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Tajiri H, Bessho K, Nakayama Y, Abukawa D, Iitsuka Y, Ito Y, Inui A, Etani Y, Suzuki M, Takano T, Tanaka A, Mizuochi T, Miyoshi Y, Murakami J. Clinical practice guidelines for the management of children with mother-to-child transmitted hepatitis C virus infection. Pediatr Int 2022; 64:e14962. [PMID: 35224815 DOI: 10.1111/ped.14962] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 08/10/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The first guidelines for care of pregnant women carrying the hepatitis C virus (HCV) and their infants were published in 2005 in Japan. Since then, evidence has gradually accumulated worldwide regarding the natural course and treatment of this condition and, especially in recent years, treatment for chronic hepatitis C in adult patients has made great progress. However, the clinical practice policy for children has not been standardized, and new clinical practice guidelines for children with mother-to-child (MTC) transmitted HCV infection have become necessary. METHODS In the development of the current guideline, we requested cooperation from The Japanese Society for Pediatric Infectious Diseases, The Japan Society of Hepatology, and the Japan Society of Obstetrics and Gynecology. The committee members were recommended and approved by each society to participate in developing the guidelines. The guideline was also created in accordance with the Minds Guide for Practice Guideline Development. The statements were prepared by consensus-building using the Delphi method, based on the comprehensively searched academic papers and guidelines. These articles were retrieved through searching the PubMed, Cochrane Library, and the Igaku Chuo Zasshi databases. RESULTS Eight clinical questions (CQs) with clinical statements were developed regarding etiology (CQs 1-3), diagnosis (CQs 4 and 5), and treatment (two CQs 6 and 7). In each statement, the consensus rate, evidence level, and recommendation level were determined. CONCLUSION The guidelines will be helpful in the management of children with hepatitis C MTC transmission.
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Affiliation(s)
- Hitoshi Tajiri
- Department of Pediatrics, Osaka General Medical Center, Osaka, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yoshiko Nakayama
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Daiki Abukawa
- Division of General Pediatrics and Gastroenterology, Miyagi Children's Hospital, Sendai, Japan
| | - Yoshinori Iitsuka
- Department of Obstetrics & Gynecology, Chiba Kaihin Municipal Hospital, Chiba, Japan
| | - Yoshinori Ito
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama City Tobu Hospital, Yokohama, Japan
| | - Yuri Etani
- Department of Gastroenterology Nutrition and Endocrinology, Osaka Women's and Children's Hospital, Osaka, Japan
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Tomoko Takano
- Department of Pediatrics, Osaka General Medical Center, Osaka, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Tatsuki Mizuochi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Yoko Miyoshi
- Department of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Jun Murakami
- Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, Yonago, Japan
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Fu Z, Dong C, Ge Z, Wang C, Zhang Y, Shen C, Li J, Zhu C, Wang Y, Huang P, Yue M. High SVR12 With 8-Week Course of Direct-Acting Antivirals in Adolescents and Children With Chronic Hepatitis C: A Comprehensive Analysis. Front Med (Lausanne) 2021; 8:608760. [PMID: 34169081 PMCID: PMC8217461 DOI: 10.3389/fmed.2021.608760] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 04/30/2021] [Indexed: 11/13/2022] Open
Abstract
Direct-acting antiviral (DAA) treatment for 8 weeks has a sustained virological response rate in adults with chronic hepatitis C. We have conducted a systematic review and meta-analysis to compare the efficacy and safety of the 8-week vs. 12/24-week DAA treatment in adolescents and children with CHC. The PubMed, Web of Science, and Cochrane databases were searched for the relevant articles from January 1, 2017 to August 28, 2020 and further screened for literature reviews on April 1, 2021. Pool proportions with 95% CIs for SVR12 were summarized with fixed/random effects models using Freeman-Tukey double arcsine transformation. Subgroup analysis was used to explore the source of heterogeneity. Thirty-six relevant publications were identified. For adolescents aged 12-17 years old, the pooled SVR12 and AE rate were 99.4% (95% CI: 98.7-99.9) and 34.7% (95% CI: 31.9-37.6). No one discontinued treatment due to drug intolerance. In addition, the SVR12 adolescents treated for 12 and 8/24 weeks were 99.3% (95% CI: 98.4-99.9) and 100%, respectively. The pooled SVR12 rate, AEs, and SAEs for children younger than 12 years were 98.9% (95% CI: 97.3-99.8), 51.6% (95% CI: 47.0-56.2), and 1.1% (95% CI: 0.4-2.5), respectively. The most common AE was fatigue (28.4%). The SVR12 was 98.8% (95% CI: 97.1-99.8) and 100% for the pediatric patients treated for 12 weeks and 8/24 weeks, respectively. Taken together, DAAs are generally effective against CHC and well-tolerated by the adolescents and children. A treatment duration of 8 weeks is equally effective and safe as 12/24 weeks in this demographic group.
