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Wang B, Wang C, Wan Y, Gao J, Ma Y, Zhang Y, Tong J, Zhang Y, Liu J, Chang L, Xu C, Shen B, Chen Y, Jiang E, Kurita R, Nakamura Y, Lim KC, Engel JD, Zhou J, Cheng T, Zhu X, Zhu P, Shi L. Decoding the pathogenesis of Diamond-Blackfan anemia using single-cell RNA-seq. Cell Discov 2022; 8:41. [PMID: 35534476 PMCID: PMC9085895 DOI: 10.1038/s41421-022-00389-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 02/21/2022] [Indexed: 11/09/2022] Open
Abstract
Ribosomal protein dysfunction causes diverse human diseases, including Diamond-Blackfan anemia (DBA). Despite the universal need for ribosomes in all cell types, the mechanisms underlying ribosomopathies, which are characterized by tissue-specific defects, are still poorly understood. In the present study, we analyzed the transcriptomes of single purified erythroid progenitors isolated from the bone marrow of DBA patients. These patients were categorized into untreated, glucocorticoid (GC)-responsive and GC-non-responsive groups. We found that erythroid progenitors from untreated DBA patients entered S-phase of the cell cycle under considerable duress, resulting in replication stress and the activation of P53 signaling. In contrast, cell cycle progression was inhibited through induction of the type 1 interferon pathway in treated, GC-responsive patients, but not in GC-non-responsive patients. Notably, a low dose of interferon alpha treatment stimulated the production of erythrocytes derived from DBA patients. By linking the innately shorter cell cycle of erythroid progenitors to DBA pathogenesis, we demonstrated that interferon-mediated cell cycle control underlies the clinical efficacy of glucocorticoids. Our study suggests that interferon administration may constitute a new alternative therapeutic strategy for the treatment of DBA. The trial was registered at www.chictr.org.cn as ChiCTR2000038510.
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Affiliation(s)
- Bingrui Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Chenchen Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.,Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Yang Wan
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jie Gao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yige Ma
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yingnan Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jingyuan Tong
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yingchi Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jinhua Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Lixian Chang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Changlu Xu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Biao Shen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Division of Transplantation Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yumei Chen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Erlie Jiang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Division of Transplantation Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Ryo Kurita
- Department of Research and Development, Central Blood Institute, Japanese Red Cross Society, Tokyo, Japan
| | - Yukio Nakamura
- Cell Engineering Division, RIKEN BioResource Research Center, Ibaraki, Japan
| | - Kim-Chew Lim
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - James Douglas Engel
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jiaxi Zhou
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.,Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China. .,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China. .,Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
| | - Xiaofan Zhu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China. .,Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
| | - Ping Zhu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China. .,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China. .,Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
| | - Lihong Shi
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China. .,Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.
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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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Fawaz R, Jonas MM. Acute and Chronic Hepatitis. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:819-837.e6. [DOI: 10.1016/b978-0-323-67293-1.00075-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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4
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Squires JE, Balistreri WF. Treatment of Hepatitis C: A New Paradigm toward Viral Eradication. J Pediatr 2020; 221:12-22.e1. [PMID: 32446469 DOI: 10.1016/j.jpeds.2020.02.082] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 01/27/2020] [Accepted: 02/28/2020] [Indexed: 12/18/2022]
Affiliation(s)
- James E Squires
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh PA.
| | - William F Balistreri
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital, Cincinnati, OH
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5
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Choi JH, Jeong K, Kim SM, Ko MK, You SH, Lyoo YS, Kim B, Ku JM, Park JH. Synergistic effect of ribavirin and vaccine for protection during early infection stage of foot-and-mouth disease. J Vet Sci 2019; 19:788-797. [PMID: 30304889 PMCID: PMC6265586 DOI: 10.4142/jvs.2018.19.6.788] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 09/03/2018] [Accepted: 09/17/2018] [Indexed: 12/25/2022] Open
Abstract
In many countries, vaccines are used for the prevention of foot-and-mouth disease (FMD). However, because there is no protection against FMD immediately after vaccination, research and development on antiviral agents is being conducted to induce protection until immunological competence is produced. This study tested whether well-known chemicals used as RNA virus treatment agents had inhibitory effects on FMD viruses (FMDVs) and demonstrated that ribavirin showed antiviral effects against FMDV in vitro/in vivo. In addition, it was observed that combining the administration of the antiviral agents orally and complementary therapy with vaccines synergistically enhanced antiviral activity and preserved the survival rate and body weight in the experimental animals. Antiviral agents mixed with an adjuvant were inoculated intramuscularly along with the vaccines, thereby inhibiting virus replication after injection and verifying that it was possible to induce early protection against viral infection prior to immunity being achieved through the vaccine. Finally, pigs treated with antiviral agents and vaccines showed no clinical signs and had low virus excretion. Based on these results, it is expected that this combined approach could be a therapeutic and preventive treatment for early protection against FMD.
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Affiliation(s)
- Joo-Hyung Choi
- Animal and Plant Quarantine Agency, Gimcheon 39660, Korea
| | - Kwiwan Jeong
- Bio-Center, Gyeonggi Business & Science Accelerator, Suwon 16229, Korea
| | - Su-Mi Kim
- Animal and Plant Quarantine Agency, Gimcheon 39660, Korea
| | - Mi-Kyeong Ko
- Animal and Plant Quarantine Agency, Gimcheon 39660, Korea
| | - Su-Hwa You
- Animal and Plant Quarantine Agency, Gimcheon 39660, Korea
| | - Young S Lyoo
- College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea
| | - Byounghan Kim
- Animal and Plant Quarantine Agency, Gimcheon 39660, Korea
| | - Jin-Mo Ku
- Bio-Center, Gyeonggi Business & Science Accelerator, Suwon 16229, Korea
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6
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Schleiss MR, Marsh KJ. Viral Infections of the Fetus and Newborn. AVERY'S DISEASES OF THE NEWBORN 2018:482-526.e19. [DOI: 10.1016/b978-0-323-40139-5.00037-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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7
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Affiliation(s)
- Deirdre Kelly
- The Liver Unit, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
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8
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Ide K, Kawasaki Y, Iketani R, Masaki N. Risk Factors for Treatment Discontinuation Caused by Adverse Events When Using Telaprevir, Peginterferon, and Ribavirin to Treat Chronic Hepatitis C: A Real-World Retrospective Cohort Study. Biol Pharm Bull 2017; 40:645-649. [PMID: 28216512 DOI: 10.1248/bpb.b16-00941] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In this study, a nationwide database was used to identify the risk factors for treatment discontinuation due to adverse events during telaprevir, peginterferon, and ribavirin (T/PR) treatment, and estimate the increase in the occurrence of adverse events when patients have multiple risk factors at the same time. The risk factors were identified using univariate logistic regression analysis, and a Cochran-Armitage trend test was used to analyze the correlation between the number of risk factors and treatment discontinuation due to adverse events. Of the 25989 individuals registered in the database, 1668 (age, mean±standard deviation (S.D.): 58.0±9.9) were included in the study. Of these, 188 (11.3%) discontinued T/PR therapy due to adverse events. In the univariate logistic regression analysis, sex, age, aspartate aminotransferase (AST) level, and platelet count were found to significantly affect the incidence of T/PR treatment discontinuation (p<0.05). Furthermore, the incidence of treatment discontinuation gradually increased from 4.6 to 27.2% as the number of risk factors increased from 0 to 4, and the Cochran-Armitage trend test showed a significant correlation (p<0.001). In conclusion, this study not only revealed the risk factors for treatment discontinuation but also showed that patients with multiple risk factors are more likely to discontinue treatment due to adverse events compared to patients with fewer risk factors.
