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Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide, with more than three million viraemic adolescents and children. Treatment of adults with HCV infection and HCV-related liver disease has advanced considerably thanks to development and improvements in therapy. Direct-acting antiviral regimens are safe and effective. Three regimens with pangenotypic activity (glecaprevir/pibrentasvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir) and three regimens with genotype-specific activity (sofosbuvir/ribavirin, sofosbuvir/ledipasvir and elbasvir/grazoprevir) have been approved with age-specific limitation for treatment of children with chronic hepatitis C by the European Medicines Agency and the United States Food and Drug Administration. The World Health Organization has set the ambitious target to eliminate hepatitis C as a major public health threat by 2030 and based its actions against HCV on the large use of direct acting antivirals. These updated European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations on treatment of hepatitis C describe the optimal therapeutic management of adolescents and children with HCV infection including specific indications for those living in resource-limited settings., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background and Aims: We evaluated the effectiveness and safety of pan-genotypic regimens, glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/daclatasvir (SOF/DCV) and other direct-acting antivirals (DAA) regimens for the treatment of hepatitis C virus (HCV)-infected adolescents (12-18 years), older children (6-11 years), and young children (3-5 years). The purpose of this systematic review and meta-analysis was to inform the World Health Organization (WHO) guidelines., Methods: We included clinical trials and observational studies published up to August 11, 2021, that evaluated DAA regimens in HCV-infected adolescents, older children, and young children. We searched MEDLINE, EMBASE, and CENTRAL databases and key conference abstracts. Sustained virological response 12 weeks after the end of treatment (SVR12), adverse events (AEs), and treatment discontinuation were the outcomes evaluated. Risk of bias was assessed using a modified version of the ROBINS-I tool. Data were pooled using random-effects models, and certainty of the evidence was assessed using the GRADE approach., Results: A total of 49 studies including 1882 adolescents, 436 older children, and 166 young children were considered. The SVR12 was 100% (95% Confidence Interval: 96-100), 96% (90-100), and 96% (83-100) for GLE/PIB in adolescents, older, and young children, respectively; 95% (90-99), 93% (86-98), and 83% (70-93), for SOF/VEL, respectively; and 100% (97-100) and 100% (94-100) for SOF/DCV in adolescent and older children, respectively. There was a clear trend towards a higher rate of any reported AE from adolescents (50%), older children (53%), to young children (72%). Serious AEs and treatment discontinuations were uncommon in adolescents and older children (<1%) but slightly higher in young children (3%)., Conclusions: All three pan-genotypic DAA regimens were highly effective and well-tolerated and are now recommended by the WHO for use in adults, adolescents, and children down to 3 years, which will simplify procurement and supply chain management. The evidence was based largely on single-arm non-randomized controlled studies. Moreover, there were also missing data regarding key variables such as route of HCV acquisition, presence or absence of cirrhosis, or HIV co-infection that precluded evaluation of the impact of these factors on outcomes., Prospero Record: CRD42020146752., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background & Aims: The aim of this study was to assess the effect of treatment with sofosbuvir/velpatasvir (SOF/VEL) on the health-related quality of life (HRQL) of children with chronic hepatitis C., Methods: In the non-commercial, non-randomized, open-label PANDAA-PED study, 50 children aged 6-18 years with chronic hepatitis C were treated with a fixed dose of SOF/VEL. All patients achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Evaluation of HRQL was performed twice: at baseline (before the treatment) and during the SVR12 analysis using the KIDSCREEN-27 questionnaires, which included 5 dimensions of HRQL, for child self-reporting and parent proxy reporting. The normal range for the population was set to T values of 50 ± 10 points. Child-parent agreement was analysed using the intra-class correlation coefficient (ICC) and Bland-Altman test., Results: Mean T values were within the normal range for all dimensions, both before and after treatment. There was a significant improvement in physical well-being based on the children's self-assessment (from 48.53 to 51.21, p = .03). In addition, a trend towards better scores in the 'social support & peers' part of the parent proxy evaluation (from 45.98 to 48.66, p = .06) was noticed. After the treatment, the proportion of children self-assessing their physical well-being as below normal significantly decreased from 17% to 5% (p = .007). HRQL scores were not associated with patients' sex, but in most cases, younger age correlated with better HRQL. Evaluation of the ICC for child self-reports versus parent proxy reports revealed poor to moderate agreement for most single measures. Bland-Altman analysis showed that in all dimensions, both before and after treatment, the limits of agreement (LoAs) exceeded ±5 points (half of the SD and considered a maximum allowed difference)., Conclusions: A significant proportion of children with chronic hepatitis C have decreased HRQL in all dimensions, but effective treatment with SOF/VEL leads to an improvement in some areas of well-being. As the effect of HCV on HRQL is more pronounced in older patients, treatment of younger children should be indicated to prevent them from experiencing decreased HRQL due to ongoing HCV infection in the future., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: The aim of this non-commercial, open-label, real-life, non-randomized clinical trial was to analyse the efficacy and safety of a pangenotypic regimen sofosbuvir/velpatasvir (SOF/VEL) in patients aged 6-18 years with chronic hepatitis C virus (HCV) infection., Methods: Fifty patients qualified for the 12-week treatment were divided into two weight groups: 15 children weighting between 17 and <30 kg received a fixed dose of 200/50 mg of SOF/VEL (tablet) once daily, and 35 patients weighting ≥30 kg were treated with 400/100 mg SOF/VEL. The primary endpoint of the study was efficacy defined as sustained viral response (undetectable HCV RNA using an real-time polymerase chain reaction method) at 12 weeks posttreatment (SVR12)., Results: Median age of the participants was 10 (IQR 8-12) years, 47 were infected vertically, and 3 patients were previously ineffectively treated with pegylated interferon and ribavirin. Thirty-seven participants were infected with HCV genotype 1, 10 with HCV genotype 3 and the remaining 3 with genotype 4. There was no case of cirrhosis. SVR12 was 100%. Thirty-three reported adverse events (AEs) were considered related to the administration of SOF/VEL, all of them were mild or moderate. Children presenting with AEs were older compared to these without AEs: 12 (9.5-13) versus 9 (IQR 8-11) years (p = 0.008)., Conclusions: Results of the PANDAA-PED study indicated a 100% effectiveness of a 12-week therapy with SOF/VEL in children aged 6-18 years with chronic HCV infection and its good safety profile, in particular in younger patients., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background and Aims: Sofosbuvir-velpatasvir-voxilaprevir is a pangenotypic regimen for chronic HCV infection. In the USA and Europe, sofosbuvir-velpatasvir-voxilaprevir once daily for 12 weeks is indicated for adults who previously received an HCV NS5A inhibitor. In Europe, sofosbuvir-velpatasvir-voxilaprevir is also indicated in the absence of prior HCV direct-acting antiviral (DAA) therapy as an 8-week or 12-week regimen. In an open-label study, we evaluated the safety, efficacy, and pharmacokinetics of sofosbuvir-velpatasvir-voxilaprevir in adolescents 12 to 17 years with chronic HCV of any genotype., Methods: In this Phase 2, multicenter study, sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg daily was administered to adolescents for 8 weeks if DAA-naïve or for 12 weeks for cirrhosis or prior DAA failure. The key efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Intensive pharmacokinetic sampling was done in 14 patients at week 2 or 4, and samples for population pharmacokinetics were collected in all patients., Results: All patients (n = 21) were naïve to HCV DAAs, and none had cirrhosis. HCV genotype 3a infection was most common, occurring in 43% of patients. Overall, 100% of patients (21 of 21) reached SVR12. The most common adverse events were abdominal pain and headache (24% each) and nausea (19%); no adverse events led to discontinuation. The only serious adverse event, hypotension, was considered related to study drug and resolved the same day without interruption of treatment. Sofosbuvir-velpatasvir-voxilaprevir exposures were similar to those observed in adults., Conclusions: The pangenotypic regimen of sofosbuvir-velpatasvir-voxilaprevir is highly efficacious and well-tolerated in treating chronic HCV infection in adolescents., (© 2022 American Association for the Study of Liver Diseases.)

