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CHALLENGES IN THE TREATMENT OF HEPATITIS C IN CHILDREN
ADVANCES IN HEPATITIS C
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CHALLENGES IN THE TREATMENT OF HEPATITIS C IN CHILDREN Maureen M. Jonas, MD
Currently, in the United States, there are no licensed therapies for hepatitis C infection in persons younger than 18 years of age. Although the prevalence of infection in the pediatric population is low, there are probably approximately 240,000 exposed or infected children in this country now, and new infections continue to occur. Identification of infected children and selection of candidates for treatment are important challenges. Implementation of appropriate therapy for this special population requires consideration of differences in epidemiology, natural history, and treatment efficacy, as well as a clear understanding of the safety of the proposed treatments. EPIDEMIOLOGY
The overall seroprevalence of antibody to hepatitic C virus (HCV) in the United States is 0.2% for persons younger than 12 years of age and 0.4% for those 12 to 19 years of age (Fig. l ) . I There are much higher infection rates in specific pediatric groups in Western Europe and in adoptees from some countries in Eastern Europe, such as Russia and Romania. Children who have been multiply transfused with either blood or blood products have infection rates ranging from 50% to 95?’0/, 19, 33 Intermediate seroprevalence rates of 10% to 20% are seen in children with moderate transfusion exposure, including those who have been
From the Department of Pediatrics, Harvard Medical School, and Children’s Hospital, Boston, Massachusetts
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Figure 1. The seroprevalence of anti-HCV in the United States by age. The seroprevalences in the two pediatric age groups, 6-11 years and 12-19 years, are 0.2% and 0.4%, respectively. (From Alter MJ, Kruszon-Moran D, Najnan OV et al; The prevalence of hepatitis C virus infection in the United States, 1998 through 1994. The New England journal of medicine 341 :556-62, 1999; with permission.)
treated for childhood malignancies,2l*34 those who have been treated with hemodialysis,12,l7 or those who have undergone surgery for congenital heart disease.27Studies in general pediatric populations without identifiable risk factors have reported widely variable seroprevalence rates from 0% to 14.5%. In a large, urban, adolescent population in Boston, the seroprevalence rate for anti-HCV was 0.1Y0.'~ These geographic differences are unexplained, but socioeconomic factors and local health practices are probably at least partly responsible. In many instances the risk factor, such as remote transfusion or an HCV-infected mother, may not be known to the clinicians caring for the children. Nonetheless, in developed countries HCV infection is not seen in children without such risk factors. Because transfusion-associated HCV infection has been virtually eliminated, perinatal transmission is now the major mode of acquisition of HCV in children. The rate of HCV transmission from anti-HCV-seropositive women is 3% to 6% in large studies.1o,24, 32 Maternal coinfection with HIV increases the rate of perinatal HCV transmission, even without simultaneous HIV transmission,ll, 28, 29, 37, 38 but aggressive treatment of maternal HIV infection may substantially decrease this rate.8 The possibility of in utero transmission in at least some cases is suggested by the detection of viremia in some infants on the day of birth. Recent reports, however, document the often transient nature of this viremia and the delay in appearance of HCVRNA in serum for several months in other perinatally infected neonates.8,lo Transmission of HCV has also been documented from women who have acute infection during the last trimester of pregnancy. Transmission occurs with both vaginal and cesarean deliveries. One
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recent study demonstrated a difference in HCV transmission between emergency and elective cesarean deliveries, the latter being characterized by rupture of membranes at the time of birth, rather than several hours previously.1oRupture of membranes for longer than 6 hours was also an independent risk factor for HCV transmission in a prospective study conducted by the Centers for Disease Control." This combination of observations indicates that transmission of HCV from infected mother to newborn is most likely to occur at or very near to the time of delivery and may be subject to intervention. NATURAL HISTORY
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. In a series from Japan, 45% of children who were transfused at the time of surgery for congenital heart disease developed chronic but none had cirrhosis within a 4 year follow-up period.25,27 Children with thalassemia requiring chronic transfusions have a high prevalence of HCV infe~tion.'~ Secondary hemochromatosis may contribute to the hepatic injury and mitigate the response to therapy in these patient^.^ Although end-stage liver disease is not common in HCVinfected children with hemophilia, HCV infection acquired during childhood contributes to early mortality in these i n d i v i d ~ a l s .Children ~~ treated for leukemia before 1990 have a high rate of HCV infection? but in one cohort prolonged follow-up (13-27 years) did not commonly reveal serious liver disease.