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Mahmood I. A Simple Method for the Prediction of Therapeutic Proteins (Monoclonal and Polyclonal Antibodies and Non-Antibody Proteins) for First-in-Pediatric Dose Selection: Application of Salisbury Rule. Antibodies (Basel) 2022; 11:antib11040066. [PMID: 36278619 PMCID: PMC9590058 DOI: 10.3390/antib11040066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 11/29/2022] Open
Abstract
In order to conduct a pediatric clinical trial, it is important to optimize pediatric dose as accurately as possible. In this study, a simple weight-based method known as ‘Salisbury Rule’ was used to predict pediatric dose for therapeutic proteins and was then compared with the observed pediatric dose. The observed dose was obtained mainly from the FDA package insert and if dosing information was not available from the FDA package insert then the observed dose was based on the dose given to an age group in a particular study. It was noted that the recommended doses of most of the therapeutic proteins were extrapolated to pediatrics from adult dose based on per kilogram (kg) body weight basis. Since it is widely believed that pediatric dose should be selected based on the pediatric clearance (CL), a CL based pediatric dose was projected from the following equation: Dose in children = Adult dose × (Observed CL in children/Observed adult CL). In this study, this dose was also considered observed pediatric dose for comparison. A ±30% prediction error (predicted vs. observed) was considered acceptable. There were 21 monoclonal antibodies, 5 polyclonal antibodies in children ≥ 2 years of age, 4 polyclonal antibodies in preterm and term neonates, and 11 therapeutic proteins (non-antibodies) in the study. In children < 30 kg body weight, the predicted doses were within 0.5−1.5-fold prediction error for 87% (monoclonal antibody), 100% (polyclonal antibody), and 92% (non-antibodies) observations. In children > 30 kg body weight, the predicted doses were within 0.5−1.5-fold prediction error for 96% (monoclonal antibody), 100% (polyclonal antibody), and 100% (non-antibodies) observations. The Salisbury Rule mimics more to CL-based dose rather than per kg body weight-based extrapolated dose from adults. The Salisbury Rule for the pediatric dose prediction can be used to select first-in-children dose in pediatric clinical trials and may be in clinical settings.
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Affiliation(s)
- Iftekhar Mahmood
- Mahmood Clinical Pharmacology Consultancy, LLC 1709, Piccard DR, Rockville, MD 20850, USA
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Atakul G, Atay Ö, Asrak HK, Erbaş İC, Asilsoy S, Belet N, Boyacıoğlu ÖK, Köse SŞ, Al S, Uzuner N, Karaman Ö. Clinical Response to Adjunctive Pegylated Interferon Alpha-2a Treatment in Disseminated Mycobacterial Infection in Children with Complete IFNGR1 Deficiency: A Case Report. J PEDIAT INF DIS-GER 2022. [DOI: 10.1055/s-0042-1749646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Objective Interferon gamma receptor 1 (IFNGR1) deficiency is a primary immunodeficiency that causes systemic infections with weakly virulent nontuberculous mycobacteria, which are very difficult to control with combined antimycobacterial agents.
Methods Disseminated mycobacterial infection that could not be controlled with combined antimycobacterial treatments in a 13-year-old patient with a novel mutation in the IFNGR1 gene. Despite receiving intravenous antibiotic therapy, fever continued, bone involvement gradually increased, and proteinuria and microscopic hematuria occurred. Peg-IFNα-2a was administered as an adjuvant therapy that resulted in good clinical response with no side effects. Fever improved and no new bone lesions occurred with edema of existing lesions regressing after 2 weeks of peg-IFNα-2a therapy.
Conclusion Aggressive treatment with antimycobacterial antibiotics and hematopoietic stem cell transplantation remains the single accepted method for the management of patients with complete IFNGR1 deficiency. Peg-IFNα-2a treatment may be an adjunct treatment in this disorder.
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Affiliation(s)
- Gizem Atakul
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Özge Atay
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Hatice Karaoğlu Asrak
- Division of Pediatric Infectious Disease, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - İrem Ceren Erbaş
- Division of Pediatric Infectious Disease, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Suna Asilsoy
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Nurşen Belet
- Division of Pediatric Infectious Disease, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Özge Kangallı Boyacıoğlu
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Seda Şirin Köse
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Serdar Al
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Nevin Uzuner
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
| | - Özkan Karaman
- Division of Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey
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Polyethylene Glycol Exposure with Antihemophilic Factor (Recombinant), PEGylated (rurioctocog alfa pegol) and Other Therapies Indicated for the Pediatric Population: History and Safety. Pharmaceuticals (Basel) 2018; 11:ph11030075. [PMID: 30049994 PMCID: PMC6160981 DOI: 10.3390/ph11030075] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 07/21/2018] [Accepted: 07/23/2018] [Indexed: 12/31/2022] Open
Abstract
Polyethylene glycol (PEG) is an inert, water soluble polymer, used for decades in pharmaceuticals. Although PEG is considered safe, concerns persist about the potential adverse effects of long-term exposure to PEG-containing therapies, specifically in children, following the introduction of PEGylated recombinant factor products used for the treatment of hemophilia. Given the absence of long-term surveillance data, and to evaluate the potential risk, we estimated PEG exposure in the pediatric population receiving PEGylated therapies with pediatric indications administered intravenously or intramuscularly. We used a range of pediatric weights and doses based on prescribing information (PI) or treatment guidelines. PIs and reporting websites were searched for information about adverse events (AEs). For a child weighing 50 kg on the highest prophylactic dose of a FVIII product, the range of total PEG exposure was 40–21,840 mg/year; for factor IX (FIX) products, the range was 13–1342 mg/year; and for other products, the range was 383–26,743 mg/year, primarily as a derivative excipient. No AE patterns attributable to PEG were found for any of these products, including potential renal, neurological, or hepatic AEs. Our analyses suggest the pediatric population has had substantial exposure to PEG for several decades, with no evidence of adverse consequences.
