Treatment of Hepatitis C in Children

Abstract

Purpose of Review

The aim of this study is to summarize the state of treatment of hepatitis C virus (HCV) infection in children.

Recent Findings

The 100 articles on HCV in children from 2011 to 2016 contained only one report of a trial with direct acting antiviral agents (DAAs) and none of these agents are yet FDA-approved for children. Thus, we will focus on issues critical to the understanding of the problem of HCV in the pediatric age group including global epidemiology and natural history, as well as results of treatment with the only agents currently FDA-approved for pediatric use: pegylated interferon alpha 2a or 2b plus ribavirin. In addition, the pediatric trials with DAAs in progress will be described.

Summary

Standard therapy is indicated for some children with HCV but the majority should await approval of DAAs. An algorithm for management and treatment of subjects <18 years of age at the present time is provided.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol. 2014;61:S45–57. doi:10.1016/j.jhep.2014.07.027.

    Article  PubMed  Google Scholar 

  2. 2.

    • Ohmer S, Honegger J. New prospects for the treatment and prevention of hepatitis C in children. Curr Opin Pediatr. 2016;28:93–100. doi:10.1097/MOP.0000000000000313. This regimen could be considered in many children who DAAs are not yet available

  3. 3.

    Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556–62. doi:10.1056/NEJM199908193410802.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Jhaveri R, Grant W, Kauf TL, McHutchison J. The burden of hepatitis C virus infection in children; estimated direct medical costs over a ten year period. J Pediatr. 2006;148:353–8. doi:10.1016/j.jpeds.2005.10.031.

    Article  PubMed  Google Scholar 

  5. 5.

    Delgado-Borrego A, Gonzalez-Peralta RP, Raza R, Negre B, Goodman ZD, Jonas MM, et al. Correlates of adiponectin in hepatitis C-infected children: the importance of body mass index. J Pediatr Gastroenterol Nutr. 2015;60:165–70. doi:10.1097/MPG.0000000000000604.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Prussing C, Bornschlegel K, Balter S. Hepatitis C surveillance among youth and young adults in New York City, 2009–2013. J Urban Health. 2015;92:387–99. doi:10.1007/s11524-014-9920-5.

    Article  PubMed  Google Scholar 

  7. 7.

    Nainan OV, Alter MJ, Kruszon-Moran D, Gao FX, Xia G, McQuillan G, et al. Hepatitis C virus genotypes and viral concentrations in participants of a general population survey in the United States. Gastroenterology. 2006;131:478–84. doi:10.1056/NEJM199908193410802.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    • El-Shabrawi MH, Kamal NM. Burden of pediatric hepatitis C. World J Gastroenterol. 2013;28:7880–8. doi:10.3748/wjg.v19.i44.7880. While no specific treatment is available during pregnancy or at the time of delivery to prevent the vertical infection, El-Shabrawi et al pointed out the global economic and emotional burden of HCV infection for children, families, and countries

  9. 9.

    Granot E, Sokal EM. Hepatitis C virus in children: deferring treatment in expectation of direct-acting antiviral agents. Isr Med Assoc J. 2015;17:707–11.

    PubMed  Google Scholar 

  10. 10.

    Elrazek AE, Amer M, Hawary B, Salah A, Bhagavathula AS, Al Boraie M, et al. Prediction of HCV vertical transmission: what are factors should be optimized using data mining computational analysis. Liver Int. 2016. doi:10.1111/liv.13146.

    PubMed  Google Scholar 

  11. 11.

    Koneru A, Nelson N, Hariri S, Canary L, Sanders KJ, Maxwell JF, et al. Increased hepatitis C virus (HCV) detection in women of childbearing age and potential risk for vertical transmission—United States and Kentucky, 2011–2014. MMWR Morb Mortal Wkly Rep. 2016;65:705–10. doi:10.15585/mmwr.mm6528a2

  12. 12.

    Mast EE, Hwang LY, Seto DS, Nolte FS, Nainan OV, Wurtzel H, Alter MJ, 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(11):1880-9. Epub 2005 Oct 28.

  13. 13.

    • Benova L, Mohamoud YA, Calvert C, Abu-Raddad LJ. Vertical transmission of hepatitis C virus: systematic review and meta-analysis. Clin Infect Dis. 2014;59(6):765–73. doi:10.1093cid/ciu447 Benova et al performed a thorough review and meta-analysis on vertical transmission of hepatitis C virus. This review emphasizes certain risk factors which promote the vertical transmission as a major mode for HCV infection in children

  14. 14.

