Hepatitis C Virus

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Hepatitis C Virus

September 4, 2009

From Guidelines for the Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children. National Institutes of Health, the Centers for Disease Control and Prevention, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Vol. 58, No. RR-4. September 4, 2009.

Epidemiology

In the United States, the prevalence of hepatitis C virus (HCV) infection is 0.2% among children aged 1-11 years and 0.4% among adolescents aged 12-19 years (696Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556-62., 697El-Kamary SS, Serwint JR, Joffe A, et al. Prevalence of hepatitis C virus infection in urban children. J Pediatr 2003;143:54-9.). The prevalence of HCV infection among HIV-infected children may be higher. In a serostudy of 535 HIV-infected children followed in pediatric HIV clinical trials, the prevalence of HCV infection by HCV antibody and RNA testing was 1.5% (698Schuval S, Van Dyke RB, Lindsey JC, et al. Hepatitis C prevalence in children with perinatal human immunodeficiency virus infection enrolled in a long-term follow-up protocol. Arch Pediatr Adolesc Med 2004;158:1007-13.). In a more recent study of 228 HIV-infected children at an inner-city hospital in the Bronx, seven HIV-infected children had chronic HCV infection (3.1% [95% CI: 1.4%-6.5%]), defined as a reactive HCV antibody and positive HCV realtime PCR (646Toussi SS, Abadi J, Rosenberg M, et al. Prevalence of hepatitis B and C virus infections in children infected with HIV. Clin Infect Dis 2007;45:795-8.). The mean age of HIV/HCV-coinfected children was 16 years, and 57% had mild elevation (up to twofold above upper limit of normal) in serum transaminase levels.

Mother-to-child transmission is the predominant mode of HCV acquisition in children (699England K, Thorne C, Newell ML. Vertically acquired paediatric coinfection with HIV and hepatitis C virus. Lancet Infect Dis 2006;6:83-90., 700Tajiri H, Miyoshi Y, Funada S, et al. Prospective study of motherto- infant transmission of hepatitis C virus. Pediatr Infect Dis J 2001;20:10-4.). Other potential sources of HCV infection in older children include injectiondrug use, body piercing, tattoos, unintentional needlestick injury, household contact, and sexual exposure (701Jara P, Resti M, Hierro L, et al. Chronic hepatitis C virus infection in childhood: clinical patterns and evolution in 224 white children. Clin Infect Dis 2003;36:275-80., 702Murray KF, Richardson LP, Morishima C, et al. Prevalence of hepatitis C virus infection and risk factors in an incarcerated juvenile population: a pilot study. Pediatrics 2003;111:153-7.). Before 1992, blood transfusion was a source of HCV infection in children; a recent retrospective study found that 3% of infants who had received blood transfusions in a neonatal intensive-care unit during 1975-1992 were anti-HCV-positive (703Cagle HH, Jacob J, Homan CE, et al. Results of a general hepatitis C lookback program for persons who received blood transfusions in a neonatal intensive care unit between January 1975 and July 1992. Arch Pediatr Adolesc Med 2007;161:125-30.). However, the incidence of HCV infection from transfusion has dramatically declined since 1992, when secondgeneration HCV EIA screening was implemented. With the current additional use of nucleic acid amplification testing, the risk for HCV infection through transfusion is approximately 1 per 2 million (704Stramer SL. Current risks of transfusion-transmitted agents: a review. Arch Pathol Lab Med 2007;131:702-7.).

Chronic HCV infection, defined as the presence of HCV RNA for >6 months, appears to spontaneously resolve in 15%-40% of adults (730Scott JD, Gretch DR. Molecular diagnostics of hepatitis C virus infection: a systematic review. JAMA 2007;297:724-32.). Findings from a limited number of longitudinal studies suggest that HCV infection resolves spontaneously in 17%-59% of children with perinatal HCV infection (731El Sherbini A, Hassan W, Abdel-Hamid M, et al. Natural history of hepatitis C virus among apparently normal schoolchildren: follow-up after 7 years. J Trop Pediatr 2003;49:384-5., 732Rerksuppaphol S, Hardikar W, Dore GJ. Long-term outcome of vertically acquired and post-transfusion hepatitis C infection in children. J Gastroenterol Hepatol 2004;19:1357-62., 733England K, Pembrey L, Tovo PA, et al. Growth in the first 5 years of life is unaffected in children with perinatally acquired hepatitis C infection. J Pediatr 2005;147:227-32., 734Resti M, Jara P, Hierro L, et al. Clinical features and progression of perinatally acquired hepatitis C virus infection. J Med Virol 2003;70:373-7., 735European Paediatric Hepatitis C Virus Network. Three broad modalities in the natural history of vertically acquired hepatitis C virus infection. Clin Infect Dis 2005;41:45-51., 736Bortolotti F, Resti M, Marcellini M, et al. Hepatitis C virus (HCV) genotypes in 373 Italian children with HCV infection: changing distribution and correlation with clinical features and outcome. Gut 2005;54:852-7.). Viral clearance occurs by age 3 years in most children and may be more frequent in children infected with HCV genotype 3 (735European Paediatric Hepatitis C Virus Network. Three broad modalities in the natural history of vertically acquired hepatitis C virus infection. Clin Infect Dis 2005;41:45-51., 737Guido M, Rugge M, Jara P, et al. Chronic hepatitis C in children: the pathological and clinical spectrum. Gastroenterology 1998;115: 1525-9.).