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Huang Y, Li MH, Hou M, Xie Y. Peginterferon alfa-2a for the treatment of chronic hepatitis C in the era of direct-acting antivirals. Hepatobiliary Pancreat Dis Int 2017; 16:470-479. [PMID: 28992878 DOI: 10.1016/s1499-3872(17)60044-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 06/23/2017] [Indexed: 02/05/2023]
Abstract
BACKGROUND The availability of novel direct-acting antivirals (DAAs) represents a new era of curative hepatitis C virus (HCV) treatment, with over 95% of patients infected with HCV genotype 1 achieving sustained virological response (SVR). Nevertheless, the majority of patients globally are unable to access these treatments because of cost and infrastructure constraints and, thus, remain untreated and uncured. DATA SOURCE Relevant articles of peginterferon (PegIFN)-based treatments in HCV and sofosbuvir-based treatments, simeprevir, daclatasvir/asunaprevir, ritonavir-boosted paritaprevir/ombitasvir/dasabuvir, and grazoprevir/elbasvir, were searched in PubMed database, including general population and special population. RESULTS PegIFN in combination with ribavirin remains an important and relevant option for some patients, achieving SVR rates of up to 79% in genotype 1 and 89% in genotype 2 or 3 infections, which increases for patients with favorable IL28B genotypes. Triple therapy of DAA plus PegIFN/ribavirin is effective in treating difficult-to-cure patients infected with HCV genotype 3 or with resistance-associated variants. Owing to its long history in HCV management, the efficacy, tolerability and long-term outcomes associated with PegIFN alfa-2a are well established and have been validated in large-scale studies and in clinical practice for many populations. Furthermore, emerging data show that IFN-induced SVR is associated with lower incidences of hepatocellular carcinoma compared with DAAs. On the contrary, novel DAAs have yet to be studied in special populations, and long-term outcomes, particularly tumor development and recurrence in patients with cirrhosis and/or hepatocellular carcinoma, and reactivation of HBV in dually infected patients, are still unclear. CONCLUSION In this interferon-free era, PegIFN-based regimens remain a safe and effective option for selected HCV patients.
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Affiliation(s)
- Yan Huang
- Shanghai Roche Pharmaceuticals Ltd., Shanghai 201203, Beijing, China
| | - Ming-Hui Li
- Liver Disease Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Min Hou
- Shanghai Roche Pharmaceuticals Ltd., Shanghai 201203, Beijing, China
| | - Yao Xie
- Liver Disease Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
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Bi J, Li X, Liu J, Chen D, Li S, Hou J, Zhou Y, Zhu S, Zhao Z, Qin E, Wei Z. Population pharmacokinetics of peginterferon α2a in patients with chronic hepatitis B. Sci Rep 2017; 7:7893. [PMID: 28801680 PMCID: PMC5555209 DOI: 10.1038/s41598-017-08205-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 07/10/2017] [Indexed: 01/17/2023] Open
Abstract
There were significant differences in response and pharmacokinetic characteristics to the peginterferon α2a treatment among Chronic Hepatitis B (CHB) patients. The aim of this study is to identify factors which could significantly impact the peginterferon α2a pharmacokinetic characteristics in CHB patients. There were 208 blood samples collected from 178 patients who were considered as CHB and had been treated with peginterferon α2a followed by blood concentration measurement and other laboratory tests. The covariates such as demographic and clinical characteristics of the patients were retrieved from medical records. Nonlinear mixed-effects modeling method was used to develop the population pharmacokinetic model with NONMEM software. A population pharmacokinetic model for peginterferon α2a has been successfully developed which shows that distribution volume (V) was associated with body mass index (BMI), and drug clearance (CL) had a positive correlation with creatinine clearance (CCR). The final population pharmacokinetic model supports the use of BMI and CCR-adjusted dosing in hepatitis B virus patients.
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Affiliation(s)
- Jingfeng Bi
- Research Center for Clinical & Translational Medicine, 302 Military Hospital, Beijing, 100039, China
| | - Xingang Li
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - Jia Liu
- Laboratory Center, 302 Military Hospital, Beijing, 100039, China
| | - Dawei Chen
- Infectious Disease Treatment Center, 302 Military Hospital, Beijing, 100039, China
| | - Shuo Li
- Ministry of Health, 302 Military Hospital, Beijing, 100039, China
| | - Jun Hou
- Research Center for Clinical & Translational Medicine, 302 Military Hospital, Beijing, 100039, China
| | - Yuxia Zhou
- Medical Information Center, 302 Military Hospital, Beijing, 100039, China
| | - Shanwei Zhu
- Department of Pharmacy, 302 Military Hospital, Beijing, 100039, China
| | - Zhigang Zhao
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - Enqiang Qin
- Infectious Disease Treatment Center, 302 Military Hospital, Beijing, 100039, China.
| | - Zhenman Wei
- Research Center for Clinical & Translational Medicine, 302 Military Hospital, Beijing, 100039, China.
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Abstract
Chronic viral hepatitis is a global health threat and financial burden. Hepatitis B and C viruses (HBV and HCV) are the most common causes of chronic viral hepatitis in the United States. Most cases are asymptomatic before adulthood. Research has resulted in effective therapy for HCV and the promise of effective therapies for HBV. For HCV, therapy is pegylated interferon and ribavirin. Clinical trials with effective direct-acting antiviral agents are underway in pediatrics. For HBV, approved agents are alpha-interferon, lamivudine, adefovir, tenofovir, and entecavir. However, treatment seldom results in functional cure and more effective therapies are urgently needed.
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Affiliation(s)
- Wikrom Karnsakul
- Pediatric Liver Center, Department of Pediatrics, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 2-117, Baltimore, MD 21287, USA.
| | - Kathleen B Schwarz
- Professor, Pediatric Liver Center, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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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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Hull M, Shafran S, Wong A, Tseng A, Giguère P, Barrett L, Haider S, Conway B, Klein M, Cooper C. CIHR Canadian HIV Trials Network Coinfection and Concurrent Diseases Core Research Group: 2016 Updated Canadian HIV/Hepatitis C Adult Guidelines for Management and Treatment. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2016; 2016:4385643. [PMID: 27471521 PMCID: PMC4947683 DOI: 10.1155/2016/4385643] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 12/15/2015] [Indexed: 12/13/2022]
Abstract
Background. Hepatitis C virus (HCV) coinfection occurs in 20-30% of Canadians living with HIV and is responsible for a heavy burden of morbidity and mortality. Purpose. To update national standards for management of HCV-HIV coinfected adults in the Canadian context with evolving evidence for and accessibility of effective and tolerable DAA therapies. The document addresses patient workup and treatment preparation, antiviral recommendations overall and in specific populations, and drug-drug interactions. Methods. A standing working group with HIV-HCV expertise was convened by The Canadian Institute of Health Research HIV Trials Network to review recently published HCV antiviral data and update Canadian HIV-HCV Coinfection Guidelines. Results. The gap in sustained virologic response between HCV monoinfection and HIV-HCV coinfection has been eliminated with newer HCV antiviral regimens. All coinfected individuals should be assessed for interferon-free, Direct Acting Antiviral HCV therapy. Regimens vary in content, duration, and success based largely on genotype. Reimbursement restrictions forcing the use of pegylated interferon is not acceptable if optimal patient care is to be provided. Discussion. Recommendations may not supersede individual clinical judgement. Treatment advances published since December 2015 are not considered in this document.