= In contrast, a study in the United States individuals treated for childhood cancer revealed one death from liver disease and two deaths caused by hepatocellular carcinoma in the decades following HCV a c q ~ i s i t i o nThe . ~ ~ same report described hepatic histologic abnormalities in most of these individuals infected with HCV, with 3 cases of cirrhosis (9%) occurring 9 to 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. Perinatally acquired HCV infection has become the major route of new infections in children, at least in developed countries. Whether the natural history of infection acquired in this manner is substantially different from that of HCV acquired in childhood by transfusion is not yet clear. Vertically infected infants followed prospectively typically have elevated alanine aminotransferase (ALT) levels for a few years, but these levels often become normal later.9Almost all children who remain viremic and undergo liver biopsy after several years of follow-up have histologic chronic hepatitis.30An Italian report describes 14 infected infants followed from birth; all had elevated ALT levels for the first year; some remained viremic but with normal ALT levels in the long term;
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and the infection resolved in 2 of the infant^.^ The same study identified and followed a cohort of older children with perinatally acquired HCV infection. In that group, fluctuating or persistent viremia was common, and most children had normal or nearly normal ALT levels, but all biopsies demonstrated chronic he pa ti ti^.^ In general, it seems that HCV infection acquired vertically is frequently associated with biochemical evidence of hepatic injury early in life, persists for many years in most, but not all, instances, and causes only mild liver disease in the first 1 or 2 decades. Recent anecdotes, however, suggest that this is not always the pattern. The author has cared for two children with perinatally acquired HCV infection whose liver disease evolved into decompensated cirrhosis at 11 and 13 years of age, respectively. Recently, three children with decompensated HCV-associated cirrhosis at ages 4, 6, and 11 years, respectively, were r e p ~ r t e dTherefore, .~ in some children, the infection takes an unusually aggressive course, but the factors responsible are as yet unidentified. In summary, the natural history of HCV infection acquired during childhood is typically benign, because it is rarely associated with severe or decompensated liver disease or extrahepatic complications during the childhood years. Hepatitis C virus infection acquired during childhood, however, most often persists for many years, causes chronic hepatic injury, and may be responsible for significant morbidity and mortality later in life. For these reasons, treatment of chronic HCV infection during childhood should be considered. Therapeutic guidelines, when available, may be different for children than for adults and for perinatally acquired infection as opposed to transfusion-associated infection, because the natural history may be different. These differences, if confirmed by large studies, will have important ramifications regarding patient selection, timing, and efficacy assessment for treatment of HCV-infected children. TREATMENT OF HEPATITIS C VIRUS INFECTION IN CHILDREN
There are no reports of treatment of acute HCV infection in children. Acute infection, which may be acquired from a transfusion or other parenteral exposure, or at the time of birth, rarely causes symptoms recognizable as acute hepatitis. Fulminant hepatitis attributed to HCV is extremely rare in children, as it is in adults. In addition, no large, multicenter, randomized, controlled therapeutic trials have been performed in children with chronic HCV infection. There are a number of reports of treatment in children, but the studies are usually 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.15 Even though the studies included several types of patients and used different dosages, schedules, and types of interferon, in general the sustained
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virologic response rate, when reported, was remarkably similar in most studies, ranging from 33% to 45%. These rates are significantly higher than the sustained virologic response rates reported in large trials of interferon monotherapy in adult patients. Meta-analysis of these heterogeneous studies, in an attempt to accumulate meaningful outcome data, was recently reported in abstract form.14This analysis included 11manuscripts and 3 abstracts that were considered evaluable for treatment and outcome. They included 270 treated children and 37 untreated controls. The sustained virologic response rate in the treated children was 35%, again substantially higher than that reported in adults after interferon monotherapy. There was a pronounced difference in response rate according to viral genotype: 26% for children infected with HCV genotype 1 and 70% 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 comorbid conditions or aggravating cofactors. Alternatively, this finding could simply be a statistical artifact resulting from the small, uncontrolled trials. In any case, given the superiority of combination therapy with interferon plus 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 with interferon plus ribavirin in children. A recent abstract described initial studies in a cohort of 61 children, aged 5 to 11 years, treated with interferon, 3 MU/m*, three times/week, and either 8, 12, or 15 mg/kg of ribavirin/day.6 The pharmacokinetic properties of the drugs were quite 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 ribavirin dose of 15 mg/kg was chosen for a larger efficacy study, because this dose was associated with the highest virologic response rate at week 24, and the toxicity was not significantly greater than that of the lower doses. This study is ongoing; preliminary efficacy data are expected in the near future. Prevention of Hepatitis C in Children
