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• W3026673909 abstract "“This unprecedented efficacy has led to speculation that HCV infection might be eradicated even in the absence of a vaccine, but there are many impediments to global eradication including ascertainment of silent carriers, access to medication, and high drug cost”. - Harvey J. Alter1Alter H.J. The Gordon Wilson lecture: the hepatitis C virus: from Hippocrates to cure.Trans Am Clin Climatol Assoc. 2019; 130: 104-118PubMed Google Scholar. In the late 1970s and early 1980s, an epidemic of silent, post-transfusion hepatitis directly led to the discovery of a novel, hepatotropic agent of the flavivirus family aptly named the hepatitis C virus (HCV, formerly known as the non-A, non-B hepatitis virus). Less than 30 years later, through advancements in viral sequencing and 3-dimensional determination of the nonstructural proteins that direct RNA polymerases required for HCV replication, a new class of medications, known as direct-acting antivirals (DAAs), were introduced to treat HCV. DAAs have demonstrated virologic response rates exceeding 95% across all genotypes after short durations of oral administration. These highly effective antiviral agents are now approved for use in children as young as 3 years of age. No virus to date has been globally eradicated without the development of a prophylactic vaccine; however, the efficacy and safety profile of DAAs enable a unique prospect—offering pediatric primary and subspecialty care providers an opportunity to cure hepatitis C. And yet, the identification of expanded pharmaceutical therapies and optimal antiviral regimens alone cannot reliably be expected to result in HCV eradication. Equally important barriers to a cure, as outlined by the National Academies of Science, Engineering, and Medicine, include improved detection of undiagnosed cases, increased linkage and access to appropriate and affordable care, and expanded treatment access.2Strom B.L. Buckley G.J. A national strategy for the elimination of hepatitis B and C: phase two report. The National Academies Press, Washington (DC)2017Google Scholar Here, we review the rapid medical advancements that have enabled the possibility of an HCV cure and underscore current and future strategies aimed at confronting the remaining impediments to eradication. Importantly, these newly developed antiviral agents will expand and decentralize the delivery of HCV care from the domain of hepatologists and infectious disease specialists to community stakeholders/midlevel providers in real-world settings. The modern era of DAA therapy has enabled dramatic changes in the medical treatment of HCV in children with recently published guidance suggesting that the regimen of pegylated-interferon (PEG-IFN) and ribavirin (RBV) should not be utilized3Indolfi G. Hierro L. Dezsofi A. Jahnel J. Debray D. Hadzic N. et al.Treatment of chronic hepatitis c virus infection in children: a position paper by the Hepatology Committee of European Society of Paediatric Gastroenterology, Hepatology and Nutrition.J Pediatr Gastroenterol Nutr. 2018; 66: 505-515Crossref PubMed Scopus (82) Google Scholar (Figure 1). To appreciate the degree of superiority of DAA therapy over previous older HCV regimens, a review of historical antiviral therapeutic strategies, including PEG-IFN/RBV, is warranted. Although sustained viral response (SVR) rates improved over time from ∼16% with IFN monotherapy to >50% with the combination of RBV and PEG-IFN, these SVR rates were frustratingly low.4Abdel-Hady M. Bansal S. Davison S.M. Brown M. Tizzard S.A. Mulla S. et al.Treatment of chronic viral hepatitis C in children and adolescents: UK experience.Arch Dis Child. 2014; 99: 505-510Crossref PubMed Scopus (17) Google Scholar, 5Afdhal N. Zeuzem S. Kwo P. Chojkier M. Gitlin N. Puoti M. et al.Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.N Engl J Med. 2014; 370: 1889-1898Crossref PubMed Scopus (1432) Google Scholar, 6Curry M.P. O'Leary J.G. Bzowej N. Muir A.J. Korenblat K.M. Fenkel J.M. et al.Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.N Engl J Med. 2015; 373: 2618-2628Crossref PubMed Scopus (601) Google Scholar, 7Druyts E. Thorlund K. Wu P. Kanters S. Yaya S. Cooper C.L. et al.Efficacy and safety of pegylated interferon alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C in children and adolescents: a systematic review and meta-analysis.Clin Infect Dis. 2013; 56: 961-967Crossref PubMed Scopus (63) Google Scholar, 8Feld J.J. Jacobson I.M. Hezode C. Asselah T. Ruane P.J. Gruener N. et al.Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection.N Engl J Med. 2015; 373: 2599-2607Crossref PubMed Scopus (808) Google Scholar, 9Foster G.R. Afdhal N. Roberts S.K. Brau N. Gane E.J. Pianko S. et al.Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.N Engl J Med. 2015; 373: 2608-2617Crossref PubMed Scopus (654) Google Scholar, 10Gane E.J. Stedman C.A. Hyland R.H. Ding X. Svarovskaia E. Symonds W.T. et al.Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C.N Engl J Med. 2013; 368: 34-44Crossref PubMed Scopus (638) Google Scholar, 11Jara P. Hierro L. de la Vega A. Diaz C. Camarena C. Frauca E. et al.Efficacy and safety of peginterferon-alpha2b and ribavirin combination therapy in children with chronic hepatitis C infection.Pediatr Infect Dis J. 2008; 27: 142-148Crossref PubMed Scopus (101) Google Scholar, 12Lawitz E. Poordad F.F. Pang P.S. Hyland R.H. Ding X. Mo H. et al.Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial.Lancet. 2014; 383: 515-523Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, 13Pawlotsky J.M. New hepatitis C therapies: the toolbox, strategies, and challenges.Gastroenterology. 2014; 146: 1176-1192Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar, 14Rehermann B. HCV in 2015: Advances in hepatitis C research and treatment.Nat Rev Gastroenterol Hepatol. 2016; 13: 70-72Crossref PubMed Scopus (24) Google Scholar, 15Schwarz K.B. Gonzalez-Peralta R.P. Murray K.F. Molleston J.P. Haber B.A. Jonas M.M. et al.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.e1Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 16Wirth S. Ribes-Koninckx C. Calzado M.A. Bortolotti F. Zancan L. Jara P. et al.High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin.J Hepatol. 2010; 52: 501-507Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 17Wisniewska-Ligier M. Pawlowska M. Pilarczyk M. Halota W. Wozniakowska-Gesicka T. Efficacy of pegylated interferon alpha-2b and ribavirin in chronic hepatitis C virus (genotypes 1 and 4) infection.J Pediatr Gastroenterol Nutr. 2013; 57: 694-699Crossref PubMed Scopus (8) Google Scholar, 18Gonzalez-Peralta R.P. Kelly D.A. Haber B. Molleston J. Murray K.F. Jonas M.M. et al.Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C in children: efficacy, safety, and pharmacokinetics.Hepatology. 2005; 42: 1010-1018Crossref PubMed Scopus (135) Google Scholar, 19Sokal E.M. Bourgois A. Stephenne X. Silveira T. Porta G. Gardovska D. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents.J Hepatol. 2010; 52: 827-831Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 20Suzuki M. Tajiri H. Tanaka Y. Takano T. Miyoshi Y. Murakami J. et al.Peginterferon therapy in children with chronic hepatitis C: A Nationwide, Multicenter Study in Japan, 2004-2013.J Pediatr Gastroenterol Nutr. 2016; 63: 88-93Crossref PubMed Scopus (7) Google Scholar, 21Wirth S. Lang T. Gehring S. Gerner P. Recombinant alfa-interferon plus ribavirin therapy in children and adolescents with chronic hepatitis C.Hepatology. 2002; 36: 1280-1284Crossref PubMed Scopus (114) Google Scholar, 22Wirth S. Pieper-Boustani H. Lang T. Ballauff A. Kullmer U. Gerner P. et al.Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis C.Hepatology. 