    Garcia-Tejedor A, Maiques-Montesinos V, Diago-Almela VJ, Pereda-Perez A, Alberola-Cuñat V, López-Hontangas JL, et al. Risk factors for vertical transmission of hepatitis C virus: a single center experience with 710 HCV-infected mothers. Eur J Obstet Gynecol Reprod Biol. 2015;194:173-7. doi: 10.1016/j.ejogrb.2015.09.009. Epub 2015 Sep 11

  15. 15.

    Benova L, Awad SF, Miller FD, Abu-Raddad LJ. Estimation of hepatitis C virus infections resulting from vertical transmission in Egypt. Hepatology. 2015;61:834–42. doi:10.1002/hep.27596.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Mahmoud RA, El-Mazary AA, Khodeary A. Seroprevalence of hepatitis C, hepatitis B, cytomegalovirus, and human immunodeficiency viruses in multitransfused thalassemic children in upper Egypt. Adv Hematol. 2016;2016:9032627. doi:10.1155/2016/9032627.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    • Kuncio DE, Newbern EC, Johnson CC, Viner KM. Failure to test and identify perinatally infected children born to hepatitis C virus-infected women. Clin Infect Dis. 2016;62:980–5. doi:10.1093/cid/ciw026.

    Article  PubMed  Google Scholar 

  18. 18.

    Resti M, Bortolotti F, Vajro P, Maggiore G, Committee of Hepatology of the Italian Society of Pediatric Gastroenterology and Hepatology. Guidelines for the screening and follow-up of infants born to anti-HCV positive mothers. Dig Liver Dis. 2003;35:453–7.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Resti M, Jara P, Hierro L, Azzari C, Giacchino R, Zuin G, et al. Clinical features and progression of perinatally acquired hepatitis C virus infection. J Med Virol. 2003;70:373–7. doi:10.1002/jmv.10405.

    Article  PubMed  Google Scholar 

  20. 20.

    Yeung LT, To T, King SM, Roberts EA. Spontaneous clearance of childhood hepatitis C virus infection. J Viral Hepatol. 2007;14:797–805. doi:10.1111/j.1365-2893.2007.00873.x.

    CAS  Article  Google Scholar 

  21. 21.

    Farmand S, Wirth S, Loffler H, Woltering T, Kenzel S, Lainka E, et al. Spontaneous clearance of hepatitis C virus in vertically infected children. Eur J Pediatr. 2012;171:253–8. doi:10.1007/s00431-011-1517-3.

    Article  PubMed  Google Scholar 

  22. 22.

    Bortolotti F, Verucchi G, Camma C, Cammà C, Cabibbo G, Zancan L, et al. Long-term course of chronic hepatitis C in children: from viral clearance to end-stage liver disease. Gastroenterology. 2008;134:1900–7. doi:10.1053/j.gastro.2008.02.082.

    Article  PubMed  Google Scholar 

  23. 23.

    Chen ST, Ni YH, Chen PJ, Chen HL, Jeng YM, Lu MY, et al. Low viraemia at enrollment in children with chronic hepatitis C favours spontaneous viral clearance. J Viral Hepat. 2009;16:796–801. doi:10.1111/j.1365-2893.2009.01135.x.

    Article  PubMed  Google Scholar 

  24. 24.

    Mousa SM, El-Ghamrawy MK, Gouda H, Khorshied M, El-Salam Ahmed DA, Shiba H. Prevalence of hepatitis C among Egyptian children with sickle cell disease and the role of IL28b gene polymorphisms in spontaneous viral clearance. Mediterr J Hematol Infect Dis. 2016;8, e2016007. doi:10.4084/MJHID.2016.007.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Casiraghi MA, De PM, Romano L, Biffi R, Assi A, Binelli G, et al. Long-term outcome (35 years) of hepatitis C after acquisition of infection through mini transfusions of blood given at birth. Hepatology. 2004;39:90–6. doi:10.1002/hep.20030.

    Article  PubMed  Google Scholar 

  26. 26.

    Vogt M, Lang T, Frosner G, Klingler C, Sendl AF, Zeller A, et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med. 1999;341:866–70. doi:10.1056/NEJM199909163411202.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Pokorska-Śpiewak M, Kowalik-Mikołajewska B, Aniszewska M, Pluta M, Walewska-Zielecka B, Marczyńska M. Determinants of liver disease progression in children with chronic hepatitis C virus infection. Pol J Pathol. 2015;66:368–75.