The incidence of new HCV infections in the United States has decreased markedly during the last several years.' The cause of this decrease is not entirely clear, because prevention of transfusion-associated infections is responsible for only a small proportion of this dramatic change. There is as yet no clear indication that the incidence of new infections in children is decreasing, however, especially because many currently infected individuals are women of childbearing age. Although pediatric cases are a minority of HCV infections and may not commonly progress to serious liver disease during the childhood years, there are certainly instances of significant morbidity and even mortality from this disease. Available therapy is cumbersome and uncomfortable, carries risks, and is ineffective in many cases. For these reasons, consideration
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must be given to measures that might be instituted to prevent new pediatric HCV infections. Prevention of new HCV infections in older children requires education of preadolescents and adolescents 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 understood by teenagers. The primary target for prevention strategies should be perinatal transmission. Postexposure prophylaxis with immune globulin does not seem to be effective in preventing HCV infection and is not recommended for infants born to HCV-infected women.13At the present time, the benefits of breastfeeding are considered greater than the theoretic increase in risk over and above that from perinatal exposure. In most studies, breastfeeding has not been shown to increase the likelihood of HCV transrnis~ion.'~,20, 36 Breast milk from a series of infected women did not contain HCV-RNA when systematically studied.31 Factors that increase the risk of perinatal transmission include maternal HIV co-infection and higher level of maternal HCV viremia. The former has been addressed with aggressive antiretroviral therapy, and an impact on vertical HCV transmission was reported in one study.a There are at present no safe measures to decrease maternal HCV viremia at delivery, because currently available treatments such as interferon and ribavirin are considered contraindicated during pregnancy. If prolonged rupture of membranes and the use of internal fetal monitoring are confirmed as risk factors for HCV transmission, major changes may become necessary in the obstetric care of infected women. Current recommendations regarding perinatal HCV transmission are summarized in Figure 2. At present, universal testing of pregnant
Universal testing of pregnant women for HCV infection is not indicated - targeted testing of women in high risk groups or with unexplained ALT elevation is recommended Elective cesarean section to prevent HCV transmission is not recommended - it may be prudent to avoid internal fetal monitoring or prolonged rupture of membranes Breast feeding is not contraindicated Infants of HCV infected women should be tested for antiHCV after 15 months of age Figure 2. Current recommendations regarding perinatal HCV transmission.
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women for HCV by avoiding infection is not recommended. To interrupt perinatal transmission while avoiding the use of fetal scalp monitors or the selective use of cesarean delivery when the duration of amniotic membrane rupture approaches 6 hours, identification of infected women before delivery will be a clearly indicated strategy. There are no clear data implicating breast-feeding as a means of HCV transmission; at this time, it is thought that the benefits of this practice outweigh a small theoretic risk. Because HCV viremia may be undetectable in some infected newborns and transient in others, detection of perinatally infected children is best accomplished by testing for anti-HCV after 15 months of age, once maternal antibody has cleared. SUMMARY Hepatitis C infection in children is associated with a unique set of challenges for clinicians and investigators. Although the prevalence of HCV infection is lower in children than in adults, it is important to identify infected children to monitor progression of liver disease and to make appropriate interventions to minimize factors that may exacerbate progression. Identification requires understanding of risk factors important in children, primarily exposure at or near the time of birth. The natural history of this infection in most children is either more benign or significantly prolonged than that of infection acquired in adulthood. Reasons for this difference in natural history must be explored and possibly even exploited in the care of adult patients with HCV infection. Identification of appropriate pediatric candidates for treatment and definition of optimal therapy for these children require ongoing study. Lastly, as perinatal transmission becomes the primary mode of acquisition for new pediatric infections, factors that increase or decrease the likelihood of this transmission must be identified, and effective preventive interventions must be put into practice. There are important differences in the clinical features, natural history, and response to therapy between pediatric and adult patients with HCV infection. Understanding of these differences will allow optimal care for affected children and perhaps better understanding of the pathophysiology and pure natural history of this disease.