2005; 41: 1013-1018Crossref PubMed Scopus (164) Google Scholar Further complicating the use of RBV plus PEG-IFN treatment were the prolonged treatment duration (48 weeks), the intensive on-therapy monitoring required, and the known side effect profiles. Adverse events such as anemia, neutropenia, leukopenia, and thrombocytopenia were reported in up to 52% of those treated, leading to a discontinuation rate of 4%.7Druyts E. Thorlund K. Wu P. Kanters S. Yaya S. Cooper C.L. et al.Efficacy and safety of pegylated interferon alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C in children and adolescents: a systematic review and meta-analysis.Clin Infect Dis. 2013; 56: 961-967Crossref PubMed Scopus (63) Google Scholar Therapy has also been shown to negatively affect body weight, linear growth, and body composition putting children at risk for developmental blunting.23Jonas M.M. Balistreri W. Gonzalez-Peralta R.P. Haber B. Lobritto S. Mohan P. et al.Pegylated interferon for chronic hepatitis C in children affects growth and body composition: results from the pediatric study of hepatitis C (PEDS-C) trial.Hepatology. 2012; 56: 523-531Crossref PubMed Scopus (61) Google Scholar Neuropsychiatric disturbances such as mood alteration, irritability, agitation, and aggressive behavior were reported in up to 30% of children.24Granot E. Sokal E.M. Hepatitis C virus in children: deferring treatment in expectation of direct-acting antiviral agents.Isr Med Assoc J. 2015; 17: 707-711PubMed Google Scholar Depression, anxiety, and suicidal ideation have been reported as well.15Schwarz K.B. Gonzalez-Peralta R.P. Murray K.F. Molleston J.P. Haber B.A. Jonas M.M. et al.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.e1Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar,16Wirth S. Ribes-Koninckx C. Calzado M.A. Bortolotti F. Zancan L. Jara P. et al.High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin.J Hepatol. 2010; 52: 501-507Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar Ultimately, the treatment of children with HCV infection with IFN and RBV regimens, with their well-documented toxicities, inconvenient modes of administration (subcutaneous IFN injections), and poor overall efficacy left pediatric hepatologists searching for alternatives. This resulted in the frequent deferral of treatment, in expectation of improved therapeutic options. The origins of these newer DAA therapies are based on an advanced understanding of HCV virology, utilizing crystallography and other tools to map the viral genome and identify potential targets for a new class of pharmaceuticals. The HCV genome is a 9.6 kb positive, single-stranded RNA; a single open reading frame encodes a 3011 amino acid residue polyprotein that undergoes proteolysis to yield 10 individual gene products, consisting of 3 structural proteins (core and envelope glycoproteins E1 and E2) and 7 nonstructural (NS) proteins that include 2 proteins required for virion production (p7 and NS2) as well as 5 proteins that form the cytoplasmic viral replication complex (NS3, NS4A, NS4B, NS5A, and NS5B) (Figure 2). Given its central role in the viral life cycle, a number of the protein components of the HCV replication complex have been identified as targets for the recently developed DAAs.25Li D.K. Chung R.T. Overview of Direct-acting antiviral drugs and drug resistance of hepatitis C virus.Methods Mol Biol. 2019; 1911: 3-32Crossref PubMed Scopus (65) Google Scholar Ever evolving treatment regimens are available that reliably achieve a >95% “real world” cure rate for all HCV genotypes.14Rehermann B. HCV in 2015: Advances in hepatitis C research and treatment.Nat Rev Gastroenterol Hepatol. 2016; 13: 70-72Crossref PubMed Scopus (24) Google Scholar In adults, efficacy has been demonstrated in all infected populations, including historically difficult to treat cohorts such as patients with pretreatment cirrhosis, renal disease, patients previously exposed to antiviral therapy, prior null responders, those with HIV co-infection, and patients following organ transplantation.26Kwo P.Y. Mantry P.S. Coakley E. Te H.S. Vargas H.E. Brown Jr., R. et al.An interferon-free antiviral regimen for HCV after liver transplantation.N Engl J Med. 2014; 371: 2375-2382Crossref PubMed Scopus (331) Google Scholar, 27Lawitz E. Gane E. Pearlman B. Tam E. Ghesquiere W. Guyader D. et al.Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial.Lancet. 