) fue de 90 por ciento u para los 14 con DC fue del 88 por ciento

Indicaciones y resultados del trasplante hepático con donante vivo relacionado en el tratamiento de la insuficiencia hepática aguda / Indications and results of hepatic transplatation using living-related donor in the treatment of acute hepatic insufficiency

La técnica de trasplante hepático(TH)con donante vivo relacionado(DVR)es un recurso valioso para resolver la escacez de donantes y la aplicabilidad del TH en niños con insuficiencia hepática aguda(IHA)Se analizan las indicaciones y resultados del TH con DVR en niñops con IHA y hepatopatía crónica severa(HCS)Entre junio de 1995 y Junio de 1998 se realizaron en nuestro centro 107 TH en 104 pacientes(77 adultos y 27 niños)De los 27 pacientes pediátricos 13(48 por ciento)fueron transplantados con DVR.La edad media fue de 38 meses con un rango de 7 meses a 9 años.De los 13 pacientes transplantados con DVR,4 presentaron complicaciones postrasplante:trombosis arterial que requirió postrsplante en un caso,fístula biliar y absceso abdominal que requirió reexploración en otro y estenosis de la anstomosis billiar tratados con dilatación percutánea en dos casos.Dos pacientes fallecieron,uno de ellos a los 18 meses del trasplante.La curva de sobrevida actuarial al año de todos los niños trasplantados con DVR(Kaplan-Meier) fue de 90 por ciento u para los 14 con DC fue del 88 por ciento