References 1. Alter MJ, Kruszon-Moran D, Najnan OV, et al: The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 341:556-562, 1999 2. Aricb M, Maggiore G, Silini E, et al: Hepatitis C virus infection in children treated for acute lymphoblastic leukemia. Blood 842919-2921, 1994 3. Bimbaum A, Shneider B, Moy L Hepatitis C in children [letter]. N Engl J Med 342290, 2000 4. Blanchette VS, Vorstmann E, Shore A, et al: Hepatitis C infection in children with hemophilia A and B. Blood 78285-289, 1991
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5. Bortolotti F, Resti M, Giacchino R, et a1 Hepatitis C virus infection and related liver disease in children of mothers with antibodies to the virus. J Pediatr 130:990-993, 1997 6. Bunn S, Kelly D, Murray KF, et al: Safety, efficacy and pharmacokinetics of interferonalfa-2b and ribavirin in children with chronic hepatitis C [abstract]. Hepatology 32350A, 2000 7. Clemente MG, Congia M, Lai ME, et al: Effect of iron overload on the response to recombinant interferon alpha treatment in transfusion-dependent patients with thalassemia major and chronic hepatitis C. J Pediatr 125:123-128, 1994 8. Conte D, Fraquelli M, Prati D, et al: Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women. Hepatology 31:751-755, 2000 9. Giacchino R, Tasso L, Timitilli A, et al: Vertical transmission of hepatitis C virus infection: Usefulness of viremia detection in HIV-seronegative hepatitis C virus-seropositive mothers. J Pediatr 132:167-169, 1998 10. Gibb DM, Goodall RL, Dunn DT, et a1 Mother-to-child transmission of hepatitis C virus: Evidence for preventable peripartum transmission. Lancet 356:904-907, 2000 11. Giovanninni M, Tagger A, Ribero ML, et al: Maternal-infant transmission of hepatitis C virus and HIV infections: A possible interaction. Lancet 335:1166, 1990 12. Greco M, Cristiano K, Leozappa G, et al: Hepatitis C infection in children and adolescents on haemodialysis and after renal transplant. Pediatr Nephrol 7424-427, 1993 13. Hunt CM, Carson KL, Sharara AI: Hepatitis C in pregnancy. Obstet Gynecol 89:883890, 1997 14. Jacobson KR, Murray KF, Zellos A, et al: Analysis of interferon monotherapy trials in children with HCV [abstract]. Presented at the World Congress of Pediatric Gastroenterology, Boston, MA, August 7, 2000 15. Jonas MM: Treatment of chronic hepatitis C in pediatric patients. In Keeffe EB (ed): Treatment of Chronic Hepatitis C, vol3. Philadelphia, WB Saunders, 1999, pp 855-867 16. Jonas MM, Robertson LM, Middleman AB: Low prevalence of antibody to hepatitis C virus in an urban adolescent population. J Pediatr 131:314-316, 1997 17. Jonas MM, Zilleruelo GE, LaRue SI, et al: Hepatitis C in a pediatric dialysis population. Pediatrics 89:707-709, 1992 18. Kumar RM, Shahul S: Role of breast-feeding in transmission of hepatitis C virus to infants of HCV-infected mothers. J Hepatol29:191-197, 1998 19. Lai ME, DeVirgilis S, Argiolu F, et al: Evaluation of antibodies to hepatitis C virus in a long-term prospective study of posttransfusion hepatitis among thalassemic children: Comparison between first-and second-generation assay. J Pediatr Gastroenterol Nutr 16:458464, 1993 20. Lin H-H, Kao J-H, Hsu H-Y, et al: Absence of infection in breast-fed infants born to hepatitis C virus-infected mothers. J Pedi ction and chronic liver 21. Locasciulli A, Gornati G, Tagger A, et a1 disease in children with leukemia in long-term remission. Blood 78:1619-1622, 1991 22. Locasciulli A, Testa M, Pontisso P, et al: Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 90:46284633, 1997 23. Makris M, Preston FE, Rosendaal F R The natural history of chronic hepatitis C in haemophiliacs. Br J Haematol94:746-752, 1996 24. Mast EE, Hwang L-Y, Set0 D, et al: Perinatal hepatitis C virus transmission: Maternal risk factors and optimal timing of diagnosis [abstract]. Hepatology 30499A, 1999 25. Matsuoka S, Tatara K, Hayabuchi Y, et al: Post-transfusion chronic hepatitis C in children. J Paediatr Child Health 30:544-546, 1994 26. Matsuoka S, Tatara K, Hayabuchi Y, et al: Serologic, virologic, and histologic characteristics of chronic phase hepatitis C virus disease in children infected by transfusion. Pediatrics 94:919-922, 1994 27. Ni Y-H, Chang M-H, Lue H-C, et al: Posttransfusion hepatitis C virus infection in children. J Pediatr 124:709-713, 1994 28. Novati R, Theirs V, Monforte AA, et a1 Mother-to-child transmission of hepatitis C virus detected by nested polymerase chain reaction. J Infect Dis 165:720-723, 1992 29. Paccagnini S, Principi N, Massironi E, et a1 Perinatal transmission and manifestation
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30. 31. 32. 33. 34. 35. 36. 37. 38.
