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Children With Hepatitis C

Maureen M. Jonas

An estimated 240,000 children in the United States have antibody to hepatitis C virus (HCV) and 68,000 to 100,000 are chronically infected with HCV. Acute HCV infection is rarely recognized in children outside of special circumstances such as a known exposure from an HCV-infected mother or after blood transfusion. Most chronically infected children are asymptomatic and have normal or only mildly abnormal alanine aminotransferase levels.

Although the natural history of HCV infection acquired in childhood seems benign in the majority of instances, the infection takes an aggressive course in a proportion of cases leading

to cirrhosis and end-stage liver disease during childhood; the factors responsible for a more

aggressive course are unidentified. An optimal approach to management of hepatitis C in children would be prevention, particularly of perinatal transmission, which is now the major cause of new cases of hepatitis C in children. Obstetrical factors may be important determi- nants of transmission, which, if confirmed, should lead to changes in the care of infected women. Therapy of HCV infection in children is also not well defined. There have been no large randomized, controlled trials of therapy in children with chronic hepatitis C. Small heterogeneous studies of interferon monotherapy have reported sustained virological re- sponse rates of 35% to 40%. There are few data regarding the use of combination therapy with interferon and ribavirin in children and no information on the use of peginterferon.

Clearly, there are important needs for future epidemiologic and clinical research on hepatitis

C in childhood. (HEPATOLOGY 2002;36:S173-S178.)

O nly a small proportion of hepatitis C virus (HCV)-infected individuals are children, and there are few, if any, manifestations of this in-

fection during childhood. Because of this, less is known about HCV infection in children as compared with adults. Most HCV-infected children develop chronic hepatitis, and, although rare, cirrhosis and end-stage liver disease can occur during childhood. There are differences in modes of acquisition, natural history, complications, and treatment between pediatric and adult HCV infec- tions.

Incidence, Prevalence, and Modes of Transmission in Children

Infection with HCV occurs in children, as in adults, throughout the world. The proportion of the 28,000 new

Abbreviation: HCV, hepatitis C virus. From the Division of Gastroenterology, Children’s Hospital Boston; and Harvard Medical School, Boston, MA. Dr. Jonas has been a consultant for and receives research support from the Scher- ing Plough Research Institute. Address correspondence to Maureen M. Jonas, M.D., Division of Gastroenterol- ogy, Children’s Hospital, 300 Longwood Ave., Boston, MA 02115. E-mail:

maureen.jonas@tch.harvard.edu; fax: 617-739-5871. Copyright © 2002 by the American Association for the Study of Liver Diseases.

0270-9139/02/3605-1021$35.00/0

doi:10.1053/jhep.2002.36799

cases each year in the United States that are in children less than 18 years of age is not clearly defined. The prev- alence of HCV infection in the United States is 1.8%; this represents approximately 3.9 million people. 1 In children, the seroprevalence is 0.2% for those less than 12 years of age, and 0.4% for those 12 to 19 years of age. 2 If the spontaneous viral clearance rate is as high as 50%, as has been occasionally observed, there are about 68,000 chronically infected children. If the clearance rate is 25%, the rate described in older children and adolescents, this number is closer to 102,000. Before 1990, the predominant risk for acquisition of HCV infection by children was transfusion of blood or blood products (such as anti-hemophilic factor, factor IX concentrates, or intravenous immune globulin). This mode of transmission is currently responsible for many cases of chronic hepatitis C, but new HCV infections in children are primarily caused by perinatal (vertical) trans- mission. 3 The risk of HCV transmission with pregnancy is low, on the order of 5%; nevertheless, the incidence of new infections in children through this route may be sub- stantial, given the prevalence of HCV infection in women of childbearing age of approximately 1.2%. 4 The prevalence of HCV in children varies both by risk factors and geographic location. Children from all parts of the world who received multiple transfusions with either