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Affiliation(s)
- Kazuki Ide
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University
- Center for the Promotion of Interdisciplinary Education and Research, Kyoto University
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Yohei Kawasaki
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Ryo Iketani
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Naohiko Masaki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine
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9
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Squires JE, Balistreri WF. Hepatitis C virus infection in children and adolescents. Hepatol Commun 2017; 1:87-98. [PMID: 29404447 PMCID: PMC5721428 DOI: 10.1002/hep4.1028] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 02/17/2017] [Accepted: 02/22/2017] [Indexed: 12/11/2022] Open
Affiliation(s)
- James E Squires
- Division of Gastroenterology, Hepatology, and Nutrition Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center Pittsburgh PA
| | - William F Balistreri
- Division of Gastroenterology Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine Cincinnati OH
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Long-Term Follow-Up of Children Treated With Peginterferon and Ribavirin for Hepatitis C Virus Infection. J Pediatr Gastroenterol Nutr 2017; 64:89-94. [PMID: 27111344 DOI: 10.1097/mpg.0000000000001239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVES The aim of the study was to describe the 5-year follow-up of children who received peginterferon and ribavirin in a global, open-label study. METHODS A 5-year follow-up study of 107 children and adolescents ages 3 to 17 years with chronic hepatitis C virus infection who received peginterferon and ribavirin for 24 or 48 weeks. No drugs were administered during follow-up. RESULTS Ninety-four patients were enrolled in the long-term follow-up portion of the study; the median duration of follow-up was 287 weeks (range, 73-339). Of 63 patients with sustained virologic response who were enrolled, 54 completed 5 years of follow-up; none had relapse in the 5-year follow-up period. Significant decreases in height z scores were observed during treatment. The effect of treatment on height z score was larger in patients treated for 48 weeks compared with those treated for 24 weeks (mean change from baseline to the end of treatment was -0.13 [P < 0.001] and -0.44 [P < 0.001] in the 24- and 48-week treatment groups, respectively). Among patients treated for 24 weeks, full recovery of height z scores to baseline was observed by 1 year of follow-up, whereas only partial recovery was observed during 5 years of follow-up in patients treated for 48 weeks (mean change from baseline to the final follow-up visit was -0.16 (P = NS) and -0.32 (P < 0.05) in the 24- and 48-week treatment groups, respectively). Similar patterns were observed for weight and body mass index z scores. CONCLUSIONS Impairment of growth should be considered when assessing the risk-benefit profile of peginterferon/ribavirin therapy in children with hepatitis C virus infection. In deciding to treat children with chronic hepatitis C virus, considerations should include both deferring treatment in patients during optimal growth periods, and the possibility that interferon-free regimens may be available to children in the next 5 to 10 years.
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Ide K, Sato I, Imai T, Hawke P, Yamada H, Kawasaki Y, Masaki N. Comparison of the Safety Profiles of Pegylated Interferon α-2a and α-2b Administered in Combination with Ribavirin for Chronic Hepatitis C Infection: A Real-World Retrospective Cohort Study. Biol Pharm Bull 2016; 39:2060-2065. [PMID: 27645378 DOI: 10.1248/bpb.b16-00617] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study compares the safety profiles of pegylated interferon (PEG-IFN) α-2a and α-2b administered in combination with ribavirin, based on the variable of time to withdrawal from treatment due to adverse events. We conducted a real-world retrospective cohort study using the Japanese interferon database. Based on eligibility criteria, individuals with chronic hepatitis C virus (HCV) infection were identified in the database covering the period December 2009 to August 2015. The primary outcome measure was defined as difference in time to withdrawal from treatment due to adverse events between patients receiving PEG-IFN α-2a combined with ribavirin and those receiving PEG-IFN α-2b combined with ribavirin. The difference was analyzed using the multivariate Cox proportional hazards regression model. A frailty model was also applied to consider regional (prefectural) variation. After eligibility evaluation, 11058 individuals were included in the analysis. 3774 were treated with PEG-IFN α-2a, and 6764 with PEG-IFN α-2b, with 11.84 and 12.30% respectively withdrawing from treatment due to adverse events. The Cox model showed no significant difference between the two groups (hazard ratio (HR), 95%CI; 0.918, 0.817 to 1.031; p=0.1475). The results were consistent even when regional variation and other confounding variables were adjusted in the frailty model. In conclusion, there may be no difference in time to withdrawal from treatment due to adverse events between PEG-IFN α-2a and PEG-IFN α-2b combined with ribavirin. Applying the method used here to future studies using novel treatment regimens may also provide important information for the treatment of chronic HCV infection in clinical practice.
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Affiliation(s)
- Kazuki Ide
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
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12
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Zhong YW, Zhang HF, Shi YM, Li YL, Chu F, Xu ZQ, Chen DW, Gan Y, Wang FC, Gu ML, Dong Y, Zhu SS, Shi C, Fan HH, Zhang XC, Zhang M. IL28B SNP rs12979860 is the Critical Predictor for Sustained Viral Response in Chinese Children Aged 1 to 6 Years with Chronic Hepatitis C. Int J Biol Sci 2016; 12:1357-1362. [PMID: 27877087 PMCID: PMC5118781 DOI: 10.7150/ijbs.16220] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 08/26/2016] [Indexed: 01/21/2023] Open
Abstract
Clinical data on children with chronic hepatitis C (CHC) remain extremely limited. This study investigated sustained virologic response (SVR) to alfa-interferon 2b plus RBV treatment in children aged 1-6 years with unsafe injection-acquired CHC. 154 children with CHC aged 1 to 6 years were enrolled, 101 of them were male (65.6%) and 53 were female (34.4%), and they were treated with alfa-interferon at a dose of 1-5 MIU/m2 3 times weekly plus oral RBV (15 mg/kg/day) for 48 weeks. 57(39.3 %) of them were genotype 1b, 73(50.3%) were genotypes 2a, 15(10.3%) were undecided type. SVR was achieved in 53 of 57(93.0%) patients with genotype 1b, in 72 (98.6%) of 73 with genotype 2a, 15(100.0%) of 15 with undecided type. There was no significant statistical difference in SVR between male and female (98.0% vs 94.3%, p=0.340), genotype 2a and those with genotype 1b(98.6% vs 93.0%, p=0.160), ALT>40U/L group and ALT≤40U/L group(96.7% vs 96.8%, p=1.000), AST>40U/L group and AST≤40U/L group(95.9% vs 98.2%, p=0.654) as well as lower baseline viral load group (<6×105 IU/ml) and higher baseline viral load group(≥6×105 IU/ml)(97.3% vs 95.3%, p=0.916). Leucopenia, neutropenia, hemoglobin concentration decrease, fever, platelet count decrease and rash were 8.4%, 69.5%, 24.0%, 50.6%, 1.9% and 4.5%, respectively. And only 12(7.8%) individuals developed thyroid autoantibodies. The SVR was higher in patients with IL-28B genotype C/C than C/T (99.0% vs 80%, p=0.002). Compared with HCV viral genotype, ALT level and baseline viral load, IL-28B rs12979860 is more suitable for predicting antiviral efficacy in children with CHC. It is inappropriate to take the increase of ALT level as an essential indicator for antiviral treatment in children aged 1-6 years.
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Affiliation(s)
- Yan-Wei Zhong
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Hong-Fei Zhang
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Yan-Min Shi
- HeBei North University, Changqing road No.36, Zhangjiakou, China
| | - Yong-Li Li
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Fang Chu
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Zhi-Qiang Xu
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Da-Wei Chen
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Yu Gan
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Fu-Chuan Wang
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Mei-Lei Gu
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Yi Dong
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Shi-Shu Zhu
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Ce Shi
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Hua-Hao Fan
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
| | - Xiu-Chang Zhang
- HeBei North University, Changqing road No.36, Zhangjiakou, China
| | - Min Zhang
- Institute of Infectious Diseases, pediatric liver disease therapy and research center, Xisihuan mid-road No.100, Beijing 302 Hospital, Beijing, China
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13
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Affiliation(s)
- Yen H Pham
- Texas Children's Hospital, Baylor College of Medicine, 18200 Katy Freeway, Suite 250, Houston, TX 77094, USA.