Clinical Manifestations

Children with perinatal HCV infection appear to have a more benign clinical course than do adults with newly acquired HCV infection (701Jara P, Resti M, Hierro L, et al. Chronic hepatitis C virus infection in childhood: clinical patterns and evolution in 224 white children. Clin Infect Dis 2003;36:275-80., 738Aach RD, Yomtovian RA, Hack M. Neonatal and pediatric posttransfusion hepatitis C: a look back and a look forward. Pediatrics 2000;105(4 Pt 1):836-42., 739Mohan P, Colvin C, Glymph C, et al. Clinical spectrum and histopathologic features of chronic hepatitis C infection in children. J Pediatr 2007;150:168-74, 174.e1.). Most HCV-infected children are asymptomatic, with minor abnormalities, such as hepatomegaly, or mild nonspecific symptoms, such as fatigue, myalgias, and poor weight gain (701Jara P, Resti M, Hierro L, et al. Chronic hepatitis C virus infection in childhood: clinical patterns and evolution in 224 white children. Clin Infect Dis 2003;36:275-80., 739Mohan P, Colvin C, Glymph C, et al. Clinical spectrum and histopathologic features of chronic hepatitis C infection in children. J Pediatr 2007;150:168-74, 174.e1., 740Davison SM, Mieli-Vergani G, Sira J, et al. Perinatal hepatitis C virus infection: diagnosis and management. Arch Dis Child 2006; 91:781-5.); however, intermittent asymptomatic elevations in transaminase levels are common during the first 2 years of life (734Resti M, Jara P, Hierro L, et al. Clinical features and progression of perinatally acquired hepatitis C virus infection. J Med Virol 2003;70:373-7., 740Davison SM, Mieli-Vergani G, Sira J, et al. Perinatal hepatitis C virus infection: diagnosis and management. Arch Dis Child 2006; 91:781-5., 741Tovo PA, Pembrey LJ, Newell ML. Persistence rate and progression of vertically acquired hepatitis C infection. European Paediatric Hepatitis C Virus Infection. J Infect Dis 2000;181:419-24.). In a large European cohort of HCV-infected children, about 20% of children had apparent clearance of HCV viremia; 50% had chronic asymptomatic infection, characterized by intermittent viremia, rare hepatomegaly, and usually normal liver transaminase levels; and 30% had chronic active infection with persistent viremia and abnormal transaminase levels (735European Paediatric Hepatitis C Virus Network. Three broad modalities in the natural history of vertically acquired hepatitis C virus infection. Clin Infect Dis 2005;41:45-51.).

Histopathologic inflammatory changes of chronic hepatitis may be present in persons with chronic HCV infection despite lack of symptoms, normal serum transaminase levels, and low HCV RNA levels (740Davison SM, Mieli-Vergani G, Sira J, et al. Perinatal hepatitis C virus infection: diagnosis and management. Arch Dis Child 2006; 91:781-5.). However, most children with chronic HCV infection who have undergone liver biopsy and are included in published studies typically have mild-to-moderate liver disease as determined by signs of structural alterations, inflammatory activity, and necrosis (701Jara P, Resti M, Hierro L, et al. Chronic hepatitis C virus infection in childhood: clinical patterns and evolution in 224 white children. Clin Infect Dis 2003;36:275-80., 715Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis 2005;192:1880-9., 739Mohan P, Colvin C, Glymph C, et al. Clinical spectrum and histopathologic features of chronic hepatitis C infection in children. J Pediatr 2007;150:168-74, 174.e1., 741Tovo PA, Pembrey LJ, Newell ML. Persistence rate and progression of vertically acquired hepatitis C infection. European Paediatric Hepatitis C Virus Infection. J Infect Dis 2000;181:419-24.). A small subset of children may develop more severe liver disease. In a study of 60 children with perinatally acquired or transfusionacquired HCV infection who were infected for a mean duration of 13 years, 12% had significant fibrosis on liver biopsy (739Mohan P, Colvin C, Glymph C, et al. Clinical spectrum and histopathologic features of chronic hepatitis C infection in children. J Pediatr 2007;150:168-74, 174.e1.). Older age at time of infection and elevated serum gamma-glutamyltranspeptidase correlated with fibrosis; serum transaminase levels correlated with inflammation (739Mohan P, Colvin C, Glymph C, et al. Clinical spectrum and histopathologic features of chronic hepatitis C infection in children. J Pediatr 2007;150:168-74, 174.e1.).