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of hepatitis C virus infection in a high risk population. Pediatr Infect Dis J 14:195199, 1995 Palomba E, Manzini P, Fiammengo P, et al: Natural history of perinatal hepatitis C virus infection. Clin Infect Dis 23:47-50, 1996 Polywka S, Feucht H, Zollner B, et al: Hepatitis C virus infection in pregnancy and the risk of mother-to-child transmission. Eur J Clin Microbiol Infect Dis 16:121-124, 1997 Resti M, Azzari C, Mannelli F, et al: Mother to child transmission of hepatitis C virus: Prospective study of risk factors and timing of infection in children born to women seronegative for HIV-1. BMJ 317:437441, 1998 Resti M, Azzari C, Rossi ME, et al: Hepatitis C virus antibodies in a long-term followup of beta-thalassaemic children with acute and chronic non-A, non-B hepatitis. Eur J Pediatr 151:573-576, 1992 Rossetti F, Cesaro S, Pizzocchero P, et al: Chronic hepatitis B surface antigen-negative hepatitis after treatment of malignancy. J Pediatr 121:3943, 1992 Strickland DK, Riely CA, Patrick CC, et al: Hepatitis C infection among survivors of childhood cancer. Blood 95:3065-3070, 2000 Tanzi M, Bellelli E, Benaglia G, et al: The prevalence of HCV infection in a cohort of pregnant women, the related risk factors and the possibility of vertical transmission. Eur J Epidemiol 13:517-521, 1997 Tovo PA, Palomba E, Ferraris G, et a1 Increased risk of maternal-infant hepatitis C virus transmission for women coinfected with human immunodeficiency virus type 1. Italian Study Group for HCV Infection in Children. Clin Infect Dis 25:1121-1124, 1997 Zanetti AR, Tanzi E, Paccagnini S, et al: Mother-to-infant transmission of hepatitis C virus. Lombardy Study Group on Vertical HCV Transmission. Lancet 345:289-291,1995
Address reprint requests to Maureen M. Jonas, MD Associate in Gastroenterology Children’s Hospital 300 Longwood Avenue Boston, MA 02115 e-mail: maureen.jonas8tch.harvard.edu
1089-3261/01 $15.00
+ .OO
CHALLENGES IN THE TREATMENT OF HEPATITIS C IN CHILDREN Maureen M. Jonas, MD
Currently, in the United States, there are no licensed therapies for hepatitis C infection in persons younger than 18 years of age. Although the prevalence of infection in the pediatric population is low, there are probably approximately 240,000 exposed or infected children in this country now, and new infections continue to occur. Identification of infected children and selection of candidates for treatment are important challenges. Implementation of appropriate therapy for this special population requires consideration of differences in epidemiology, natural history, and treatment efficacy, as well as a clear understanding of the safety of the proposed treatments. EPIDEMIOLOGY
The overall seroprevalence of antibody to hepatitic C virus (HCV) in the United States is 0.2% for persons younger than 12 years of age and 0.4% for those 12 to 19 years of age (Fig. l ) . I There are much higher infection rates in specific pediatric groups in Western Europe and in adoptees from some countries in Eastern Europe, such as Russia and Romania. Children who have been multiply transfused with either blood or blood products have infection rates ranging from 50% to 95?’0/, 19, 33 Intermediate seroprevalence rates of 10% to 20% are seen in children with moderate transfusion exposure, including those who have been
From the Department of Pediatrics, Harvard Medical School, and Children’s Hospital, Boston, Massachusetts
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Figure 1. The seroprevalence of anti-HCV in the United States by age. The seroprevalences in the two pediatric age groups, 6-11 years and 12-19 years, are 0.2% and 0.4%, respectively. (From Alter MJ, Kruszon-Moran D, Najnan OV et al; The prevalence of hepatitis C virus infection in the United States, 1998 through 1994. The New England journal of medicine 341 :556-62, 1999; with permission.)
treated for childhood malignancies,2l*34 those who have been treated with hemodialysis,12,l7 or those who have undergone surgery for congenital heart disease.27Studies in general pediatric populations without identifiable risk factors have reported widely variable seroprevalence rates from 0% to 14.5%. In a large, urban, adolescent population in Boston, the seroprevalence rate for anti-HCV was 0.1Y0.'~ These geographic differences are unexplained, but socioeconomic factors and local health practices are probably at least partly responsible. In many instances the risk factor, such as remote transfusion or an HCV-infected mother, may not be known to the clinicians caring for the children. Nonetheless, in developed countries HCV infection is not seen in children without such risk factors. Because transfusion-associated HCV infection has been virtually eliminated, perinatal transmission is now the major mode of acquisition of HCV in children. The rate of HCV transmission from anti-HCV-seropositive women is 3% to 6% in large studies.1o,24, 32 Maternal coinfection with HIV increases the rate of perinatal HCV transmission, even without simultaneous HIV transmission,ll, 28, 29, 37, 38 but aggressive treatment of maternal HIV infection may substantially decrease this rate.8 The possibility of in utero transmission in at least some cases is suggested by the detection of viremia in some infants on the day of birth. Recent reports, however, document the often transient nature of this viremia and the delay in appearance of HCVRNA in serum for several months in other perinatally infected neonates.8,lo Transmission of HCV has also been documented from women who have acute infection during the last trimester of pregnancy. Transmission occurs with both vaginal and cesarean deliveries. One
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recent study demonstrated a difference in HCV transmission between emergency and elective cesarean deliveries, the latter being characterized by rupture of membranes at the time of birth, rather than several hours previously.1oRupture of membranes for longer than 6 hours was also an independent risk factor for HCV transmission in a prospective study conducted by the Centers for Disease Control." This combination of observations indicates that transmission of HCV from infected mother to newborn is most likely to occur at or very near to the time of delivery and may be subject to intervention. NATURAL HISTORY
