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Background: The aim of this study was to evaluate the influence of treatment of hepatitis C with sofosbuvir and velpatasvir (SOF/VEL) on children's growth., Methods: Fifty children 6-18 years of age were successfully treated for hepatitis C with a 12-week course of SOF/VEL fixed dose adjusted to the body weight in the PANDAA-PED (Treatment of chronic hepatitis C in children 6-18 years of age using a pangenotypic direct-acting antiviral sofosbuvir/velpatasvir) project. Growth parameters were compared at 1 year after treatment with baseline (at the start of treatment) and 12-week-posttreatment values. Body mass index (BMI), weight and height Z scores adjusted to sex and age were calculated according to the World Health Organization reference data., Results: Forty-nine participants (23 boys and 26 girls) completed all the visits. The mean age at 1 year after treatment was 10.9 ± 2.5 years, and all children had undetectable hepatitis C virus RNA at this point. Significant weight and height gains were observed after treatment irrespective of the patients' age and sex. Height Z scores did not vary significantly both at 12 weeks and 1 year after treatment, confirming a normal increase in participants' height. Weight Z scores for 16 children below 10 years of age decreased at 1 year after treatment. BMI Z score values decreased at 12 weeks after treatment compared to the baseline in boys, but no difference was found between 1-year posttreatment and baseline BMI Z scores in both girls and boys., Conclusions: Results of the PANDAA-PED study showed normal growth up to 1 year after successful treatment with SOF/VEL in children 6-18 years of age. Despite the decrease in BMI Z score in boys observed at 12 weeks after treatment, no differences were found between baseline and 1-year posttreatment values. Our observations confirm the long-term safety of the SOF/VEL treatment in children 6-18 years of age., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

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: There are limited data available on the influence of direct-acting antivirals used to treat chronic hepatitis C (CHC) on growth in children. In this study, we aimed to analyze the growth parameters in children treated with ledipasvir/sofosbuvir (LDV/SOF). Methods: We included 38 patients (16 girls and 22 boys) aged 10−17 years treated with LDV/SOF for CHC (33 infected with genotype 1 and 5 with genotype 4; 36 were treated for 12 weeks, and 2 for 24 weeks according to the current guidelines). Patient weight and height were measured at baseline, after 4 weeks of treatment, at the end of the treatment (EOT), and 12 weeks and one year after the EOT. Body mass index (BMI), BMI z and height-for-age (HA) z scores were calculated according to the WHO Child Growth Standards and Growth reference data using the WHO anthropometric calculator AnthroPlus v. 1.0.4. In addition, correlations between BMI z scores and liver fibrosis (liver stiffness measurement, LSM), the aspartate transaminase (AST)-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4) and liver steatosis (controlled attenuation parameter, CAP) were analyzed. Results: At baseline, 5/38 (13%) patients were obese (BMI z score >2 SD), 4/38 (11%) were overweight, and 29 (76%) were normal. A significant increase was observed in mean weight, height and BMI both 12 weeks and one year after the treatment compared to the baseline, whereas no differences were observed for BMI z scores and HA z scores. Baseline BMI z scores correlated with alanine aminotransferase levels (r = 0.33, 95% CI 0.01−0.58, p = 0.04), LSM (r = 0.40, 95% CI 0.09−0.65, p = 0.01), the APRI (r = 0.33, 95% CI 0.02−0.59, p = 0.03), and the CAP (r = 0.40, 95% CI 0.08−0.64, p = 0.01). No similar correlations were reported at 12 weeks posttreatment. Conclusions: Treatment with LDV/SOF in children with CHC (genotypes 1 and 4) did not negatively influence the patients’ growth. However, higher baseline BMI z scores correlated with more advanced liver fibrosis and steatosis in children with CHC., Competing Interests: The authors declare no conflicts of interest.