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Affiliation(s)
- Zuqiang Fu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
- Eastern Theater Command Centers for Disease Control and Prevention, Institute of Epidemiology and Microbiology, Nanjing, China
| | - Chen Dong
- Department of Epidemiology and Statistics, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Zhijun Ge
- Department of Critical Care Medicine, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Chunhui Wang
- Eastern Theater Command Centers for Disease Control and Prevention, Institute of Epidemiology and Microbiology, Nanjing, China
| | - Yun Zhang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
- Eastern Theater Command Centers for Disease Control and Prevention, Institute of Epidemiology and Microbiology, Nanjing, China
| | - Chao Shen
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
- Eastern Theater Command Centers for Disease Control and Prevention, Institute of Epidemiology and Microbiology, Nanjing, China
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chuanlong Zhu
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yan Wang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Peng Huang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
- Eastern Theater Command Centers for Disease Control and Prevention, Institute of Epidemiology and Microbiology, Nanjing, China
| | - Ming Yue
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Transient Hypothyroidism and Autoimmune Thyroiditis in Children With Chronic Hepatitis C Treated With Pegylated-interferon-α-2b and Ribavirin. Pediatr Infect Dis J 2018; 37:287-291. [PMID: 28953189 DOI: 10.1097/inf.0000000000001791] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Autoimmune thyroid disease and thyroid dysfunction are common in adults receiving interferon (IFN)-based treatment for chronic hepatitis C (CHC). Few data are available in children with CHC. This study is aimed to evaluate the appearance and timing of thyroid dysfunction and antithyroid autoimmunity in children with CHC treated with pegylated IFN-α-2b and ribavirin (RBV). METHODS Sixty-one otherwise healthy children with CHC, 3-17 years of age, infected perinatally and treatment naïve, receiving therapy with pegylated IFN-α-2b and RBV and 183 age- and sex-matched controls were included in a multicenter, prospective, case-control study. Thyroid-stimulating hormone, free thyroxine, antithyroglobulin antibodies and antithyroid peroxidase antibodies were assessed before, during and 24 weeks after the end of treatment. RESULTS From baseline to the end of treatment, subclinical hypothyroidism and autoimmune thyroiditis were diagnosed in 17 of 61 (27.94%) and in 4 of 61 (6.6%) of the children treated, respectively, and in 5 of 183 (2.7%) and in none of the controls (P < 0.0001, relative risk: 10.2, 95% confidence interval: 3.9-26.5; P = 0.03, relative risk: 26.8, 95% confidence interval: 1.5-489.1, respectively). Twenty-four weeks after the end of treatment, subclinical hypothyroidism persisted in only 4 of 61 (6.6%). Autoimmune thyroiditis persisted in 3 of 4 (75%) of the cases. CONCLUSIONS Subclinical hypothyroidism is common in children with CHC receiving treatment with pegylated IFN-α-2b and RBV, but in most cases is transient. Autoimmune thyroiditis, which is less common, generally persists after treatment completion. Thyroid function should be carefully monitored in patients presenting with antithyroid autoantibodies and thyroid dysfunction during and after pegylated IFN-α-based treatment.
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El-Karaksy HM, Mogahed EA, El-Raziky MS, Saleh D, Besheer M, Mubarak S. Safety and Efficacy of Combined Treatment with Pegylated Interferon Alpha-2b and Ribavirin for HCV Genotype 4 in Children. J Interferon Cytokine Res 2016; 36:1-8. [PMID: 26406390 DOI: 10.1089/jir.2015.0066] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Combined treatment with pegylated interferon (PEG-IFN)-α2b and ribavirin (RBV) is the only currently approved treatment for hepatitis C virus (HCV) infection in children. The aim of this study was to assess the safety and efficacy of combined treatment with PEG-IFN-α2b and RBV in Egyptian children and adolescents with genotype 4 (GT4) HCV infection. The study included 66 patients (3-17 years of age), of both sexes, infected with HCV GT4, treated with PEG-IFN-α2b (60 μg/m(2)), subcutaneously once weekly plus RBV (15 mg/kg/day) in 2 divided oral doses. Efficacy was assessed by achievement of sustained virological response (SVR). Safety was assessed by questionnaires directed to the patients at specific intervals, growth assessment and laboratory tests. SVR was achieved in 28 patients (42.4%). Nonresponders had significantly commoner history of treated malignancies (P = 0.03), baseline lower absolute neutrophil count (ANC; P = 0.009), higher gamma glutamyl transpeptidase (GGT; P = 0.003), and higher viral load (P = 0.03). Fever was the most frequently reported side effect occurring in 98.5% of the patients followed by musculoskeletal symptoms. Neutropenia was observed in 36 patients (54.6%) and necessitated treatment discontinuation in 1 patient. Decline in both weight and height percentiles was observed in 70% of children who received the combined therapy for a total of 48 weeks. In conclusion, the currently available treatment for HCV GT4 in pediatric patients has modest SVR with numerous adverse events necessitating meticulous monitoring to optimize care of the patients. Side effects could be managed with dose modifications and specific treatment when necessary.