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Affiliation(s)
- Mark Hull
- British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia, Vancouver, BC, Canada V6T 1Z4
| | | | - Alex Wong
- Regina Qu'Appelle Health Region, Regina, SK, Canada S4P 1E2
| | - Alice Tseng
- Toronto General Hospital, Toronto, ON, Canada M5G 2C4
| | | | - Lisa Barrett
- Dalhousie University, Halifax, NS, Canada B3H 4R2
| | | | - Brian Conway
- Vancouver Infectious Diseases Centre, Vancouver, BC, Canada V6Z 2C7
| | | | - Curtis Cooper
- The Ottawa Hospital, General Campus, G12, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6
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Suzuki M, Tajiri H, Tanaka Y, Takano T, Miyoshi Y, Murakami J, Shimizu T, Brooks S. Peginterferon Therapy in Children With Chronic Hepatitis C: A Nationwide, Multicenter Study in Japan, 2004-2013. J Pediatr Gastroenterol Nutr 2016; 63:88-93. [PMID: 26825765 DOI: 10.1097/mpg.0000000000001120] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVES The aim of the present study was to review the medical treatment of Japanese children and adolescents with chronic hepatitis C in the past 10 years. METHODS This nationwide, multicenter study evaluated patients who were younger than 18 years of age when diagnosed with chronic hepatitis C virus (HCV) infection and were treated with pegylated interferon (PEG-IFN) monotherapy or PEG-IFN/ribavirin (RBV) combination therapy between 2004 and 2013. The subjects' median age was 10 (3-18) years, with a male to female ratio of 52:50 and a genotype-1 to genotype-2 ratio of 45:57. Among the 102 patients, 18 received PEG-IFN monotherapy and 84 received PEG-IFN/RBV combination therapy. The IL28B genotype polymorphism was analyzed in patients infected with genotype-1. RESULTS In patients with HCV genotype-1 infections, sustained virological response (SVR) rates obtained by PEG-IFN monotherapy and by PEG-IFN/RBV combination therapy were 100% (2/2) and 72% (31/43), respectively. In patients with HCV genotype-2 infections, SVRs were 75% (12/16) and 100% (41/41), respectively. In 32 genotype-1 patients available for the IL28B genotype (rs8099917), SVR was achieved in more patients in the IL28B major allele group than in the minor allele group (15/17 vs 7/15, P = 0.021) after PEG-IFN/RBV combination therapy. The frequencies of adverse events were similar between the treatment regimens. CONCLUSIONS Overall, both therapies showed encouraging results, and were reasonably safe in children and adolescents with chronic hepatitis C. The IL28B genotype was useful for predicting the treatment response to PEG-IFN/RBV combination therapy in this cohort.
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Affiliation(s)
- Mitsuyoshi Suzuki
- *Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan†Department of Pediatrics, Osaka General Medical Center, Osaka, Japan‡Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan§Department of Pediatrics, Osaka University, Graduate School of Medicine, Osaka, Japan||Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, Tottori, Japan¶Department of Microbiology/Immunology, State University of New York, Buffalo, NY
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Brennan BJ, Lemenuel-Diot A, Snoeck E, McKenna M, Solsky J, Wat C, Mallalieu NL. Use of an integrated modelling and simulation approach to develop a simplified peginterferon alfa-2a dosing regimen for children with hepatitis C. Br J Clin Pharmacol 2016; 81:658-66. [PMID: 26529640 DOI: 10.1111/bcp.12816] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 10/23/2015] [Accepted: 11/01/2015] [Indexed: 12/20/2022] Open
Abstract
AIM The aim of the study was to simplify the dosing regimen of peginterferon alfa-2a in paediatric patients with chronic hepatitis C. METHODS A population pharmacokinetic (PK) model was developed using PK data from 14 children aged 2-8 years and 402 adults. Simulations were produced to identify a simplified dosing regimen that would provide exposures similar to those observed in the paediatric clinical trials and in the range known to be safe/efficacious in adults. Model predictions were evaluated against observed adult and paediatric data to reinforce confidence of the proposed dosing regimen. RESULTS The final model was a two compartment model with a zero order resorption process. Covariates included a linear influence of body surface area (BSA) on apparent oral clearance (CL/F) and a linear influence of body weight on apparent volume of distribution of the central compartment (V1 /F). A simplified dosing regimen was developed which is expected to provide exposures in children aged ≥5 years similar to the dosing formula used in the paediatric clinical trial and within the range that is safe/efficacious in adults. This simplified regimen is approved in the EU and in other countries for the treatment of chronic hepatitis C in treatment-naive children/adolescents aged ≥5 years in combination with ribavirin. CONCLUSION Pre-existing adult PK data were combined with relatively limited paediatric PK data to develop a PK model able to predict exposure in both populations adequately. This provided increased confidence in characterizing PK in children and helped in the development of a simplified dosing regimen of peginterferon alfa-2a in paediatric patients.
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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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Gupta M, Bahirwani R, Levine MH, Malik S, Goldberg D, Reddy KR, Shaked A. Outcomes in pediatric hepatitis C transplant recipients: analysis of the UNOS database. Pediatr Transplant 2015; 19:153-63. [PMID: 25495572 DOI: 10.1111/petr.12408] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/07/2014] [Indexed: 12/20/2022]
Abstract
HCV may lead to the development of ESLD in late childhood and, consequently, contributes to the need for liver transplantation. The aim of this study was to examine post-transplant outcomes in HCV-positive pediatric patients with ESLD from any cause and to determine the impact of the PELD scoring system, introduced in February 2002, on post-transplant patient and graft survival. A retrospective analysis of the UNOS database from 1994 to 2010 was performed to assess graft and patient survival in pediatric HCV-seropositive liver transplant recipients. Graft survival and patient survival comparing subjects in the pre-PELD era and post-PELD era were analyzed using Kaplan-Meier statistics. Factors associated with survival were identified using Cox regression analysis. Of 120 pediatric HCV transplant recipients, 80 were transplanted in the pre-PELD era and 40 were transplanted post-PELD. Median serum total bilirubin, INR, and creatinine were 4.8 mg/dL, 1.6, and 0.7 mg/dL in the pre-PELD era vs. 5.5 mg/dL, 1.7, and 0.6 mg/mL, respectively, in the post-PELD era (p NS). One-yr graft survival in the pre-PELD vs. post-PELD era was 65.0% and 89.7%, respectively (p < 0.01); corresponding three-yr graft survival was 57.3% vs. 76.2% (p = 0.04). One-yr patient survival in the pre-PELD vs. post-PELD era was 79.0% and 97.5%, respectively (p < 0.01); corresponding three-yr survival was 79.0% vs. 89.4% (p = 0.17). Twenty-eight patients (23.3%) were retransplanted: 24 (30%) in the pre-PELD era (median time to retransplant 272 days) and four (10%) in the post-PELD era (median time to retransplant 586 days). Early follow-up demonstrates a trend toward improved pediatric HCV liver transplant graft and patient survival in the post-PELD era. Superior outcomes may be attributed to pretransplant factors, improved surgical technique and better treatment options for HCV infection.