In HIV/HCV-coinfected adults, the natural history of HCV infection appears to be accelerated, with more rapid progression to cirrhosis, decompensated liver disease, HCC, and death (742Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001;33:562-9., 743Merchante N, Girön-González JA, González-Serrano M, et al. Survival and prognostic factors of HIV-infected patients with HCV-related end-stage liver disease. AIDS 2006;20:49-57. 120 MMWR September 4, 2009). Data are minimal on the effect of HIV/ HCV coinfection on the natural history of HCV infection in children and are insufficient to draw conclusions about HCV disease progression in coinfected children (699England K, Thorne C, Newell ML. Vertically acquired paediatric coinfection with HIV and hepatitis C virus. Lancet Infect Dis 2006;6:83-90.).

Data on the impact of HCV infection on HIV disease progression in adults conflict; some studies suggest higher rates of HIV progression, and others do not (699England K, Thorne C, Newell ML. Vertically acquired paediatric coinfection with HIV and hepatitis C virus. Lancet Infect Dis 2006;6:83-90.). The effect of pediatric coinfection on HIV disease progression also is unclear because the number of coinfected children is small, and few studies have evaluated this. Two studies of children with perinatal HIV/HCV coinfection found no increase in HIV progression, but a study of older HIV/HCV-coinfected children with thalassemia infected through transfusion observed more rapid disease progression and higher mortality than in children infected only with HIV (720Papaevangelou V, Pollack H, Rochford G, et al. Increased transmission of vertical hepatitis C virus (HCV) infection to human immunodeficiency virus (HIV)-infected infants of HIV- and HCV-coinfected women. J Infect Dis 1998;178:1047-52., 728Nigro G, D'Orio F, Catania S, et al. Mother to infant transmission of coinfection by human immunodeficiency virus and hepatitis C virus: prevalence and clinical manifestations. Arch Virol 1997;142:453-7., 744Shivraj SO, Chattopadhya D, Grover G, et al. Role of HCV coinfection towards disease progression and survival in HIV-1 infected children: a follow-up study of 10 years. J Trop Pediatr 2006;52:206-11.).

Diagnosis

Testing for HCV infection should be considered for any child whose mother is known to have HCV infection. All HIV-infected adults or adolescents should be tested for HCV infection.

Serologic and nucleic acid tests are used to diagnose HCV infection. HCV RNA first becomes detectable 1-3 weeks after HCV infection and precedes serologic response to HCV (730Scott JD, Gretch DR. Molecular diagnostics of hepatitis C virus infection: a systematic review. JAMA 2007;297:724-32.). A third-generation EIA is available for detecting antibody to HCV (anti-HCV). Passively transferred maternal anti-HCV can be detected for up to 18 months in infants born to HCV-infected mothers. In a large cohort of HCV-exposed but HCV-uninfected children, anti-HCV was present in 15% of children at 12 months, 5% at 15 months, and 2% at 18 months (715Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis 2005;192:1880-9.). Therefore, only the presence of persistent HCV viremia can be used to reliably verify HCV infection in at-risk infants aged <18 months (745Dunn DT, Gibb DM, Healy M, et al. Timing and interpretation of tests for diagnosing perinatally acquired hepatitis C virus infection. Pediatr Infect Dis J 2001;20:715-6.). HCV infection can be diagnosed in such infants using a nucleic acid test to detect HCV RNA after 1 month of age; the sensitivity of the HCV RNA testing is low at birth (22%), but increases to 85% at 6 months (746Polywka S, Pembrey L, Tovo PA, et al. Accuracy of HCV-RNA PCR tests for diagnosis or exclusion of vertically acquired HCV infection. J Med Virol 2006;78:305-10.). Most children with perinatal HCV infection will have a positive HCV RNA test by age 12 months. However, because of intermittent viremia, a single negative HCV RNA test is not conclusive evidence of lack of infection, and HCV RNA should be tested on at least two occasions between age 2 months and 6 months to definitively exclude HCV infection in an HCV-exposed infant (746Polywka S, Pembrey L, Tovo PA, et al. Accuracy of HCV-RNA PCR tests for diagnosis or exclusion of vertically acquired HCV infection. J Med Virol 2006;78:305-10.).

