Significant fibrosis was noted in five children at the initial biopsy at a mean duration of 8 years of infection. Worsening of fibrosis was noted in 13 children in whom there was no correlation with the mode of acquisition of HCV infection, demographic, clinical, or laboratory variables such as ALT or presence

of autoimmune antibodies. To our knowledge, this is the largest series of treatment-naïve pediatric patients who have been evaluated for histologic progression of CHC liver disease based on repeat liver biopsies. This study provides a unique opportunity to explore the natural history Cell Cycle inhibitor of pediatric HCV infection in an untreated pediatric population in a longitudinal manner. There are only a few reports involving repeat liver biopsies in untreated children with CHC.[6, 24-26] The prognostic factors in predicting liver disease progression have been variable in these studies; JAK2 inhibitors clinical trials in some of the adult series serum ALT, duration of infection,

viral load, and steatosis have been associated with fibrosis progression.[13-20] In one of the pediatric studies involving repeat biopsies, Guido et al.[24] identified 13 children who had paired liver biopsies from a retrospective multicenter study comprising of 112 children with chronic CHC. The main finding from this study was that age at biopsy and the duration of infection correlated with the stage of fibrosis.[24] In a study spanning 35 years involving 31 adults who were infected with HCV from mini-transfusions in infancy, Casiraghi et al.[2]

reported five patients who had a repeat liver biopsy after 5 years; only one patient showed an increase in fibrosis by one stage. Key pediatric studies involving single liver biopsies in the evaluation of the natural history of untreated CHC have also shown conflicting results.[1-7, 25] In a retrospective study of 40 children with CHC, Badizadegan et al.[5] found varying degrees of portal fibrosis in 78% of pediatric patients including cirrhosis in 8% at a mean age of 11 years. In contrast, large PLEK2 long-term follow-up studies of transfusion-acquired HCV infection early in life indicate a relatively benign course over a 20 to 35-year interval with fibrosis progression in only a few subjects.[1, 2] Perinatal transmission has been implicated as a factor leading to a more aggressive course for CHC-related liver disease including hepatocellular carcinoma in case reports and a few series.[6, 7, 26] Our data showed that mode of transmission was not a predictive factor for progression. One of the limitations of this study is the sampling variability inevitable in a retrospective study and the relatively small number of subjects. Liver biopsy sizes were excellent, with 11 portal tracts only in 40/97 biopsies.[22] They were adequate, although possibly suboptimal, containing six portal tracts in 43/97 biopsies.