2015; 385: 1075-1086Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 28Poordad F. Hezode C. Trinh R. Kowdley K.V. Zeuzem S. Agarwal K. et al.ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.N Engl J Med. 2014; 370: 1973-1982Crossref PubMed Scopus (754) Google Scholar, 29Sulkowski M. Hezode C. Gerstoft J. Vierling J.M. Mallolas J. Pol S. et al.Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial.Lancet. 2015; 385: 1087-1097Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, 30Zeuzem S. Jacobson I.M. Baykal T. Marinho R.T. Poordad F. Bourliere M. et al.Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.N Engl J Med. 2014; 370: 1604-1614Crossref PubMed Scopus (502) Google Scholar DAA regimens have also been shown to be effective in children and adolescents and are now approved by the Food and Drug Administration (FDA) for all HCV genotypes in those as young as 3 years of age. The first study assessing the IFN-free treatment of children with HCV infection was a phase 2, multicenter, open-label study which evaluated the efficacy and safety of ledipasvir-sofosbuvir in 100 adolescents (age 12-17 years) with chronic HCV genotype 1 infection.31Balistreri W.F. Murray K.F. Rosenthal P. Bansal S. Chuan-Hao L. Kersey K. et al.The Safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12 to 17 years old with hepatitis C virus genotype 1 infection.Hepatology. 2016; 66: 371-378Crossref Scopus (127) Google Scholar Each subject received a fixed-dose combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. The primary efficacy endpoint was the percentage of patients with a SVR 12 weeks post-treatment (SVR12). Most subjects (80%) were HCV treatment naïve, and 84% were infected through mother-to-child transmission (MTCT). Overall, 98% of patients reached SVR12 and no patient had virologic failure. The 2 subjects who could not be considered to have reached a SVR12 were lost to follow-up either during or after treatment. No serious adverse events were reported; commonly reported minor events were headache, diarrhea, and fatigue.31Balistreri W.F. Murray K.F. Rosenthal P. Bansal S. Chuan-Hao L. Kersey K. et al.The Safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12 to 17 years old with hepatitis C virus genotype 1 infection.Hepatology. 2016; 66: 371-378Crossref Scopus (127) Google Scholar Since this initial publication, further case series, center experiences, and clinical trials with various DAA regimens have been reported which universally recapitulate and expand the findings to demonstrate that effectiveness and safety can be achieved in all genotypes, ages, and weight classes (Table I).Table IPublished studies of DAA regimens in children and adolescentsAuthorsYearParticipant age in y (n)HCV genotypeTherapy (duration)SVR12 (%)Balistreri et al31Balistreri W.F. Murray K.F. Rosenthal P. Bansal S. Chuan-Hao L. Kersey K. et al.The Safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12 to 17 years old with hepatitis C virus genotype 1 infection.Hepatology. 2016; 66: 371-378Crossref Scopus (127) Google Scholar201612-17 (100)1Ledipasvir 90 mg + sofosbuvir 400 mg (12 wk)98Wirth et al32Wirth S. Rosenthal P. Gonzalez-Peralta R.P. Jonas M.M. Balistreri W.F. Lin C.H. et al.Sofosbuvir and ribavirin in adolescents 12-17 years old with hepatitis C virus genotype 2 or 3 infection.Hepatology. 2017; 66: 1102-1110Crossref PubMed Scopus (74) Google Scholar201712-17 (52)2 or 3Sofosbuvir 400 mg + ribavirin (variable)98Hashmi et al33Hashmi M.A. Cheema H.A. Effectiveness and Safety of sofosbuvir in treatment-naivechildren with hepatitis C infection.J Coll Phys Surg Pak. 2017; 27: 423-426PubMed Google Scholar20175-18 (35)1 or 3Sofosbuvir 400 mg + ribavirin (variable)97Murray et al34Murray K.F. Balistreri W.F. Bansal S. Whitworth S. Evans H.M. Gonzalez-Peralta R.P. et al.Safety and Efficacy of ledipasvir-sofosbuvir with or without ribavirin for chronic hepatitis c in children ages 6-11.Hepatology. 