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Affiliation(s)
- Hanaa M El-Karaksy
- 1 Department of Pediatrics, Kasr Alainy Medical School, Cairo University , Cairo, Egypt
| | - Engy A Mogahed
- 1 Department of Pediatrics, Kasr Alainy Medical School, Cairo University , Cairo, Egypt
| | - Mona S El-Raziky
- 1 Department of Pediatrics, Kasr Alainy Medical School, Cairo University , Cairo, Egypt
| | - Doaa Saleh
- 2 Department of Community Medicine, Kasr Alainy Medical School, Cairo University , Cairo, Egypt
| | - Mahmoud Besheer
- 1 Department of Pediatrics, Kasr Alainy Medical School, Cairo University , Cairo, Egypt
| | - Samah Mubarak
- 1 Department of Pediatrics, Kasr Alainy Medical School, Cairo University , Cairo, Egypt
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El Sherbini A, Mostafa S, Ali E. Systematic review with meta-analysis: comparison between therapeutic regimens for paediatric chronic hepatitis C. Aliment Pharmacol Ther 2015; 42:12-9. [PMID: 25926269 DOI: 10.1111/apt.13221] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 11/25/2014] [Accepted: 04/10/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND To decide when and how to treat children with chronic hepatitis C is an ongoing debate. AIM To compare the outcomes of therapy for children with chronic hepatitis C. METHODS An electronic database assessed clinical trials with sustained virological response rates specified by genotype. The data were extracted according to the therapeutic regimen; interferonα±ribavirin and pegylated interferonα±ribavirin. RESULTS The search sourced 23 peer-reviewed articles which enrolled 934 cases, aged 2-19 years. Sustained virological response rates were significantly higher with the addition of ribavirin to either interferonα or pegylated nterferonα vs. their monotherapies for genotypes 1,2&3 with crude and weighted estimates. The weighted estimate indicated higher sustained virological response rates for those treated with pegylated interferonα+ribavirin vs. interferonα+ribavirin for genotype 1 (50% vs. 40%) and genotypes 2&3 (90% vs. 84%), (odds ratio 1.5, 95% confidence interval 1.2-1.8, and 1.8, 1.2-2.9 respectively). Cases with genotype 4 treated with pegylated interferonα+ribavirin had a lower sustained virological response (41%) vs. genotype 1 (1.4, 1.2-1.8), and vs. genotypes 2&3 (13.5, 10.3-17.9). Some adverse events were significantly higher among cases treated with pegylated interferonα+ribavirin vs. interferonα+ribavirin. CONCLUSIONS Despite the superiority of pegylated interferonα+ribavirin to interferonα+ribavirin for the treatment of chronic hepatitis C among children, the significant higher adverse events along with the modest outcome for genotypes 1&4 render that regimen a suboptimal therapy. These data indicated the need for the future comparison with clinical trials of direct anti-viral drugs for children with chronic hepatitis C.
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Affiliation(s)
| | - S Mostafa
- Preventive Medicine & Epidemiology Department, Institute of Postgraduate Childhood Studies, Ain-Shams University, Cairo, Egypt
| | - E Ali
- Research Unit, Tanta Fever Hospital, Tanta, Egypt
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Abdel-Hady M, Bansal S, Davison SM, Brown M, Tizzard SA, Mulla S, Barnes E, Davies P, Mieli-Vergani G, Kelly DA. Treatment of chronic viral hepatitis C in children and adolescents: UK experience. Arch Dis Child 2014; 99:505-10. [PMID: 24492797 DOI: 10.1136/archdischild-2013-304601] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
AIM To review the efficacy and tolerability of pegylated interferon-α and ribavirin for treatment of chronic hepatitis C (CHC) in children in the UK. METHODS Retrospective review of children treated for CHC in 3 UK paediatric specialist liver centres between 2005 and 2010. Data on viral response to treatment, demographic and clinical details were collected. Treatment outcome was assessed by the absence of detectable viral RNA in blood 24 weeks after treatment-sustained viral response (SVR). RESULTS 75 children were included; 34 genotype 1; 39 genotypes 2 and 3; 2 genotype 4. Overall SVR was achieved in 54/71 (76%); 65% genotype 1; 89% genotypes 2 and 3; 100% genotype 4. Early response at 12 weeks was achieved in 53 and sustained in 47 (89%). Data on rapid response after 4 weeks of treatment were available in 25; 17/25 (68%) responded and 16 of these (94%) achieved SVR. IL28 T/T genotype was associated with higher SVR. There were no significant changes in weight and height z scores from baseline compared with 24 weeks post-treatment follow-up. No child discontinued treatment due to side effects, although 43 required dose modification. Treatment affected quality of life (QoL) in the initial 12 weeks of treatment, which improved by the end of treatment. CONCLUSIONS Children respond well to therapy for CHC. Treatment was tolerated with minimal impact on QoL and no significant effect on growth. Knowledge of viral and IL28 genotypes and early viral response is useful to plan treatment in children and provide appropriate counselling.