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blood or acellular blood products before 1992 have infec- tion rates from 50% to 95%. 5-7 Children with moderate transfusion exposure before 1992 have intermediate sero- prevalence rates of 10% to 20%. 8-12 Studies in general pediatric populations, without identiable risk factors, have reported seroprevalence rates ranging from as low as 0% in Japan, 13 Taiwan, 14 and Egypt, 15 0.4% in Italy, 16 and 0.9% in Saudi Arabia, 17 to as high as 14.5% in Cam- eroon. 18 In an urban adolescent population in Boston, the seroprevalence of antibody to HCV was 0.1%. 19 Socio- economic differences are likely to explain much of the geographic variability in the prevalence of antibody to HCV. Screening of donated blood and plasma for antibody to HCV and the use of recombinant and heat-inactivated clotting factors have drastically reduced the incidence of parenteral HCV transmission. However, this practice was instituted only in the last 10 years. Many children in- fected with HCV by transfusions before 1992 are now being followed in clinical practices, while others are yet to be identied. Perinatal transmission, discussed elsewhere, is the route of acquisition for nearly all new cases of HCV in childhood. Nonsexual (nonspouse) seroprevalence rates in house- hold contacts of infected individuals have ranged from 0% to 6.5%. Risk of antibody to HCV positivity increases with age and/or duration of exposure for both sexual and nonsexual contacts. 20,21 The risk to children in the house- holds of chronically HCV-infected individuals, separate from perinatal risk, is probably quite low. The mechanism of nonsexual, nonperinatal infection of children in fami- lies is not known. There are few data regarding the transmission of HCV from infected children to others. In a study from Spain, 1 sibling and no parents (out of 80 household contacts) of 27 HCV-infected children were infected. 22 In an Italian study of 44 index children with various sources of infec- tion, 1 parent was infected through an accidental needle stick, and no transmission to other children was shown. 23 Thus, horizontal transmission of HCV between children is rare. Recommendations of the American Academy of Pediatrics are that there is no need to restrict school or day care attendance, or participation in any routine activity including contact sports for HCV-infected children. 24 The prevalence of HCV infection in children not cur- rently explained by risk factors is not known, but is likely very low.

Clinical Features of HCV Infection in Children

Acute hepatitis C is rarely recognized in children, and fulminant cases have not been reported. Children with

HEPATOLOGY, November 2002

chronic infection are typically asymptomatic, with nor- mal or mildly abnormal alanine aminotransferase levels. 8,10,25-30 Non organ-specic autoantibodies are commonly reported in European series, 31,32 but clinically apparent autoimmune manifestations are rare. HCV- associated cryoglobulinemia, vasculitis, and porphyria cu- tanea tarda have not been reported in children. This lack of clinical signs or symptoms, and the fact that routineserum alanine aminotransferase determinations are not performed as part of pediatric medical care, indicate that chronic HCV infection in children is probably under- recognized.

Natural History of HCV Infection in Children

Although factors that inuence the natural history of HCV infection in adults have been dened, they are less clear in children. The natural history of transfusion-asso- ciated HCV infection may differ according to the under- lying disease for which the transfusion was given. Forty-ve to 50% of children who received blood transfusions at the time of surgery for congenital heart disease developed chronic infection. 32,33 Among 29 children followed for a minimum of 4 years, half of those with persistent viremia had chronic hepatitis histologically, but none had cirrhosis. 34 Children treated for leukemia before 1990 are reported to have a high rate of HCV infection. 35 In one study, prolonged follow-up (13 to 27 years) of these children showed no evi- dence for serious liver disease. 36 The authors hypothesized that acquisition of HCV during a period of immunosuppres- sion induced by chemotherapeutic agents may have pre- vented the development of an immune response that would cause the chronic injury in this disease. However, in a cohort of children treated for cancer at St. Judes Childrens Re- search Hospital, (Memphis, TN), 1 child died of liver failure 9 years after onset of HCV infection, and 2 others died of hepatocellular carcinoma after 25 and 27 years. 37 Among 58 surviving children with HCV infection who were followed longitudinally, 3 of 35 (8.5%) who underwent liver biopsy had cirrhosis. 37 Children with thalassemia requiring chronic transfusions have a very high prevalence of HCV infection. 6 Secondary hemochromatosis may contribute to the hepatic injury in this patient group, and response to therapy may be affected by the degree of hepatic iron overload. 38 Studies have also shown that HCV infection acquired from anti- hemophilic factor treatment of children with hemophilia can cause early mortality. 39 The natural history of perinatally acquired HCV infec- tion is of particular importance, as this mode has become the major route of infection for the pediatric population. In general, HCV infection acquired vertically is often as- sociated with biochemical evidence of hepatic injury early

HEPATOLOGY, Vol. 36, No. 5, Suppl. 1, 2002

in life, which persists for many years in the majority of, but not all, instances, and causes only mild liver disease in the rst 1 or 2 decades. However, a small proportion of perinatally infected children develop advanced liver dis- ease during childhood. According to the Studies of Pedi- atric Liver Transplantation (SPLIT) Registry that collects data from 37 North American pediatric liver transplant centers, chronic hepatitis C was the reason for transplan- tation in 9 of 941 children who underwent liver trans- plantation between 1995 and 2001. In summary, the natural history of HCV infection in childhood is relatively benign because hepatitis C is rarely associated with severe or decompensated liver disease dur- ing the childhood years. However, HCV infection ac- quired during childhood persists for many years, causes chronic hepatic damage, and may, at least in some in- stances, be responsible for signicant morbidity and mor- tality later in life.