| | - Philip Rosenthal
- UCSF Benioff Children's Hospital, University of California San Francisco, 550 16th Street, 5th Floor, San Francisco, CA 94143, USA
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14
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Puri P, Saraswat VA, Dhiman RK, Anand AC, Acharya SK, Singh SP, Chawla YK, Amarapurkar DN, Kumar A, Arora A, Dixit VK, Koshy A, Sood A, Duseja A, Kapoor D, Madan K, Srivastava A, Kumar A, Wadhawan M, Goel A, Verma A, Shalimar, Pandey G, Malik R, Agrawal S. Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016. J Clin Exp Hepatol 2016; 6:119-145. [PMID: 27493460 PMCID: PMC4963318 DOI: 10.1016/j.jceh.2016.07.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
India contributes significantly to the global burden of HCV. While the nucleoside NS5B inhibitor sofosbuvir became available in the Indian market in March 2015, the other directly acting agents (DAAs), Ledipasvir and Daclatasvir, have only recently become available in the India. The introduction of these DAA in India at a relatively affordable price has led to great optimism about prospects of cure for these patients as not only will they provide higher efficacy, but combination DAAs as all-oral regimen will result in lower side effects than were seen with pegylated interferon alfa and ribavirin therapy. Availability of these newer DAAs has necessitated revision of INASL guidelines for the treatment of HCV published in 2015. Current considerations for the treatment of HCV in India include the poorer response of genotype 3, nonavailability of many of the DAAs recommended by other guidelines and the cost of therapy. The availability of combination DAA therapy has simplified therapy of HCV with decreased reliance of evaluation for monitoring viral kinetics or drug related side effects.
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Key Words
- ALT, alanine aminotransferase
- ANC, absolute neutrophil count
- AST, aspartate aminotransferase
- CH-C, chronic hepatitis C
- CTP, Child-Turcotte-Pugh
- DAA, directly acting antiviral agents
- DCV, daclatasvir
- EIA, enzyme immunoassay
- ESRD, end-stage renal disease
- EVR, early virological response
- FCH, fibrosing cholestatic hepatitis
- GT, genotype
- HCV
- HCV, hepatitis C virus
- HCWs, healthcare workers
- HIV, human immunodeficiency virus
- INASL, Indian National Association for Study of the Liver
- IU, international units
- LDV, ledipasvir
- LT, liver transplantation
- NS, nonstructural protein
- NSI, needlestick injury
- PCR, polymerase chain reaction
- Peg-IFNα, pegylated interferon alfa
- RBV, ribavirin
- RVR, rapid virological response
- SOF, sofosbuvir
- SVR, sustained virological response
- ULN, upper limit of normal
- anti-HCV, antibody to HCV
- antiviral therapy
- chronic hepatitis
- hepatitis C virus
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Affiliation(s)
- Pankaj Puri
- Department of Internal Medicine, Armed Forces Medical College, Pune 411040, India
| | - Vivek A. Saraswat
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Anil C. Anand
- Department of Gastroenterology and Hepatology, Indraprastha Apollo Hospital, New Delhi 110076, India
| | - Subrat K. Acharya
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Shivaram P. Singh
- Department of Gastroenterology, SCB Medical College, Cuttack 753007, India
| | - Yogesh K. Chawla
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | | | - Ajay Kumar
- Department of Gastroenterology and Hepatology, Fortis Escorts Liver and Digestive Diseases Institute, New Delhi 110076, India
| | - Anil Arora
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Vinod K. Dixit
- Department of Gastroenterology, Banaras Hindu University, Varanasi 221005, India
| | - Abraham Koshy
- Department of Hepatology, Lakeshore Hospital, Cochin 682304, India
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College, Ludhiana 141001, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Dharmesh Kapoor
- Department of Gastroenterology, Global Hospital, Hyderabad 500004, India
| | - Kaushal Madan
- Department of Gastroenterology, Artemis Hospital, Gurgaon 122001, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Ashish Kumar
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Manav Wadhawan
- Department of Gastroenterology and Hepatology, Fortis Escorts Liver and Digestive Diseases Institute, New Delhi 110076, India
| | - Amit Goel
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Abhai Verma
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Gaurav Pandey
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Rohan Malik
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Swastik Agrawal
- Department of Gastroenterology, Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, Ambala, India
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15
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Ide K, Kawasaki Y, Yamada H, Masaki N. Regional differences in hepatitis C treatment with peginterferon and ribavirin in Japan: a retrospective cohort study. Drug Des Devel Ther 2016; 10:1217-1223. [PMID: 27042013 PMCID: PMC4809336 DOI: 10.2147/dddt.s102458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The aims of this study were to investigate regional differences in hepatitis C virus (HCV) infection treatment with peginterferon and ribavirin in Japan and to develop and validate statistical models for analysis of regional differences, using generalized linear mixed models. METHODS Individuals with chronic HCV infection were identified from the Japanese Interferon Database (registered from December 2009 to April 2013). The total sustained virologic response rate and the rate in each prefecture were calculated. In the analysis using generalized linear mixed models, the following four models were constructed: 1) prefecture as a fixed effect, 2) prefecture and other confounding variables as fixed effects, 3) prefecture as a random effect, and 4) prefecture as a random effect and other confounding variables as fixed effects. The quality of the model fit was assessed using the Akaike information criterion and the Bayesian information criterion. All statistical analyses were performed using SAS Version 9.4 for Windows. RESULTS From 36 prefectures, 16,349 cases were recorded in the study period. Of these, 4,677 were excluded according to certain criteria. The total sustained virologic response rate was 59.9% (range, 43.9%-71.6%). The statistical model including prefecture as a random effect and other confounding variables as fixed effects showed the best fit based on the Akaike information criterion (13,830.92) and Bayesian information criterion (13,845.17). CONCLUSION Regional differences may exist in HCV infection treatment in Japan. The model including prefecture as a random effect and other confounding variables as fixed effects was appropriate for analysis of such regional differences. Additional studies considering the medical situations of each patient would provide useful information that could contribute to improve and standardize HCV infection treatment.
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Affiliation(s)
- Kazuki Ide
- Department of Drug Evaluation and Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Yohei Kawasaki
- Department of Drug Evaluation and Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Hiroshi Yamada
- Department of Drug Evaluation and Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Naohiko Masaki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
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16
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The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: management of hepatitis C. Clin Mol Hepatol 2016; 22:76-139. [PMID: 27044763 PMCID: PMC4825161 DOI: 10.3350/cmh.2016.22.1.76] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 02/22/2016] [Indexed: 12/11/2022] Open
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17
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Wen J, Ohmer S, Honegger J. Hepatitis C Virus Infection in Pregnancy and Childhood. HEPATITIS C VIRUS II 2016:187-222. [DOI: 10.1007/978-4-431-56101-9_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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18
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Zhu SS, Zeng QL, Dong Y, Xu ZQ, Wang LM, Chen DW, Gan Y, Wang FC, Yan JG, Cao LL, Wang P, Han J, Zhang XX, Zhang Z, Zhang HF, Wang FS. Interferon-α plus ribavirin yields 98 % sustained virologic response in children aged 1-5 years with iatrogenic chronic hepatitis C. Hepatol Int 2015; 9:578-585. [PMID: 26449425 DOI: 10.1007/s12072-015-9671-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 07/19/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND OBJECTIVES The clinical features and efficacies of antivirals for children with hepatitis C virus (HCV) infections that are acquired through different transmission routines are poorly understood worldwide. This study investigated the clinical characteristics of children who were infected via iatrogenic means and analyzed the efficacy of antiviral therapy in children with chronic hepatitis C (CHC). METHODS In total, 256 children with HCV infections aged 1 to 5 years were enrolled and surveyed. Interferon-α plus ribavirin was administered to 162 children with CHC for 24 or 48 weeks. The sustained virologic response (SVR) at 24 weeks post-treatment was determined. RESULTS The median duration of infection was 11.5 (range 6-24) months. The median age was 2.7 years, and 64.5 % of the subjects were male. Ninety-three children (36.3 %, 93/256) exhibited spontaneous resolution of the HCV infection. The remaining 163 (63.7 %) were HCV RNA-positive and had HCV genotypes 1b and 2a, which were identified in 42 and 58 %, respectively, of the 133 tested children. Liver biopsies were performed in all HCV RNA-detectable children. A total of 23.9 % cases exhibited grade 2 activity, and 30.1 % exhibited stage 2/3 liver fibrosis. The serum HCV RNA levels were positively correlated with the aminotransferases. Of the 162 treated CHC children, 158 (97.5 %) achieved SVR. The side effects were mild, and 158 (97.5 %) of the treated patients tolerated the treatment well. CONCLUSIONS This study revealed that histological liver disease can be present within 6-24 months of acquiring an HCV infection in children aged 1-5 years. Interferon-α plus ribavirin therapy is a highly effective and cost-effective means of managing children with early-stage chronic HCV infection.