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. In a series from Japan, 45% of children who were transfused at the time of surgery for congenital heart disease developed chronic but none had cirrhosis within a 4 year follow-up period.25,27 Children with thalassemia requiring chronic transfusions have a high prevalence of HCV infe~tion.'~ Secondary hemochromatosis may contribute to the hepatic injury and mitigate the response to therapy in these patient^.^ Although end-stage liver disease is not common in HCVinfected children with hemophilia, HCV infection acquired during childhood contributes to early mortality in these i n d i v i d ~ a l s .Children ~~ treated for leukemia before 1990 have a high rate of HCV infection? but in one cohort prolonged follow-up (13-27 years) did not commonly reveal serious liver disease.= In contrast, a study in the United States individuals treated for childhood cancer revealed one death from liver disease and two deaths caused by hepatocellular carcinoma in the decades following HCV a c q ~ i s i t i o nThe . ~ ~ same report described hepatic histologic abnormalities in most of these individuals infected with HCV, with 3 cases of cirrhosis (9%) occurring 9 to 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. Perinatally acquired HCV infection has become the major route of new infections in children, at least in developed countries. Whether the natural history of infection acquired in this manner is substantially different from that of HCV acquired in childhood by transfusion is not yet clear. Vertically infected infants followed prospectively typically have elevated alanine aminotransferase (ALT) levels for a few years, but these levels often become normal later.9Almost all children who remain viremic and undergo liver biopsy after several years of follow-up have histologic chronic hepatitis.30An Italian report describes 14 infected infants followed from birth; all had elevated ALT levels for the first year; some remained viremic but with normal ALT levels in the long term;
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and the infection resolved in 2 of the infant^.^ The same study identified and followed a cohort of older children with perinatally acquired HCV infection. In that group, fluctuating or persistent viremia was common, and most children had normal or nearly normal ALT levels, but all biopsies demonstrated chronic he pa ti ti^.^ In general, it seems that HCV infection acquired vertically is frequently associated with biochemical evidence of hepatic injury early in life, persists for many years in most, but not all, instances, and causes only mild liver disease in the first 1 or 2 decades. Recent anecdotes, however, suggest that this is not always the pattern. The author has cared for two children with perinatally acquired HCV infection whose liver disease evolved into decompensated cirrhosis at 11 and 13 years of age, respectively. Recently, three children with decompensated HCV-associated cirrhosis at ages 4, 6, and 11 years, respectively, were r e p ~ r t e dTherefore, .~ in some children, the infection takes an unusually aggressive course, but the factors responsible are as yet unidentified. In summary, the natural history of HCV infection acquired during childhood is typically benign, because it is rarely associated with severe or decompensated liver disease or extrahepatic complications during the childhood years. Hepatitis C virus infection acquired during childhood, however, most often persists for many years, causes chronic hepatic injury, and may be responsible for significant morbidity and mortality later in life. For these reasons, treatment of chronic HCV infection during childhood should be considered. Therapeutic guidelines, when available, may be different for children than for adults and for perinatally acquired infection as opposed to transfusion-associated infection, because the natural history may be different. These differences, if confirmed by large studies, will have important ramifications regarding patient selection, timing, and efficacy assessment for treatment of HCV-infected children. TREATMENT OF HEPATITIS C VIRUS INFECTION IN CHILDREN
There are no reports of treatment of acute HCV infection in children. Acute infection, which may be acquired from a transfusion or other parenteral exposure, or at the time of birth, rarely causes symptoms recognizable as acute hepatitis. Fulminant hepatitis attributed to HCV is extremely rare in children, as it is in adults. In addition, no large, multicenter, randomized, controlled therapeutic trials have been performed in children with chronic HCV infection. There are a number of reports of treatment in children, but the studies are usually 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.15 Even though the studies included several types of patients and used different dosages, schedules, and types of interferon, in general the sustained
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virologic response rate, when reported, was remarkably similar in most studies, ranging from 33% to 45%. These rates are significantly higher than the sustained virologic response rates reported in large trials of interferon monotherapy in adult patients. Meta-analysis of these heterogeneous studies, in an attempt to accumulate meaningful outcome data, was recently reported in abstract form.14This analysis included 11manuscripts and 3 abstracts that were considered evaluable for treatment and outcome. They included 270 treated children and 37 untreated controls. The sustained virologic response rate in the treated children was 35%, again substantially higher than that reported in adults after interferon monotherapy. There was a pronounced difference in response rate according to viral genotype: 26% for children infected with HCV genotype 1 and 70% 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 comorbid conditions or aggravating cofactors. Alternatively, this finding could simply be a statistical artifact resulting from the small, uncontrolled trials. In any case, given the superiority of combination therapy with interferon plus 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 with interferon plus ribavirin in children. A recent abstract described initial studies in a cohort of 61 children, aged 5 to 11 years, treated with interferon, 3 MU/m*, three times/week, and either 8, 12, or 15 mg/kg of ribavirin/day.6 The pharmacokinetic properties of the drugs were quite 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 ribavirin dose of 15 mg/kg was chosen for a larger efficacy study, because this dose was associated with the highest virologic response rate at week 24, and the toxicity was not significantly greater than that of the lower doses. This study is ongoing; preliminary efficacy data are expected in the near future. Prevention of Hepatitis C in Children
