Maureen M. Jonas, MD

NIH Consensus Development Conference on
Management of Hepatitis C: 2002 

Bethesda, Maryland
June 10-12, 2002

Less is known about HCV infection in children compared to infection in adults, due to the small proportion of HCV-infected individuals that are children and the lack of manifestations of this infection during childhood. Nonetheless, most HCV-infected children develop chronic hepatitis, and, although rare, cirrhosis and end-stage liver disease have been described. There are differences in modes of acquisition, natural history, complications, and treatment between pediatric and adult HCV infection.

The seroprevalence of anti-HCV is 0.2 percent in children less than 12 years of age, and 0.4 percent in those 12 to 19 years of age. Using these figures, it can be estimated that there are somewhere around 240,000 exposed or infected children in this country. Although there has been a significant decrease in the incidence of new HCV infections in adults, new infections continue to occur in children via perinatal transmission. Because receipt of blood or blood products prior to 1992 was an important mode of transmission of HCV to children, there is a cohort of adolescents who have had HCV for 10–20 years. Perinatal transmission provides a cohort of infected children from newborns through the teenage years. Horizontal transmission, from adult to child in the household, or child-to-child at home or at school, does not seem to be an important factor in the epidemiology. The prevalence of HCV infection in children not currently explained by risk factors, i.e., sporadic or community-acquired HCV, is felt to be low. Many children infected with HCV are yet to be identified.

Acute HCV infection is rarely recognized in children, outside of special circumstances like a transfusion-associated outbreak. Fulminant hepatitis due to HCV has not been described in children. Chronically infected children are asymptomatic or have non-specific fatigue and/or abdominal pain, with normal or mildly abnormal ALT levels. Clinically apparent autoimmune manifestations are rare. Independent effects of age at acquisition and mode of acquisition on natural history are difficult to separate in pediatric studies. In addition, the natural history of transfusion-associated HCV infection may differ according to the underlying disease for which transfusion is required.

Some children who were transfused at the time of surgery for congenital heart disease developed chronic hepatitis, but others cleared the infection. Secondary hemochromatosis may contribute to the hepatic injury in children with thalassemia, and may mitigate the response to therapy in this group. Children treated for leukemia prior to 1990 have a very high rate of HCV infection, but in one cohort prolonged followup (13–27 years) did not commonly reveal serious liver disease. In contrast, an American study of individuals treated for childhood cancer revealed one death from liver disease and two deaths due to hepatocellular carcinoma in the decades following HCV acquisition. The same report described 3 (9 percent) cases of cirrhosis 9–27 years after diagnosis of the primary malignancy. Clearly, some cases of HCV infection acquired in childhood by transfusion are associated with serious liver disease in the decades following infection.

Whether the natural history of infection acquired perinatally is different from HCV acquired by transfusion is not yet clear. Vertically infected infants typically have elevated  alanine aminotransferase (ALT) levels for a few years, and those levels often become normal. Virtually all children who undergo liver biopsy have histologic chronic hepatitis. Thus it appears that HCV infection acquired vertically is frequently associated with biochemical evidence of hepatic injury early in life, persists in the majority, but not all, instances, and causes only mild liver disease in the first decades. However, in some children the infection takes an aggressive course leading to cirrhosis and even end-stage liver disease during childhood; the factors responsible for this are as yet unidentified.

There are no reports of treatment of acute HCV infection in children; acute infection is rarely recognized. In addition, no large, multicenter, randomized, controlled therapeutic trials have been performed in children with chronic HCV infection. Studies of treatment in children are most often uncontrolled, include small numbers of patients, and sometimes include only select patient groups, such as hemophiliacs or individuals with thalassemia. Details of the interferon monotherapy trials in children with chronic HCV infection were recently reviewed: even though the studies included several types of patients and used different dosages, schedules, and types of interferon, in general the sustained virologic response (SVR) rate was remarkably similar in most studies, ranging from 33–45 percent. This is significantly higher than the SVR rates reported in large trials of interferon monotherapy in adult patients.

An analysis of these heterogeneous studies that included 11 manuscripts and 3 abstracts (in total included 270 treated children and 37 control subjects) describes a SVR rate of 35 percent, 26 percent for genotype 1 and 70 percent for others. This higher response rate in children could be related to factors such as earlier stage of disease, higher relative interferon dosage, or lack of co-morbid conditions or aggravating cofactors. Alternatively, this finding could simply be a statistical artifact of the small, uncontrolled trials. In any case, given the superiority of combination therapy with interferon and ribavirin in adults, it is unlikely that a large, randomized, controlled trial of interferon monotherapy will be undertaken in children with chronic HCV infection.

There are few data regarding the use of combination therapy in children. A recent abstract described a cohort of 61 children treated with 3 MU/m 2 of interferon thrice weekly, and 8, 12, or 15 mg/kg of ribavirin daily. The pharmacokinetic properties of the drugs were similar to those in adults, and the therapy was well tolerated, with dose-dependent anemia from the ribavirin that was somewhat less severe than that observed in adults. The 15 mg/kg ribavirin dose was chosen for a larger efficacy study which has recently been completed; results are expected in the coming months. There are no data regarding the use of the pegylated interferons in children.

Prevention of new HCV infections in older children requires education about high-risk behaviors. Although commercial body piercing and tattooing are not clearly associated with risk, self-tattooing and self-piercing with shared needles are fairly common practices and might be associated with HCV acquisition. Transmission of infection in intravenous drug users is well understood, but the risk from sharing straws or other implements for intranasal cocaine administration may not be appreciated by teenagers.

The primary target for prevention strategies should be perinatal transmission. Currently, universal testing of pregnant women for HCV infection is not recommended. Post-exposure immune globulin is not effective. Maternal HIV co-infection has been addressed with aggressive antiretroviral therapy. There are no safe measures to decrease maternal HCV viremia at delivery,  since interferon and ribavirin are contraindicated during pregnancy. If the importance of  obstetrical factors is confirmed, changes may become necessary in the care of infected women.

In summary, HCV infection in children is not rare and is under-recognized. The natural history is either more benign or more prolonged when compared to adult-onset infection. Children may have a better response rate to current therapies, but well-designed studies have not yet been done. Prevention efforts should focus on perinatal transmission.

References

1. Jonas MM. Treatment of chronic hepatitis C in pediatric patients. In Treatment of Chronic Hepatitis C, Keeffe EB, ed. Clin Liv Dis 1999;3:855–68.

2. Jonas MM. Hepatitis C in Children. In Hepatitis C, Liang TJ and Hoofnagle JH, eds. Biomed Res Rep 2000; San Diego, CA: Academic Press; p. 389–404.

3. Kelley DA, Bunn SK, Apelian D, et al. Safety, efficacy and pharmacokinetics of interferon alfa-2b plus ribavirin in children with chronic hepatitis C (abstract). Hepatology 2001;34:342A.

4. Jacobson KR, Murray K, Zellos A, and Schwarz KB. An analysis of published trials of interferon monotherapy in children with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2002;34:52–8.