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Hepatitis C: Current approaches in pediatrics
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Carolina Rumbo
Division of Pediatric Hepatology and Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY, USA
Pediatric Transplantation
Volume 9 Issue 5 Page 662 - October 2005
"....HCV in pediatric patients is in general terms a slow progressive disease, but a number of patients have a more aggressive course leading to early cirrhosis. Therefore, children with chronic HCV need to have early evaluation, consistent follow-up and despite repeated normal or mildly abnormal transaminases, it is advisable to obtain baseline liver histology with potential follow-up biopsies in 5-10 yr to tailor timing for treatment... The aim of... treatment is to clear HCV RNA, thus to improve liver histology avoiding progression to cirrhosis, to reduce transmission to other individuals and other potential complications such as hepatocellular carcinoma and need for liver transplantation, as well as eliminating social stigmata related to this chronic disease...."
Abstract: Chronic hepatitis C virus is one of the leading causes of liver diseases in adults and it is the most common cause of liver transplantation in the USA. Hepatitis C infection in children is less frequent; there is less information about its clinical course. Compared with adults, there are differences in its mode of acquisition, natural history, complications and even available treatments. The aim of this paper is to give an overview of chronic hepatitis C in children.
Chronic hepatitis C is one of the leading causes of liver disease in adults and it is the most common cause of liver transplantation in the USA. Hepatitis C infection in children is less frequent. Compared with adults there are differences about its mode of acquisition, natural history, complications, and even available treatment. One of the main problems regarding HCV in pediatric patients is that it affects a reduced number of individuals and so the literature is scarce. The majority of studies performed in this population are retrospective; therefore, facts about natural course of the disease, rate of transmission and viral clearance are biased. The aim of this paper is to give an overview of mode of acquisition, natural history, and treatment for chronic hepatitis C in children.
Prevalence and modes of transmission
The prevalence of HCV infection in the general population in the USA is 1.8%; in children, the seroprevalence varies according to age, being 0.2% for those <12 yr and 0.4% for those 12-19 yr of age (1).
The main mode of transmission in children has changed overtime. Before 1990, when HCV had not been identified and there were no diagnostic tests, transfusion of blood and blood products (such as intravenous immune globulin, factor IX concentrates and anti-hemophilic factor) was the usual mode of acquisition. Currently, perinatal transmission accounts for the majority of the cases. Household transmission is a third mode that deserves mention. The route of infection in this case is not clear; a potential explanation is sharing utensils that might contain small amount of blood such as razors or tooth-brushes (2, 3) although there is not strong evidence in the literature to prove this.
The rate of transmission in perinatally acquired hepatitis C ranges from 2 to 5% (4). The presence of large amount of maternal blood in the birth canal as in cases of lacerations as well as high maternal viremia at time of birth increase the risk of HCV transmission (5). There is very little information regarding the risks of HCV vertical transmission during invasive procedures such as amniocentesis, periumbilical blood sampling or invasive fetal monitoring (6, 7). A well-described factor that increases significantly the rate of HCV transmission is maternal-HIV coinfection (8); in coinfected patients the rate of transmission increases by two to threefold, rising the average rate up to 15%. On the contrary, HCV genotype and disease activity have not been associated with a higher rate of mother to infant transmission (9, 10-12). Cesarean section is only indicated in HIV-HCV coinfected women (13).
Diagnosis
Virological diagnosis and monitoring of HCV infection are based on indirect and direct tests (14). The indirect tests are serologic assays detecting HCV antibodies. Direct tests detect or quantify viral particles, such as HCV RNA. The initial screening for hepatitis C is carried out by indirect tests, and the confirmation is usually performed by RNA PCR testing. The HCV genotype is an intrinsic characteristic of the HCV strain and it does not change during the course of the infection. There are six major genotypes (1-6); close to 70% of the USA population is genotype 1. Response to treatment varies according to the genotype.