Objectives: To prospectively describe the epidemiology and long-term outcome of childhood-acquired hepatitis C virus (HCV) infection in a large cohort of children followed at a single center., Methods: All children with chronic HCV infection followed at the Liver Unit of our tertiary Hospital in Florence (Italy) from January 1, 1988, to September 30, 2021, were included in the analysis., Results: The final sample consisted of 163 children (median age at enrollment 4 years, interquartile range (IQR): 10; median age at last follow-up 14 years, IQR: 7). The median duration of follow-up was 86 months (IQR: 112). One hundred twenty-five children were vertically infected and 26 acquired the infection horizontally. Twenty-six of the 125 children who were vertically infected (20.8%) underwent spontaneous clearance of HCV RNA at a median age of 4 years (IQR: 2), whereas all the others remained persistently viremic. One patient was diagnosed with cirrhosis; 2 presented clinically detectable extrahepatic manifestations (chronic urticaria). Thirty-two children (19.6%) received antiviral therapy: 8 out of 32 (25%) were treated with pegylated-interferon alfa-2b [sustained virological response (SVR) 24 weeks after the end of treatment in 7/8]; 24 out of 32 (75%) were treated with direct-acting antivirals (SVR 12 weeks after the end of treatment in 23/24)., Conclusions: The present study describes the largest cohort of children with chronic HCV infection prospectively evaluated with a long follow-up at a single center. HCV infection in children is often a chronic infection that can be cured with modern antiviral therapy. Early treatment could prevent the development of advanced liver disease., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction : Sofosbuvir/velpatasvir is a combination of direct-acting antivirals with pangenotypic activity for treatment of chronic hepatitis C virus infection. It was approved in 2020 for use in children aged 6-17 years and in June 2021 by the United States Food and Drug Administration for the age group 3-5 years. Areas covered : A literature search of PUBMED and EMBASE was conducted on April 30th and updated on June 10th. Other citations were identified in references of available literature and from ClinicalTrials.gov. The aim of the present research was to outline and discuss the pharmacokinetics, clinical efficacy, tolerability and safety of sofosbuvir/velpatasvir, exploring its actual and potential use in children and adolescents with chronic hepatitis C virus infection. Expert opinion : Five combinations of direct-acting antivirals, of whom three with pangenotypic activity, are now approved for children. No major differences in efficacy and safety profile have been described. Limited access to treatment still is a major issue, especially in low and middle-income countries.