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Affiliation(s)
- Meera Gupta
- Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA
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Gill KK, Kaddoumi A, Nazzal S. PEG–lipid micelles as drug carriers: physiochemical attributes, formulation principles and biological implication. J Drug Target 2014; 23:222-31. [DOI: 10.3109/1061186x.2014.997735] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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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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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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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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Druyts E, Thorlund K, Wu P, Kanters S, Yaya S, Cooper CL, Mills EJ. Efficacy and safety of pegylated interferon alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C in children and adolescents: a systematic review and meta-analysis. Clin Infect Dis 2012; 56:961-7. [PMID: 23243171 DOI: 10.1093/cid/cis1031] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND A systematic review and meta-analysis were conducted to examine the efficacy and safety of pegylated interferon (peg-IFN) alfa-2a and peg-IFN alfa-2b plus ribavirin (RBV) in children and adolescents with chronic hepatitis C virus (HCV). METHODS Medline, Embase, and Cochrane Central Register of Controlled Trials were searched. Clinical trials examining peg-IFN alfa-2a or peg-IFN alfa-2b plus RBV among persons ages 3-18 years with HCV were included. Data were abstracted for complete early virologic response (EVR), sustained virologic response (SVR), relapse, treatment discontinuations, hematologic and dermatologic adverse events, and growth inhibition. RESULTS Eight trials met the inclusion criteria. Results indicate that 70% of subjects (95% confidence interval [CI], 58%-81%) achieved EVR, and 58% (95% CI, 53%-64%) achieved SVR. EVR and SVR were higher for those with HCV genotypes 2/3 than 1/4. Discontinuation due to adverse events and discontinuation due to viral breakthrough were each 4%, discontinuation due to a lack of response was 15%, and relapse was 7%. Anemia, neutropenia, leukopenia, and thrombcytopenia were 11%, 32%, 52%, and 5%, respectively. Alopecia, injection site erythema, and pruritus were 13%, 27%, and 10%, respectively. Small growth inhibitions were observed during treatment. CONCLUSION The results of this meta-analysis indicate that peg-IFN/RBV combination treatment is effective and safe in treating children and adolescents with HCV.
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Affiliation(s)
- Eric Druyts
- Faculty of Health Sciences, University of Ottawa, Ottawa, Canada
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18
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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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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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Hepatitis C Virus Clearance after Discontinuation of Pegylated Interferon Alpha-2a Monotherapy in a Child. Case Rep Med 2012; 2012:597348. [PMID: 23118765 PMCID: PMC3483865 DOI: 10.1155/2012/597348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 09/27/2012] [Indexed: 12/03/2022] Open
Abstract
The present patient was a 4-year-old boy. His hepatitis C virus genotype was 2a, and his viral load was high (1400,000 U/mL). The pretreatment liver biopsy revealed no fibrosis or malignancy and mild chronic hepatitis; his Knodell's histological activity (HAI) score was 4. Single nucleotide polymorphism of IL28B (rs8099917) was major type. The patient began antiviral treatment with pegylated interferon alpha 2a (90 μg/week). At week 9, serum HCV RNA became undetectable, with a sensitivity of 50 copies/mL. Antiviral treatment was discontinued at week 11 because the ALT level increased to 610 U/L. After discontinuation of therapy, the patient's serum HCV RNA status became positive again. The serum viral load increased to 100,000 U/mL. During this period, he had been observed without medication. Sixteen months after stopping treatment, serum HCV became undetectable. Over a 4-year period, HCV RNA became negative and his anti-HCV antibody titer gradually decreased. In conclusion, though antiviral therapy resulted in failure or incomplete therapy, a reduced viral load resulted in viral clearance in the present patient. Interleukin 28B genotype might have association with the clearance of hepatitis C virus after discontinuation of antiviral therapy.
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Tsunoda T, Inui A, Etani Y, Kiyohara Y, Sugiura T, Ito K, Miyazawa R, Nagata I, Ida S, Fujisawa T. Efficacy of pegylated interferon-α2a monotherapy in Japanese children with chronic hepatitis C. Hepatol Res 2011; 41:399-404. [PMID: 21518401 DOI: 10.1111/j.1872-034x.2011.00789.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM There is little information available on the efficacy of pegylated interferon (PEG IFN) therapy for children with chronic hepatitis C. The aim of this study was to evaluate the efficacy and tolerability of PEG IFN-α2a monotherapy for children infected by chronic hepatitis C virus (HCV). METHODS From 2004-2006, we conducted a prospective, open-label, multicenter study of 22 patients aged 4-18 years, including eight with genotype 1 and 14 with genotype 2. None had previously received IFN. The patients were treated with s.c. PEG IFN-α2a at a dose of 3 µg/kg once a week for 48 weeks. Rapid virological response (RVR) was defined as: undetectable serum HCV RNA at week 4; early viral response (EVR) as a 2 or more log reduction or undetectable serum HCV RNA at week 12; and sustained viral response (SVR) as undetectable serum HCV RNA at 24 weeks after the cessation of treatment. RESULTS SVR was achieved in 10 (45%) of the 22 patients (three with genotype 1, seven with genotype 2). Retrospectively, the patients with SVR included five with RVR (one with genotype 1, four with genotype 2) and five with EVR (two with genotype 1, three with genotype 2). PEG IFN-α2a monotherapy was well tolerated, except in one patient in whom alanine aminotransferase activity flared (>500 IU/L) during treatment. CONCLUSION The efficacy of PEG IFN-α2a monotherapy in children is similar to that for adults, while tolerability seems to be better in children than in adults.
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Affiliation(s)
- Tomoyuki Tsunoda
- Children's Center for Health and Development, Yokohama Eastern Hospital, Tsurumi, Yokohama, Japan
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23
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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, 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] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [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, Maryland, USA.