A positive anti-HCV test in a child aged >18 months indicates HCV infection. Supplemental testing with a more specific assay, such as HCV RNA testing, is recommended to prevent the reporting of a false-positive result. A positive HCV RNA test confirms HCV infection and, if positive for >6 months, suggests chronic infection. HCV RNA can be measured qualitatively or quantitatively. Qualitative nucleic acid tests include qualitative PCR and transcription-mediated amplification. Quantitative tests include branched-chain DNA amplification, quantitative PCR, and real-time PCR and are most useful for monitoring response to anti-HCV therapy (730Scott JD, Gretch DR. Molecular diagnostics of hepatitis C virus infection: a systematic review. JAMA 2007;297:724-32.). Quantitative HCV RNA level (i.e., HCV viral load) does not correlate with degree of liver damage and does not serve as a surrogate for measuring disease severity, but it does provide important information about the response to antiviral therapy. Assays vary substantially, and if serial values are required to monitor antiviral therapy, continued use of the same quantitative assay for all assessments is strongly recommended.

Liver biopsy is the most accurate test to assess the severity of hepatic disease and quantitate the amount of hepatic fibrosis present. A liver biopsy may be useful for determining whether to initiate therapy for chronic HCV infection (652Koziel MJ, Peters MG. Viral hepatitis in HIV infection. N Engl J Med 2007;356:1445-54., 657Shneider BL, González-Peralta R, Roberts EA. Controversies in the management of pediatric liver disease: hepatitis B, C and NAFLD. Summary of a single topic conference. Hepatology 2006;44:1344-54.). However, liver biopsy is not required before the initiation of anti-HCV therapy, particularly in patients with a high probability of responding to therapy.

At least six HCV genotypes are known, with genotype 1 occurring most commonly in the United States (730Scott JD, Gretch DR. Molecular diagnostics of hepatitis C virus infection: a systematic review. JAMA 2007;297:724-32.). Persons with HCV genotypes 2 and 3 are more likely than those with genotype 1 to achieve sustained virologic response to anti-HCV therapy; thus, results from a liver biopsy may be less likely to affect decisions about the need for treatment in patients with genotypes 2 or 3 (657Shneider BL, González-Peralta R, Roberts EA. Controversies in the management of pediatric liver disease: hepatitis B, C and NAFLD. Summary of a single topic conference. Hepatology 2006;44:1344-54., 687Gonzalez-Peralta R, Kelly DA, Haber B, et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology 2005;42:1010-8.).

Prevention Recommendations

Prevention of Exposure

All HIV-infected persons should be screened for HCV. No reliable strategy exists to prevent perinatal HCV transmission. Cesarean delivery is not associated with reduced perinatal transmission of HCV infection and is not recommended for this purpose for women with chronic HCV infection who are HIV-uninfected. Scheduled cesarean delivery is recommended for HIV-infected women who have HIV RNA levels >1000 copies/mL near delivery to prevent perinatal HIV transmission (AII). Limited data suggest that breast-feeding does not transmit HCV. However, to prevent HIV transmission in the United States, where safe infant formula is available, HIV-infected women should not breast-feed (AII) (747Perinatal HIV Guidelines Working Group. Public Health Service Task Force Recommendations for use of antiretroviral drugs in pregnant HIV-infected women for mternal health and interventions to reduce perinatal HIV-1 transmission in the United States. July 8, 2008:1-98. Available at http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf.).

No vaccines are available to prevent HCV infection. Adolescents considering tattooing or body-piercing should be informed about potential risks for acquiring HCV, which could be transmitted if equipment is not sterile or if proper infection-control procedures are not followed, and to avoid injection-drug use and unprotected sex (BIII) (748CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47(No. RR-19).). HCV-infected persons should be advised not to share toothbrushes, razors, and other personal-care articles that might be contaminated with blood to prevent transmission of HCV.

Preventing First Episode of Disease

Patients with chronic liver disease can develop fulminant hepatitis from hepatitis A or B infection; all children (regardless of HIV and HCV infection status) should receive standard vaccination with hepatitis A and B vaccines (AIII) (39CDC. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR 2006;55(No. RR-7)., 40CDC. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2005;54(No. RR-7)., 748CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47(No. RR-19).).

Treatment Recommendations

Treatment of Disease

Published studies are limited on treatment recommendations for HCV-infected children. Current pediatric trials in the United States - including the PEDS-C study, a randomized, double-blind, placebo-controlled trial of pegylated interferonalfa with and without ribavirin - should provide additional data. Data on treating children coinfected with HCV and HIV are even more limited. Consultation with experts in treating chronic HCV infection in children is recommended.