Background: Therapy with pegylated interferon and ribavirin (PEG-IFN+RBV) for chronic hepatitis C (CHC) remains the only option available for children in many Eurasian and European countries. Our aim was to evaluate the influence of host and viral factors on response to IFN-based therapy to optimize it for those in whom directly acting antivirals (DAA) are currently unavailable., Methods: Seventeen vertically infected, treatment naive children (10 male and 7 female) aged 5-16 years with CHC underwent a course of PEG-IFN+RBV. The end point was sustained virologic response (SVR). Host and virus factors were divided into pre- and on-treatment predictors of response to therapy., Results: Eleven patients obtained SVR (64%), 4 were non-responders (23%), and 2 were relapsers (12%). Significant relationship was found between HCV RNA elimination and following variables: virus genotype and early virologic response (EVR) (P<0.037, P<0.029 respectively). Higher eradication rate was observed in patients infected with genotype 3 HCV (100% vs. 65% with genotype 1 or 4), and in those with undetectable HCV RNA by week 12 (88% vs. 66% with viremia). EVR was associated with SVR (83% vs. 0% in nonresponders; P<0.004). C allele of IL28B rs12979860 was a predictor of EVR (P<0.043). The SVR rates among CC, CT, and TT carriers were as follows: 75%, 67%, and 33%., Conclusions: Detection of favorable HCV and IL28B genotype prior to commencement of PEG-IFN+RBV and continuing it in patients with EVR is of major importance for those in whom DAA are still unavailable.

Abstract: We present the efficacy and safety of 12 weeks of therapy with a fixed dose of ledipasvir/sofosbuvir in 2 teenagers with HIV/hepatitis C virus coinfection. Patient 1 presented with compensated cirrhosis, whereas patient 2 had evidence of previous hepatitis B virus infection. Both patients achieved a sustained virologic response 12 weeks after the end of treatment. No serious adverse effects were reported., Competing Interests: The authors have conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Chronic hepatitis C (CHC) is a global health burden. Mother-to-child transmission (MTCT) accounts for most HCV infections in pediatric patients. Spontaneous viral clearance may occur in early childhood but is uncommon thereafter. Infection is usually asymptomatic during childhood, although without an effective treatment, vertically infected children may develop serious liver complications including cirrhosis and hepatocellular carcinoma in adulthood. Despite the lack of vaccine against hepatitis C and effective post-exposure methods of prevention of MTCT, treatment with direct-acting antiviral agents (DAAs) raised the prospect of eliminating HCV on a population level. Highly effective, well-tolerated, oral, and interferon-free regimens of short duration have revolutionized treatment of CHC. However, access to these therapies might be limited because of its high cost. In this review, we provide the current state of knowledge on the epidemiology, testing, monitoring and treating of HCV in children. We outline the remaining gaps in therapy and barriers to disease eradication., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

One-year outcomes after therapy with ledipasvir/sofosbuvir (LDV/SOF) in children with chronic hepatitis C (CHC) presenting with and without significant liver fibrosis were analyzed. We included patients aged 12-17 years treated with LDV/SOF, presenting with significant fibrosis (F ≥ 2 on the METAVIR scale) in transient elastography (TE) at the baseline and we compared the outcomes with that of patients without fibrosis. Patients were followed every 4 weeks during the treatment, at the end of the therapy, at week 12 posttreatment, and one year after the end of treatment. Liver fibrosis was established using noninvasive methods: TE, aspartate transaminase-to-platelet ratio index (APRI), and Fibrosis-4 index (FIB-4). There were four patients with significant fibrosis at baseline: one with a fibrosis score of F2 on the METAVIR scale, and three with cirrhosis (F4) at baseline. One year after the end of treatment, the hepatitis C viral load was undetectable in three of them. One patient was lost to follow-up after week 4. In two out of the four patients, a significant improvement and regression of liver fibrosis was observed (from stage F4 and F2 to F0-F1 on the METAVIR scale). In one patient, the liver stiffness measurement median increased 12 weeks after the end of the treatment and then decreased, but still correlated with stage F4. An improvement in the APRI was observed in all patients. In four patients without fibrosis, the treatment was effective and no progression of fibrosis was observed. A one-year observation of teenagers with CHC and significant fibrosis treated with LDV/SOF revealed that regression of liver fibrosis is possible, but not certain. Further observations in larger groups of patients are necessary to find predictors of liver fibrosis regression.