2018; 68: 2158-2166Crossref PubMed Scopus (59) Google Scholar20186-11 (90)1Ledipasvir 45 mg + sofosbuvir 200 mg (12 wk)98El-Karaksy et al35El-Karaksy H. Mogahed E.A. Abdullatif H. Ghobrial C. El-Raziky M.S. El-Koofy N. et al.Sustained viral response in genotype 4 chronic hepatitis c virus-infected children and adolescents treated with sofosbuvir/ledipasvir.J Pediatr Gastroenterol Nutr. 2018; 67: 626-630Crossref PubMed Scopus (31) Google Scholar201812-18 (40)4Ledipasvir 90 mg + sofosbuvir 400 mg (12 wk)100Leung et al36Leung D.H. Wirth S. Yao B.B. Viani R.M. Gonzalez-Peralta R.P. Jonas M.M. et al.Ombitasvir/Paritaprevir/ritonavir with or without dasabuvir and with or without ribavirin for adolescents with HCV genotype 1 or 4.Hepatol Commun. 2018; 2: 1311-1319Crossref PubMed Scopus (18) Google Scholar201812-17 (38)1 or 4Ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (variable)100Alkaaby et al37Alkaaby B.A. Al-Ethawi A.E. The effectiveness of oral antiviral (Sofosbuvir/Ledipasvir) in treating children with HCV infection.Pak J Med Sci. 2018; 34: 1353-1356PubMed Google Scholar20187-18 (22)Ledipasvir + sofosbuvir ± Ribavirin (variable)91Tucci et al38Tucci F. Calbi V. Barzaghi F. Migliavacca M. Ferrua F. Bernardo M.E. et al.Successful treatment with ledipasvir/sofosbuvir in an infant with severe combined immunodeficiency caused by adenosine deaminase deficiency with HCV allowed gene therapy with strimvelis.Hepatology. 2018; 68: 2434-2437Crossref PubMed Scopus (10) Google Scholar20180.5 (1)4Ledipasvir 22.5 mg + sofosbuvir 100 mg (12 wk)100El-Shabrawi et al39El-Shabrawi M.H.F. Kamal N.M. El-Khayat H.R. Kamal E.M. AbdElgawad M. Yakoot M. A pilot single arm observational study of sofosbuvir/ledipasvir (200 + 45 mg) in 6- to 12- year old children.Aliment Pharmacol Ther. 2018; 47: 1699-1704Crossref PubMed Scopus (22) Google Scholar20186-12 (20)4Ledipasvir 45 mg + sofosbuvir 200 mg (12 wk)95Quintero et al40Quintero J. Juamperez J. Julio E. Cabello V. Mercadal-Hally M. Soler-Palacin P. et al.An Pediatr (Barc). 2019; 90: 141-147Crossref PubMed Scopus (6) Google Scholar20196-18 (9)1 or 4Ledipasvir + sofosbuvir (variable)100Ghaffar et al41Abdel Ghaffar T.Y. El Naghi S. Abdel Gawad M. Helmy S. Abdel Ghaffar A. Yousef M. et al.Safety and efficacy of combined sofosbuvir/daclatasvir treatment of children and adolescents with chronic hepatitis C Genotype 4.J Viral Hepat. 2019; 26: 263-270Crossref PubMed Scopus (27) Google Scholar20198-18 (40)4Sofosbuvir + daclatasvir (variable)97.5Fouad et al42Fouad H.M. Ahmed Mohamed A. Sabry M. Abdel Aziz H. Eysa B. Rabea M. The effectiveness of ledipasvir/sofosbuvir in youth with genotype 4 hepatitis c virus: a single Egyptian center study.Pediatr Infect Dis J. 2019; 38: 22-25Crossref PubMed Scopus (11) Google Scholar201911-17.5 (51)4Ledipasvir 90 mg + sofosbuvir 400 mg (12 wk)100Ohya et al43Ohya K. Kawaoka T. Imamura M. Morio K. Nakahara T. Murakami E. et al.Three Children treated with direct-acting antivirals for chronic hepatitis C virus genotype 1B infection.Intern Med. 2019; : 1-5Google Scholar201910-13 (3)1bOmbitasvir + paritaprevir + ritonavir (12 wk)Or glecaprevir + pibrenastavir (8 wk)100Kamal et al44Kamal E.M. El-Shabrawi M. El-Khayat H. Yakoot M. Sameh Y. Fouad Y. et al.Effects of sofosbuvir/ledipasvir therapy on chronic hepatitis C virus genotype 4, infected children of 3-6 years of age.Liver Int. 2020; 40: 319-323Crossref PubMed Scopus (10) Google Scholar20203-6 (22)4Ledipasvir 45 mg + sofosbuvir 200 mg (8 or 12 wk)100El-Araby et al45El-Araby H.A. Behairy B.E. El-Guindi M.A. Adawy N.M. Allam A.A. Sira A.M. et al.Generic sofosbuvir/ledipasvir for the treatment of genotype 4 chronic hepatitis C in Egyptian children (9-12 years) and adolescents.Hepatol Int. 2019; 13: 706-714Crossref PubMed Scopus (12) Google Scholar20209-12 (100)4Ledipasvir 90 mg + sofosbuvir 400 mg (12 wk)100Rosenthal et al46Rosenthal P. Schwarz K.B. Gonzalez-Peralta R.P. Lin C.H. Kelly D.A. Nightingale S. et al.Sofosbuvir and Ribavirin therapy for children aged 3 to <12 years with hepatitis C virus genotype 2 or 3 infection.Hepatology. 