Histological Features of the Liver in HCV Infection in Children

The spectrum of histological ndings in HCV-infected children has been the topic of 3 published studies. In all 3 series, the characteristic histological lesions of HCV in- fection, including portal lymphoid aggregates or follicles, sinusoidal lymphocytes, and steatosis, were seen with ap- proximately the same frequency as in adults. 40-42 Kage et al., 40 from Japan, described ndings in 109 children, most of whom were infected by blood transfusion. Necro- inammatory activity was on average mild (average score, 3.8 in the Scheuer system). No child had cirrhosis, and only 3.6% had bridging brosis with architectural distor- tion (stage 3 brosis). Viral genotypes were not reported, and the average duration of infection was only 2.6 years. In contrast, in a series from the United States, overall histological activity (using the Scheuer and METAVIR scoring systems) was generally mild, but portal brosis was much more frequent, described in 78% of 40 chil- dren. 41 The degree of brosis was rated as mild in 26%, moderate in 22%, severe in 22%, and as cirrhosis in 8% of children. Two children with cirrhosis were young adoles- cents who had acquired HCV infection perinatally. In this series, 60% of children had HCV genotype 1a and 32% had genotype 1b. Mean duration of infection in children for whom it could be determined was 6.8 5.3 years. A third histological series consisted of 80 children from Italy and Spain, most of whom were infected with HCV genotype 1, with a mean duration of infection of 3.5 4.3 years. 42 Overall, necroinammatory scores were low (grade 1 or 2). The frequency and severity of the bile duct damage and lymphoid follicles increased with patient age. Fibrosis was present in 72.5% of cases, and

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Table 1. Special Considerations Regarding Therapy for Children With Hepatitis C

Differences in natural history Mode of acquisition—perinatal Shorter duration of infection Co-morbid diseases Longer anticipated life expectancy Differences in liver disease Milder grades of necroinflammation Less frequent severe fibrosis or cirrhosis Differences in response to interferon alfa Higher frequency of response* Lower frequency of relapse* Less correlation of ultimate response with HCV RNA at 12 weeks* Fewer instances of drug discontinuation because of side effects Unknown long-term side effects No cost-benefit data Few data about ribavirin pharmacokinetics, safety, and efficacy Very preliminary data about peginterferon pharmacokinetics

*Studies leading to these conclusions include relatively small numbers of patients. Adapted and reprinted from Jonas. 43

increased in frequency with duration of disease and pa- tient age, just as in the American series. Only 1 child (1.3%) had cirrhosis. Thus, histological features of chronic hepatitis C in childhood are similar to those reported in adults. Al- though necrosis and inammation are usually mild, bro- sis is common and appears to progress with increasing age and duration of infection. This progressive brosis sug- gests that the natural history of HCV infection acquired in childhood may lead to signicant morbidity as the children enter young adulthood.

Treatment of HCV Infection in Children

Currently, in the United States, there are no therapies for hepatitis C that are licensed and approved for individ- uals less than 18 years of age. Identication of infected children and selection of candidates for treatment repre- sent important challenges. Appropriate therapy for this special population requires consideration of the differ- ences in epidemiology, natural history, and treatment ef- cacy, as well as understanding of the safety of the proposed treatments (Table 1). Details of the interferon monotherapy trials in children with chronic HCV infection have been reviewed in de- tail. 43 Even though the studies included several types of patients, and different dosages, schedules and types of interferon were used, the sustained virological response rates, when reported, were remarkably similar among the studies, ranging from 33% to 45%. 29,44-51 These sus- tained virological response rates are signicantly higher than those reported in large trials of interferon mono- therapy in adult patients. A systematic analysis of these