The incidence of new HCV infections in the United States has decreased markedly during the last several years.' The cause of this decrease is not entirely clear, because prevention of transfusion-associated infections is responsible for only a small proportion of this dramatic change. There is as yet no clear indication that the incidence of new infections in children is decreasing, however, especially because many currently infected individuals are women of childbearing age. Although pediatric cases are a minority of HCV infections and may not commonly progress to serious liver disease during the childhood years, there are certainly instances of significant morbidity and even mortality from this disease. Available therapy is cumbersome and uncomfortable, carries risks, and is ineffective in many cases. For these reasons, consideration
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must be given to measures that might be instituted to prevent new pediatric HCV infections. Prevention of new HCV infections in older children requires education of preadolescents and adolescents 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 understood by teenagers. The primary target for prevention strategies should be perinatal transmission. Postexposure prophylaxis with immune globulin does not seem to be effective in preventing HCV infection and is not recommended for infants born to HCV-infected women.13At the present time, the benefits of breastfeeding are considered greater than the theoretic increase in risk over and above that from perinatal exposure. In most studies, breastfeeding has not been shown to increase the likelihood of HCV transrnis~ion.'~,20, 36 Breast milk from a series of infected women did not contain HCV-RNA when systematically studied.31 Factors that increase the risk of perinatal transmission include maternal HIV co-infection and higher level of maternal HCV viremia. The former has been addressed with aggressive antiretroviral therapy, and an impact on vertical HCV transmission was reported in one study.a There are at present no safe measures to decrease maternal HCV viremia at delivery, because currently available treatments such as interferon and ribavirin are considered contraindicated during pregnancy. If prolonged rupture of membranes and the use of internal fetal monitoring are confirmed as risk factors for HCV transmission, major changes may become necessary in the obstetric care of infected women. Current recommendations regarding perinatal HCV transmission are summarized in Figure 2. At present, universal testing of pregnant
Universal testing of pregnant women for HCV infection is not indicated - targeted testing of women in high risk groups or with unexplained ALT elevation is recommended Elective cesarean section to prevent HCV transmission is not recommended - it may be prudent to avoid internal fetal monitoring or prolonged rupture of membranes Breast feeding is not contraindicated Infants of HCV infected women should be tested for antiHCV after 15 months of age Figure 2. Current recommendations regarding perinatal HCV transmission.
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women for HCV by avoiding infection is not recommended. To interrupt perinatal transmission while avoiding the use of fetal scalp monitors or the selective use of cesarean delivery when the duration of amniotic membrane rupture approaches 6 hours, identification of infected women before delivery will be a clearly indicated strategy. There are no clear data implicating breast-feeding as a means of HCV transmission; at this time, it is thought that the benefits of this practice outweigh a small theoretic risk. Because HCV viremia may be undetectable in some infected newborns and transient in others, detection of perinatally infected children is best accomplished by testing for anti-HCV after 15 months of age, once maternal antibody has cleared. SUMMARY Hepatitis C infection in children is associated with a unique set of challenges for clinicians and investigators. Although the prevalence of HCV infection is lower in children than in adults, it is important to identify infected children to monitor progression of liver disease and to make appropriate interventions to minimize factors that may exacerbate progression. Identification requires understanding of risk factors important in children, primarily exposure at or near the time of birth. The natural history of this infection in most children is either more benign or significantly prolonged than that of infection acquired in adulthood. Reasons for this difference in natural history must be explored and possibly even exploited in the care of adult patients with HCV infection. Identification of appropriate pediatric candidates for treatment and definition of optimal therapy for these children require ongoing study. Lastly, as perinatal transmission becomes the primary mode of acquisition for new pediatric infections, factors that increase or decrease the likelihood of this transmission must be identified, and effective preventive interventions must be put into practice. There are important differences in the clinical features, natural history, and response to therapy between pediatric and adult patients with HCV infection. Understanding of these differences will allow optimal care for affected children and perhaps better understanding of the pathophysiology and pure natural history of this disease.