    Article  PubMed  Google Scholar 

  28. 28.

    Valva P, Casciato P, Lezama C, Galoppo M, Gadano A, Galdame O, et al. Serum apoptosis markers related to liver damage in chronic hepatitis C: sFas as a marker of advanced fibrosis in children and adults while M30 of severe steatosis only in children. PLoS One. 2013;8, e53519. doi:10.1371/journal.pone.0053519.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Viswanathan P, Kogan-Liberman D, Thompson JF, Schwartz D, Pan DH. Hepatocellular carcinoma in a child with chronic hepatitis C and α-1 antitrypsin heterozygosity. J Pediatr Gastroenterol Nutr. 2017;64:e22–4. doi:10.1097/MPG.0000000000000574.

    Article  PubMed  Google Scholar 

  30. 30.•

    European Paediatric HIVHCV Co-infection Study Group in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) in EuroCoord. Coinfection with HIV and hepatitis C virus in 229 children and young adults living in Europe. AIDS. 2017;31(1):127–35. doi:10.1097/QAD.0000000000001285. One of the risk factors is HIV/HCV co-infection and this was extensively reported by European Paediatric HIV/HCV study group with progressive liver disease among this vertically acquired HCVinfected children and young adults

    Article  Google Scholar 

  31. 31.

    Mohan P, Barton BA, Narkewicz MR, Molleston JP, Gonzalez-Peralta RP, Rosenthal P, et al. Evaluating progression of liver disease from repeat liver biopsies in children with chronic hepatitis C: a retrospective study. Hepatology. 2013;58:1580–6. doi:10.1002/hep.26519.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Gupta M, Bahirwani R, Levine MH, Malik S, Goldberg D, Reddy KR, et al. Outcomes in pediatric hepatitis C transplant recipients: analysis of the UNOS database. Pediatr Transplant. 2015;19:153–63. doi:10.1111/petr.12408.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Roy A, Wang C, Li C, Lu L, Torbenson M, Hagedorn CH, et al. Phenotypic and genotypic differences between a child with vertically acquired severe hepatitis C liver disease and his mother. J Pediatr Gastroenterol Nutr. 2012;54:567–9. doi:10.1097/MPG.0b013e318229d96f.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Abdelaziz DH, Elhosseiny NM, Khaleel SA, Sabry NA, Attia AS, El-Sayed MH. Association between combined presence of hepatitis C virus and polymorphisms in different genes with toxicities of methotrexate and 6-mercaptopurine in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2016;63:1539–45. doi:10.1002/pbc.26045.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Stallings-Smith S, Krull KR, Brinkman TM, Hudson MM, Ojha RP. Long-term follow-up for incident cirrhosis among pediatric cancer survivors with hepatitis C virus infection. J Clin Virol. 2015;71:18–21. doi:10.1016/j.jcv.2015.07.306.

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Abu Faddan NH, Shehata GA, Abd Elhafeez HA, Mohamed AO, Hassan HS, et al. Cognitive function and endogenous cytokine levels in children with chronic hepatitis C. J Viral Hepat. 2015;22:665–70. doi:10.1111/jvh.12373.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    •• Mack CL, Gonzalez-Peralta RP, Gupta N, Leung D, Narkewicz MR, Roberts EA, et al. NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants, children, and adolescents. J Pediatr Gastroenterol Nutr. 2012;54:838–55. doi:10.1097/MPG.0b013e318258328d. These two papers focus on pediatric aspects of HCV infection in children. The work from Mack et al in 2012 discussed the guideline which details the epidemiology and natural history of HCV infection in children, the diagnostic workup, monitoring and treatment of disease, and provides an update on future treatment options and areas of research

  38. 38.

    • Druyts E, Thorlund K, Wu P, et al. Efficacy and safety of pegylated interferon alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C in children and adolescents: a systematic review and meta-analysis. Clin Infect Dis. 2013;56:961–7. doi:10.1093/cid/cis1031. Despite the promising DAAs regimens, the current cost is high and may not be available for children in developing countries. A systematic review and meta-analysis conducted by Druyts et al indicates effectiveness and safety in treating HCV-infected children with peg-IFN alfa-2a or peg-IFN alfa-2b plus ribavirin

  39. 39.