In terms of testing for HCV in the newborn period and first year of life, there is controversy. There is no established timing for testing or standardized definitions. Criteria for a high suspicion of mother to infant transmission of HCV that would prompt further investigations include (4): (i) detectable HCV antibodies beyond 18 months of age; (ii) detection of HCV RNA in an infant older than 3 months; (iii) finding elevated transaminases on the child. It has been suggested to consider HCV infected only those infants with at least two separate HCV-RNA positive tests at least 3-4 months apart (15). Spontaneous viral clearance during the first 1-2 yr of life has been well documented (15, 16). In a very comprehensive long-term prospective study, Ceci et al. (15) demonstrate the presence of a very high HCV rate of transmission to the newborn (50%), but also a very high viral clearance leaving no memory in the immune system. This study was carried out on 60 babies born to HCV viremic mothers. The babies were tested at fixed times (birth 12, 18, and 24 months) with HCV RNA PCR and HCV antibodies. Thirty-seven percent of the babies had one time positive PCR and negative antibodies, 13% had two positive PCR tests but negative HCV antibodies and only 3.3% of the patients were persistently positive by PCR and had HCV antibodies at the end of follow-up. They have hypothesized that the higher rate of vertical transmission as well as viral clearance in this study may depend on the timing of RNA testing.
Natural history
Children with HCV typically have an indolent infection with mild or even no transaminases elevation. The patients very often are asymptomatic or have non-specific constitutional complaints such as easy fatigability and anorexia.
In general, it has been surmise that HCV in children has a less aggressive course with a low rate of fibrosis formation compared with adults infected for the same length of time. There are few studies with long-term follow-up on pediatric patients with chronic HCV that support this information. Casiraghi et al. (17) did a study on 16 patients that contracted HCV during the neonatal period and were evaluated 31 yr later adding a prospective follow-up period of 5 yr. In this group of patients, 87.5% had normal or slightly abnormal transaminases, 68.8% of the patients (n = 11/16) underwent liver biopsy; the mean Ishak score was on those 1.4 for fibrosis staging. In addition, Guido et al. (18) have analyzed liver histology in a multicenter retrospective study on 112 children with chronic HCV. The major finding of this work is a low rate of fibrosis progression in children; only 0.8% (n = 1/112) of those patients had cirrhosis and 4% severe fibrosis. A European multicenter study (19) published in 2003 describes characteristics and clinical course of 224 pediatric patients with chronic HCV with a mean follow-up of 6.2 yr. The results on this study show that only 2% of children with chronic HCV infection are likely to develop cirrhosis; however, higher rates of fibrosis were observed in adolescents compared with young children. According to these findings, an insidious progression of disease is to be expected. The reduced frequency of co-morbid factors such as alcohol consumption, hemochromatosis, and non-alcoholic fatty liver disease in children when compared with adults, may account in part for the milder course of HCV disease in the pediatric population.
Despite the consensus on slow progression of HCV in children there have been cases reported in the literature as well as at least one study (20-22) that describe opposite data. Badizadegan et al. (21) report 8% of cirrhotic patients in a group of 40 children with chronic HCV with a mean age of 11.4 yr. What is more, Birnbaum et al. (20) presented three children with perinatally acquired HCV presenting at an early age (4, 6, and 11 yr) with decompensated cirrhosis requiring liver transplantation.
In conclusion, HCV in pediatric patients is in general terms a slow progressive disease, but a number of patients have a more aggressive course leading to early cirrhosis. Therefore, children with chronic HCV need to have early evaluation, consistent follow-up and despite repeated normal or mildly abnormal transaminases, it is advisable to obtain baseline liver histology with potential follow-up biopsies in 5-10 yr to tailor timing for treatment.