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heterogeneous studies was recently reported. 52 This anal- ysis included results from 11 published manuscripts and 3 abstracts that were felt to be evaluable for treatment and outcome. The analysis included 270 treated children and 37 control subjects. The overall sustained virological re- sponse rate in treated children was 35%, which is substan- tially higher than that reported in adults after interferon monotherapy. There was a pronounced difference in re- sponse rate by viral genotype: 26% for genotype 1 and 70% for others. The high response rates may be related to favorable prognostic factors in children, such as earlier stage of disease, higher relative interferon dosage, or lack of co-morbid conditions or aggravating cofactors. Alter- natively, the higher rates could simply be because of sta- tistical artifact resulting from the small, uncontrolled trials and publication bias. In any case, given the superi- ority of combination therapy with interferon and ribavi- rin in adults, it is unlikely that a large, randomized, controlled trial of standard interferon monotherapy ver- sus combination therapy will be undertaken in children with chronic HCV infection. There are few data regarding the use of combination therapy with interferon and ribavirin in children. A report in abstract form described ndings in a cohort of 61 chil- dren, ages 5 to 11 years, treated with 3 MU per meter squared of body surface area of interferon alfa-2b thrice weekly combined with either 8, 12, or 15 mg/kg of body weight of ribavirin daily. 53 The pharmacokinetic proper- ties of the drugs were very similar to those in adults, and the therapy was well tolerated. The dose-dependent ane- mia from ribavirin was somewhat less severe in children than that observed in adults. The overall sustained viro- logical response rate was 38% (31% in genotype 1). The ribavirin dose of 15 mg/kg was chosen for a larger efcacy study because this dose was associated with the highest virological response rate and the toxicity was not signi- cantly greater than that of the lower doses. The larger study has been completed, and data analysis is underway. Efcacy and safety data are expected in the coming months. There are no reports of the use of peginterferon in children with chronic hepatitis C. A study of pharmaco- kinetic properties of peginterferon-alfa 2a in a small group of children is in progress. In general, children tolerate interferon alfa well and are able to complete the courses of treatment. There have been no reports of long-term sequelae of interferon alfa therapy for chronic hepatitis in childhood. Interferon may have effects on body weight and linear growth, par- ticularly when given for a prolonged period of time, 53,54 but this appears to resolve when therapy is stopped. The effects of interferon therapy on growth and development

HEPATOLOGY, November 2002

Table 2. Rationale and Considerations for Treatment of Hepatitis C in Children

Children have sustained virological response rates at least as high as adults.

Children tolerate interferon and ribavirin well.

Children with mild liver disease may benefit from treatment.

Children less than 2 years of age should probably not be treated.

Currently, treatment of children should be in the context of clinical trials.

have not been systematically and prospectively studied. There have been few reports of severe complications of interferon alfa therapy in children. In very young children treated with interferon alfa for life-threatening hemangi- omas, several infants developed spastic diplegia. 55 A single case report described a young child with HCV infection who developed seizures during interferon therapy. 56 Thus, in very young children, central nervous system tox- icity of interferon is a concern. Ribavirin has been well tolerated in the majority of treated children, but the numbers of children studied has been small. Although dose-dependent hemolytic anemia was observed, it did not require drug discontinuation in any of 61 treated children. 53 Children with chronic hepatitis C may benet from treatment. Although advanced liver disease is rarely en- countered during childhood, it can occur. In addition, the social stigmatism of HCV-infected children and their families is often a signicant source of anxiety and mor- bidity and a rationale for therapy. The clinical challenge is identication of those children who are most likely to benet from therapy, while considering long-term safety in this special population (Table 2).

Future Research Needs

Although the incidence of new HCV infections in the United States is decreasing, the estimated 3 million exist- ing cases are expected to cause an increase in the number of people with end-stage liver disease in the next several decades. The contribution of pediatric cases to this health care burden is difcult to quantify because the majority of HCV-infected children have probably not yet been iden- tied. Pediatric cases of chronic hepatitis C, however, will continue to contribute to the health care burden of this disease because new pediatric infections will primarily be the result of perinatal transmission, a mode of transmis- sion for which there are no proven methods of prevention. At present, there are no licensed therapies for chronic hepatitis C in children, and there are insufcient data to recommend any particular regimen of therapy or specic indications to initiate treatment. Thus, the needs for fu- ture research are great. Of prime importance are studies of the factors that predict perinatal transmission and interventions that

HEPATOLOGY, Vol. 36, No. 5, Suppl. 1, 2002

might interrupt this most important source of infection in children. Also important are studies of the course and natural history of hepatitis C acquired in the perinatal period. Delineation of the factors that predict progression and particularly the development of brosis in children is important. The effects of hepatitis C on growth and gen- eral health are important to elucidate. Finally, there is a pressing and immediate need to initiate carefully de- signed, prospective controlled trials of antiviral therapy in children with chronic hepatitis C. These studies need not compare therapy with no therapy, or one treatment to another, so much as to help dene the optimal dose and regimen of treatment for children and to carefully delin- eate the benecial as well as adverse effects of treatment, particularly on childhood physical and emotional devel- opment.

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