    Schwarz KB, Gonzalez-Peralta RP, Murray KF, Molleston JP, Haber BA, Jonas MM, et al. Peds-C Clinical Research Network. The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C. Gastroenterology. 2011;140:450-458.e1. doi: 10.1053/j.gastro.2010.10.047

  40. 40.

    Jonas MM, Balistreri W, Gonzalez-Peralta RP, Haber B, Lobritto S, Mohan P, et al. Pegylated interferon for chronic hepatitis C in children affects growth and body composition: results from the pediatric study of hepatitis C (PEDS-C) trial. Hepatology. 2012;56:523–31. doi:10.1097/MPG.0b013e318185998f.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Haber B, Alonso E, Pedreira A, Rodriguez-Baez N, Ciocca M, Lacaille F, et al. Long-term follow-up of children treated with peginterferon and ribavirin for hepatitis C virus infection. J Pediatr Gastroenterol Nutr. 2017;64:89–94. doi:10.1097/MPG.0000000000001239.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Simmons B, Saleem J, Heath K, Cooke GS, Hill A. Long term treatment outcomes of patients infected with hepatitis C virus: a systematic review and meta analysis of the survival benefit of achieving a sustained virological response. Clin Infect Dis. 2015;61:730–40. doi:10.1093/cid/civ396.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Alqahtani SA, Afdhal N, Zeuzem S, Gordon SC, Mangia A, Kwo P, et al. Safety and tolerability of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic hepatitis C virus genotype 1 infection: analysis of phase III ION trials. Hepatology. 2015;62:25–30. doi:10.1002/hep.27890.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Kowdley KV, Gordon SC, Reddy KR, Chojkier M, Herring R, Di Bisceglie AM, et al. ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879–88. doi:10.1056/NEJMoa1402355.

    Article  PubMed  Google Scholar 

  45. 45.

    •• Balistreri WF, Murray KF, Rosenthal P, Bansal S, Chuan-Hao L, Kersey K, et al. The safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12 to 17 years old with hepatitis C virus genotype 1 infection. Hepatology. 2016. doi:10.1002/hep.28995. The recently published phase 2, multi-center, open-label study to evaluate the efficacy and safety of ledipasvir-sofosbuvir in adolescents with chronic HCV genotype 1 infection is a breakthrough in pediatric hepatology field. This study has blazed a trail to a safe, stepwise evaluation of DAAs as all-oral DAAs regimens for the pediatric population

    PubMed  Google Scholar 

  46. 46.

    Graf Einsiedel H, Christiansen H, Wiegand J. Eight weeks treatment with sofosbuvir/ledipasvir in a 4-year-old child with chronic hepatitis C virus genotype 1 infection. Pediatr Infect Dis J. 2016;35(12):1373. doi:10.1097/INF.0000000000001336.

    Article  PubMed  Google Scholar 

  47. 47.

    Smith SK, Rosenthal P. Clearance of hepatitis C virus after fixed-dose combination ledipasvir/sofosbuvir in an adolescent female with decompensated cirrhosis. J Pediatr Gastroenterol Nutr. 2016;63:516–7. doi:10.1097/MPG.0000000000001278.

    CAS  Article  PubMed  Google Scholar 

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Correspondence to Wikrom Karnsakul.

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Conflict of Interest

Kathleen B. Schwarz reports grants from Gilead, grants from Roche/Genentech, and personal fees from Up to Date, outside the submitted work.

Wikrom Karnsakul has had a relationship with Gilead as a sponsor for an Open-Label, Multicenter, Multi-cohort, Single-Arm Study to Investigate the Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and Children with Genotype 2 or 3 Chronic HCV Infection and a Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination in Adolescents and Children with Chronic HCV-Infection and a Long Term Follow-up Registry for Adolescent and Pediatric Subjects Who Received a Gilead Hepatitis C Virus Direct Acting Antiviral (DAA) in Chronic Hepatitis C Infection Trials.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Hepatitis C

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Schwarz, K.B., Karnsakul, W. Treatment of Hepatitis C in Children. Curr Hepatology Rep 16, 18–25 (2017). https://doi.org/10.1007/s11901-017-0334-1

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Keywords

  • Hepatitis C
  • Viral hepatitis
  • Pediatric liver disease
  • Direct acting antivirals
  • Pegylated interferon and ribavirin
  • Epidemiology of HCV in children