Chronic infections by hepatitis B virus (HBV) and hepatitis C virus (HCV) major causes of advanced liver disease and mortality worldwide. Although regarded as benign infections in children, their persistence through adulthood is undoubtedly of concern. Recent advances in HCV treatment have restored the visibility of these conditions and raised expectations for HBV treatment, which is currently far from being curative. Herein we describe direct-acting antivirals available for pediatric HCV (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir) and their real-world use. A critical review of the HBV pediatric classification is provided. Anti-HBV investigational compounds are reviewed in light of the pathophysiology in the pediatric population, including capsid assembly modulators, antigen secretion inhibitors, silencing RNAs, and immune modifiers. Recommendations for screening and management of immunosuppressed children or those with other risk factors or comorbidities are also summarized., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objectives: Sofosbuvir/Ledipasvir (SOF/LDV) has been approved by the European Medicine Agency (EMA) for the treatment of children and adolescents (at least 3 years of age) with chronic hepatitis C (CHC) genotype 1, 3, and 4 infection. The aim of this study was to evaluate the efficacy and safety of SOF/LDV in adolescents (12 to <18 years old) with CHC in the real-world setting., Methods: Prospective, open-label, multicentre study involving 12 Italian centres. Patients received the fixed-dose combination of SOF/LDV (400/90 mg) once daily ± ribavirin as per EMA approval and recommendations. The key efficacy endpoint was sustained virological response 12 weeks after the end of treatment (SVR12) as per intention-to-treat analysis. Safety was assessed by adverse events and clinical/laboratory data., Results: Seventy-eight consecutive adolescents (median age 15.2 years, range 12-17.9; girls 53.8%) were enrolled and treated between June 2018 and December 2019. Genotype distribution was as follows: genotype 1 (82.1%), 3 (2.5%), and 4 (15.4%). Seventy-six (97.4%) patients completed treatment and follow-up. Overall, SVR12 was 98.7%. One patient was lost to follow-up after 4 weeks of treatment; 1 patient completed treatment and missed the follow-up visit. No virological breakthrough or relapse were observed. No patient experienced grade 3 to 4 adverse event or serious adverse event., Conclusions: The results of this real-world study confirmed the high efficacy and the optimal safety profile of SOF/LDV for treatment of CHC in adolescents., (Copyright © 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: The effect of direct-acting anti-virals (DAAs) in children and adolescents with chronic hepatitis C virus (HCV) infection is difficult to determine, since few, aged between 3 and 18 years, have been enrolled in clinical trials, and some data come from observational studies., Aim: To summarise the evidence on efficacy and safety of DAAs in children and adolescents with chronic HCV infection., Methods: We performed a systematic review and meta-analysis of prospective studies on the efficacy and safety of DAAs in subjects <18 years of age. We considered the sustained virological response at post-treatment week 12 as efficacy outcome and adverse events as safety outcome. We considered intervention effect for each study arm by calculating the proportion of sustained virologic response at post-treatment week 12 in subjects receiving all doses of treatment and proportion of adverse events in subjects receiving at least one dose of treatment. Pooled proportions were calculated using the Freeman-Tukey double arcsine transformation. Random effects model was used for all analyses., Results: Among 39 included studies (1796 subjects), the pooled proportion among those receiving all doses of treatment and reaching sustained virologic response at post-treatment week 12 was 100% (95% confidence interval: 100-100). Considering subjects receiving at least one dose of treatment, lowest estimates were reported among children with cirrhosis (83%). Headache and fatigue were the most common adverse events. Serious adverse events were uncommon., Conclusions: Children and adolescents with chronic HCV infection can be safely treated with DAAs with similar efficacy as reported in adults., (© 2020 John Wiley & Sons Ltd.)

Hepatitis C is a global public health threat. The introduction of direct-acting antivirals (DAAs) brings the prospect of curing the 71 million people living with the disease, dramatically changing the landscape of hepatitis C. The World Health Organization developed a roadmap for the elimination and cure of hepatitis C by 2030 with a clear goal with measurable targets. However, there is a lack of a well-defined strategy to tackle the hepatitis C virus (HCV) problem in children and adolescents vis-à-vis the adult population. Hepatitis C in children and adolescents can be addressed as part of a national policy for elimination in the whole population, namely macroelimination, or could be fragmented into a microelimination approach targeting the high-risk population groups. Children born to HCV-infected mothers, adolescents who are injecting drugs, migrants, and those suffering from inherited blood diseases are important target populations. After the U.S. Food and Drug Administration approval for the use of DAAs in children aged 3 years and above, evidence from clinical trials and real-world experience was accumulated using brand and generic medicines, with sustained virological response rates exceeding 95%. The evidence created should guide policies on the management of hepatitis C in children and adolescents. There are many challenges in managing HCV in this left-behind marginalized population. The lack of awareness and epidemiological data, consent age, prohibitive prices of medicines, and absence of policies on access to diagnostics, treatment, and linkage to care are among the many barriers to service delivery that should be addressed to achieve the elimination goal by 2030., Competing Interests: The authors report that they have nothing to disclose., (Thieme. All rights reserved.)