2020; 71: 31-43Crossref PubMed Scopus (35) Google Scholar20203-11 (54)1 or 4Sofosbuvir 400 mg + ribavirin (variable)98Schwarz et al47Schwarz K.B. Rosenthal P. Murray K.F. Honegger J.R. Hardikar W. Hague R. et al.Ledipasvir-sofosbuvir for 12 weeks in children 3 to <6 years old with chronic hepatitis C.Hepatology. 2020; 71: 422-430Crossref PubMed Scopus (44) Google Scholar20203-<6 (34)1 or 4Ledipasvir + sofosbuvir (variable)97Jonas et al48Jonas M.M. Squires R.H. Rhee S.M. Lin C.W. Bessho K. Feiterna-Sperling C. et al.Pharmacokinetics, safety, and efficacy of glecaprevir/pibrentasvir in adolescents with chronic hepatitis c virus: part 1 of the DORA Study.Hepatology. 2020; 71: 456-462Crossref PubMed Scopus (53) Google Scholar202012-17 (47)1, 2, 3, or 4Glecaprevir 300 mg + pibrentasvir 120 mg (8-16 wk)100 Open table in a new tab The first FDA-approved DAA regimen for children was the fixed-dose combination of ledipasvir (90 mg) plus sofosbuvir (400 mg) (Harvoni) administered by mouth once daily for 12 weeks for the treatment of HCV genotypes 1, 4, 5, or 6 in children 12 years of age and older, or 35 kg in weight. In August of 2019, the FDA expanded the pediatric indications for ledipasvir plus sofosbuvir to include children 3-11 years of age meeting certain clinical criteria (Table II). In April of 2019, the FDA approved the fixed dose combination of glecaprevir (300 mg) and pibrentasvir (120 mg) (Mavyret), administered orally for 8 weeks, to treat all 6 genotypes of HCV in children 12-17 years of age. In September of 2019 the weight based sofosbuvir plus ribavirin regimen was FDA-approved; extending Interferon-free treatment to young children (age 3 through 11 years) with HCV genotype 2 or 3 (Table II).Table IIFDA-approved DAA therapy in childrenTherapiesAge (y)GenotypeClinical scenarioWeight (kg)Dose (mg)Duration (wk)Ledipasvir/Sofosbuvir≥3-181, 4, 5, or 6Treatment naïve AND w/o cirrhosis or with compensated cirrhosis<1733.75/1501217-<3545/20012≥3590/400121, 4, 5, or 6Compensated cirrhosis<1733.75/1502417-<3545/20024≥3590/400241 or 4Treatment Experienced<1733.75/1501217-<3545/20012≥3590/40012Glecaprevir/Pibrentasvir12-171, 2, 3, 4, 5, or 6Treatment naïve AND no cirrhosis≥35300/12081, 2, 4, 5, or 6Treatment Experienced AND no cirrhosis81, 2, 3, 4, 5, or 6Treatment naïve AND cirrhosis121, 2, 4, 5, or 6Treatment Experienced AND cirrhosis123Treatment Experienced ± cirrhosis16Sofosbuvir + Ribavirin≥3-182Treatment naïve or IFN experienced (±Ribavirin) without cirrhosis or with compensated cirrhosis<17150 + 15 mg/kg1217-<35200 + 15 mg/kg12≥35∗Weight based ribavirin dosing needed for those >47 kg.400 + 15 mg/kg123<17150 + 15 mg/kg2417-<35200 + 15 mg/kg24≥35∗Weight based ribavirin dosing needed for those >47 kg.400 + 15 mg/kg24∗ Weight based ribavirin dosing needed for those >47 kg. Open table in a new tab Collectively, DAA therapy is now FDA-approved for all children older than 3 years of age, regardless of genotype, weight, presence of cirrhosis, or history of treatment experience. The attainment of FDA approval along with the demonstrated efficacy and relatively minor side effect profiles of DAA therapy for the treatment of HCV in children has resulted in a substantial shift in the management of affected patients. The historical approach of treatment deferment has been replaced by a more aggressive strategy of initiating DAA therapy as soon as the diagnosis has been established in children ≥3 years of age.49Karnsakul W. Schwarz K.B. Management of hepatitis C infection in children in the era of direct-acting antiviral agents.J Viral Hepat. 2019; 26: 1034-1039PubMed Google Scholar The one exception to this may be in those children with genotype 2 or 3 in whom there is no compelling need for immediate antiviral therapy. This is in part due to the expectation of future FDA approval for ribavirin free regimens that have shown efficacy in recently completed clinical trials using sofosbuvir/valpatasvir50Jonas M.M. Romero R. Sokal E.M. Rosenthal P. Verucchi G. Lin C.H. et al.Safety and efficacy of sofosbuvir/velpatasvir in pediatric patients 6 to <18 years old with chronic hepatitis C infection [abstract 748].2019Google Scholar and glecaprevir/pibrentasvir.51Jonas M.M. Lon