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Affiliation(s)
- Shi-Shu Zhu
- Treatment and Research Center for Children's Liver Disease, Beijing 302 Hospital, Beijing, 100039, China
| | - Qing-Lei Zeng
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, 100039, China
| | - Yi Dong
- Treatment and Research Center for Children's Liver Disease, Beijing 302 Hospital, Beijing, 100039, China
| | - Zhi-Qiang Xu
- Treatment and Research Center for Children's Liver Disease, Beijing 302 Hospital, Beijing, 100039, China
| | - Li-Min Wang
- Treatment and Research Center for Children's Liver Disease, Beijing 302 Hospital, Beijing, 100039, China
| | - Da-Wei Chen
- Treatment and Research Center for Children's Liver Disease, Beijing 302 Hospital, Beijing, 100039, China
| | - Yu Gan
- Treatment and Research Center for Children's Liver Disease, Beijing 302 Hospital, Beijing, 100039, China
| | - Fu-Chuan Wang
- Treatment and Research Center for Children's Liver Disease, Beijing 302 Hospital, Beijing, 100039, China
| | - Jian-Guo Yan
- Treatment and Research Center for Children's Liver Disease, Beijing 302 Hospital, Beijing, 100039, China
| | - Li-Li Cao
- Treatment and Research Center for Children's Liver Disease, Beijing 302 Hospital, Beijing, 100039, China
| | - Pu Wang
- Treatment and Research Center for Children's Liver Disease, Beijing 302 Hospital, Beijing, 100039, China
| | - Jin Han
- Genetic Testing Center, Beijing 302 Hospital, Beijing, 100039, China
| | - Xue-Xiu Zhang
- The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, 100039, China
| | - Zheng Zhang
- The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, 100039, China
| | - Hong-Fei Zhang
- Treatment and Research Center for Children's Liver Disease, Beijing 302 Hospital, Beijing, 100039, China.
| | - Fu-Sheng Wang
- The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, 100039, China.
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19
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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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20
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Viral hepatitis C therapy: pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet 2014; 53:409-27. [PMID: 24723109 DOI: 10.1007/s40262-014-0142-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C is a global health problem. To prevent or reduce complications, the hepatitis C virus (HCV) infection needs to be eradicated. There have been several developments in treating these patients since the discovery of the virus. As of 1 January 2014, the drugs that are approved for treatment of chronic HCV infection are peginterferon-α, ribavirin, boceprevir, telaprevir, simeprevir and sofosbuvir. In this review we provide an overview of the clinical pharmacokinetic characteristics of these agents by describing their absorption, distribution, metabolism and excretion. In the pharmacodynamic part we summarize what is known about the relationships between the pharmacokinetics of each drug and efficacy or toxicity. We briefly discuss the pharmacokinetics and pharmacodynamics of chronic hepatitis C treatment in special patient populations, such as patients with liver cirrhosis, renal insufficiency or HCV/HIV coinfection, and children. With this knowledge, physicians, pharmacists, nurse practitioners, etc. should be educated to safely and effectively treat HCV-infected patients.
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21
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Adis Medical Writers. Consider drug pharmacokinetics when selecting the most suitable treatments for hepatitis C infection. DRUGS & THERAPY PERSPECTIVES 2014. [DOI: 10.1007/s40267-014-0161-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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22
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Khaderi S, Shepherd R, Goss JA, Leung DH. Hepatitis C in the pediatric population: Transmission, natural history, treatment and liver transplantation. World J Gastroenterol 2014; 20:11281-11286. [PMID: 25170212 PMCID: PMC4145766 DOI: 10.3748/wjg.v20.i32.11281] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 05/14/2014] [Indexed: 02/06/2023] Open
Abstract
The number of children affected by the hepatitis C virus (HCV) in the United States is estimated to be between 23000 to 46000. The projected medical cost for children with HCV in the United States is upwards of 200 million over the next decade. The implementation of routine screening of blood supply has virtually eliminated transmission via transfusion and vertical transmission is now the most common mode of infection in children. Infections acquired during infancy are more likely to spontaneously resolve and fibrosis of the liver tends to increase with age suggesting slow progressive histologic injury. Anti-viral treatment may be warranted in children with persistently elevated liver enzymes or with significant fibrosis on liver biopsy. Current standard of care includes weekly pegylated interferon and ribavirin twice daily. Predictors of high sustained viral response include genotype 2 and 3 and low viral load in children with genotype 1 (< 600000 IU/mL). Triple therapy is associated with a significantly higher rate of sustained virologic response (> 90%). Only 34 pediatric patients were transplanted with hepatitis C between January 2008 and April 2013. The majority of pediatric patients were born prior to universal screening of blood products and, as of June 2013, there are only two pediatric patients awaiting liver transplantation for end-stage liver disease secondary to hepatitis C. Pediatric survival rates post-transplant are excellent but graft survival is noticeably reduced compared to adults (73.73% for pediatric patients at one year compared to 87.69% in adult patients). New safe potent, and all-oral effective antiviral therapies for recurrent HCV should help increase graft survival.
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23
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KASL clinical practice guidelines: management of hepatitis C. Clin Mol Hepatol 2014; 20:89-136. [PMID: 25032178 PMCID: PMC4099340 DOI: 10.3350/cmh.2014.20.2.89] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 05/20/2014] [Indexed: 12/16/2022] Open
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24
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Wu RR, Liu FQ, Zhu SS, Han J. Association of Hepatitis C Virus Infection and Interleukin-28B Gene Polymorphism in Chinese Children. Pak J Med Sci 2014; 30:519-24. [PMID: 24948971 PMCID: PMC4048498 DOI: 10.12669/pjms.303.4267] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 02/10/2014] [Accepted: 02/12/2014] [Indexed: 12/17/2022] Open
Abstract
Objective: To preliminarily explore the association of rs12979860 and rs8099917 SNPs with chronic HCV infection in Chinese Han children. Methods: Chronic HCV infection patients (n=277; 1-17 years old, 4.5 years old in average) and healthy subjects (n=150, children; 2-17 years old, 5.2 years old in average) were recruited and tested by PCR combining direct sequencing. The differences between the rs12979860 and rs8099917 genotypes in patients and healthy subjects were compared. Results: The genetic variations at rs12979860 and rs8099917 in chronic hepatitis C (CHC) children and healthy subjects did not differ significantly. The frequency of spontaneous clearance in CHC children was higher (47%), which is related to the genetic variations. The histological changes of patients were more significant compared to their clinical and biochemical indices, but they did not correlate with the genetic mutations at rs12979860 and rs8099917 significantly. Conclusion: The rs12979860 and rs8099917 SNPs are independent factors predicting the spontaneous clearance of Chinese CHC children patients. The correlation between diseases outcomes are in need of further study.
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Affiliation(s)
- Rong-Rong Wu
- Rong-Rong Wu, Department of Pharmacy, Beijing 302 Hospital, Beijing China
| | - Feng-Qun Liu
- Feng-Qun Liu, Department of Pharmacy, Beijing 302 Hospital, Beijing China
| | - Shi-Shu Zhu
- Shi-Shu Zhu, Department of Pediatric Hepatology, Beijing 302 Hospital, Beijing China
| | - Jin Han
- Jin Han, Department of Pharmacy, Beijing 302 Hospital, Beijing China
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25
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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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26
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Barker CIS, Germovsek E, Hoare RL, Lestner JM, Lewis J, Standing JF. Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology. Adv Drug Deliv Rev 2014; 73:127-39. [PMID: 24440429 PMCID: PMC4076844 DOI: 10.1016/j.addr.2014.01.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 12/09/2013] [Accepted: 01/11/2014] [Indexed: 02/02/2023]
Abstract
Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future.