Objective: This position paper written by the Hepatitis Expert Team of the Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition aimed to systematically evaluate clinical practice guidelines (CPGs), medical consensus, and position papers on the use of direct-acting antivirals (DAA) to treat chronic hepatitis C virus (HCV) infection in adolescents and children in order to compare recommendations and provide the basis for developing a unified position statement., Methods: MEDLINE, Cochrane-Library, National Guideline Clearinghouse and select websites of relevant societies/organizations were used to identify CPGs, medical consensus and position papers between 2011-2019., Results: A total of 5 documents were analysed: 3 CPGs, 1 medical consensus, and 1 position paper. All publications were consistent in recommending DAA treatment for adolescents (12-17 years old) with chronic HCV infection. Similarly, all of these publications consistently recommended deferring therapy for children between 3 and 11 years of age until DAA became available as standard of care. Finally, none of the included publications recommended treating children younger than 3 years old. By contrast, there was significant discrepancy across the retrieved documents regarding specific DAA regimens and treatment strategies., Conclusions: There is strong consensus on treating all adolescents with chronic HCV infection with DAA and on delaying therapy in younger children until these agents are approved for them. Interferon-based therapies should be avoided. Specific recommendations regarding which DAA regimen to use and treatment duration varied significantly. Key stakeholders need to convene to standardize therapeutic strategies at a global level if we are to eradicate HCV in children.

Currently, the only approved hepatitis C virus (HCV) treatment for children aged <12 years is pegylated interferon plus ribavirin. In an open-label study, we evaluated the safety and efficacy of sofosbuvir plus ribavirin for 12 weeks in children aged 3 to <12 years chronically infected with genotype 2 or for 24 weeks in patients with genotype 3. Patients aged 3 to <6 years weighing <17 kg received sofosbuvir 150 mg, and patients aged 3 to <6 years weighing ≥17 kg and all patients aged 6 to <12 years received sofosbuvir 200 mg once daily. Intensive pharmacokinetic sampling conducted in each age group confirmed the appropriateness of sofosbuvir doses. For all patients, ribavirin dosing was determined by baseline weight (up to 1,400 mg/day, two divided doses). The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Fifty-four patients were enrolled (41 aged 6 to <12 years and 13 aged 3 to <6 years). Most were treatment naïve (98%) and infected perinatally (94%). All but one patient achieved SVR12 (53/54, 98%; 95% confidence interval, 90%-100%). The patient who did not achieve SVR12 was a 4-year-old who discontinued treatment after 3 days because of "abnormal drug taste." The most commonly reported adverse events in patients aged 6 to <12 years were vomiting (32%) and headache (29%), and those in patients aged 3 to <6 years were vomiting (46%) and diarrhea (39%). One 3-year-old patient had a serious adverse event of accidental ribavirin overdose requiring hospitalization for monitoring; this patient completed treatment and achieved SVR12. Conclusion: Sofosbuvir plus ribavirin was well tolerated and highly effective in children aged 3 to <12 years with chronic HCV genotype 2 or 3 infection., (© 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

Treatment-naïve, noncirrhotic adults with chronic hepatitis C virus genotype 1 infection and with viremia levels <6 million IU/mL could be effectively treated with sofosbuvir/ledipasvir for 8 weeks. The aim of this pilot, prospective, open-label, multicenter study was to evaluate the efficacy and safety of this shortened treatment course in adolescents (≥12 years). The efficacy endpoint was sustained virological response 12 weeks after the end of treatment. Safety was assessed by adverse events and clinical/laboratory data. Fourteen consecutive adolescents (median age 16.5 years, Q1 14.1-Q3 17.4; female 57.1%), vertically infected, were enrolled and treated (June 2018-January 2019). Overall, the end of treatment response and sustained virological response 12 weeks after the end of treatment were 100%. No grade 3 to 4 adverse event or a serious adverse event was observed. Further studies are needed to confirm the optimal efficacy of the shortened 8-week treatment with sofosbuvir/ledipasvir for treatment-naïve, noncirrhotic adolescents with chronic hepatitis C virus genotype 1 infection and pretreatment viremia level < 6 million IU/mL.