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25
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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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26
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Re-treatment of children with chronic hepatitis C who did not respond to interferon-alpha treatment. J Pediatr Gastroenterol Nutr 2010; 51:187-90. [PMID: 20512050 DOI: 10.1097/mpg.0b013e3181d9c7f6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Many patients with chronic hepatitis C do not respond to antiviral treatment. In adult patients the re-treatment of these patients has been extensively investigated. Because the response to re-treatment in children is not well defined we evaluated the efficacy and safety of interferon (IFN)-alpha plus ribavirin in patients who have failed to respond to previous treatment. PATIENTS AND METHODS In an open-label, uncontrolled study, 18 chronically infected children were investigated. Fifteen children had been treated with IFN-alpha plus ribavirin and 3 patients with IFN-alpha alone. Fourteen patients were nonresponders; 4 experienced viral breakthrough during treatment and/or relapse after treatment. Patients received IFN-alpha 3 times per week subcutaneously plus ribavirin for 48 weeks. Sixteen patients were infected with hepatitis C virus (HCV) genotype 1, 2 with genotype 4, and 1 with genotype 3 and co-infection with hepatitis B. RESULTS Four patients showed early viral response to therapy and became HCV-RNA negative after 12 weeks. Sustained viral response (HCV-RNA negative 6 months after end of treatment) was documented in 2 of them. These 2 patients belonged to the group of 4 children who relapsed or experienced a viral breakthrough during previous treatment. None of the 14 patients with prior nonresponse had sustained viral response. CONCLUSIONS Re-treatment with IFN-alpha plus ribavirin may be useful in children who relapsed in a previous antiviral treatment but seems not to be useful in nonresponders. These results are in line with studies from adult patients and should be therefore encouraged to provide a second chance for healing in a subgroup of patients.
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27
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Hu J, Doucette K, Hartling L, Tjosvold L, Robinson J. Treatment of hepatitis C in children: a systematic review. PLoS One 2010; 5:e11542. [PMID: 20644626 PMCID: PMC2903479 DOI: 10.1371/journal.pone.0011542] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Accepted: 06/11/2010] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Current guidelines recommend children be treated for hepatitis C virus (HCV) using the same principles applied in adults. There are however few published studies which assess the efficacy and safety of HCV therapy in children. METHODOLOGY/PRINCIPAL FINDINGS A systematic review of the literature was completed for studies of any design that evaluated HCV therapy in children. The primary outcome was sustained virologic response (SVR), with sub-group analysis of response rates by genotype. There were 4 randomized controlled trials (RCTs) and 31 non-randomized studies, all involving interferon, pegylated interferon (PEG-IFN), or combinations of these drugs with ribavirin. The SVR rate could not be directly compared as the populations and interventions differed across studies. Genotype was not reported or differed substantially from study to study. The overall SVR rate for PEG-IFN and ribavirin ranged from 30 to 100% which is comparable to the rate in adults. Similar to adults, the SVR rates were significantly higher in children with genotype 2 or 3 compared to genotype 1. Adverse effects were primarily flu-like symptoms and neutropenia. There were insufficient data to assess the applicability of the week 12 stop rule (stopping therapy at week 12 if there is less than a 2 log drop in HCV RNA) or the efficacy of shortening therapy to 24 weeks in children with genotype 2 and 3. CONCLUSIONS/SIGNIFICANCE Current guidelines for the treatment of HCV in children are based on limited data. Further research is needed to define the optimal therapy for HCV in children.
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Affiliation(s)
- Jia Hu
- Department of Pediatrics, University of Alberta, Edmonton, Canada
| | - Karen Doucette
- Department of Medicine, University of Alberta, Edmonton, Canada
| | - Lisa Hartling
- Department of Pediatrics, University of Alberta, Edmonton, Canada
- Alberta Research Centre for Health Evidence, University of Alberta, Edmonton, Canada
| | - Lisa Tjosvold
- Department of Pediatrics, University of Alberta, Edmonton, Canada
- Alberta Research Centre for Health Evidence, University of Alberta, Edmonton, Canada
| | - Joan Robinson
- Department of Pediatrics, University of Alberta, Edmonton, Canada
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Sokal EM, Bourgois A, Stéphenne X, Silveira T, Porta G, Gardovska D, Fischler B, Kelly D. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents. J Hepatol 2010; 52:827-31. [PMID: 20400194 DOI: 10.1016/j.jhep.2010.01.028] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2009] [Revised: 01/14/2010] [Accepted: 01/17/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS This multi-center study aimed to prospectively evaluate the safety and efficacy of a genotype-based Pegylated Interferon alfa-2a/Ribavirin therapy in treatment-naïve hepatitis C virus (HCV), positive HCV serology, and quantifiable HCV RNA, infected children. METHODS Eighteen children with genotypes 2 and 3 patients (group A) were assigned to medication for 24weeks, and 47 children with genotypes 1, 4, 5 and 6 patients (group B) for 48weeks. RESULTS Early response at week 12 was observed in 83% of group A patients and in 57% of group B patients (p<0.05). End of treatment response was achieved in 94% of patients in group A and in 57% in group B (p<0.001). Sustained virologic response was maintained in 89% of patients in group A and in 57% of patients in group B (p<0.01). Ten patients stopped prematurely the treatment, 2 for serious adverse event (acute hepatitis and thyrotoxicosis), and 8 because of no virologic response at week 24. Peginterferon alfa-2a and Ribavirin dose was adjusted in 15 patients (23%), 11 for neutropenia (17%), and 3 patients (5%), for anemia, respectively. Treatment-related adverse events included fever and flu-like symptoms (54%), irritability-depression-change of mood (34%), vomiting (23%), abdominal pain (38%), loss of appetite (21.5%) and dermatitis (29%). No influence on height growth was observed. CONCLUSIONS Pegylated inteferon alfa-2a and Ribavirin treatment allowed to achieve SVR in 57% of pediatric patients with genotypes 1, 4, 5 and 6, and in 94% of genotypes 2 and 3. These results show an improved SVR as compared to reference series in adults with similar regimen.
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Affiliation(s)
- Etienne M Sokal
- Université Catholique de Louvain, Cliniques universitaires St Luc, Bruxelles, Belgium.
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Abdel-Aziz DH, Sabry NA, El-Sayed MH, El-Gazayerly ON. Efficacy and safety of pegylated interferon in children and adolescents infected with chronic hepatitis C: a preliminary study. J Pharm Pract 2010; 24:203-10. [PMID: 21712215 DOI: 10.1177/0897190010367737] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
This study researches the efficacy and safety of pegylated interferon alpha-2a (pegIFNα-2a) in Egyptian children and adolescents diagnosed with hepatitis C virus. Thirty patients were enrolled to receive pegIFN once a week with ribavirin twice daily for 12 weeks; viral load and experienced adverse effects were then assessed. Of the 30 patients, 16 (53.33%) were cleared from the virus, showing early virologic response (EVR). Three patients (10%) showed a 2-log reduction by week 12, with an overall early response rate of 63.33%. Three patients who showed EVR after 4 weeks relapsed by week 12. Levels of serum alanine aminotransferase (ALT) normalized at week 12. Adverse events included fever, myalgia, headache, flu-like symptoms, fatigue, anemia, and leucopenia; 63.33% of the patients showed significant reduction in their body weight. Although the patients showed a reduction in average body mass index, this reduction was not significant. Hemoglobin values decreased within the first 2 weeks and then stabilized but not back to baseline. A significant reduction in the level of absolute neutrophil count (ANC) was observed by the 4th week and started to improve by the 12th week. Of the recruited patients, 29.4% were subjected to IFN dose reduction. None of the patients with neutropenia developed serious infection or sepsis. The authors concluded that pegIFN plus ribavirin therapy is promising when tested on Egyptian children.