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Affiliation(s)
- Charlotte I S Barker
- Paediatric Infectious Diseases Research Group, Division of Clinical Sciences, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK; Infectious Diseases and Microbiology Unit, University College London, Institute of Child Health, London WC1N 1EH, UK
| | - Eva Germovsek
- Infectious Diseases and Microbiology Unit, University College London, Institute of Child Health, London WC1N 1EH, UK
| | - Rollo L Hoare
- Infectious Diseases and Microbiology Unit, University College London, Institute of Child Health, London WC1N 1EH, UK; CoMPLEX, University College London, Physics Building, Gower Street, London WC1E 6BT, UK
| | - Jodi M Lestner
- Paediatric Infectious Diseases Research Group, Division of Clinical Sciences, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK; Faculty of Medicine, Imperial College London, London, UK
| | - Joanna Lewis
- Infectious Diseases and Microbiology Unit, University College London, Institute of Child Health, London WC1N 1EH, UK; CoMPLEX, University College London, Physics Building, Gower Street, London WC1E 6BT, UK
| | - Joseph F Standing
- Infectious Diseases and Microbiology Unit, University College London, Institute of Child Health, London WC1N 1EH, UK; CoMPLEX, University College London, Physics Building, Gower Street, London WC1E 6BT, UK.
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27
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Walzer N, Flamm SL. Pegylated IFN-α and ribavirin: emerging data in the treatment of special populations. Expert Rev Clin Pharmacol 2014; 2:67-76. [PMID: 24422772 DOI: 10.1586/17512433.2.1.67] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Hepatitis C virus (HCV) is one of the most common causes of chronic liver disease and is currently the leading indication for liver transplantation in the USA. Pegylated IFN-α (PEG-IFN-α) and ribavirin comprise the standard of care for the treatment of chronic HCV. The expansion of antiviral therapy to include special populations that were not well represented or excluded from registration trials has occurred in recent years. Data have emerged that demonstrate that these groups have variable responses to therapy and, in some cases, different side-effect profiles. The etiologies for the varied response rates remain under investigation. This review will address the clinical efficacy and safety profiles of PEG-IFN-α and ribavirin in populations of patients coinfected with HIV, obese patients, liver transplant recipients, children and African-Americans.
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Affiliation(s)
- Natasha Walzer
- Northwestern Feinberg School of Medicine, 675 N St Clair Galter 15-250, Chicago, IL 60611, USA
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Hardikar W, Schwarz KB. Treatment options for chronic hepatitis B and C infection in children. Expert Rev Anti Infect Ther 2014; 4:583-91. [PMID: 17009938 DOI: 10.1586/14787210.4.4.583] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
There has been a dramatic increase in treatment options for both chronic hepatitis B (CHB) and chronic hepatitis C (CHC) infection in adults over the past 5-10 years, resulting in standardized regimes for initial treatment, relapsers and even infection in the setting of recurrence post-liver transplantation. These regimes have resulted in the halting of the disease progression, reduction in the risk of hepatocellular carcinoma and removal of these infections as a contraindication for liver transplantation. However, treatment in children must be considered carefully in the context of the natural history of these infections and host factors, particularly the immunological mileu, which may affect response to therapy. The as yet unknown long-term effects of medications must also be balanced with the probability of significant life-long morbidity or mortality from chronic hepatitis and its complications. Furthermore, the development of drug resistance, particularly in the case of CHB, has significant implications for the pediatric patient who may exhaust effective therapeutic options at a relatively young age. For these reasons, initiation of therapy must be based on sound criteria. Based on the current data, we recommend that therapy should be offered to children with CHB who have an elevation in alanine aminotransferase (>2-3 x upper limit of normal) for more than 6 months. Therapy with interferon-alpha should be offered in the majority of cases with the aim of immune clearance as measured by early antigen seroconversion. By contrast, treatment indication for CHC in children remains controversial. If used, combination therapy with pegylated interferon and ribavirin is likely to produce the highest rates of sustained viral response.
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Affiliation(s)
- Winita Hardikar
- Royal Children's Hospital, Department of Gastroenterology and Nutrition, Melbourne, Australia.
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29
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Shah U. Infections of the Liver. DISEASES OF THE LIVER IN CHILDREN 2014. [PMCID: PMC7121352 DOI: 10.1007/978-1-4614-9005-0_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
The portal vein carries blood from the gastrointestinal tract to the liver and in so doing carries microbes as well. The liver may therefore be involved in infections with a myriad number of microbial organisms. While some of these infections most commonly occur in the immunocompromised host, others affect the immune competence. Hepatic infections may be primary in nature or secondary, as part of systemic or contagious disease. The purpose of this chapter is to provide a brief overview of the various infections of the liver in the pediatric patient.
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Population pharmacokinetics of peginterferon alfa-2b in pediatric patients with chronic hepatitis C. Eur J Clin Pharmacol 2013; 69:2045-54. [PMID: 23975236 DOI: 10.1007/s00228-013-1574-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Accepted: 07/31/2013] [Indexed: 01/26/2023]
Abstract
PURPOSE The aim of this study was to characterize the population pharmacokinetics of peginterferon (PEG-IFN) alfa-2b in pediatric patients with chronic hepatitis C and to identify covariates influencing PEG-IFN alfa-2b disposition. METHODS Pharmacokinetic data from a multicenter open-label study of subcutaneously administered peginterferon alfa-2b (60 μg/m(2)/wk) plus oral ribavirin (15 mg/kg/day) in patients with chronic hepatitis C aged 3-17 years old was used to develop a population pharmacokinetic nonlinear mixed-effects model. RESULTS The final population pharmacokinetic analysis was conducted with the pooled data from 107 pediatric patients. A one-compartment model with first-order absorption, first-order elimination, exponential inter-individual variability on clearance, and a combination additive and proportional residual error model adequately described the PEG-IFN alfa-2b pharmacokinetic profile. Age (apparent clearance and apparent volume of distribution) and sex (apparent clearance) were significant covariates. The mean body surface area normalized apparent clearance of PEG-IFN alfa-2b was 0.56 L/h/m(2), and was similar when evaluated across the pediatric age groups. CONCLUSION The final population model suggests age-dependent increases in clearance and volume of distribution of PEG-IFN alfa-2b in pediatric patients with chronic hepatitis C. The apparent clearance normalized to body surface area was similar across pediatric age groups, supporting the use of body size-adjusted dosing in pediatric subjects.
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Pawłowska M, Halota W, Smukalska E. Vertical genotype 1 HCV infection treated successfully in the second year of life: a case report. Med Sci Monit 2012; 18:CS113-6. [PMID: 23222845 PMCID: PMC3560799 DOI: 10.12659/msm.883620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background Perinatal HCV transmission appears to be an important cause of HCV in children. Treatment of chronic hepatitis C in young children is controversial because of spontaneous HCV clearance and possible adverse events. Case Report Vertical HCV genotype 1 infection was diagnosed in a 3-month-old infant. In the subsequent clinical examination we still observed hepatomegaly, fluctuations of ALT, AST and GGT activity, with the highest values 2206 U/L, 1319 U/L, and 297 U/L, respectively. In qPCR, HCV RNA was >700.000 IU/ml. In the 42nd week of observation, liver biopsy was performed with Grade 1 grading and Grade 1 staging. At age 12 months, interferon-alpha2b (1.5 MU 3 times a week) and ribavirin (2×80 mg daily) were administered for 48 weeks. At the beginning of the treatment we observed fever after IFN injection. In the 12th week of therapy, HCV RNA disappeared followed by SVR, and it was sustained for 6 years. To our knowledge, this is the first report of a pediatric (1-year-old) patient treated with combined IFN alpha-2b and ribavirin therapy. Conclusions This case report confirms the possibility of successful anti-HCV treatment in a young child, with 6-year sustained virological response without significant adverse events.