The burden of paediatric Hepatitis C virus (HCV) infection across Europe is unknown, as are current policies regarding monitoring and treatment. This collaborative study aimed to collect aggregate data to characterise the population of ≤18-year-olds with HCV infection in specialist follow up in a 12-month period (2016) across the PENTAHep European consortium, and investigate current policies around monitoring and treatment. A cross-sectional, web-based survey was distributed in April 2017 to 50 paediatricians in 19 European countries, covering patients' profile, and monitoring and treatment practices. Responses were received from 38/50 clinicians collectively caring for 663 children with chronic HCV infection of whom three-quarters were aged ≥6 years and 90% vertically infected. HCV genotype 1 was the most common (n 380; 57.3%), followed by genotype 3, 4 and 2. Seventeen children (3%) with chronic HCV infection were diagnosed with cirrhosis, and six were reported to have received liver transplantation for HCV-related liver disease. The majority (n 425; 64.1%) of the European children with HCV infection remained treatment-naive in 2016. Age affected clinicians' attitudes towards treatment; 94% reported being willing to use direct-acting antivirals, if available, in adolescents (aged ≥11 years), 78% in children aged 6-10 and 42% in those 3-5 years of age (Pearson correlation coefficient -0.98; P 0.0001). This survey provides the largest characterisation of the population of children in clinical follow-up for chronic HCV infection in Europe, alongside important contextual information on their management and treatment. Discussion is needed around strategies and criteria for use of direct-acting antivirals in these children., (© 2019 John Wiley & Sons Ltd.)

Russia has one of the highest prevalences of paediatric chronic hepatitis C infection (CHC). Our aim was to provide a detailed characterization of children and adolescents with CHC including treatment outcomes. Thus, an observational study of children with CHC aged <18 years was conducted in three hepatology centres from November 2014 to May 2017. Of 301 children (52% male), 196 (65%) acquired HCV vertically, 70 (23%) had a history of blood transfusion or invasive procedures, 1 injecting drug use and 34 (11%) had no known risk factors. Median age at HCV diagnosis was 3.1 [interquartile range, IQR 1.1, 8.2] and 10.8 [7.4, 14.7] at last follow-up. The most common genotype was 1b (51%), followed by 3 (37%). Over a quarter of patients (84, 28%) had raised liver transaminases. Of 92 with liver biopsy, 38 (41%) had bridging fibrosis (median age 10.4 [7.1, 14.1]). Of 223 evaluated by transient elastography, 67 (30%) had liver stiffness ≥5.0 kPa. For each year, increase in age mean stiffness increased by 0.09 kPa (95% CI 0.05, 0.13, P < 0.001). There was significant correlation between liver stiffness and biopsy results (Tau-b = 0.29, P = 0.042). Of 205 treated with IFN-based regimens, 100 (49%) had SVR24. Most children (191, 93%) experienced adverse reactions, leading to treatment discontinuation in 6 (3%). In conclusion, a third of children acquired HCV via nonvertical routes and a substantial proportion of those with liver biopsy had advanced liver disease. Only half of children achieved SVR24 with IFN-based regimens highlighting the need for more effective and better-tolerated treatments with direct-acting antivirals. Further studies are warranted in Russia on causes and prevention of nonvertical transmission of HCV in children., (© 2019 The Authors. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.)

Preexistence and appearance of resistance-associated substitutions limit the efficacy of direct-acting antivirals in treatment of hepatitis C. This is the first case report of an adolescent with chronic hepatitis C virus genotype 4 infection and cirrhosis who failed treatment with ombitasvir/paritaprevir/ritonavir and ribavirin. Resistance analysis showed baseline resistance-associated substitutions M28V and Y93C and emergent D168H.

Background: Autoimmune thyroid disease and thyroid dysfunction are common in adults receiving interferon (IFN)-based treatment for chronic hepatitis C (CHC). Few data are available in children with CHC. This study is aimed to evaluate the appearance and timing of thyroid dysfunction and antithyroid autoimmunity in children with CHC treated with pegylated IFN-α-2b and ribavirin (RBV)., Methods: Sixty-one otherwise healthy children with CHC, 3-17 years of age, infected perinatally and treatment naïve, receiving therapy with pegylated IFN-α-2b and RBV and 183 age- and sex-matched controls were included in a multicenter, prospective, case-control study. Thyroid-stimulating hormone, free thyroxine, antithyroglobulin antibodies and antithyroid peroxidase antibodies were assessed before, during and 24 weeks after the end of treatment., Results: From baseline to the end of treatment, subclinical hypothyroidism and autoimmune thyroiditis were diagnosed in 17 of 61 (27.94%) and in 4 of 61 (6.6%) of the children treated, respectively, and in 5 of 183 (2.7%) and in none of the controls (P < 0.0001, relative risk: 10.2, 95% confidence interval: 3.9-26.5; P = 0.03, relative risk: 26.8, 95% confidence interval: 1.5-489.1, respectively). Twenty-four weeks after the end of treatment, subclinical hypothyroidism persisted in only 4 of 61 (6.6%). Autoimmune thyroiditis persisted in 3 of 4 (75%) of the cases., Conclusions: Subclinical hypothyroidism is common in children with CHC receiving treatment with pegylated IFN-α-2b and RBV, but in most cases is transient. Autoimmune thyroiditis, which is less common, generally persists after treatment completion. Thyroid function should be carefully monitored in patients presenting with antithyroid autoantibodies and thyroid dysfunction during and after pegylated IFN-α-based treatment.