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5. Bortolotti F, Resti M, Giacchino R, et a1 Hepatitis C virus infection and related liver disease in children of mothers with antibodies to the virus. J Pediatr 130:990-993, 1997 6. Bunn S, Kelly D, Murray KF, et al: Safety, efficacy and pharmacokinetics of interferonalfa-2b and ribavirin in children with chronic hepatitis C [abstract]. Hepatology 32350A, 2000 7. Clemente MG, Congia M, Lai ME, et al: Effect of iron overload on the response to recombinant interferon alpha treatment in transfusion-dependent patients with thalassemia major and chronic hepatitis C. J Pediatr 125:123-128, 1994 8. Conte D, Fraquelli M, Prati D, et al: Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women. Hepatology 31:751-755, 2000 9. Giacchino R, Tasso L, Timitilli A, et al: Vertical transmission of hepatitis C virus infection: Usefulness of viremia detection in HIV-seronegative hepatitis C virus-seropositive mothers. J Pediatr 132:167-169, 1998 10. Gibb DM, Goodall RL, Dunn DT, et a1 Mother-to-child transmission of hepatitis C virus: Evidence for preventable peripartum transmission. Lancet 356:904-907, 2000 11. Giovanninni M, Tagger A, Ribero ML, et al: Maternal-infant transmission of hepatitis C virus and HIV infections: A possible interaction. Lancet 335:1166, 1990 12. Greco M, Cristiano K, Leozappa G, et al: Hepatitis C infection in children and adolescents on haemodialysis and after renal transplant. Pediatr Nephrol 7424-427, 1993 13. Hunt CM, Carson KL, Sharara AI: Hepatitis C in pregnancy. Obstet Gynecol 89:883890, 1997 14. Jacobson KR, Murray KF, Zellos A, et al: Analysis of interferon monotherapy trials in children with HCV [abstract]. Presented at the World Congress of Pediatric Gastroenterology, Boston, MA, August 7, 2000 15. Jonas MM: Treatment of chronic hepatitis C in pediatric patients. In Keeffe EB (ed): Treatment of Chronic Hepatitis C, vol3. Philadelphia, WB Saunders, 1999, pp 855-867 16. Jonas MM, Robertson LM, Middleman AB: Low prevalence of antibody to hepatitis C virus in an urban adolescent population. J Pediatr 131:314-316, 1997 17. Jonas MM, Zilleruelo GE, LaRue SI, et al: Hepatitis C in a pediatric dialysis population. Pediatrics 89:707-709, 1992 18. Kumar RM, Shahul S: Role of breast-feeding in transmission of hepatitis C virus to infants of HCV-infected mothers. J Hepatol29:191-197, 1998 19. Lai ME, DeVirgilis S, Argiolu F, et al: Evaluation of antibodies to hepatitis C virus in a long-term prospective study of posttransfusion hepatitis among thalassemic children: Comparison between first-and second-generation assay. J Pediatr Gastroenterol Nutr 16:458464, 1993 20. Lin H-H, Kao J-H, Hsu H-Y, et al: Absence of infection in breast-fed infants born to hepatitis C virus-infected mothers. J Pedi ction and chronic liver 21. Locasciulli A, Gornati G, Tagger A, et a1 disease in children with leukemia in long-term remission. Blood 78:1619-1622, 1991 22. Locasciulli A, Testa M, Pontisso P, et al: Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 90:46284633, 1997 23. Makris M, Preston FE, Rosendaal F R The natural history of chronic hepatitis C in haemophiliacs. Br J Haematol94:746-752, 1996 24. Mast EE, Hwang L-Y, Set0 D, et al: Perinatal hepatitis C virus transmission: Maternal risk factors and optimal timing of diagnosis [abstract]. Hepatology 30499A, 1999 25. Matsuoka S, Tatara K, Hayabuchi Y, et al: Post-transfusion chronic hepatitis C in children. J Paediatr Child Health 30:544-546, 1994 26. Matsuoka S, Tatara K, Hayabuchi Y, et al: Serologic, virologic, and histologic characteristics of chronic phase hepatitis C virus disease in children infected by transfusion. Pediatrics 94:919-922, 1994 27. Ni Y-H, Chang M-H, Lue H-C, et al: Posttransfusion hepatitis C virus infection in children. J Pediatr 124:709-713, 1994 28. Novati R, Theirs V, Monforte AA, et a1 Mother-to-child transmission of hepatitis C virus detected by nested polymerase chain reaction. J Infect Dis 165:720-723, 1992 29. Paccagnini S, Principi N, Massironi E, et a1 Perinatal transmission and manifestation
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Address reprint requests to Maureen M. Jonas, MD Associate in Gastroenterology Children’s Hospital 300 Longwood Avenue Boston, MA 02115 e-mail: maureen.jonas8tch.harvard.edu