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Affiliation(s)
- M Abdel-Hady
- Liver Unit, Birmingham Children's Hospital, Birmingham, UK
| | - S Bansal
- Children's Liver Centre, King's College Hospital, London, UK
| | - S M Davison
- Liver Unit, Leeds Teaching Hospitals, Leeds, UK
| | - M Brown
- Liver Unit, Birmingham Children's Hospital, Birmingham, UK
| | - S A Tizzard
- Children's Liver Centre, King's College Hospital, London, UK
| | - S Mulla
- Liver Unit, Leeds Teaching Hospitals, Leeds, UK
| | - E Barnes
- Peter Medawar Building for Pathogen Research and Oxford NIHR BRC, Oxford University, Oxford, UK
| | - P Davies
- Institute of Child's Health, Birmingham Children's Hospital, Birmingham, UK
| | - G Mieli-Vergani
- Children's Liver Centre, King's College Hospital, London, UK
| | - D A Kelly
- Liver Unit, Birmingham Children's Hospital, Birmingham, UK
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Emerging hepatitis C virus inhibitors. Med Chem Res 2013. [DOI: 10.1007/s00044-012-0148-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Druyts E, Thorlund K, Wu P, Kanters S, Yaya S, Cooper CL, Mills EJ. 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 2012; 56:961-7. [PMID: 23243171 DOI: 10.1093/cid/cis1031] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND A systematic review and meta-analysis were conducted to examine the efficacy and safety of pegylated interferon (peg-IFN) alfa-2a and peg-IFN alfa-2b plus ribavirin (RBV) in children and adolescents with chronic hepatitis C virus (HCV). METHODS Medline, Embase, and Cochrane Central Register of Controlled Trials were searched. Clinical trials examining peg-IFN alfa-2a or peg-IFN alfa-2b plus RBV among persons ages 3-18 years with HCV were included. Data were abstracted for complete early virologic response (EVR), sustained virologic response (SVR), relapse, treatment discontinuations, hematologic and dermatologic adverse events, and growth inhibition. RESULTS Eight trials met the inclusion criteria. Results indicate that 70% of subjects (95% confidence interval [CI], 58%-81%) achieved EVR, and 58% (95% CI, 53%-64%) achieved SVR. EVR and SVR were higher for those with HCV genotypes 2/3 than 1/4. Discontinuation due to adverse events and discontinuation due to viral breakthrough were each 4%, discontinuation due to a lack of response was 15%, and relapse was 7%. Anemia, neutropenia, leukopenia, and thrombcytopenia were 11%, 32%, 52%, and 5%, respectively. Alopecia, injection site erythema, and pruritus were 13%, 27%, and 10%, respectively. Small growth inhibitions were observed during treatment. CONCLUSION The results of this meta-analysis indicate that peg-IFN/RBV combination treatment is effective and safe in treating children and adolescents with HCV.
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Affiliation(s)
- Eric Druyts
- Faculty of Health Sciences, University of Ottawa, Ottawa, Canada
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Suzuki M, Inage E, Minowa K, Saito N, Naritaka N, Tsubahara M, Ohtsuka Y, Tokita A, Shimizu T. Prophylaxis for ribavirin-related anemia using eicosapentaenoic acid in chronic hepatitis C patients. Pediatr Int 2012; 54:528-31. [PMID: 22375604 DOI: 10.1111/j.1442-200x.2012.03603.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Ribavirin-related anemia is a serious side-effect of the pegylated interferon and ribavirin therapy used for hepatitis C, and may be cause for a reduction in ribavirin dose or even cessation of treatment. The aim of this study was to evaluate the prophylactic effects of oral eicosapentaenoic acid (EPA) supplementation on ribavirin-induced hemolytic anemia in pediatric and young adult patients. METHODS Twelve chronic hepatitis C patients ranging in age from 3 to 21 years (mean, 13.9 ± 5.1 years) who received pegylated interferon α-2b and ribavirin combination therapy were randomized to either the control group (n = 6) or EPA group (n = 6). Blood samples were collected before, and at 4, 8, and 16 weeks after treatment to measure clinical laboratory parameters. RESULTS The reduction in hemoglobin levels of the EPA group was significantly ameliorated at 8 and 16 weeks when compared to the control group (P < 0.05). There was no significant difference in plasma ribavirin concentrations between the two groups during the treatment. However, one patient in the control group had a reduction in ribavirin dose. CONCLUSION EPA supplementation prevented ribavirin-induced hemolytic anemia during combination therapy with pegylated interferon α-2b and ribavirin in pediatric and young adult patients.
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Affiliation(s)
- Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan.
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Wirth S. Current treatment options and response rates in children with chronic hepatitis C. World J Gastroenterol 2012; 18:99-104. [PMID: 22253515 PMCID: PMC3257449 DOI: 10.3748/wjg.v18.i2.99] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2011] [Revised: 06/16/2011] [Accepted: 06/23/2011] [Indexed: 02/06/2023] Open
Abstract
Vertical transmission has become the most common mode of transmission of hepatitis C virus (HCV) in children. The rate of perinatal transmission from an HCV-infected mother to her child ranges from 2% to 5% and the prevalence of HCV in children in developed countries ranges between 0.1% and 0.4%. Spontaneous viral clearance seems to be dependent on the genotype and has been reported between 2.4%-25%. For chronically infected patients, treatment with recombinant polyethylene glycol (PEG)-interferon α-2b and daily ribavirin has now been approved as standard treatment for children 2-17 years of age. In five large prospective studies, a total of 318 children and adolescents aged 3-17 years were treated either with subcutaneous PEG-interferon α-2b at a dose of 1-1.5 μg/kg or 60 μg/m² once a week in combination with oral ribavirin (15 mg/kg per day) or PEG-interferon α-2a with ribavirin. Subjects with genotype 1 and 4 received the medication for 48 wk and individuals with genotype 2 and 3 mainly for 24 wk. Overall sustained viral response (SVR) was achieved in 193/318 (60.7%) of treated patients. Stratified for genotype; 120/234 (51%) with genotype 1, 68/73 (93%) with genotype 2/3, and 6/11 (55%) with genotype 4 showed SVR. Relapse rate was between 7.7% and 17%. Overall, treatment was well tolerated; however, notable side effects were present in approximately 20%. According to recent experiences in the treatment of chronic hepatitis C in children and adolescents, a combination of PEG-interferon α with ribavirin has been found to be well tolerated and highly efficacious, particularly in individuals with genotype 2/3. Thus, this treatment can be recommended as standard of care until more effective treatment options will become available for genotype 1 patients.