In 2017, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved the fixed-dose direct-acting antiviral (DAA) combination sofosbuvir and ledipasvir and the combination sofosbuvir plus ribavirin for the treatment of adolescents (aged 12-17 years) with chronic hepatitis C. Preliminary results on the use of DAAs in paediatric patients are available for the fixed-dose combination sofosbuvir and ledipasvir in children aged 6-17 years for genotype 1 or 4 infection; for combination sofosbuvir plus ribavirin for adolescents aged 12-17 years for genotype 2 or 3 infection; for the fixed-dose combination ombitasvir, paritaprevir, and ritonavir with or without dasabuvir and with or without ribavirin for adolescents aged 12-17 years with genotype 1 or 4 infection; and for the combination of sofosbuvir plus daclatasvir for children with genotype 4 infection. All the results available indicated positive efficacy and favourable safety profiles of the different combinations of DAAs. With the approval of the new drugs, indications for treatment of children with chronic hepatitis C have changed. DAA therapy is recommended for all adolescents aged 12-17 years with chronic hepatitis C virus infection independent of treatment history and disease severity. If and when DAAs are approved for younger age cohorts, all children older than 3 years infected with hepatitis C will benefit from antiviral therapy. In this Review, we aim to provide an up-to-date overview of the existing evidence on the paediatric use of DAAs, summarising indications to treatment and recommendations for monitoring., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: In 2017, the European Medicines Agency and the Food and Drug Administration approved the use of the fixed-dose combination of ledipasvir/sofosbuvir and of the combination of sofosbuvir and ribavirin for treatment of adolescents (12-17 years or weighing >35 kg) with chronic hepatitis C virus (HCV) genotype 1, 4, 5, and 6 and genotype 2 and 3 infections, respectively. Although trials with direct-acting antivirals are ongoing for younger children, the only available treatment in the United States and Europe for those <12 years is still the dual therapy of pegylated interferon and ribavirin. There is currently a lack of a systematic approach to the care of these patients. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition developed an evidence-based position paper for the management of chronic HCV infection in children., Methods: A systematic literature search and meta-analysis were performed using MEDLINE and Embase from June 1, 2007 to June 1, 2017. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. European Society of Pediatric Gastroenterology, Hepatology and Nutrition Committee members voted on each recommendation, using the nominal voting technique., Results: The efficacy of the different direct-acting antivirals combinations tested was higher, the relapse and the treatment discontinuation rates lower when compared to pegylated interferon and ribavirin., Conclusions: This position paper addresses therapeutic management issues including goals, endpoints, indications, contraindications, and the optimal treatment regimen in children with chronic HCV infection.

The development of oral hepatitis C virus (HCV) direct-acting antivirals (DAAs) has revolutionized the therapeutic field. Nowadays, multiple safe and highly effective antiviral regimens are commercially available to treat adults with hepatitis C infection. These new regimens for the first time genuinely raise the prospects of eradicating HCV. Many challenges, however, remain from identifying infected individuals to optimizing treatment and ensuring global access to antiviral therapy to all population groups, including children. Recently, in April 2017, the association of sofosbuvir with ribavirin and the fixed-dose combination sofosbuvir/ledipasvir have been approved by the Food and Drug Administration for treatment of children with chronic HCV infection 12 years of age and older. The only drugs currently approved for children younger than 12 years are pegylated interferon and ribavirin. There are 6 registered ongoing pediatric trials assessing safety and efficacy of DAAs, but their current completion timelines are years away. Herein, we summarize the state of the art of DAAs' development for adult and children and highlight the crucial importance of overcoming barriers to treating children with HCV.

Background: Chronic hepatitis C is a global health problem. Although new, highly effective and safe direct-acting antivirals have been approved for adults, the only drugs currently registered for children are pegylated interferon and ribavirin. The timelines for the pediatric approval of the new treatment regimens are far off. Three phase II-III pediatric trials with direct-acting antivirals are recruiting, and the estimated dates of completion of these studies range between April 2018 and January 2023., Methods: The aim of this study was to evaluate the value of on-treatment virologic response (VR) as predictor of sustained virologic response (SVR) in a cohort of Italian children with chronic hepatitis C and to establish possible stopping rules., Results: Sixty-four children were enrolled (January 2012 to December 2015). SVR rate was 79.7% (51/64). VR at weeks 2 to 12 were shown to be robust predictors for the attainment of SVR. The positive predictive values of VR at weeks 8 and 12 were 98% and 92.7%, respectively. The negative predictive values at the same treatment weeks were 92.9% and 100%, indicating that no child who did not achieve VR at week 12 obtained SVR and that the likelihood of achieving SVR if still positive at week 8 was very low., Conclusions: Our results suggest for the first time that VR at week 8 could be considered a reliable predictor of SVR. Monitoring viral kinetics is useful for predicting the success of pegylated interferon and ribavirin therapy in children.