HIV/HCV-coinfected adults and adolescents

Treatment should be considered in any nonpregnant HCV-infected adult, regardless of HIV coinfection status, who has abnormal serum transaminase levels with a liver biopsy showing chronic hepatitis with significant fibrosis and compenstated liver disease (749Strader DB, Wright T, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:1147-71.). Treatment should be considered for HIV/ HCV-coinfected adults for whom potential benefits of treatment are judged to outweigh potential risks, including those infected with HCV genotype 2 or 3, those with stable HIV infection not requiring antiretroviral therapy, and those with cryoglobulinemic vasculitis or glomerulonephritis (652Koziel MJ, Peters MG. Viral hepatitis in HIV infection. N Engl J Med 2007;356:1445-54., 750Soriano V, Puoti M, Sulkowski M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS 2007;21:1073-89.). Baseline serum HCV RNA level and HCV genotype are the primary predictors of response to treatment; younger age, higher CD4 count, elevated transaminase levels, lack of liver fibrosis, low body mass index, lack of insulin resistance, and white race are other variables associated with better treatment response (750Soriano V, Puoti M, Sulkowski M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS 2007;21:1073-89.). The recommended treatment is combined pegylated-interferon-alfa-2a or-2b plus daily oral ribavirin for 48 weeks regardless of HCV genotype. In HIV/HCVcoinfected adults, rates of sustained virologic response range from 44% to 73% for treatment of HCV genotype 2 and 3 infection and from 14% to 29% for HCV genotype 1 infection(641Elisofon SA, Jonas MM. Hepatitis B and C in children: current treatment and future strategies. Clin Liver Dis 2006;10:133-48., 751Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-82., 752Chung RT, Andersen J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004;351:451-9.). Although some preliminary data from clinical treatment trials suggest better rates of sustained virologic response, these may result from better preselection of patients for therapy or improved adherence after dose adjustment(s). Response to anti-HCV treatment improves in HIV/HCV-coinfected adults with CD4 count >200 cells/mm³; therefore, HAART should be considered before anti-HCV therapy is initiated in HIV/HCV-coinfected patients with CD4 count <200 cells/mm³. Anti-HCV treatment usually is not recommended during pregnancy for HCV-infected women because ribavirin is teratogenic.

HCV-infected children without HIV infection

Treatment of HIV-uninfected children aged <3 years who have HCV infection usually is not recommended because spontaneous HCV clearance can occur in this age group (DIII). All decisions about treatment of HCV infection in children should be individualized because HCV usually causes mild disease in children, and few data exist to identify risk factors differentiating those at greater risk for progression of liver disease (641Elisofon SA, Jonas MM. Hepatitis B and C in children: current treatment and future strategies. Clin Liver Dis 2006;10:133-48., 753Narkewicz MR, Cabrera R, Gonzalez-Peralta RP. The ”C” of viral hepatitis in children. Semin Liver Dis 2007;27:295-311.).

The only currently FDA-approved therapy for HCV-infected children aged 3-17 years with compensated liver disease is combined standard interferon-alfa-2b and ribavirin. Standard interferon-alfa is administered by subcutaneous injection three times per week. Ribavirin oral solution has been approved for treatment of chronic HCV infection among children aged ≥3 years. For HIV-uninfected children with HCV infection, a 24-week course of therapy is recommended for genotypes 2 and 3; 48-week courses are administered for other HCV genotypes. Combination therapy with standard interferon-alfa and ribavirin results in overall rates of sustained virologic response of 46%-65% and is well-tolerated in children (657Shneider BL, González-Peralta R, Roberts EA. Controversies in the management of pediatric liver disease: hepatitis B, C and NAFLD. Summary of a single topic conference. Hepatology 2006;44:1344-54., 687Gonzalez-Peralta R, Kelly DA, Haber B, et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology 2005;42:1010-8., 754Christensson B, Wiebe T, Akesson A, et al. Interferon-alpha and ribavirin treatment of hepatitis C in children with malignancy in remission. Clin Infect Dis 2000;30:585-6., 755Lackner H, Moser A, Deutsch J, et al. Interferon-alpha and ribavirin in treating children and young adults with chronic hepatitis C after malignancy. Pediatrics 2000;106:E53., 756Kowala-Piaskowska A, Sluzewski W, Figlerowicz M, et al. Early virological response in children with chronic hepatitis C treated with pegylated interferon and ribavirin. Infection 2007;35:175-9., 757Wirth S, Lang T, Gehring S, et al. Recombinant alfa-interferon plus ribavirin therapy in children and adolescents with chronic hepatitis C. Hepatology 2002;36:1280-4.). Similar to adults, children infected with genotype 1 were less likely to have a sustained virologic response (36%) than those infected with genotype 2 or 3 (84%) (687Gonzalez-Peralta R, Kelly DA, Haber B, et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology 2005;42:1010-8.). Other factors associated with favorable response to anti- HCV treatment in children include lower pretreatment HCV RNA levels, white race, and possibly younger age (657Shneider BL, González-Peralta R, Roberts EA. Controversies in the management of pediatric liver disease: hepatitis B, C and NAFLD. Summary of a single topic conference. Hepatology 2006;44:1344-54.).