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Uslu N, Baysoy G, Demir H, Temizel INS, Yuce A. Safety of ribavirin in adolescent thalassemic patients with chronic hepatitis C virus infection. J Clin Virol 2010; 48:66-8. [PMID: 20347610 DOI: 10.1016/j.jcv.2010.02.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2009] [Revised: 11/03/2009] [Accepted: 02/17/2010] [Indexed: 02/03/2023]
Affiliation(s)
- Nuray Uslu
- Hacettepe University, Faculty of Medicine, Department of Pediatric, Gastroenterology Hepatology & Nutrition, Altindag, Ankara, Turkey
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Abstract
The aim of this review was to evidence the actual treatment used for chronic hepatitis C virus (HCV) in children. A review of the use of interferon (IFN) as monotherapy in children demonstrates a sustained virological response (SVR) of 33%-45%. This is significantly better than the SVR rate for IFN monotherapy observed for adults. When the data are further scrutinized, the SVR for genotype 1 is 26% and 70% for other genotypes. The higher response rate observed in children might be the result of the earlier stage of the disease, higher relative IFN dosage, or lack of comorbid conditions. The use of IFN-alpha2b in combination with ribavirin was reported by Gonzalez-Peralta et al and has led to Food and Drug Administration approval of this therapy for children with a SVR significantly higher in children with HCV genotype 2/3 (84%) than in those with HCV genotype 1 (36%). About the use of pegylated IFN in combination with ribavirin, the first-line treatment in adult patients affected by chronic hepatitis C, there are few experiences. These preliminary experiences evidenced that combination treatment of PEG-IFN-alpha2b with ribavirin shows encouraging results and was well tolerated in children and adolescents with chronic hepatitis C.
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Abstract
Hepatitis C affects 4-10% of children born to infected mothers, and 80% of them develop chronic infection. Most patients with chronic hepatitis C virus infection are asymptomatic, with persistent or intermittent biochemical abnormalities. Severe liver disease may develop 10 years after onset of infection, with a less than 2% overall risk during the pediatric age. Available therapies have no contraindication in children if otherwise healthy. The US FDA and EMEA have recently approved combined pegylated-IFN-alpha 2b plus ribavirin treatment for children, who should be over 3 years of age in order to avoid severe side effects. Experiences in pilot trials and international studies indicate a response rate of 50% in genotype 1 patients, and more than 90% in genotype 2 or 3 patients, indicating resolution of chronic disease.
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Affiliation(s)
- Paloma Jara
- Servicio de Hepatología, Hospital Infantil Universitario La Paz, Paseo Castellana 261, 28046 Madrid, Spain.
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Karnsakul W, Alford MK, Schwarz KB. Managing pediatric hepatitis C: current and emerging treatment options. Ther Clin Risk Manag 2009; 5:651-60. [PMID: 19707281 PMCID: PMC2731021 DOI: 10.2147/tcrm.s5078] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Indexed: 12/18/2022] Open
Abstract
Since 1992, the maternal–fetal route of transmission has become the dominant route for acquisition of hepatitis C (HCV) infection by children. With increasing knowledge of antiviral treatment for HCV infection, the main goal of therapy is to achieve a sustained virological response (SVR) as defined by undetectable serum HCV RNA by polymerase chain reaction assay six months after cessation of therapy. In young children, interferon therapy is more effective than in adults with chronic HCV infection (CHC). Although children clearly have a milder degree of liver pathology, data have indicated that hepatic inflammation from HCV infection can progress to fibrosis or cirrhosis in children. Hepatocellular carcinoma has been reported in adolescents with CHC. In this article, recent improvements in therapy of children with CHC and in the clinical development of new emerging drugs with potential use in children will be reviewed.
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Affiliation(s)
- Wikrom Karnsakul
- Pediatric Liver Center, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Rotman Y, Katz L, Cohen M, Cohen-Ezra O, Manhaim V, Braun M, Ben-Ari Z, Tur-Kaspa R. Low weight predicts neutropenia and peginterferon alfa-2a dose reductions during treatment for chronic hepatitis C. J Viral Hepat 2009; 16:340-5. [PMID: 19220735 DOI: 10.1111/j.1365-2893.2009.01079.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Treatment-induced neutropenia frequently complicates the treatment course of patients treated with pegylated interferon alfa and ribavirin for chronic hepatitis C. We investigated the effect of weight on the risk for dose reductions caused by neutropenia in patients treated with a weight-independent dose of peginterferon alfa-2a. We retrospectively analysed single centre data for 172 patients enrolled in a multi-centre, open-label trial of peginterferon alfa-2a and ribavirin for chronic hepatitis C. Low body weight was significantly associated with dose reductions due to neutropenia. Patients weighing less than 62 kg had a 35% risk for significant neutropenia as opposed to a 12% risk for heavier patients (P = 0.001), and this side-effect occurred earlier during treatment. Low weight was an independent risk factor by multivariate analysis (hazard ratio 0.956/kg). The risk for treatment-induced neutropenia was associated with body surface area more than with the body mass index. In conclusion, a low pre-treatment weight strongly predicts the need for peginterferon alfa-2a dose reductions. This apparently reflects overall body size more than body fat content. It is prudent to frequently monitor blood counts for smaller-sized patients, especially during the first weeks of treatment.
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Affiliation(s)
- Y Rotman
- Liver Institute, Rabin Medical Center, Bellinson Hospital, Petach-Tiqwa, Israel.
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Sequential antiviral and iron chelation treatment in a teenage boy with congenital anemia, chronic hepatitis C, and secondary hemosiderosis. J Pediatr Gastroenterol Nutr 2009; 48:382-5. [PMID: 19274798 DOI: 10.1097/mpg.0b013e3181602190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
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Sugiura T, Yamada T, Kimpara Y, Fujita N, Goto K, Koyama N. Effects of pegylated interferon alpha-2a on hepatitis-C-virus-associated glomerulonephritis. Pediatr Nephrol 2009; 24:199-202. [PMID: 18696119 DOI: 10.1007/s00467-008-0948-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2008] [Revised: 06/09/2008] [Accepted: 06/10/2008] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection leads to chronic liver disease, but it has also been associated with extrahepatic manifestations. Membranoproliferative glomerulonephritis (MPGN) is the most common renal disease associated with HCV. Although renal disease related to HCV in adults has been well studied, it has not been well studied in children because it is rare. A recent study found that antiviral therapy was effective for adult patients with HCV-associated MPGN. We report a 9-year-old girl with HCV-associated MPGN. Her HCV genotype was 1b, and her virus load was high. The first renal biopsy showed mesangial proliferation and partial double contours of the basement membrane on light microscopy and immunofluorescence staining with immunoglobulin (Ig) M, IgG, and C3. The patient was successfully treated with pegylated interferon (IFN) alpha-2a monotherapy. The antiviral therapy was generally well tolerated. After antiviral therapy, a sustained virological response-defined as negative HCV ribonucleic acid (RNA) at least 24 weeks after antiviral treatment-was achieved, the proteinuria disappeared, and the second renal biopsy showed improvement.