H.K. Rhee S. Gilmour S.M. Gonzalez-Peralta R.P. Leung D. et al.Pharmacokinetics of glecaprevir/pibrentasvir in children with chronic HCV infection: interim analysis of part 2 of the DORA study [abstract 1551].2019Google Scholar This new era of DAA medicines has transformed the landscape of HCV management in the pediatric population and curative therapy is now available. Still, additional avenues of pursuit remain in the march toward viral eradication. The global disease burden of HCV infection is estimated to be 71 million affected persons.52Cooke G.S. Andrieux-Meyer I. Applegate T.L. Atun R. Burry J.R. Cheinquer H. et al.Accelerating the elimination of viral hepatitis: a Lancet Gastroenterology and Hepatology Commission.Lancet Gastroenterol Hepatol. 2019; 4: 135-184Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar The estimates are that ∼5 million children and adolescents are HCV-infected, with prevalence rates ranging from 0.05%-0.36% in the US and Europe to 1.8%-5.8% in certain developing countries.53Gower E. Estes C. Blach S. Razavi-Shearer K. Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection.J Hepatol. 2014; 61: S45-S57Abstract Full Text Full Text PDF PubMed Scopus (1374) Google Scholar,54El-Shabrawi M.H. Kamal N.M. Burden of pediatric hepatitis C.World J Gastroenterol. 2013; 19: 7880-7888Crossref PubMed Scopus (90) Google Scholar However, for several reasons, these reports likely underestimate the true prevalence. Most patients with HCV infection are asymptomatic and, thus, are unaware of their status. Furthermore, there have been major changes in recent HCV epidemiologic patterns, primarily driven by the opioid epidemic in the US. There has been a significant increase in reported HCV infections in those who participate in high-risk activities such as intravenous drug abuse, with published reports demonstrating a 364% increase in HCV infection among people 12-29 years of age living in the Appalachia states of the US.55Centers for Disease Control and Prevention (CDC) Hepatitis C virus infection among adolescents and young adults:Massachusetts, 2002-2009.MMWR Morb Mortal Wkly Rep. 2011; 60: 537-541PubMed Google Scholar, 56Suryaprasad A.G. White J.Z. Xu F. Eichler B.A. Hamilton J. Patel A. et al.Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006-2012.Clin Infect Dis. 2014; 59: 1411-1419Crossref PubMed Scopus (376) Google Scholar, 57Zibbell J.E. Iqbal K. Patel R.C. Suryaprasad A. Sanders K.J. Moore-Moravian L. et al.Increases in hepatitis C virus infection related to injection drug use among persons aged </=30 years–Kentucky, Tennessee, Virginia, and West Virginia, 2006-2012.MMWR Morb Mortal Wkly Rep. 2015; 64: 453-458PubMed Google Scholar Although this region has been identified as the epicenter of this new wave of HCV, similar observations are being reported across the country,58Perfect C. Jhaveri R. Hepatitis C virus in children: trying to overcome the domestic and global challenges of cases and cost.J Pediatric Infect Dis Soc. 2019; : 1-4PubMed Google Scholar the majority of new infections occur in persons who inject drugs (PWID). According to data from the National Health and Nutrition Examination Survey that included 46 465 participants, in 2011-2016, ∼1.9 million US adults remained viremic with HCV, with 50% unaware of their infection status.59Zou B. Yeo Y.H. Le M.H. Henry L. Chang E.T. Lok A.S. et al.Prevalence of viremic HCV infection by age, race/ethnicity, birthplace and disease awareness among viremic persons in the US, 1999-2016.J Infect Dis. 2020; 221: 408-418PubMed Google Scholar An increased HCV disease burden in young adults has been directly linked to an increased rate of HCV infection in pregnant women and in infants exposed to HCV." @default.
• W3026673909 created "2020-05-29" @default.
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• W3026673909 date "2020-06-01" @default.
• W3026673909 modified "2023-10-03" @default.
• W3026673909 title "Treatment of Hepatitis C: A New Paradigm toward Viral Eradication" @default.
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