Chronic hepatitis C in children is usually considered a clinically mild and slowly progressive disease. Few pediatric studies focused on histopathology of children with hepatitis C are available. Those available show, overall, a wide spectrum of findings ranging from normal liver to cirrhosis and hepatocellular carcinoma. The present systematic review provides a comprehensive overview of the studies that explored histopathology in children with hepatitis C. Factors affecting the presence and the degree of necroinflammation, fibrosis and steatosis and the risk of progression to advanced liver disease were extensively evaluated. Insights on the possible role of histopathology findings in the decision-making process of whether or not to treat children with hepatitis C are provided.

Pegylated interferon (IFN) α-2a or 2b in combination with ribavirin for children aged 3 years and older is the standard treatment for paediatric chronic hepatitis C. This treatment regimen was developed firstly in adults. In recent years, a number of direct-acting antiviral agents (DAAs) are under development for treatment of chronic hepatitis C virus (HCV) infection. These agents block viral replication inhibiting directly one of the several steps of HCV lifecycle. DAAs are classified into several categories based on their molecular target: HCV NS3/4A protease inhibitors, HCV NS5B polymerase inhibitors and HCV NS5A inhibitors. Other promising compounds are cyclophilin A inhibitors, mi-RNA122 and IFN-λ. Several new drugs associations will be developed in the near future starting from the actual standard of care. IFN-based and IFN-free regimens are being studied in adults. In this constantly evolving scenario new drug regimens targeted and suitable for children would be possible in the next future. Especially for children, it is crucial to identify the right combination of drugs with the highest potency, barrier to resistance and the best safety profile.

The purpose of the present review is to summarise the current knowledge on the association between single nucleotide polymorphisms (SNPs) in the interferon L3 (IFNL3) gene and hepatitis C virus (HCV) infection in children. Many studies in adults have demonstrated that genetic variation in IFNL3 is a strong predictor of the virological response in treatment-naive patients with HCV genotype 1 who were treated with Pegylated-IFN-α and ribavirin. Genetic variation in IFNL3 is also associated with the spontaneous clearance of HCV. Thus far, few paediatric studies have explored the association between variations in the IFNL3 gene and either spontaneous or treatment-induced clearance of HCV. The CC genotype of the rs12979860 SNP is associated with the spontaneous clearance of HCV in children independently of HCV genotype. Four paediatric studies have shown that both the CC genotype of the rs12979860 SNP and the TT genotype of the rs8099917 SNP are associated with the treatment-induced (IFN monotherapy and Pegylated-IFN-α and ribavirin association) clearance of HCV, while the rs12980275 SNP did not affect the virological response. The possible role of IFNL3 gene variation as a pre-treatment and on-treatment predictor of virological response in children is highly attractive but still undetermined. Further paediatric studies are needed to evaluate if testing for SNPs in IFNL3, either alone or together with other predictors of response to treatment, could be used to direct treatment strategies, including an avoidance of unnecessary protease inhibitor therapy and the duration of treatment.

Objective: Recent genome-wide association studies performed in adults correlated single-nucleotide polymorphisms (SNPs rs12979860 and rs8099917) located on chromosome 19, upstream of the interleukin 28B gene, with spontaneous clearance of hepatitis C virus and with response to treatment with paginated interferon and ribavirin. The aim of the present collaborative study was to evaluate the rs12979860 SNP in a large cohort of Italian children with perinatal acquisition of hepatitis C., Methods: Children were prospectively enrolled in 2 Italian centers. The interleukin 28B rs12979860 SNP was studied according to the diagnosis of chronic infection or spontaneous clearance., Results: One hundred thirty children (86.7%) with chronic infection and 23 (13.3%) with spontaneous clearance of the virus were enrolled. Overall, the interleukin 28B C/C and C/T-T/T genotypes were found in 57 (37.3%) and 96 (62.7%) children, respectively. The proportion of C/C genotype was higher among children who cleared infection (14/23; 60.9%) compared with children with chronic infection (43/130; 33.1%; P = 0.01; odds ratio 3.15; 90% confidence intervals 1.34-7.53)., Conclusions: The present study showed that, as already demonstrated in adults, children with the rs12979860 C/C SNP of the interleukin 28B gene have a higher probability of spontaneous clearance of hepatitis C virus.

Hepatitis C virus (HCV) infection has been associated with autoimmunity and extrahepatic manifestations in adults. Few data are available on these topics in children. Nonorgan specific auto-antibodies development is part of the natural course of chronic hepatitis C in children. Smooth muscle autoantibody is the most common autoantibody found, while liver-kidney microsomal type-1 antibody positivity is the most peculiar autoimmune feature of children with HCV infection. The clinical significance of non-organ specific autoantibodies in the course of paediatric chronic hepatitis C is still debated. Autoantibody positivity can be considered neutral for most patients, while it can be associated with negative connotations for others, especially those positive for liver-kidney microsomal type-1 autoantibody. Subclinical hypothyroidism but not autoimmune thyroiditis has been demonstrated in HCV infection in children, while only few cases of HCV-associated membranoproliferative glomerulonephritis have been described. Single reports are available in the literature reporting the anecdotal association between chronic hepatitis C and other extrahepatic manifestations such as myopathy and opsoclonus-myoclonus syndrome. Despite the low incidence of extrahepatic manifestations of chronic hepatitis C in children, overall, available data suggest a careful monitoring.