Background: The aim of this prospective study was to analyze liver fibrosis in teenagers with chronic hepatitis C (CHC) using noninvasive methods., Methods: Thirty-five patients with CHC, 12-17 years of age (mean 14.2 ± 1.8 years; 22/35, 63% male) were included. Most of them (29/35, 83%) were infected vertically, 21/35 (60%) were treatment-naive, 30/35 (86%) were infected with genotype 1 and 5/35 (14%) were infected with genotype 4 HCV. In all patients, evaluation of liver fibrosis was performed using transient elastography (TE) and measurement of the following serum biomarkers: aspartate transaminase-to-platelet ratio index (APRI) and Fibrosis-4 index (FIB-4). Using liver stiffness measurement (LSM) results as a reference, the diagnostic performance of APRI and FIB-4 was assessed by calculating area under the receiver operating characteristics curve., Results: Transient elastography results revealed no or mild fibrosis (F0/1 in METAVIR scale) in 31/35 (89%) patients. In 4/35 (11%) patients, significant fibrosis was observed (F ≥ 2), including 3/35 (9%) with cirrhosis (F4). The median APRI was 0.32, and the median FIB-4 was 0.32. LSM was associated with both APRI and FIB-4 [r = 0.61, 95% confidence interval (CI) 0.35-0.79, P = 0.0001; and r = 0.60, 95% CI 0.32-0.78, P = 0.0002, respectively]. For the diagnosis of significant fibrosis, the area under the receiver operating characteristics (95% CI) for both APRI and FIB-4 was 0.855 (0.695-0.951). APRI, with a cutoff >0.374, predicted significant fibrosis, with 100% sensitivity and 67.7% specificity, whereas FIB-4, with a cutoff >0.402, predicted significant fibrosis, with 75.0% sensitivity and 90.3% specificity., Conclusions: Significant fibrosis, including cirrhosis, may occur in teenagers with CHC. Serum biomarkers (APRI, FIB-4) correlate positively with LSM., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Difficulties in achieving elimination targets of the World Health Organization's Global Strategy on viral hepatitis might be overcome through a new micro-elimination approach that allows for a quick, efficient targeting of treatment and prevention services. Particular focus on identification of high-risk and so far marginalized populations, such as children and adolescents, increases chances for HCV elimination on a country, and ultimately on a population level. Therefore, a broad access to safe and highly effective direct-acting antiviral drugs is of upmost importance in the pediatric population., (© National Institute of Public Health – National Institute of Hygiene.)

Background: There is a need for validation of noninvasive alternatives to liver biopsy for the evaluation of fibrosis in children with chronic hepatitis C (CHC). The aim of this study was to evaluate the diagnostic performance of serum biomarkers modified by the body mass index z-score (BMI z-score) for the detection of fibrosis and steatosis in children with CHC., Methods: Thirty children aged 9.4 ± 3.7 years (14 males, 16 females) with CHC underwent liver biopsy. Fibrosis was scored using a 5-point METAVIR scale (≥2 = significant fibrosis). For all the children, the following noninvasive markers were calculated: The aspartate transaminase (AST)-to-platelets ratio index (APRI), the modified APRI (M-APRI: BMI z-score × APRI), the Fibrosis-4 index (FIB-4), the modified FIB-4 (M-FIB-4: BMI z-score × FIB-4), and a novel marker, B-AST (BMI z-score × AST). The area under the receiver operator characteristic curve (AUROC) was calculated to detect significant fibrosis and steatosis., Results: In the histopathological evaluation, 22/30 (73%) patients presented with fibrosis, and 8/30 (27%) presented with steatosis. For the detection of significant fibrosis, the AUROCs for M-APRI, M-FIB-4 and B-AST were 0.842, 0.823, and 0.848, respectively. For significant steatosis, the AUROCs were more than 0.9 for all markers that included the BMI z-score. B-AST, with a cut-off of 92.8, showed 71% sensitivity and 95% specificity for detecting significant fibrosis. For predicting severe steatosis, B-AST had 100% sensitivity and 92% specificity. Negative values of all three markers that included BMI z-scores excluded all patients with both significant fibrosis and significant steatosis., Conclusions: Including the BMI z-score in serum biomarker formulas enhances their diagnostic ability to detect significant fibrosis and steatosis. B-AST may thus act as an effective alternative to liver biopsy.