Treatment
The only FDA approved treatment for HCV in pediatric patients (3-18 yr) consists of subcutaneous interferon alfa-2B administered three times a week in combination with oral ribavirin (liquid form or tablets) every 12 h. Duration of treatment is based on viral genotype, being 24 wk for genotypes 2 and 3 and a total of 48 wk for genotype 1. The aim of this treatment is to clear HCV RNA, thus to improve liver histology avoiding progression to cirrhosis, to reduce transmission to other individuals and other potential complications such as hepatocellular carcinoma and need for liver transplantation, as well as eliminating social stigmata related to this chronic disease. This combination therapy has proven to have a higher viral clearance than interferon monotherapy previously used (23, 24). Tolerance to combined interferon ribavirin has been similar to monotherapy.
There are not many studies regarding the use of combination therapy and rate of viral clearance in children. The rate of response reported so far is similar or even higher in children than in adults when using the same regimen (25-27). Wirth et al. reported sustained viral response of 61% and only one of 41 patients discontinued treatment secondary to side effects. Similarly, Figlerowicz et al. (28) found a sustained viral response of 50% in a group of 30 patients aged 5-18 yr. Finally, Gonzalez-Peralta et al. (29) documented undetectable HCV RNA 24 wk after finishing treatment in 34 of 70 patients (49%) in an international multicenter trial. The side effects described in those studies are: pseudoinfluenza, lack of appetite with no significant weight loss, anemia, and leukopenia. In a smaller proportion also, hair loss and development of thyroid autoantibodies that required thyroid hormone supplementation until treatment was finalized. All described side effects resolved at the end of the treatment.
ED NOTE from Jules Levin: several preliminary studies with peginterferon in children have been conducting finding good results. More studies should be conducted to gain FDA approval & so authors like this will support it's use in children.
Pegylated interferon was developed to achieve a sustained plasma concentration; its molecular structure gives a steady concentration in plasma for a prolonged period, allowing the administration of the drug once a week. In the same way, the avoidance of drug level fluctuations seems to achieve a higher rate of response compared with interferon alfa-2B in adult patients. Those advantages make this drug very attractive to the pediatric population. Currently, this preparation is approved by FDA for patients 18 yr of age or older. Up-to-date there is few data on the use of pegylated interferon in patients younger than 18 yr (30, 31). Until more data in terms of dosing and side effects profile is available, younger patients should be treated with pegylated interferon in the context of clinical trials.
When considering treatment for chronic hepatitis C in children one should take into account viral genotype, age of the patient, and stage of fibrosis in liver tissue. Treatment benefits need to balance against possible side effects and the rate of response with the available treatment. The use of pegylated interferon and other future developments may improve outcome.
Conclusions
Chronic hepatitis C in pediatrics affects a reduced number of patients when compared with adults; therefore, the literature is scarce.
At present, the primary mode of acquisition of new pediatric infections is perinatal. So far, there is no treatment available to be administered to pregnant women in order to decrease rate of transmission. In the same way, there is no medication to decrease transmission or increase viral clearance in the newborn. Until those factors or interventions are identified, the preemptive strategy would be to treat adolescents or young adults before family planning, taking into account in the timing of this equation the potential teratogenic and embryocidal effects of interferon and ribavirin.
Although there are no standards defined to test for HCV during the first 2 yr of life, a good approach to consider an infant as infected would be to have a positive HCV PCR in two different opportunities at least 3 months apart, starting with the first measurement at 12-15 months of age. However, if the infant is to be put up for adoption, testing for viral RNA should begin at a younger age as only repeatdly negative HCV RNA tests can assure the HCV negative state of the infant.
Hepatitis C, generally, is a slow progressive disease in the first two decades of life. Nevertheless, attention and continued evaluation should be given to infected pediatric patients in order to identify early in the disease course those cases with accelerated progression.
Currently, the only FDA approved treatment for HCV in pediatrics is the combination of interferon alfa-2B and ribavirin. Pegylated interferon and ribavirin have been used in children in pilot studies and may show improved rates of response. Before pegylated interferon is approved for children, it needs to be tested in larger number of patients to define the appropriate dosing and long-term safety profile.
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