Background and Aim: Treatment of chronic hepatitis C in children is controversial and its role in the clinical practice is unknown. We retrospectively investigated the impact of treatment in a large cohort of children with chronic hepatitis C over the past 20 years., Methods: 376 hepatitis C virus RNA positive children were recruited consecutively in five Italian centres since 1990 and followed for 1-17 years., Results: 86 (23%) subjects were treated: 73 with recombinant interferon alone and 13 with pegylated-interferon and ribavirin. Sustained clearance of hepatitis C virus RNA was observed in 25% of the former, in 92% of the latter and in 9% of untreated cases (p < 0.001). Loss of viraemia was recorded in all children with genotype 2-3 and in 6 of 7 with hepatitis C virus genotype 1 treated with combination therapy. At last evaluation 45% of patients were young adults and 15% had cleared viraemia. Overall, 152 (40%) were putative candidates to therapy., Conclusions: Few Italian children with chronic hepatitis C have been treated in the past 20 years. The poor propensity to spontaneous clearance of viraemia and the efficacy of combination therapy should encourage to consider treatment in attempt to shorten the duration of viral replication., (Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: The natural course of chronic hepatitis C (CHC) in children is not well understood. The aim of this study was to assess the long-term course of CHC in a large sample of otherwise healthy children., Methods: From 1990 to 2005, 504 consecutive antihepatitis C virus (HCV)-positive children were enrolled at 12 centers of a national observatory and were followed up retrospectively/prospectively., Results: Putative exposure was perinatal in 283 (56.2%) cases, parenteral in 158 (31.3%), and unknown in 63 (12.5%). At baseline, 477 (94.6%) cases were HCV RNA seropositive, 118 (24.7%) of which were treated with standard interferon alpha. Ten years after putative exposure, the outcome in 359 HCV RNA-positive, untreated patients was (1) undetectable viremia in 27 (7.5%) (by Cox regression analysis, spontaneous viral clearance was independently predicted by genotype 3 [hazard ratio 6.44; 95% confidence interval: 2.7-15.5]) and (2) persistent viremia in 332 (92%) cases. Six of these 332 cases (1.8%) progressed to decompensated cirrhosis (mean age, 9.6 years). This latter group included 5 Italian children perinatally infected with genotype 1a (4 of the mothers were drug users). Thirty-three (27.9%) treated patients achieved a sustained virologic response., Conclusions: Over the course of a decade, few children with chronic HCV infection cleared viremia spontaneously, and those who did were more likely to have genotype 3. Persistent viral replication led to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a. Children with such features should be considered for early treatment.

Objective: The reported data on thyroid function and anti-thyroid autoantibodies in adults with untreated hepatitis C virus (HCV) infection are controversial. Data are scarce for HCV-infected children, and only in those treated with interferon-alpha (IFN-alpha). We investigated thyroid function and anti-thyroid autoantibodies in a cohort of untreated children with vertically acquired, chronic, HCV infection., Design and Patients: FT4 and TSH serum levels (measured by immunometric assays) and anti-thyroglobulin (TgA) and anti-thyroperoxidase (TPOA) antibodies (evaluated by fluorescence enzymatic immunoassays) were studied in 36 consecutive HCV-infected children and 150 age- and sex-matched controls. The prevalence of thyroid involvement was also related to family history of autoimmune disease, distribution of HCV genotypes, and duration and activity of HCV infection., Results: Four out of 36 (11.1%) HCV-infected children and 4/150 controls (2.7%) showed subclinical hypothyroidism [P = 0.04; relative risk (RR) 4.56, 95% confidence interval (CI) 1.08-19.21]. None of these had anti-thyroid autoantibodies. Two out of 36 (5.6%) HCV-infected children and 1/150 (0.7%) controls had increased TgA values with normal levels of TSH (P > 0.05). Subclinical hypothyroidism and anti-thyroid autoantibodies were not related to family history of autoimmune disease, duration of infection, HCV viral load, liver function or different HCV genotype distribution, but seemed to be related to the presence of active HCV infection., Conclusions: Our data suggest a role for HCV infection in the development of nonautoimmune thyroid disease in untreated HCV-infected children, confirming previous studies in adults. Clinicians should be aware of thyroid dysfunction even in untreated children.

Mother-child human leukocyte antigen (HLA)diversity is protective for vertical transmission of some viruses. The aim of this study is to evaluate the role of mother-child HLA diversity on hepatitis C virus (HCV) vertical transmission. Forty consecutive HCV infected and 46 consecutive control uninfected children born to HCV-RNA positive mothers were evaluated for HLA class-1 type concordance with their mothers. No significant difference in the degree of HLA concordance was found between HCV infected and uninfected children both when A, B, C (p=0.30) and when only A and B alleles were evaluated (p=0.59). Mother-infant HLA concordance does not affect HCV vertical transmission.