Only scarce data on liver steatosis in children with chronic hepatitis B and C (CHB and CHC) are available. The objective of this study was to evaluate the prevalence, predictors, and impact of hepatic steatosis on children with CHB and CHC. A total of 78 patients aged 11.5 ± 3.4 years were included: 30 (38%) had CHB, and 48 (62%) had CHC. Steatosis was scored on a 5-point scale, as follows: absent; minimal (≤5% hepatocytes affected), mild (6-33%), moderate (34-66%), and severe (>66%). Stepwise logistic regression was used to determine the factors associated with steatosis and moderate-to-severe steatosis. Steatosis was observed in 4/30 (13%) patients with CHB and 13/48 (27%) patients with CHC (P = 0.17). Moderate-to-severe steatosis was observed in 6/78 (8%) patients: 1/30 (3%) had CHB and 5/48 (10%) had CHC (P = 0.40). The body mass index (BMI) z-score was positively associated with the presence of steatosis in children with CHB (odds ratio [OR] = 3.3, 95% confidence interval [CI]: 1.02-10.64). In CHC, steatosis occurred more frequently in patients with hepatitis C virus genotype 3 compared with other genotypes (P = 0.002). In patients with non-3 genotype hepatitis C virus, steatosis was associated with the stage of fibrosis (OR = 3.35, 95% CI: 1.01-11.07) and inversely associated with the duration of infection (OR = 0.74, 95% CI: 0.55-0.97). Moderate-to-severe steatosis was positively associated with the BMI z-score (OR = 3.62, 95% CI: 1.22-10.75) and stage of fibrosis (OR = 3.89, 95% CI: 1.05-14.47). Steatosis is a common finding in children with chronic viral hepatitis. It is associated with metabolic factors in CHB, whereas in patients with CHC, metabolic and viral factors may have a combined effect, leading to more advanced grades of steatosis in children with higher BMI z-scores. Moderate-to-severe steatosis is a predictor of advanced fibrosis in children with CHC., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Histopathological features and determinants of liver disease progression were analyzed in 42 treatment-naïve children (mean age: 10.7 ±3.7) with chronic hepatitis C (14/42 infected vertically and 26/42 horizontally). Histopathological evaluation was performed according to Knodell's modified system. Predictors of necroinflammation and fibrosis were identified using linear regression analyses. Most children presented with mild necroinflammation and fibrosis (mean grade 4.3 ±2.7, mean staging 1.2 ±0.8), irrespective of the mode of transmission. Vertically infected children were younger than those infected horizontally (8.6 ±2.5 vs. 11.5 ±3.7 years, p = 0.02). Alanine and aspartate aminotransferase (ALT and AST) levels were associated with necroinflammation (p = 0.003 and p = 0.01 for ALT and AST, respectively) and fibrosis (p = 0.01 and p = 0.04, respectively). Other positive independent predictors of fibrosis included duration of infection (p = 0.03) and body mass index (BMI) z-score (p = 0.03). Children with chronic hepatitis C presented with mild liver changes over a decade after the infection, irrespective of the mode of transmission. Since fibrosis is a time-dependent process, progression of the liver disease in vertically infected children may occur at a younger age compared to patients infected horizontally. Aminotransferase levels were associated with necroinflammation and fibrosis. Longer duration of infection and a higher BMI z-score were associated with more severe fibrosis.

Liver biopsy is a standard method used for obtaining liver tissue for histopathological evaluation. Since reliable serological and virological tests are currently available, liver biopsy is no longer needed for the etiological diagnosis of chronic hepatitis B and C. However, liver histology remains the gold standard as a prognostic tool, providing information about the liver disease progression (grading of necroinflammatory activity and staging of fibrosis) and serving clinicians in the management and therapeutic decisions. In general, histopathological evaluation is indicated before starting the antiviral treatment. Main limitations of the liver biopsy include its invasive and painful procedure, sampling errors and the inter- and intra-observer variability. In addition, indications for the liver biopsy in pediatric patients with chronic viral hepatitis were questioned recently, and efforts have been made toward the development of non-invasive methods as an alternative to the liver biopsy. The most commonly used methods are novel imaging studies (elastography) and combinations of biomarkers. However, to date, none of these tests was validated in children with chronic viral hepatitis. In this review, we present the current status of the liver biopsy in the management of chronic viral hepatitis B and C in pediatric population, including specific indications, complications, contraindications, problems, limitations, and alternative non-invasive methods.