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Affiliation(s)
- Małgorzata Pawłowska
- Chair of Infectious Diseases and Hepatology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
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Jonas MM, Balistreri W, Gonzalez-Peralta RP, Haber B, Lobritto S, Mohan P, Molleston JP, Murray KF, Narkewicz MR, Rosenthal P, Schwarz KB, Barton BA, Shepherd JA, Mitchell PD, Duggan C. 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. [PMID: 22383118 PMCID: PMC3382022 DOI: 10.1002/hep.25690] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Accepted: 02/20/2012] [Indexed: 12/12/2022]
Abstract
UNLABELLED Weight loss and changes in growth are noted in children treated with interferon alpha (IFN-α). The aim of this study was to prospectively determine changes in weight, height, body mass index (BMI), and body composition during and after treatment of children with hepatitis C virus (HCV). Children treated with pegylated interferon alpha-2a (Peg-IFN-α2a) ± ribavirin in the Pediatric Study of Hepatitis C (PEDS-C) trial underwent anthropometric measurements, dual-energy X-ray absorptiometry scan, as well as dietary and activity assessments during and after treatment. One hundred and fourteen (55% male) children, with a mean age of 11 ± 3 years, were randomized, and 107 received treatment for at least 24 weeks. Subjects were divided into three groups according to duration of treatment: 24 (N = 14), 48 (N = 82), or 72 (N = 11) weeks. Decrements of up to 0.50 z score were observed for weight, height, and BMI while on therapy among all groups (P ≤ 0.01, compared to baseline). In the group treated for 48 weeks, 29 (33%) subjects had greater than 0.5-unit decrement in height-for-age z (HAZ) score. Though weight-for-age and BMI z scores returned to baseline after cessation of therapy, mean HAZ score was slower to rebound, still lower than baseline at 96 weeks post-therapy for the long-treatment duration group (P = 0.03) and lower than baseline in most children treated for 48 weeks. Percent body fat, fat-free mass z scores, and triceps skinfold z scores decreased with therapy. Dietary energy intake and levels of physical activity did not change during treatment. CONCLUSIONS Peg-IFN-α2a was associated with significant changes in body weight, linear growth, BMI, and body composition in children. These effects were generally reversible with cessation of therapy, although HAZ scores had not returned to baseline after 2 years of observation in many. Longer term growth data are needed among children treated for chronic HCV.
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Affiliation(s)
| | | | | | - Barbara Haber
- Children's Hospital of Philadelphia, Philadelphia, PA
| | - Steven Lobritto
- Morgan Stanley Children's Hospital of New York, New York, NY
| | | | | | | | - Michael R. Narkewicz
- University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO
| | | | | | - Bruce A. Barton
- University of Massachusetts School of Medicine, Worcester, MA
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NASPGHAN practice guidelines: Diagnosis and management of hepatitis C infection in infants, children, and adolescents. J Pediatr Gastroenterol Nutr 2012; 54:838-55. [PMID: 22487950 DOI: 10.1097/mpg.0b013e318258328d] [Citation(s) in RCA: 149] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Hepatitis C virus (HCV) is an RNA virus that affects >180 million individuals worldwide with a high propensity for chronic infection. Children with HCV infection differ from adults in several ways including some modes of transmission, rates of clearance, progression of fibrosis, and the duration of potential chronic infection when acquired at birth. Since the discovery of HCV in 1989, there have been significant advances in the understanding of the virology and natural history of chronic HCV infection in children. In addition, there are now several treatment options for children with chronic hepatitis C infection and many new therapies on the horizon. As a consequence, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition brought together experts in pediatric hepatology to review the available data in children and provide clinicians with approaches to the diagnosis, management, and prevention of HCV infection in children and adolescents. The guideline 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.
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Kelly DA, Haber B, González-Peralta RP, Murray KF, Jonas MM, Molleston JP, Narkewicz MR, Sinatra FR, Lang T, Lachaux A, Wirth S, Shelton M, Te HS, Pollack H, Deng W, Noviello S, Albrecht JK. Durability of sustained response shown in paediatric patients with chronic hepatitis C who were treated with interferon alfa-2b plus ribavirin. J Viral Hepat 2012; 19:263-70. [PMID: 22404724 DOI: 10.1111/j.1365-2893.2011.01544.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Long-term studies in adults indicate that sustained virologic response (SVR) after combination treatment for chronic hepatitis C (CHC) predicts long-term clearance. Although peginterferon plus ribavirin is now standard care for children with CHC, long-term follow-up studies are not yet available. This study evaluated durability of virologic response over 5 years in children previously treated with interferon alfa-2b plus ribavirin (IFN/R). Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed the 6-month follow-up in two previous clinical trials, participated in this long-term follow-up study. All were assessed annually for up to 5 years; patients with SVR were assessed for durability of virologic response. Children with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA 24-week post-treatment (n = 41) were followed for a median of 284 weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with the same genotype. Kaplan-Meier estimate for sustained response at 5 years was 98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels (n = 4) or missing HCV RNA at the 24-week follow-up visit (n = 2) in the initial treatment studies had virologic response during this long-term follow-up study. Linear growth rate was impaired during treatment with rapid increases in the immediate 6 months post-treatment. Mean height percentile at the end of the 5-year follow-up was slightly less than the mean pretreatment height percentile. Five patients experienced serious adverse events; none related to study drug exposure. SVR after IFN/R predicts long-term clearance of HCV in paediatric patients; growth normalized in the majority of children during the long-term follow-up. Similar long-term results could be expected after peginterferon alfa-2b plus ribavirin treatment.
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Affiliation(s)
- D A Kelly
- Liver Unit, Birmingham Children's Hospital, Birmingham, UK.
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Strader DB, Seeff LB. A brief history of the treatment of viral hepatitis C. Clin Liver Dis (Hoboken) 2012; 1:6-11. [PMID: 31186837 PMCID: PMC6490695 DOI: 10.1002/cld.1] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
- Doris B. Strader
- Division of Gastroenterology and Hepatology, Fletcher Allen Health Care, University of Vermont College of Medicine, Burlington, VT
| | - Leonard B. Seeff
- Hill Group, Bethesda, MD,Food and Drug Administration, Silver Spring, MD
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36
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Spontaneous clearance of hepatitis C virus in vertically infected children. Eur J Pediatr 2012; 171:253-8. [PMID: 21735055 DOI: 10.1007/s00431-011-1517-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Accepted: 06/09/2011] [Indexed: 02/08/2023]
Abstract
UNLABELLED Spontaneous viral clearance of hepatitis C virus (HCV) has been reported to occur in children with vertical HCV infection. However, factors which are associated with or predispose for clearance are largely unknown. In this case series we retrospectively analyzed laboratory parameters associated with spontaneous clearance of HCV in vertically infected children. The charts of six patients with documented spontaneous viral clearance by the age of 5 years were reviewed regarding clinical course, liver function tests (LFTs) and trend of HCV gene copy numbers. Spontaneous viral elimination was observed between the 25th and 52nd months of age. All patients had elevated LFTs, which peaked before 20 months of life. Peak LFT elevation was followed by normalization of LFTs and decline in viral load. These findings suggest that, in vertically HCV-infected children, a potent inflammatory response in the liver precedes viral clearance. Therefore, temporarily elevated LFTs, followed by a decline of viral load may be indicative of a near viral clearance in early childhood. CONCLUSION Further investigations regarding the development of optimal treatment algorithms should take into account factors, which are associated with possible spontaneous viral resolution, such as viral genotype, favourable host factors as well as direct and indirect parameters of antiviral immunity, and the individual course of viral replication.