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Affiliation(s)
- Tokio Sugiura
- Department of Pediatrics, Toyohashi Municipal Hospital, 50 Hachiken-nishi, Aotake, Toyohashi, Aichi, 441-8570, Japan.
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Chang MH. Natural history and clinical management of chronic hepatitis B virus infection in children. Hepatol Int 2008; 2:28-36. [PMID: 19669296 DOI: 10.1007/s12072-008-9050-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2007] [Accepted: 01/20/2008] [Indexed: 01/17/2023]
Abstract
Hepatitis B virus (HBV) infection may cause acute, fulminant, or chronic hepatitis, leading to liver cirrhosis or hepatocellular carcinoma. Despite the availability of effective vaccine, HBV infection during infancy or early childhood is common in areas of high endemicity. In these regions, mother-to-infant transmission accounts for approximately 50% of chronic infections. Although the natural history of HBV infection in adults is well characterized, little information is available in the literature regarding the natural history of HBV infection in children. Similar to infection in adults, chronic HBV infection in children can be divided into distinct phases: immune tolerant, immune clearance, and inactive carrier state. However, acute exacerbation, with reactivation of HBV replication and re-elevation of alanine aminotransferase levels after hepatitis B e antigen seroconversion, is relatively rare in children, in comparison to adults. Although several potent antiviral agents are now available for the treatment of chronic hepatitis B, experience with these agents in the pediatric setting is limited. To date, conventional interferon alpha and lamivudine are the only two antiviral agents approved to treat chronic hepatitis B in children. The rapid emergence of resistant HBV associated with long-term lamivudine therapy, as well as poor tolerability associated with conventional interferon alpha, are factors that should be considered before initiating antiviral therapy. This article reviews current knowledge regarding the natural history and treatment of chronic hepatitis B in children. Factors that affect the natural history of HBV infection in children are also reviewed.
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Affiliation(s)
- Mei-Hwei Chang
- Division of Gastroenterology and Hepatology, Department of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan S. Road, Taipei, Taiwan,
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Abstract
Chronic hepatitis C virus (HCV) infection is a major cause of morbidity and mortality worldwide. Progression to cirrhosis and hepatocellular carcinoma occurs in 20% of infected adults. The natural history following childhood infection is less well defined, although cirrhosis in children is described. Since blood product screening for HCV infection was introduced in 1990, most children who acquire HCV do so by vertical transmission from an infected mother. Transmission to offspring occurs in approximately 5%. Most children with HCV infection are asymptomatic. Diagnosis is made by testing those at risk for HCV RNA by polymerase chain reaction (PCR) and HCV antibody (anti-HCV) by enzyme immunoassay (EIA). The clinical impact of HCV infection is assessed by monitoring symptoms and signs, blood testing of liver enzymes, ultrasound imaging, and by liver biopsy. Improved efficacy and tolerability of treatment strategies in adults have had a significant impact on the management of children with HCV infection. The emphasis is now on promoting awareness, early diagnosis, and treatment. Treatment strategies have evolved from monotherapy with interferon alfa (IFNalpha), to combination therapy with ribavirin. Pegylated IFNalpha is superior to conventional IFNalpha, and forms the basis of current recommendations. The genotype of HCV influences treatment efficacy. Treatment is generally well tolerated in children, although adverse effects are common. Preparation and support throughout treatment for the whole family is needed. A proportion of children with HCV infection have co-morbidity, including viral co-infection or hematologic disease. Although treatment may be contraindicated, risks and benefits must be considered before denying treatment. Anemia is more common in those with HIV co-infection, renal insufficiency, thalassemia, or cirrhosis, and may be aggravated by treatment. Children with thalassemia may have iron overload, and transfusion requirements may increase during treatment. Further refinements of combination therapy and development of new drugs are in progress. Vaccine candidates are undergoing phase I and II treatment trials.
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Affiliation(s)
- Suzanne M Davison
- Children's Liver and GI Unit, St James's University Teaching Hospital, Leeds, UK.
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Abstract
PURPOSE OF REVIEW Hepatitis C virus infection has recently been recognized as a viral infection with the potential to cause significant complications, including cirrhosis and hepatocellular carcinoma in adults. Changes in our understanding of its natural history in children and recent advances in therapy for acute and chronic hepatitis C are reviewed. RECENT FINDINGS Recent work has demonstrated that, although uncommon, vertical transmission is the most frequent mode of hepatitis C acquisition in children and is enhanced in the setting of maternal co-infection with HIV. Chronic hepatitis C during childhood leads in some cases to development of advanced hepatic fibrosis, with complications including liver failure and liver cancer, which has changed our general approach to this infection. Perhaps the most significant recent advance in this area is our improved understanding of the safety and efficacy of interferon-based antiviral therapies for children with hepatitis C. SUMMARY Hepatitis C virus infection has reached epidemic proportions worldwide; despite its being less prevalent in children than in adults, it poses a significant clinical problem in this age group. Emerging antiviral therapies are currently in clinical trials for adult patients with hepatitis C with encouraging preliminary results, which should be extended to children.
