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Review Article Chronic Hepatitis C Infection in Children: Current Treatment and New Therapies Andrew Lee1,2*, Jeremy Rajanayagam1,3 and Mona Abdel-Hady1 1Birmingham Children’s Hospital, Liver Unit, Birmingham, United Kingdom; 2The University of Queensland, School of Medicine, Brisbane, Australia; 3University of Birmingham, School of Infection and Immunity, Birmingham, United Kingdom Abstract remains the most common method of infection in the developing world.1,2 The overall rate of spontaneous viral Viral hepatitis C is responsible for a large burden of disease clearance following childhood infection is low, with the worldwide. Treatment of hepatitis C infection is currently majority of children developing chronic hepatitis C (CHC) undergoing a revolution with the development of new direct (54–86%).2 The clinical course of CHC in children is usually acting antivirals that offer higher cure rates and fewer side silent, with mildly abnormal liver function tests (LFTs) and effects than other medications currently available. Treatment minimal inflammation and fibrosis on histology.2–4 options for children, although well-defined and evidence- Nevertheless, fibrosis tends to progress with time, culminat- based, are limited relative to adults as there are few trials ing in cirrhosis in 5–10% or hepatocellular carcinoma (HCC) regarding the use of these newly developed agents in in 2–5% in adulthood.2,3 Thus, continued efforts to effectively children. With so much optimism in the development of novel treat children and reduce the long-term health and social therapeutic options for hepatitis C, it is timely to review and consequences in pediatric CHC are justified. summarize the current standard of care treatment and indications for treatment of chronic hepatitis C in children. Whom and when to treat We provide here an overview of recent drug developments and their potential for use in children. Children with CHC are generally asymptomatic, but long-term E 2015 The Second Affiliated Hospital of Chongqing Medical infection may lead to cirrhosis and HCC over time, and it is University. Published by XIA & HE Publishing Ltd. All rights recognized that the degree of hepatic fibrosis correlates with reserved. age and duration of infection.3 The benefits of treating children with CHC include prevention of disease progression Introduction and future complications and elimination of social stigma and caregiver stress. From a population health point of view, Chronic infection with hepatitis C virus (HCV) carries a treating children with CHC reduces the global and financial significant global health burden in both children and adults, burden of disease that, although not approaching that of adult with approximately 3% of the world’s population infected. CHC, is significant.5 The prevalence of HCV in children is estimated to be 0.4% in Guidelines recommend interferon (IFN) based treatment the United Kingdom (UK), with a greater than ten-fold rise in after age three; IFN is not recommended under the age of 2 prevalence in some developing nations.1,2 Vertical, compared because of the increased chance for spontaneous serocon- to parenteral transmission, is increasingly the major route of version in the first three years of life.6 acquiring HCV in childhood. Transmission rates from non- Children with persistently elevated serum aminotrans- human immunodeficiency virus (HIV) mothers are reported in ferases or those with progressive fibrosis should be consid- around 5% of cases and account for nearly half of all infected ered for treatment. 1 children within the UK. In contrast, parenteral transmission Despite these guidelines, questions still remain regard- ing whom to treat. Uncertainty exists for a number of reasons. Most children with CHC lack clinical or labora- Keywords: Hepatitis C; Children; Treatment; Direct acting antivirals; Host targeting agents. tory evidence of inflammation or progression of disease, Abbreviations: BMI, body mass index; CHC, chronic hepatitis C; Cyp, although they may benefit from treatment. Even in patients cytochrome; DAA, directly acting antivirals; eRVR, extended rapid virologic with mild to moderate evidence of disease, the rate of response; EVR, early viral response; G2/3, genotypes 2 and 3; HCC, hepatocel- progression to significant fibrosis, cirrhosis, and HCC is lular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HTA, host targeting antivirals; IFN, interferon; LFTs, liver function tests; NIs, slow. The decision to initiate treatment is also impacted by nucleos(t)ide analogue inhibitors; NNPI, non-nucleoside polymerase inhibitors; cost, efficacy, and side effects of current treatments, which NS, nonstructural; PEG-IFN-a, pegylated interferon-a; PEG-IFN-a-2a, Pegasys; although proven to be tolerated and effective in certain PEG-IFN-a-2b, PegIntron; PIs, protease inhibitors; RBV, ribavirin; RNA, ribonu- populations, still have much room for improvement. cleic acid; RVR, rapid viral response; SOC, standard of care; SVR, sustained viral response; UK, United Kingdom. Furthermore, new treatment options are becoming more Received: 17 November 2014; Revised: 08 December 2014; Accepted: 08 readily available for adults, raising the question of whether December 2014 q to wait for approval of these new treatments in children. DOI: 10.14218/JCTH.2014.00036. Experience dictates, however, that it will still be many years *Correspondence to: Andrew Lee, Toowoomba Hospital, Department of Medicine, Pechey St, South Toowoomba, QLD 4350, Australia. Tel: +61- before these options are available for children on a non-trial 746166000, Fax: +61-746166793, E-mail: [email protected] basis. 