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Tsunoda T, Inui A, Etani Y, Kiyohara Y, Sugiura T, Ito K, Miyazawa R, Nagata I, Ida S, Fujisawa T. Efficacy of pegylated interferon-α2a monotherapy in Japanese children with chronic hepatitis C. Hepatol Res 2011; 41:399-404. [PMID: 21518401 DOI: 10.1111/j.1872-034x.2011.00789.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM There is little information available on the efficacy of pegylated interferon (PEG IFN) therapy for children with chronic hepatitis C. The aim of this study was to evaluate the efficacy and tolerability of PEG IFN-α2a monotherapy for children infected by chronic hepatitis C virus (HCV). METHODS From 2004-2006, we conducted a prospective, open-label, multicenter study of 22 patients aged 4-18 years, including eight with genotype 1 and 14 with genotype 2. None had previously received IFN. The patients were treated with s.c. PEG IFN-α2a at a dose of 3 µg/kg once a week for 48 weeks. Rapid virological response (RVR) was defined as: undetectable serum HCV RNA at week 4; early viral response (EVR) as a 2 or more log reduction or undetectable serum HCV RNA at week 12; and sustained viral response (SVR) as undetectable serum HCV RNA at 24 weeks after the cessation of treatment. RESULTS SVR was achieved in 10 (45%) of the 22 patients (three with genotype 1, seven with genotype 2). Retrospectively, the patients with SVR included five with RVR (one with genotype 1, four with genotype 2) and five with EVR (two with genotype 1, three with genotype 2). PEG IFN-α2a monotherapy was well tolerated, except in one patient in whom alanine aminotransferase activity flared (>500 IU/L) during treatment. CONCLUSION The efficacy of PEG IFN-α2a monotherapy in children is similar to that for adults, while tolerability seems to be better in children than in adults.
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Affiliation(s)
- Tomoyuki Tsunoda
- Children's Center for Health and Development, Yokohama Eastern Hospital, Tsurumi, Yokohama, Japan
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Wirth S, Kelly D, Sokal E, Socha P, Mieli-Vergani G, Dhawan A, Lacaille F, Saint Raymond A, Olivier S, Taminiau J. Guidance for clinical trials for children and adolescents with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2011; 52:233-7. [PMID: 21076340 DOI: 10.1097/mpg.0b013e3181f6f09c] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Most children with chronic hepatitis C are infected vertically, have a low natural seroconversion rate, and carry a lifetime risk of cirrhosis and cancer. Affected children are usually asymptomatic, and histological findings are mild with a low risk of progression, although 5% develop significant liver disease in childhood.The use of combination treatment with pegylated interferon-α and ribavirin has changed the outcome and prognosis for this disease, with approximately 60% of children achieving sustained viral clearance. Combination therapy is not ideal for children because pegylated interferon is administered subcutaneously, impairs growth velocity, and both interferon and ribavirin have significant adverse effects that affect compliance. In addition, approximately 50% of children infected with genotype 1 do not respond to therapy. Thus, additional treatment options are required including improvement in dosing, reduction in the length of treatment, and evaluation of new drugs, such as protease inhibitors, which could be more effective for patients infected with genotype 1.The primary goal of treatment is to eradicate the infection. The future clinical trial design should ensure that any new drugs demonstrate noninferiority to the present standard regimen in both children and adults. The measure for documenting substantial improvement above present therapy should be increased viral clearance rate or the same clearance rate, with a shorter duration of treatment and/or fewer adverse effects. We do not believe there is any need for a placebo arm because approved therapy is available and new treatments can be compared with present therapy.Safety measures should include the standard recommended laboratory investigations, growth parameters, quality-of-life or psychological measures, and a requirement for long-term follow-up for up to 5 years.
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Affiliation(s)
- Stefan Wirth
- Clinic for Children and Adolescence, HELIOS Klinikum Wuppertal, Witten-Herdecke-University, Germany.
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Indolfi G, Bartolini E, Casavola D, Resti M. Chronic hepatitis C virus infection in children and adolescents: Epidemiology, natural history, and assessment of the safety and efficacy of combination therapy. ADOLESCENT HEALTH MEDICINE AND THERAPEUTICS 2010; 1:115-28. [PMID: 24600267 PMCID: PMC3915892 DOI: 10.2147/ahmt.s6750] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) is the most common cause of chronic liver disease of infectious etiology in children. Most of the children infected with HCV are asymptomatic, and only a few of them develop signs and symptoms of end-stage liver disease early in life. It is not possible to predict either in which patients HCV infection will have a bad outcome or the critical time in early adulthood when disease progression will accelerate. The experiences with therapy in children with chronic hepatitis C are based on earlier and continuing data from adult trials. The currently recommended treatment for chronic HCV infection in adults is the combination of peginterferon-á and ribavirin. The choice of this regimen is based on the results of randomized clinical trials that demonstrated the superiority of this combination treatment over standard interferon-á and ribavirin. Recently, results of pivotal, multicenter, interventional open-label studies on combined treatment with peginterferon-á and ribavirin in children have been published, and the US Food and Drug Administration and the European Medicines Agency have approved the combination therapy in those older than 3 years. The aim of this review is to evaluate critically the available data regarding the safety and efficacy of combination treatment with peginterferon-á and ribavirin in children.