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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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Velmishi V, Dervishi E, Cullufi P, Bali D, Durro V. Treatment and follow up of children with chronic hepatitis C in Albania. Virol J 2012; 9:17. [PMID: 22244498 PMCID: PMC3271956 DOI: 10.1186/1743-422x-9-17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2011] [Accepted: 01/13/2012] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Treatment of Hepatitis C in children has a better outcome than in adults, and for this reason the treatment had different views. However, in pediatric age hepatitis C is seen to have an evolution towards chronicity. Today is a normal option to treat chronic hepatitis C as early as possible according to certain criteria. The aim of this study is to show the results of treatment with interferon and ribavirin and the follow-up of children diagnosed with chronic hepatitis C in our service. PATIENTS AND METHODS This is a prospective study which has included children 3 up to 15 years old (13 boys and 4 girls) diagnosed with chronic hepatitis C. All patients underwent a certain protocol, including liver biopsy prior to treatment. Treatment consisted in use for 48 weeks of INF α-2b, 3 MIU/m2 three times a week s/c and ribavirin 15 mg/kg orally divided bid. Two patients were treated with PEGINF α-2b with dose 1.5 mcg/kg once a week s/c and ribavirin 15 mg/kg. After the treatment all patients have stayed under our control for an average period of 24 weeks. RESULTS At the end of the treatment we detected a patient with HCV-RNA positive. End Treatment Viral Response was 94%. Six months later we found three patients who showed relapse of disease. Sustained Viral Response was approximately 83% CONCLUSION The combination therapy of interferon with Ribavirin in treatment of children with chronic hepatitis C provides a higher SVR when treatment is initiated at the earliest stages of hepatic changes. Side effects of therapy are insignificant in comparison with results obtained.
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Affiliation(s)
- Virtut Velmishi
- Service of Pediatric Gastrohepatology, University Hospital Center "Mother Theresa", Rruga "Dibres" No. 372, Tirana, Albania
| | - Ermira Dervishi
- Service of Pediatric Gastrohepatology, University Hospital Center "Mother Theresa", Rruga "Dibres" No. 372, Tirana, Albania
| | - Paskal Cullufi
- Service of Pediatric Gastrohepatology, University Hospital Center "Mother Theresa", Rruga "Dibres" No. 372, Tirana, Albania
| | - Donjeta Bali
- Service of Pediatric Oncohematology, University Hospital Center "Mother Theresa", Rruga "Dibres" No. 372, Tirana, Albania
| | - Vjollca Durro
- Hospital Planning Directory, Ministry of Health, Bulevardi " Bajram Curri", no 1, Tirana, Albania
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Schleiss MR, Patterson JC. Viral Infections of the Fetus and Newborn and Human Immunodeficiency Virus Infection during Pregnancy. AVERY'S DISEASES OF THE NEWBORN 2012:468-512. [DOI: 10.1016/b978-1-4377-0134-0.10037-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Venturi C, Bueno J, Castells L, Quintero J, Casas I, Allende H, Martinez-Ibañez V, Charco R. Long-term outcome of hepatitis C virus infections acquired after pediatric liver transplantation. Liver Transpl 2011; 17:1474-80. [PMID: 21932378 DOI: 10.1002/lt.22439] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The outcomes and characterization of hepatitis C virus (HCV) infections after pediatric liver transplantation (LT) have rarely been reported. We describe our experience with HCV infections after pediatric LT. Ten of 207 children (4.8%) who underwent LT at our institution (1985-2010) developed previously undiagnosed HCV disease. Eight received a liver graft before blood product and donor screening for HCV became available. The mean age at transplantation was 8.9 ± 4.3 years, and the median time from transplantation to the diagnosis of HCV was 15.1 years (range = 0.2-19.7 years). The genotypes were 1 (n = 8), 3 (n = 1), and undetermined (n = 1). At the time of this writing, all the patients were still alive with a mean follow-up of 7.3 ± 5.5 years after the diagnosis of HCV. Five patients did not receive treatment; 2 of these patients achieved spontaneous viral clearance (SVC). Four of the 5 treated patients achieved a sustained virological response, and 3 had an early virological response (EVR). Two of these 4 patients developed chronic rejection while they were on treatment, but this was resolved with a conversion from cyclosporine A to tacrolimus. The remaining patient was continuing treatment and had achieved EVR. In conclusion, despite the limitations of our series, de novo HCV infections after pediatric LT seem to have a slow histological progression. Even with genotype 1, the patients have a good long-term prognosis and respond well to treatment. Nevertheless, chronic rejection during antiviral therapy may develop. In addition, SVC may occur in this population.
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Affiliation(s)
- Carla Venturi
- Pediatric Surgery and Transplant Unit, Saint Luc University Clinics, Brussels, Belgium
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Abdel-Hady M, Bunn SK, Sira J, Brown RM, Brundler MA, Davies P, Kelly DA. Chronic hepatitis C in children--review of natural history at a National Centre. J Viral Hepat 2011; 18:e535-40. [PMID: 21914074 DOI: 10.1111/j.1365-2893.2011.01456.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The natural history of hepatitis C virus (HCV) infection in adults has been established, but less is known about outcome in children. We conducted a retrospective review of patients referred to Birmingham Children's Hospital Liver Unit, from 1991 till 2008, with the diagnosis of HCV was undertaken. Only children with documented positive HCV RNA and a minimum duration of follow-up of 6 months were included. One hundred and thirty-three children were identified. The route of transmission was transfusion acquired in 47%, vertically acquired in 49% and transplantation in 2%. Since 2000, most children were infected vertically. The overall rate of spontaneous viral clearance was 17.5% with higher clearance (27%) in the transfusion group compared to the vertically acquired group (9%). Seventy-six had a liver biopsy at diagnosis. There was no evidence of fibrosis in 46%, mild fibrosis in 50% and moderate to severe fibrosis in 4%. None had cirrhosis. There was a statistically significant relationship between fibrosis score and older age at the time of biopsy (P = 0.02) and longer duration of infection (P = 0.05). Eighty children received treatment for HCV. Sustained viral response (SVR) was influenced by viral genotypes, with significantly increased response rates in genotypes (G) 2 and 3 compared to G 1 and 4. Vertical infection is now the major route of HCV infection in children in the UK. Histological changes were mild at diagnosis, but the severity of fibrosis progressed with age. Consideration should be given to improve detection and diagnosis to refer children to specialist centres for management and antiviral therapy before developing fibrosis.
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Affiliation(s)
- M Abdel-Hady
- Liver Unit, Birmingham Children's Hospital, Birmingham, UK.
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42
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Rodrigue JR, Balistreri W, Haber B, Jonas MM, Mohan P, Molleston JP, Murray KF, Narkewicz MR, Rosenthal P, Smith LJ, Lobritto SJ, Schwarz KB, Robuck PR, Barton B, González-Peralta RP. Peginterferon with or without ribavirin has minimal effect on quality of life, behavioral/emotional, and cognitive outcomes in children. Hepatology 2011; 53:1468-75. [PMID: 21351116 PMCID: PMC3082614 DOI: 10.1002/hep.24248] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
UNLABELLED The aim of this study was to prospectively assess the quality of life (QOL), behavioral/emotional functioning, and cognitive status of children undergoing treatment for hepatitis C virus (HCV) infection. In all, 114 children (5 to 18 years old) enrolled in a multisite randomized clinical trial (Peds-C) to evaluate peginterferon alpha 2a (PEG 2a) with ribavirin (RV) or with placebo (PL) completed several standardized measures prior to treatment and at 24 weeks, 48 weeks, 6 months following treatment, and at two annual follow-up visits. After 24 weeks of treatment, mean physical QOL scores declined significantly for both groups from baseline to 24 weeks of treatment (F = 5.8, P = 0.004), although scores remained in the average range. There were no significant time or group effects for behavioral/emotional or cognitive functioning. Three children (5%) in the PEG 2a + RV group and no children in the PEG 2a + PL group had a clinically significant increase in depression symptoms. For those children who received 48 weeks of treatment, there were no significant time or group effects on any of the outcome measures (P > 0.05). A majority of children in both the PEG 2a + RV and PEG 2a + PL groups experienced no clinically significant change in physical QOL, behavioral adjustment, depression, or cognitive functioning during or after treatment. CONCLUSION Overall QOL and psychosocial functioning are not deleteriously impacted by PEG 2a + RV or PL treatment of children with HCV.