HIV/HCV-coinfected children

No specific treatment studies have been done of children with HIV/HCV-coinfection, and recommendations are based primarily on data from adults. Because therapy for HCV infection is more likely to be effective in younger patients and in those without advanced disease or immunodeficiency, treatment should be considered for all HIV/HCV-coinfected individuals, including HIV-infected children aged >3 years who have no contraindications to treatment (BIII). Some specialists would treat children infected with HCV genotypes 2 or 3 without first obtaining a liver biopsy (BIII). Pegylated interferon-alfa, which is administered by injection once weekly for 48 weeks combined with ribavirin, is recommended for treatment of HCV infection in adults. However, pegylated interferon-alfa is not FDA-approved for use in HCV-infected children - although it is under study. On the basis of the increased efficacy of combination therapy with ribavirin and either standard or pegylated interferon-alfa and on data from adults, treatment of HCV-infected children, regardless of HIV status, should include combination therapy with ribavirin and interferon-alfa (BIII). In HIV/HCV-coinfected adults, the recommended duration of treatment is 48 weeks for infections with all HCV genotypes, including 2 and 3, because coinfected adults may not respond as well as those without HIV infection and may have greater relapse rates. Moreover, the efficacy of shorter treatment duration has not been adequately evaluated in HIV-infected persons (750Soriano V, Puoti M, Sulkowski M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS 2007;21:1073-89.). By extrapolation, 48 weeks of therapy also are recommended for HIV/HCV-coinfected children (BIII). Potential drug interactions complicate the concomitant use of antiretroviral therapy and anti-HCV therapy. Ribavirin enhances phosphorylation of didanosine, which could increase the risk for toxicity; therefore, these drugs should not be used together (EIII). Ribavirin and zidovudine both are associated with anemia and, when possible, should not be administered together (DII) (750Soriano V, Puoti M, Sulkowski M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS 2007;21:1073-89.).

Monitoring and Adverse Events, Including IRIS

Although no evidence-based long-term monitoring guidelines exist for children with perinatally acquired HCV, many experts monitor HCV RNA levels and serum transaminase levels every 6-12 months and hemogram and serum alpha fetoprotein levels annually (748CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47(No. RR-19).). Serum transaminase levels can fluctuate and do not necessarily correlate with histologic liver damage because significant liver disease can be present in patients with normal serum transaminase levels. In HCV-infected persons without HIV, HCC rarely is seen in the absence of cirrhosis. The benefits of serum alpha fetoprotein and abdominal sonography as screening tools for HCC have not been studied in children. Some experts will perform periodic sonographic screening at defined intervals (every 2-5 years) in children with chronic HCV infection; others will do these tests only in those with advanced liver disease and/ or rising serum alpha fetoprotein concentrations (748CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47(No. RR-19).). The risk for HCC in HCV-infected children, with or without HIV infection, is not known.

HCV RNA quantitation is used to monitor response to antiviral therapy. HCV RNA levels should be performed at baseline, after 12 and 24 weeks of antiviral therapy, at treatment completion (48 weeks), and 6 months after treatment cessation. Some experts continue to perform serial HCV RNA testing at 6- to 12-month intervals for an additional 1-5 years to exclude late virologic relapse. Decreases in HCV RNA ≥2 logs below the baseline during the first 12 weeks of therapy constitute an early virologic response (730Scott JD, Gretch DR. Molecular diagnostics of hepatitis C virus infection: a systematic review. JAMA 2007;297:724-32.). A sustained virologic response is defined as absence of detectable HCV RNA using an HCV RNA assay with a lower limit of detection of ≥50 IU/mL at 24 weeks after antiviral treatment ends. Relapse is defined as HCV RNA rebound at the end of therapy after an initial response to undetectable HCV RNA levels. Nonresponse is defined as failure to suppress HCV RNA below detection at any time during treatment; breakthrough is the reemergence of detectable HCV RNA after suppression below the limits of detection despite the continuation of therapy.

In the absence of data from HIV/HCV-coinfected children, the same criteria for determining response to therapy in HIV/ HCV-coinfected adults should be used. If an early virologic response is observed after the first 12 weeks of treatment, completion of additional HCV therapy is recommended. Adults who do not achieve an early virologic response by week 12 have a limited chance (<3%) of achieving sustained virologic response, regardless of duration of therapy, and treatment can be discontinued after 12 weeks in such patients. Persons who achieve a ≥2 log₁₀ reduction in HCV RNA level but who have detectable HCV RNA after 12 weeks of therapy should be retested after completion of 24 weeks of therapy. If HCV RNA remains detectable after 24 weeks, anti-HCV treatment should be stopped, whereas an additional 24 weeks of therapy is indicated (total 48 weeks) if HCV RNA is not detected at that time. Persons who achieve an undetectable HCV RNA level after 12 weeks of therapy should complete an additional 36 weeks of anti-HCV treatment (total 48 weeks).

