Chronic hepatitis C is usually a mild disease in children; however, the evolution of children co-infected with HIV is unknown. We report the liver biopsy results of seven adolescents co-infected for over 13 years. According to the Metavir scoring system, liver specimens were classified A1–F1 in three patients and A2–F1 in four. Mild fibrosis progression is mainly explained by young age at hepatitis C virus contamination and the lack of severe immunodeficiency in the study population.
In children, both low alanine aminotransferase (ALT) levels and viral load as well as mild histological changes characterize chronic hepatitis C [1–3]. Slow fibrosis progression can be partly attributed to young age at contamination leading to a possible degree of immune tolerance to hepatitis C virus (HCV) and a lack of alcohol consumption. However, fibrosis appears to progress with age, and the progression of chronic hepatitis C appears to be influenced by other factors such as immunodeficiency or drug-induced hepatotoxicity. Increases of piecemeal necrosis, lobular inflammation and fibrosis were found in HIV-positive/HCV-positive-co-infected adults when compared with HCV-positive/HIV-negative patients. Whether co-infected paediatric patients share this evolution is unknown. We describe in this report histological changes in seven teenagers who underwent liver biopsy for HIV- positive/HCV-positive co-infection lasting for a median of 16 years.
Among 10 HIV-positive/HCV-positive-co-infected adolescents followed in two centres, seven consented to liver biopsy. Co-infection was related to neonatal transfusion (three cases), maternal–infant transmission (two cases) or clotting factor-replacement therapy in two children with haemophilia. Six patients had been receiving antiretroviral treatment for 9–14 years. None of the patients was hepatitis B serum antigen-positive or had experienced significant alterations in liver function tests related to antiretroviral drug toxicity. At the time of histological evaluation, three children had dual nucleoside analogue treatment and three received triple or quadruple drug combination therapy. All the patients had CD4 cell counts higher than 200 × 106/l and only one had a history of transient severe immunosuppression. HIV RNA (Amplicor HIV monitor; Roche Diagnosic Systems, Meylan, France) was undetectable for one patient and ranged from 3.5 to 4.74 log copies/ml for the six patients with detectable viral loads. Liver biopsy specimens were fixed in 10% formalin buffer and stained with haematoxylin-eosin, Gordon–Sweet for reticulin network, Masson trichrome for collagen and Perl's method for iron. All of the histological examinations were reviewed by a single pathologist (D.C.). Liver inflammation and fibrosis were assessed by the Metavir scoring system. The grading of activity was indicated as follow: A0, no histological activity; A1, mild activity; A2, moderate activity; and A3, severe activity. Liver fibrosis was staged on a scale of 0 to 4: F0, no fibrosis; F1, portal fibrosis without septa; F2, few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis.
None of the seven patients developed symptoms such as jaundice, ascites, bleeding or liver failure. Ultrasound examination of the liver showed normal findings in all patients. The ALT values, regularly assessed during the period ranging from 9 to 17 years were only moderately elevated. HCV virus genotypes (INNO-LIPA HCVII) 1a, 1b and 4 were found in four, two and one patient, respectively. HCV-RNA levels (Amplicor HCV monitor; Roche Diagnostic Systems) ranged from 5.5 to 5.9 log copies/ml. The results of liver biopsy interpretations and patient characteristics are given in Table 1. Fibrosis was always restricted to the portal tracts and no bridging fibrosis was found. Portal mononuclear inflammation was mild (sprinkling of inflammatory cells in less than a third of the portal tracts) in four cases and moderate (one-third to two-thirds of portal tracts) in three. Lymphocyte infiltration of the lobules was most often moderate or marked. Focal necrosis was present and mild in all specimens. As piecemeal necrosis was always mild, the Metavir activity index was A1 or A2. Minimal steatosis was found in three cases. Iron staining was negative in all cases.
Liver histological data concerning co-infected children have not previously been reported in the literature. In our series, as is usually noted in HCV mono-infected children, patients had only mildly elevated ALT levels and a mild degree of fibrosis. Young age at HCV infection is associated with low rates of cirrhosis . In our report, five children were infected during the first month of life, and for the two haemophiliac patients the estimated age at HCV contamination was 4 years. Nonetheless, the risk of liver fibrosis progression after HCV mono-infection in childhood is currently not well known . It was reported as mild or moderate in two large paediatric studies after a mean duration of infection of 4 years. Kage et al.  found only a 3.6% prevalence of bridging fibrosis with architectural distortion in 109 Japanese children. Guido et al.  reported 80 children with only one case of cirrhosis and absent or mild fibrosis in more than 80% of cases. A long-term study of patients who were infected by transfusion during cardiac surgery in infancy or childhood was very reassuring . On the contrary, Badizadegan et al.  reported more severe fibrosis progression in 40 children with chronic hepatitis C infection, with a mean duration of infection of 6.8 years; bridging fibrosis with or without architectural distortion was found in 44% of cases and cirrhosis was found in 8% of cases . Such disparity in the severity of histological features could be explained by host factors, such as the underlying disease for which the transfusion was given. In several paediatric studies an association between the extent of fibrosis and the duration of infection was noted . In our report, despite the long duration of HCV infection and HIV co-infection the degree of fibrosis was not significant. The lack of a negative impact of HIV co-infection on fibrosis progression was probably explained by the quiet mild course of HIV infection in the seven adolescents reported. Their CD4 cell counts ranged from 275 to 1100 cells/mm3. Numerous studies described the aggravating role of HIV co-infection in HCV-positive adult patients [6–8], but accelerated fibrosis progression and cirrhosis were clearly associated with CD4 lymphocyte depletion of less than 200 cells/μl rather than with HIV infection per se.
In our study, intralobular inflammation seemed more marked than has been reported in children and adolescents infected with HCV alone. HIV co-infection may explain this higher grade of intralobular activity; this feature being a frequent finding in co-infected adults with or without severe immunodeficiency [7,8].
The life expectancy of children with HIV infection has dramatically increased with highly active antiretroviral therapy, and HCV co-infection may become at adult age a leading cause of morbidity. The main finding of our small paediatric study is that despite co-infection with HIV and a long duration of HCV infection, fibrosis remained mild in all seven patients investigated.
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