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Affiliation(s)
- Giuseppe Indolfi
- Department of Sciences for Women and Child's Health, Liver and Pediatric Unit, Anna Meyer Children's Hospital, University of Florence, Florence, Italy
| | - Elisa Bartolini
- Department of Sciences for Women and Child's Health, Liver and Pediatric Unit, Anna Meyer Children's Hospital, University of Florence, Florence, Italy
| | - Davide Casavola
- Department of Sciences for Women and Child's Health, Liver and Pediatric Unit, Anna Meyer Children's Hospital, University of Florence, Florence, Italy
| | - Massimo Resti
- Department of Sciences for Women and Child's Health, Liver and Pediatric Unit, Anna Meyer Children's Hospital, University of Florence, Florence, Italy
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Hu J, Doucette K, Hartling L, Tjosvold L, Robinson J. Treatment of hepatitis C in children: a systematic review. PLoS One 2010; 5:e11542. [PMID: 20644626 PMCID: PMC2903479 DOI: 10.1371/journal.pone.0011542] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Accepted: 06/11/2010] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Current guidelines recommend children be treated for hepatitis C virus (HCV) using the same principles applied in adults. There are however few published studies which assess the efficacy and safety of HCV therapy in children. METHODOLOGY/PRINCIPAL FINDINGS A systematic review of the literature was completed for studies of any design that evaluated HCV therapy in children. The primary outcome was sustained virologic response (SVR), with sub-group analysis of response rates by genotype. There were 4 randomized controlled trials (RCTs) and 31 non-randomized studies, all involving interferon, pegylated interferon (PEG-IFN), or combinations of these drugs with ribavirin. The SVR rate could not be directly compared as the populations and interventions differed across studies. Genotype was not reported or differed substantially from study to study. The overall SVR rate for PEG-IFN and ribavirin ranged from 30 to 100% which is comparable to the rate in adults. Similar to adults, the SVR rates were significantly higher in children with genotype 2 or 3 compared to genotype 1. Adverse effects were primarily flu-like symptoms and neutropenia. There were insufficient data to assess the applicability of the week 12 stop rule (stopping therapy at week 12 if there is less than a 2 log drop in HCV RNA) or the efficacy of shortening therapy to 24 weeks in children with genotype 2 and 3. CONCLUSIONS/SIGNIFICANCE Current guidelines for the treatment of HCV in children are based on limited data. Further research is needed to define the optimal therapy for HCV in children.
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Affiliation(s)
- Jia Hu
- Department of Pediatrics, University of Alberta, Edmonton, Canada
| | - Karen Doucette
- Department of Medicine, University of Alberta, Edmonton, Canada
| | - Lisa Hartling
- Department of Pediatrics, University of Alberta, Edmonton, Canada
- Alberta Research Centre for Health Evidence, University of Alberta, Edmonton, Canada
| | - Lisa Tjosvold
- Department of Pediatrics, University of Alberta, Edmonton, Canada
- Alberta Research Centre for Health Evidence, University of Alberta, Edmonton, Canada
| | - Joan Robinson
- Department of Pediatrics, University of Alberta, Edmonton, Canada
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Abdel-Aziz DH, Sabry NA, El-Sayed MH, El-Gazayerly ON. Efficacy and safety of pegylated interferon in children and adolescents infected with chronic hepatitis C: a preliminary study. J Pharm Pract 2010; 24:203-10. [PMID: 21712215 DOI: 10.1177/0897190010367737] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
This study researches the efficacy and safety of pegylated interferon alpha-2a (pegIFNα-2a) in Egyptian children and adolescents diagnosed with hepatitis C virus. Thirty patients were enrolled to receive pegIFN once a week with ribavirin twice daily for 12 weeks; viral load and experienced adverse effects were then assessed. Of the 30 patients, 16 (53.33%) were cleared from the virus, showing early virologic response (EVR). Three patients (10%) showed a 2-log reduction by week 12, with an overall early response rate of 63.33%. Three patients who showed EVR after 4 weeks relapsed by week 12. Levels of serum alanine aminotransferase (ALT) normalized at week 12. Adverse events included fever, myalgia, headache, flu-like symptoms, fatigue, anemia, and leucopenia; 63.33% of the patients showed significant reduction in their body weight. Although the patients showed a reduction in average body mass index, this reduction was not significant. Hemoglobin values decreased within the first 2 weeks and then stabilized but not back to baseline. A significant reduction in the level of absolute neutrophil count (ANC) was observed by the 4th week and started to improve by the 12th week. Of the recruited patients, 29.4% were subjected to IFN dose reduction. None of the patients with neutropenia developed serious infection or sepsis. The authors concluded that pegIFN plus ribavirin therapy is promising when tested on Egyptian children.