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Affiliation(s)
| | | | - Barbara Haber
- Children's Hospital of Philadelphia, Philadelphia, PA
| | | | | | | | - Karen F. Murray
- Children's Hospital and Regional Medical Center, Seattle, Washington
| | - Michael R. Narkewicz
- University of Colorado Denver School of Medicine, Children's Hospital, Aurora, CO
| | | | | | | | | | - Patricia R. Robuck
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
| | - Bruce Barton
- University of Massachusetts Medical School, Worcester, MA
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Management of chronic hepatitis C in childhood: the impact of therapy in the clinical practice during the first 2 decades. Dig Liver Dis 2011; 43:325-9. [PMID: 21111693 DOI: 10.1016/j.dld.2010.10.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2010] [Revised: 09/28/2010] [Accepted: 10/14/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Treatment of chronic hepatitis C in children is controversial and its role in the clinical practice is unknown. We retrospectively investigated the impact of treatment in a large cohort of children with chronic hepatitis C over the past 20 years. METHODS 376 hepatitis C virus RNA positive children were recruited consecutively in five Italian centres since 1990 and followed for 1-17 years. RESULTS 86 (23%) subjects were treated: 73 with recombinant interferon alone and 13 with pegylated-interferon and ribavirin. Sustained clearance of hepatitis C virus RNA was observed in 25% of the former, in 92% of the latter and in 9% of untreated cases (p < 0.001). Loss of viraemia was recorded in all children with genotype 2-3 and in 6 of 7 with hepatitis C virus genotype 1 treated with combination therapy. At last evaluation 45% of patients were young adults and 15% had cleared viraemia. Overall, 152 (40%) were putative candidates to therapy. CONCLUSIONS Few Italian children with chronic hepatitis C have been treated in the past 20 years. The poor propensity to spontaneous clearance of viraemia and the efficacy of combination therapy should encourage to consider treatment in attempt to shorten the duration of viral replication.
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Abstract
A thorough understanding of the structure and biology of a biotherapeutic is crucial to defining a suitable strategy for pharmacokinetic characterization in proof-of-concept disease models, toxicology species as well as the healthy and disease indication patient populations. This manuscript summarizes parameters that impact bioanalytical strategy for over 50 biotherapeutics indicated for the treatment of oncology, rheumatoid arthritis, allergy, multiple sclerosis, hematology, metabolism and infectious disease. We have addressed numerous therapeutic modalities including chimeric, humanized and fully human monoclonal antibodies, replacement proteins, peptides and fusion proteins, including polyethylene glycol and Fc fusions, as well as antibody–drug conjugates. With the rapid evolution of biotherapeutics over the last 20 years and the contraction of the pharmaceutical and biotechnology labor force, efficient workflow management becomes a crucial bioanalytical component. Thus, we have also addressed new technologies that have demonstrated either increased throughput or enhanced characterization, including Meso Scale Discovery, Gyrolab and affinity MS.
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Schwarz KB, Gonzalez-Peralta RP, Murray KF, Molleston JP, Haber BA, Jonas MM, Rosenthal P, Mohan P, Balistreri WF, Narkewicz MR, Smith L, Lobritto SJ, Rossi S, Valsamakis A, Goodman Z, Robuck PR, Barton BA, The 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. [PMID: 21036173 PMCID: PMC3042126 DOI: 10.1053/j.gastro.2010.10.047] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2010] [Revised: 08/19/2010] [Accepted: 10/15/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Although randomized trials of adults infected with hepatitis C virus (HCV) have shown that ribavirin increases the efficacy of pegylated interferon (PEG), such trials have not been performed in children. We conducted a randomized controlled trial of PEG and ribavirin, compared with PEG and placebo, in children 5 to 17 years old with chronic hepatitis C. METHODS HCV RNA-positive children from 11 university medical centers were randomly assigned to receive either PEG alfa-2a (PEG-2a; 180 μg/1.73 m(2) body surface area, subcutaneously each week; n = 55) and ribavirin (15 mg/kg orally in 2 doses daily) or PEG-2a and placebo (n = 59) for 48 weeks. The primary end point was sustained virologic response (SVR; lack of detectable HCV RNA at least 24 weeks after stopping therapy). RESULTS SVR was achieved in 53% of children treated with PEG-2a and ribavirin, compared with 21% of children who received PEG-2a and placebo (P < .001). Early virologic response (HCV RNA reduction >2 log(10) IU at 12 weeks) had a negative predictive value of only 0.89 in children with genotype 1, indicating that these children might benefit from 24 weeks of therapy before stopping treatment. Side effects, especially neutropenia, led to dose modification in 40% of children. Eighty-two percent of the PEG/ribavirin and 86% of the PEG/placebo group were in compliance with the year 2 follow-up visit; the durability of virologic response was 100% in both groups. CONCLUSIONS The combination of PEG and ribavirin is superior to PEG and placebo as therapy for chronic hepatitis C in children and adolescents.
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Affiliation(s)
- Kathleen B. Schwarz
- Department of Pediatrics, Division of Gastroenterology and Nutrition, the, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Regino P. Gonzalez-Peralta
- Section of Hepatology and Liver Transplantation, Department of Pediatrics, University of Florida College of Medicine and Shand's Childrens Hospital, Gainesville, FL
| | - Karen F. Murray
- Divison of Gastroenterology and Hepatology, Seattle Children's,, Seattle, WA
| | - Jean P. Molleston
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, IN
| | - Barbara A. Haber
- Clinical and Translational Science Award Research Center, Children's Hospital of Philadelphia, The University of Pennsylvania, Philadelphia, PA
| | - Maureen M. Jonas
- Division of Gastroenterology, Children's Hospital Boston, Boston, MA
| | - Philip Rosenthal
- Department of Pediatrics, University of California, San Francisco, CA
| | - Parvathi Mohan
- Division of Gastroenterology, Hepatology and Nutrition, Children's National Medical Center, Washington DC
| | | | - Michael R. Narkewicz
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado Denver School of Medicine and The Children's Hospital, Aurora CO
| | - Lesley Smith
- Pediatric Gastroenterology, Hepatology and Nutrition, Columbia University Medical Center, New York, NY
| | - Steven J. Lobritto
- Pediatric Gastroenterology, Hepatology and Nutrition, Columbia University Medical Center, New York, NY
| | | | - Alexandra Valsamakis
- Johns Hopkins Clinical Virology Laboratory, Johns Hopkins University School of Medicine, Baltimore MD
| | | | - Patricia R. Robuck
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Washington DC
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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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Karnsakul W, Schwarz KB. Hepatitis. INFECTIOUS DISEASES OF THE FETUS AND NEWBORN 2011:800-813. [DOI: 10.1016/b978-1-4160-6400-8.00025-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Fawaz R, Jonas MM. Acute and Chronic Hepatitis. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2011:811-828.e5. [DOI: 10.1016/b978-1-4377-0774-8.10075-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Shi R, Derendorf H. Pediatric Dosing and Body Size in Biotherapeutics. Pharmaceutics 2010; 2:389-418. [PMID: 27721364 PMCID: PMC3967145 DOI: 10.3390/pharmaceutics2040389] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Revised: 12/09/2010] [Accepted: 12/15/2010] [Indexed: 01/19/2023] Open
Abstract
Although pediatric doses for biotherapeutics are often based on patients' body weight (mg/kg) or body surface area (mg/m2), linear body size dose adjustment is highly empirical. Growth and maturity are also important factors that affect the absorption, distribution, metabolism and excretion (ADME) of biologics in pediatrics. The complexity of the factors involved in pediatric pharmacokinetics lends to the reconsideration of body size based dose adjustment. A proper dosing adjustment for pediatrics should also provide less intersubject variability in the pharmacokinetics and/or pharmacodynamics of the product compared with no dose adjustment. Biological proteins and peptides generally share the same pharmacokinetic principle with small molecules, but the underlying mechanism can be very different. Here, pediatric and adult pharmacokinetic parameters are compared and summarized for selected biotherapeutics. The effect of body size on the pediatric pharmacokinetics for these biological products is discussed in the current review.
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Affiliation(s)
- Rong Shi
- Department of Pharmaceutics, University of Florida, Gainesville, FL, 32610, USA.
| | - Hartmut Derendorf
- Department of Pharmaceutics, University of Florida, Gainesville, FL, 32610, USA.
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