In addition to HCV RNA quantitation, patients receiving antiviral therapy for HCV infection should be closely monitored for medication side effects with complete blood count, serum transaminase levels, and tests of thyroid function. If the child also is initiating HAART, some experts would monitor transaminase levels more frequently during the first few months of therapy (e.g., monthly for 3 months) because of the risk for IRIS (see below).

Side effects of interferon-alfa in children, although frequent, usually are not severe; approximately 5% of children require treatment discontinuation because of side effects. The most common side effects include influenza-like symptoms (e.g., fever, chills, headache, myalgias, arthralgias, abdominal pain, nausea, and vomiting) in 80% of patients during the first month of treatment. However, these symptoms usually resolve over time and usually are not treatment-limiting; premedication with acetaminophen or ibuprofen might reduce the incidence of side effects. Subtle personality changes that resolve when therapy is discontinued have been reported in 42% of children (686Sokal EM, Conjeevaram HS, Roberts EA, et al. Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial. Gastroenterology 1998;114:988-95.). Depression and suicidal ideation also have been reported in clinical trials of children treated with interferon-alfa (687Gonzalez-Peralta R, Kelly DA, Haber B, et al. Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics. Hepatology 2005;42:1010-8.). Neutropenia, which resolves after discontinuation of therapy, is the most common laboratory abnormality; anemia and thrombocytopenia are less common. Abnormalities in thyroid function (hypothyroidism or hyperthyroidism) have been reported with interferon-alfa therapy (688Kuloglu Z, Kansu A, Berberoglu M, et al. The incidence and evolution of thyroid dysfunction during interferon-alpha therapy in children with chronic hepatitis B infection. J Pediatr Endocrinol Metab 2007;20:237-45.). Loss of appetite, with transient weight loss and impaired height growth, can occur but usually resolves after completion of therapy (689Comanor L, Minor J, Conjeevaram HS, et al. Impact of chronic hepatitis B and interferon-alpha therapy on growth of children. J Viral Hepat 2001;8:139-47.). Less commonly observed side effects of interferon-alfa include epistaxis and transient mild alopecia. Certain children have developed antinuclear autoantibodies. Interferon-alfa therapy is contraindicated for children with decompensated liver disease; substantial cytopenias; severe renal, cardiac, or neuropsychiatric disorders; and autoimmune disease (EII) (690Jara P, Bortolotti F. Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children. J Pediatr Gastroenterol Nutr 1999;29:163-70.).

Side effects of ribavirin include hemolytic anemia and lymphopenia. Ribavirin-induced hemolytic anemia is dosedependent and usually presents with a substantial decrease in hemoglobin within 1-2 weeks after ribavirin initiation, but the trend usually stabilizes. Significant anemia (hemoglobin <10 g/dL) occurs in about 10% of ribavirin-treated children (753Narkewicz MR, Cabrera R, Gonzalez-Peralta RP. The ”C” of viral hepatitis in children. Semin Liver Dis 2007;27:295-311.). Use of erythropoietin for managing clinically significant anemia during HCV treatment can be considered (BIII). Coadministration of didanosine is contraindicated in children receiving ribavirin because this combination can increase the risk for mitochondrial toxicity and hepatic decompensation (EIII). Children receiving concomitant zidovudine may be more likely to experience bone marrow suppression; if possible, zidovudine should be avoided in children receiving ribavirin (DIII). If zidovudine and ribavirin are administered together, the child should be monitored closely for neutropenia and anemia. Ribavirin is teratogenic and should not be used in pregnant women. Sexually active adolescent boys and girls or those likely to become sexually active who are receiving ribavirin should be counseled about the risks and need for consistent contraceptive use during, and for 6 months after completion of, ribavirin therapy.

As with HIV/HBV coinfection, the institution of HAART in HIV/HCV-coinfected patients can worsen hepatitis, with increases in serum transaminase levels and clinical signs of liver disease, including hepatomegaly and jaundice. This does not represent a failure of HAART but rather a sign of immune reconstitution. IRIS manifests by an increase in serum transaminase levels as the CD4 count increases during the first 6-12 weeks of HAART. Thus, serum transaminase levels should be monitored closely after introduction of HAART in HIV/ HCV-coinfected children. The prognosis for most persons with IRIS is favorable because a robust inflammatory response may predict an excellent response to HAART in terms of immune reconstitution and, perhaps, improved survival. In a patient experiencing a hepatic flare, differentiating between IRIS and drug-induced liver toxicity may be difficult, and no reliable clinical or laboratory predictors exist to distinguish between the two. Close interaction of the HIV specialist with a specialist in hepatic disease is recommended for such patients; prompt consultation with a hepatologist should be sought if elevated aminotransferases are associated with clinical jaundice or other evidence of liver dysfunction (e.g., low serum albumin).