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Wirth S, Ribes-Koninckx C, Calzado MA, Bortolotti F, Zancan L, Jara P, Shelton M, Kerkar N, Galoppo M, Pedreira A, Rodriguez-Baez N, Ciocca M, Lachaux A, Lacaille F, Lang T, Kullmer U, Huber WD, Gonzalez T, Pollack H, Alonso E, Broue P, Ramakrishna J, Neigut D, Valle-Segarra AD, Hunter B, Goodman Z, Xu CR, Zheng H, Noviello S, Sniukiene V, Brass C, Albrecht JK. High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin. J Hepatol 2010; 52:501-7. [PMID: 20189674 DOI: 10.1016/j.jhep.2010.01.016] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2009] [Revised: 09/11/2009] [Accepted: 09/30/2009] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Pegylated interferon (PEG-IFN) alfa-2b plus ribavirin (RBV) is the standard of care for adults with chronic hepatitis C but was not approved for the treatment of children at the time of this study. The aim of this study was to evaluate the efficacy and safety of PEG-IFN alfa-2b plus RBV in children. METHODS Children and adolescents ages 3-17 years were treated with PEG-IFN alfa-2b (60microg/m(2)/week) plus RBV (15mg/kg/day). The duration of therapy was 24 weeks for genotype (G) 2 and G3 patients with low viral load (<600,000IU/ml) and 48 weeks for G1, G4, and G3 with high viral load (>or=600,000IU/ml). The primary end point was sustained virologic response (SVR), defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of therapy. RESULTS SVR was attained by 70 (65%) children. Genotype was the main predictor of response: G1, 53%; G2/3, 93%; G4, 80%. SVRs were similar in younger and older children. Baseline viral load was the main predictor of response in the G1 cohort. No new safety signals were identified, and adverse events (AEs) were generally mild or moderate in severity. Dose was modified because of AEs in 25% of children; 1 child discontinued because of an AE (thrombocytopenia). No serious AEs related to study drugs were reported. CONCLUSION Therapy with PEG-IFN alfa-2b plus RBV in children and adolescents with chronic hepatitis C offers favorable efficacy, reduced injection frequency, and an acceptable safety profile.
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Affiliation(s)
- Stefan Wirth
- Children's Hospital, HELIOS Klinikum Wuppertal, Witten/Herdecke University, Heusnerstrasse 40, Wuppertal, Germany.
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17
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Uslu N, Baysoy G, Demir H, Temizel INS, Yuce A. Safety of ribavirin in adolescent thalassemic patients with chronic hepatitis C virus infection. J Clin Virol 2010; 48:66-8. [PMID: 20347610 DOI: 10.1016/j.jcv.2010.02.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2009] [Revised: 11/03/2009] [Accepted: 02/17/2010] [Indexed: 02/03/2023]
Affiliation(s)
- Nuray Uslu
- Hacettepe University, Faculty of Medicine, Department of Pediatric, Gastroenterology Hepatology & Nutrition, Altindag, Ankara, Turkey
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Abstract
The aim of this review was to evidence the actual treatment used for chronic hepatitis C virus (HCV) in children. A review of the use of interferon (IFN) as monotherapy in children demonstrates a sustained virological response (SVR) of 33%-45%. This is significantly better than the SVR rate for IFN monotherapy observed for adults. When the data are further scrutinized, the SVR for genotype 1 is 26% and 70% for other genotypes. The higher response rate observed in children might be the result of the earlier stage of the disease, higher relative IFN dosage, or lack of comorbid conditions. The use of IFN-alpha2b in combination with ribavirin was reported by Gonzalez-Peralta et al and has led to Food and Drug Administration approval of this therapy for children with a SVR significantly higher in children with HCV genotype 2/3 (84%) than in those with HCV genotype 1 (36%). About the use of pegylated IFN in combination with ribavirin, the first-line treatment in adult patients affected by chronic hepatitis C, there are few experiences. These preliminary experiences evidenced that combination treatment of PEG-IFN-alpha2b with ribavirin shows encouraging results and was well tolerated in children and adolescents with chronic hepatitis C.
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Karnsakul W, Alford MK, Schwarz KB. Managing pediatric hepatitis C: current and emerging treatment options. Ther Clin Risk Manag 2009; 5:651-60. [PMID: 19707281 PMCID: PMC2731021 DOI: 10.2147/tcrm.s5078] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Indexed: 12/18/2022] Open
Abstract
Since 1992, the maternal–fetal route of transmission has become the dominant route for acquisition of hepatitis C (HCV) infection by children. With increasing knowledge of antiviral treatment for HCV infection, the main goal of therapy is to achieve a sustained virological response (SVR) as defined by undetectable serum HCV RNA by polymerase chain reaction assay six months after cessation of therapy. In young children, interferon therapy is more effective than in adults with chronic HCV infection (CHC). Although children clearly have a milder degree of liver pathology, data have indicated that hepatic inflammation from HCV infection can progress to fibrosis or cirrhosis in children. Hepatocellular carcinoma has been reported in adolescents with CHC. In this article, recent improvements in therapy of children with CHC and in the clinical development of new emerging drugs with potential use in children will be reviewed.