36 Journal of Clinical and Translational Hepatology 2015 vol. 3 | 36–41 Lee A. et al: Current and new treatments of chronic hepatitis C in children Table 1. Recommended treatment regimen for CHC in children Genotype Duration (weeks) Regimen 1 & 4 48 Ribavirin 15 mg/kg/day PEG-IFN-a-2a 180 mg/1.73 m2/week OR 2 & 3 24 AND PEG-IFN-a-2b 60 mg/m2/week PEG-IFN-a-2a, Pegasys; PEG-IFN-a-2b, PegIntron. Standard of care treatment for health, compliance, and quality of life, therefore necessi- tating close monitoring.23,24 Adverse events include flu-like For children with CHC, the current standard of care (SOC) is symptoms, bone marrow suppression, hemolytic anemia, to use 24–48 weeks of subcutaneous pegylated interferon-a growth impairment, and psychiatric symptoms (Table 3). (PEG-IFN-a) in combination with oral ribavirin (RBV) Flu-like symptoms, including fever, headaches, myalgia, and (Table 1).3 IFN-a is a cytokine with a broad mechanism of fatigue, occur almost universally in patients within the first few action that includes increasing antigen presentation of viral days of treatment but commonly recede by 2 months of peptides, stimulating the activation of CD8+ T-cells and therapy. Up to 30% of patients are reported to have some natural killer cells, and inducing the synthesis of several key degree of bone marrow suppression related to PEG-IFN-a, antiviral protein mediators.7,8 The addition of a polyethylene typically manifesting as neutropenia and a reduction in total 16,18 glycol molecule (i.e. PEG-IFN-a) maintains an active drug white cell count. The nadir of cell count often occurs with a longer half-life, allowing for weekly dosing, better following 8 weeks of therapy, and this may prompta dose compliance, and improvement of sustained viral response reduction in PEG-IFN-a. Hemolytic anemia is believed to occur (SVR, Table 2). PEG-IFN-a is available as a subcutaneous consequent to oxidative stress secondary to RBV and often 24 injection, in the forms of PEG-IFN-a-2a (Pegasys; Genentech/ occurs by week four of treatment. Disruption of growth Roche, USA) or PEG-IFN-a-2b (PegIntron; Merck & Co, Inc., velocity and loss of weight occur in up to 70% of patients, and USA), and no demonstrable difference in efficacy has been as such treatment is often avoided during anticipated periods 18 established between these forms.3 The dose of PEG-IFN-a-2a of rapid growth. A dose reduction in both RBV and PEG-IFN-a is 180 mg/1.73 m2 weekly, while PEG-IFN-a-2b is 60 mg/m2 is recommended if a decline of greater than 10% in weight or 3 weekly. body mass index (BMI) is observed. Neuropsychiatric dis- RBV is a guanosine analogue that interferes with HCV turbances are important adverse effects, with most affected ribonucleic acid (RNA) polymerase, leading to rapid and lethal patients experiencing agitation or irritability, occasionally low mutations and intracellular GTP depletion.9–11 RBV is avail- mood, and rarely suicidal ideation or attempts. These dis- able as an orally active agent and RBV in combination with turbances, when present, often instigate cessation of therapy PEG-IFN-a acts synergistically to improve SVR rates, while in children. Cutaneous drug reactions are also not uncommon, limiting the development of viral resistance.3,7 The dose of ranging from injection site reaction, nonspecific erythema, to alopecia. Other less common adverse effects include thyroid RBV is 15 mg/kg/day, given as two split doses per day. 24 Duration of therapy depends on HCV genotype, with 24 abnormalities and ocular complications. weeks for genotypes 2 and 3 (G2/3) and 48 weeks for While the experience of using dual therapy offers accep- genotypes 1 and 4 (G1/4) (Table 1). These recommendations table efficacy, clinical vigilance is necessary to manage side were derived from studies and systematic reviews in noncir- effects and ensure compliance during prolonged periods of therapy. New antivirals endeavour to provide improved rhotic children with CHC. The overall SVR was 30–100%, with efficacy and reduced side effects, while continuing to limit improved response rates in G2/3 typically greater than 80% viral resistance. and in G1/4 predominantly greater than 50%.12–22 Reporting of genotype and rapid viral response (RVR) and early viral response (EVR) (Table 2) have been inconsistent among New therapies studies, making analysis of these responses difficult.