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Affiliation(s)
- Nizar N Zein
- Department of Gastroenterology and Hepatology, the Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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Bibliography. Current world literature. Cardiovascular medicine. Curr Opin Pediatr 2007; 19:601-6. [PMID: 17885483 DOI: 10.1097/mop.0b013e3282f12851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Kowala-Piaskowska A, Mozer-Lisewska I, Figlerowicz M, Słuzewski W. Adverse effects during the treatment with pegylated interferon and ribavirin in children with chronic hepatitis C. Pharmacoepidemiol Drug Saf 2007; 16:1095-103. [PMID: 17724740 DOI: 10.1002/pds.1458] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
PURPOSE Administration of pegylated interferon-alpha (IFN-alpha) and ribavirin in adults with chronic hepatitis C (CHC) is a recommended therapeutic standard. Nevertheless, this therapeutic regimen rises numerous controversies. The aim of this study was to analyze adverse effects during the treatment with pegylated IFN-alpha and ribavirin in children with CHC. METHODS Study group comprised 30 children with CHC, age 8-19 years (mean 13,6 years), 9 girls and 21 boys. All patients were administered two medication therapy with pegylated IFN-alpha-2b in the dose of 1.5 microg/kg of body weight 1x/week subcutaneously and daily oral ribavirin 15 mg/kg of bodyweight for 48 weeks. Blood samples were taken at baseline and every 4 weeks during the whole treatment and 24 weeks of follow-up period. Panel of test included: cellular blood count and smear, ALT activity, bilirubin level. Patients complaints were noticed during every visit. Thyroid hormones and antibodies were checked every 3 months. Children were divided into group A that responded to treatment and group B-nonresponders. RESULTS Abnormalities in laboratory tests (white blood cells, neutrophils, haemoglobin) were observed mainly during first weeks of treatment. Mean bilirubin level and platelets were normal. Mean ALT normalized during the treatment. After 12-16 weeks of the therapy somatic adverse effects decreased significantly. CONCLUSIONS Administration of pegylated IFN-alpha and ribavirin in children with CHC is related to characteristic adverse effects. Periodical dose reduction was necessary. Although side effects and subjective patient complaints were present, children attended school without difficulties. Constant monitoring is required during the whole treatment.
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Affiliation(s)
- Arleta Kowala-Piaskowska
- Department of Infectious Diseases and Child Neurology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
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Iorio R, Verrico A, Giannattasio A. Is liver biopsy mandatory in children with chronic hepatitis C? World J Gastroenterol 2007; 13:4025-4026. [PMID: 17663524 PMCID: PMC4171182 DOI: 10.3748/wjg.v13.i29.4025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2007] [Revised: 06/03/2007] [Accepted: 06/18/2007] [Indexed: 02/06/2023] Open
Abstract
Liver biopsy is considered the most accurate means to estimate the necroinflammatory activity and the extent of fibrosis. However, histology evaluation is an invasive procedure associated with risk to the patient, risk of sampling error and diagnostic inconsistencies due to inter- and intra-observer error. On the basis of histological studies performed so far, chronic hepatitis C in children appears morphologically benign in the majority of cases. At the Pediatric Liver Unit of our university, a total of 67 children with chronic hepatitis C underwent liver biopsy. Liver biopsy was repeated 5.5 years after the initial histological evaluation in 21 children. On a total number of 88 liver biopsies, micronodular cirrhosis was detected only in one genotype 1b-infected obese child. Since liver histology investigation of a child with chronic hepatitis C has few chances to highlight severe lesions, we question how liver biopsy helps in the management of children with chronic hepatitis C.
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McCaughan GW, Omata M, Amarapurkar D, Bowden S, Chow WC, Chutaputti A, Dore G, Gane E, Guan R, Hamid SS, Hardikar W, Hui CK, Jafri W, Jia JD, Lai MY, Wei L, Leung N, Piratvisuth T, Sarin S, Sollano J, Tateishi R. Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection. J Gastroenterol Hepatol 2007; 22:615-33. [PMID: 17444847 DOI: 10.1111/j.1440-1746.2007.04883.x] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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John Wiley & Sons, Ltd.. Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiol Drug Saf 2007. [DOI: 10.1002/pds.1373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Murray KF, Rodrigue JR, González-Peralta RP, Shepherd J, Barton BA, Robuck PR, Schwarz KB, PEDS-C Clinical Research Network. Design of the PEDS-C trial: pegylated interferon +/- ribavirin for children with chronic hepatitis C viral infection. Clin Trials 2007; 4:661-73. [PMID: 18042575 PMCID: PMC3755272 DOI: 10.1177/1740774507085445] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND PEDS-C is the first multicenter placebo-controlled trial for the treatment of chronic hepatitis C (HCV) in childhood that has ever been conducted in the United States (USA). Establishment of the research team, protocol, administrative infrastructure, and ancillary contributors for the pediatric trial took years of planning. PURPOSE To study the safety and efficacy of pegylated-interferon alpha (PEG-2a) plus ribavirin (RV) with PEG-2a monotherapy in children aged 5 years through 18 years. To assess the health-related quality of life and growth and body composition in children with chronic hepatitis C infection, before, during, and after treatment. METHODS Eleven centers of pediatric hepatobiliary clinical research were united in a National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) funded grant with financial support from the Food and Drug Administration (FDA) and a corporate sponsor to conduct the treatment trial. LIMITATIONS The most important initial limitation in the design of this complex study was securing the financial support and infrastructural organization, a process that took several years. Challenges faced by the study group included identifying the optimal study design given the limited study population, and determining what ancillary studies could be incorporated into the treatment trial. CONCLUSIONS In this article the process taken to design the study and administrative infrastructure, the lessons learned, and the controversial issues deliberated during the planning process are discussed. The evolution of the study and the considerations taken in the development of the protocol are valuable tools which can be applied to pediatric clinical trials in general.
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Affiliation(s)
- Karen F Murray
- Division of Gastroenterology and Nutrition, Department of Pediatrics, University of Washington, Children's Hospital and Regional Medical Center, Seattle, Washington 98105, USA.
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Byrnes AA, Li DY, Park K, Thompson D, Mocilnikar C, Mohan P, Molleston JP, Narkewicz M, Zhou H, Wolf SF, Schwarz KB, Karp CL. Modulation of the IL-12/IFN-γ axis by IFN-α therapy for hepatitis C. J Leukoc Biol 2006; 81:825-34. [PMID: 17148690 DOI: 10.1189/jlb.1006622] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Although IFN-alpha forms the foundation of therapy for chronic hepatitis C, only a minority of patients has a sustained response to IFN-alpha alone. The antiviral activities of IFN-alpha formed the rationale for its use in viral hepatitis. However, IFN-alpha and the other Type I IFNs are also pleiotropic immune regulators. Type I IFNs can promote IFN-gamma production by activating STAT4 but can also inhibit production of IL-12, a potent activator of STAT4 and IFN-gamma production. The efficacy of IFN-alpha in the treatment of hepatitis C may therefore depend in part on the balance of IFN-gamma-inducing and IL-12-suppressing effects. We characterized the effects of pegylated IFN-alpha therapy for hepatitis C on the capacity of patients' PBMC to produce IL-12 and IFN-gamma ex vivo. Cells from patients with a sustained virological response to therapy had significantly greater levels of IFN-alpha-driven IFN-gamma production prior to treatment than those from nonresponding patients. No differences in pretreatment IL-12 productive capacity were seen between patient groups. However, therapy with IFN-alpha led to suppression of inducible IL-12 production throughout the course of therapy in both groups of patients.
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Affiliation(s)
- Adriana A Byrnes
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
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