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Affiliation(s)
- Wikrom Karnsakul
- Pediatric Liver Center, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Chang MH. Natural history and clinical management of chronic hepatitis B virus infection in children. Hepatol Int 2008; 2:28-36. [PMID: 19669296 DOI: 10.1007/s12072-008-9050-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2007] [Accepted: 01/20/2008] [Indexed: 01/17/2023]
Abstract
Hepatitis B virus (HBV) infection may cause acute, fulminant, or chronic hepatitis, leading to liver cirrhosis or hepatocellular carcinoma. Despite the availability of effective vaccine, HBV infection during infancy or early childhood is common in areas of high endemicity. In these regions, mother-to-infant transmission accounts for approximately 50% of chronic infections. Although the natural history of HBV infection in adults is well characterized, little information is available in the literature regarding the natural history of HBV infection in children. Similar to infection in adults, chronic HBV infection in children can be divided into distinct phases: immune tolerant, immune clearance, and inactive carrier state. However, acute exacerbation, with reactivation of HBV replication and re-elevation of alanine aminotransferase levels after hepatitis B e antigen seroconversion, is relatively rare in children, in comparison to adults. Although several potent antiviral agents are now available for the treatment of chronic hepatitis B, experience with these agents in the pediatric setting is limited. To date, conventional interferon alpha and lamivudine are the only two antiviral agents approved to treat chronic hepatitis B in children. The rapid emergence of resistant HBV associated with long-term lamivudine therapy, as well as poor tolerability associated with conventional interferon alpha, are factors that should be considered before initiating antiviral therapy. This article reviews current knowledge regarding the natural history and treatment of chronic hepatitis B in children. Factors that affect the natural history of HBV infection in children are also reviewed.
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Affiliation(s)
- Mei-Hwei Chang
- Division of Gastroenterology and Hepatology, Department of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan S. Road, Taipei, Taiwan,
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Inui A, Komatsu H, Sogo T, Hashimoto T, Fujisawa T. Pegylated interferon-α2b and ribavirin combination therapy for pediatric patients with chronic hepatitis C. ACTA ACUST UNITED AC 2008. [DOI: 10.2957/kanzo.49.386] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
PURPOSE OF REVIEW Hepatitis C virus infection has recently been recognized as a viral infection with the potential to cause significant complications, including cirrhosis and hepatocellular carcinoma in adults. Changes in our understanding of its natural history in children and recent advances in therapy for acute and chronic hepatitis C are reviewed. RECENT FINDINGS Recent work has demonstrated that, although uncommon, vertical transmission is the most frequent mode of hepatitis C acquisition in children and is enhanced in the setting of maternal co-infection with HIV. Chronic hepatitis C during childhood leads in some cases to development of advanced hepatic fibrosis, with complications including liver failure and liver cancer, which has changed our general approach to this infection. Perhaps the most significant recent advance in this area is our improved understanding of the safety and efficacy of interferon-based antiviral therapies for children with hepatitis C. SUMMARY Hepatitis C virus infection has reached epidemic proportions worldwide; despite its being less prevalent in children than in adults, it poses a significant clinical problem in this age group. Emerging antiviral therapies are currently in clinical trials for adult patients with hepatitis C with encouraging preliminary results, which should be extended to children.
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Affiliation(s)
- Nizar N Zein
- Department of Gastroenterology and Hepatology, the Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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Kowala-Piaskowska A, Mozer-Lisewska I, Figlerowicz M, Słuzewski W. Adverse effects during the treatment with pegylated interferon and ribavirin in children with chronic hepatitis C. Pharmacoepidemiol Drug Saf 2007; 16:1095-103. [PMID: 17724740 DOI: 10.1002/pds.1458] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
PURPOSE Administration of pegylated interferon-alpha (IFN-alpha) and ribavirin in adults with chronic hepatitis C (CHC) is a recommended therapeutic standard. Nevertheless, this therapeutic regimen rises numerous controversies. The aim of this study was to analyze adverse effects during the treatment with pegylated IFN-alpha and ribavirin in children with CHC. METHODS Study group comprised 30 children with CHC, age 8-19 years (mean 13,6 years), 9 girls and 21 boys. All patients were administered two medication therapy with pegylated IFN-alpha-2b in the dose of 1.5 microg/kg of body weight 1x/week subcutaneously and daily oral ribavirin 15 mg/kg of bodyweight for 48 weeks. Blood samples were taken at baseline and every 4 weeks during the whole treatment and 24 weeks of follow-up period. Panel of test included: cellular blood count and smear, ALT activity, bilirubin level. Patients complaints were noticed during every visit. Thyroid hormones and antibodies were checked every 3 months. Children were divided into group A that responded to treatment and group B-nonresponders. RESULTS Abnormalities in laboratory tests (white blood cells, neutrophils, haemoglobin) were observed mainly during first weeks of treatment. Mean bilirubin level and platelets were normal. Mean ALT normalized during the treatment. After 12-16 weeks of the therapy somatic adverse effects decreased significantly. CONCLUSIONS Administration of pegylated IFN-alpha and ribavirin in children with CHC is related to characteristic adverse effects. Periodical dose reduction was necessary. Although side effects and subjective patient complaints were present, children attended school without difficulties. Constant monitoring is required during the whole treatment.
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Affiliation(s)
- Arleta Kowala-Piaskowska
- Department of Infectious Diseases and Child Neurology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
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