Management of Treatment Failure

No data exist on which to base recommendations for treatment of HIV/HCV-coinfected children or adults in whom initial HCV treatment fails. In HIV/HCV-coinfected adults, a second course of treatment for nonresponders (those who do not achieve early virologic response by week 12 or undetectable HCV load at week 24) or patients whose HCV relapses has limited chances of resulting in sustained virologic response. Therapeutic interventions for such patients need to be individualized according to prior response, tolerance, and adherence to therapy; severity of liver disease; viral genotype; and other underlying factors that might influence response. Some experts might extend the duration of treatment (e.g., to 72 weeks) for adults who experience a virologic response followed by relapse after adequate HCV therapy or for patients with advanced fibrosis, long-term administration of low-dose pegylated interferon. No data exist for HIV/HCV-coinfected children on which to base a recommendation.

Prevention of Recurrence

Not applicable.

Discontinuing Secondary Prophylaxis

Not applicable.

Recommendations for treatment of opportunistic infections in HIV-exposed and HIV-infected infants and children, United States*†: Hepatitis C virus

Preferred therapies and duration

Alternative therapies

Other options or issues

Excerpted from Table 4

* HIV=human immunodeficiency virus; PCP=Pneumocystis pneumonia; TB=tuberculosis; IV=intravenous; IV=intravenous; IM=intramuscularly; CSF=cerebrospinal fluid;CNS=central nervous system; TMP/SMX=trimethoprim-sulfamethoxazole; HAART=highly active antiretroviral therapy; CMV=cytomegalovirus. HBV=hepatitis B virus; HBeAg=hepatitis B e antigen; HCV=hepatitis C virus; IRIS=immune reconstitution inflammatory syndrome; PCR=polymerase chain reaction; HSV=herpes simplex virus; HPV=human papillomavirus

† Information in these guidelines might not represent Food and Drug Administration (FDA) approval or approved labeling for products or indications. Specifically, the terms safe and effective might not be synonymous with the FDA-defined legal standards for product approval. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendations and the quality of evidence supporting it (see Box).

Interferon-alfa PLUS ribavirin combination therapy (BIII):

		Interferon-alfa-2a or -2b, 3-5 million units/ m² body surface area subcutaneously or IM 3 times weekly (max 3 million units/dose); PLUS

		Ribavirin (oral), 15 mg/kg body weight daily in 2 divided doses (fixed dose by weight recommended):

— 25-36 kg: 200 mg a.m. and p.m.

— >36-49 kg: 200 mg in a.m. and 400 mg in p.m.

— >49-61 kg: 400 mg in a.m. and p.m.

— >61-75 kg: 400 mg in a.m. and 600 mg in p.m..

— >75 kg: 600 mg in a.m. and p.m.

Treatment duration: 48 wks, regardless of HCV genotype (BIII)

For children in whom ribavirin is contraindicated (e.g., who have unstable cardiopulmonary disease, preexisting anemia or hemoglobinopathy):

		Interferon-alfa-2a or -2b, 3-5 million units/m² body surface area (max 3 million units/dose) subcutaneously or IM 3 times weekly (BII)

Length of treatment for HIV/HCV-coinfected children is unknown and based on recommendations for HIV/HCV-coinfected adults (BIII).

Treatment of HCV in children <3 yrs generally is not recommended (DIII).

Indications for treatment are based on recommendations in HIV/ HCV-coinfected adults; because HCV therapy is more likely to be effective in younger patients and in patients without advanced disease or immunodeficiency, treatment should be considered for all HIV/HCV-infected children >3 yrs who have no contraindications for treatment (BIII).

IRIS may be manifested by dramatic increase in transaminases as CD4 counts rise within the first 6-12 wks of HAART. Distinguishing between druginduced hepatotoxicity or other causes of hepatitis and IRIS may be difficult.

Interferon-alfa is contraindicated in children with decompensated liver disease, significant cytopenias, severe renal or cardiac disorders, and autoimmune disease (EII).

Ribavirin is contraindicated in children with unstable cardiopulmonary disease, severe preexisting anemia or hemoglobinopathy (EII).

Didanosine combined with ribavirin may lead to increased mitochondrial toxicities; concomitant use is contraindicated (EIII).

Ribavirin and zidovudine both are associated with anemia and when possible should not be administered together (DII).

Pegylated interferon-alfa is not approved for use in children, although it is under study; in adults, pegylated interferon-alfa–2a (180 µg) or –2b (1.5 µg/kg) subcutaneously once weekly PLUS ribavirin is the treatment of choice in adults with chronic HCV hepatitis warranting treatment (AI).

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