Direct-acting antivirals (DAAs) have revolutionized hepatitis C virus (HCV) treatment and enabled the treatment of those who could not be treated using interferon. The aim of this work was to assess the efficacy and safety of oral DAAs in HCV-infected children with associated comorbidities. This analytical retrospective study included children with HCV mono-infection versus those with associated comorbidities. The study included 187 HCV-infected children aged 6-18 years; 114 patients (61%) had associated comorbidities. The most frequent comorbidities were hematological disorders (30.7%), followed by renal and cardiac diseases. Baseline total bilirubin, aspartate aminotransferase, and gamma glutamyl transpeptidase were significantly more elevated in patients with comorbidities. Sustained virologic response (SVR) was achieved in 100% of patients with HCV mono-infection versus 98.2% of patients with comorbidities. The most frequently reported treatment adverse effects were headache, asthenia, and irritability. All side effects were transient and did not necessitate treatment discontinuation.

DAAs allowed treatment of HCV-infected children with comorbidities with high SVR and excellent safety profile. Treatment with sofosbuvir/ledipasvir achieved an SVR of 98.9% in HCV-infected children with comorbidities. Treatment was safe and well tolerated with mild transient adverse events.

• The novel DAAs have revolutionized the landscape of HCV treatment and enabled the treatment of those who could not be treated using IFN. • When treating HCV, clinicians should take into consideration the presence of other comorbid conditions. In the IFN-RBV era, many HCV patients with comorbidities were ineligible for therapy.

• There are limited data in the literature about the efficacy and tolerability of DAAs in children with comorbidities. • We reported in the current study that DAAs allowed treatment of HCV-infected children with comorbidities with high SVR and excellent safety profile. These patients should be offered treatment with oral DAAs to help decrease the infectious pool and hence reach the ambitious final goal of global eradication.

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.

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.

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%).

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.

CRD42020146752.

Childhood obesity, with associated comorbidities such as nonalcoholic fatty liver disease (NAFLD), is an increasing global health problem. Although lifestyle management is the mainstay of treatment, its efficacy on liver fibrosis has not yet been established.

Children and adolescents admitted for severe obesity at a tertiary center (Zeepreventorium, De Haan, Belgium) were enrolled in this prospective study. Intensive lifestyle therapy encompassed caloric restriction, physical activity, education on a healthy lifestyle, and psychosocial support. At baseline, 6 months, and 12 months, liver ultrasound and transient elastography with controlled attenuation parameter were performed to assess liver steatosis and fibrosis.

A total of 204 patients (median age, 14.0 y; body mass index Z-score, +2.8) were evaluated at admission. NAFLD on ultrasound was present in 71.1%, whereas 68.6% had controlled attenuation parameter values of 248 dB/m or greater. A total of 32.8% of patients had at least F2 fibrosis, including 10.3% with transient elastography of 9 kPa or greater. After 6 months, the median body weight loss was 16.0% in the 167 patients evaluated. Fibrosis improved in 75.0% (P < .001). Baseline severity of liver fibrosis and steatosis were predictors of fibrosis resolution. Seventy-nine patients had reached the 1-year time point. The improvements were sustained because fibrosis regressed at least 1 stage in all patients with baseline fibrosis. Fasting serum alanine aminotransferase and homeostasis model assessment of insulin resistance decreased significantly over the 1-year period (P < .001).

NAFLD and associated fibrosis are highly prevalent in children and adolescents with severe obesity. An intensive multidisciplinary lifestyle management program that causes significant weight loss not only improves liver steatosis, but also fibrosis.

Direct-acting antiviral (DAA) regimens targeting hepatitis C virus (HCV) are now approved for young children. This review examines recent DAA experience in children, current treatment recommendations and challenges, and potential treatment-as-prevention strategies.

In 2021, the US FDA extended approval of two pan-genotypic DAA regimens, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir, to children as young as age 3 years based on high success rates and reassuring safety profiles in registry trials. Similar performance has been replicated with real-world DAA use in thousands of adolescents and in limited reports of children with high-risk conditions, including cirrhosis, cancer, thalassemia and HIV-coinfection. Treatment without delay is now recommended in the USA for viremic children aged 3 years and up to prevent disease progression and future spread. To date, treatment expansion is limited by high rates of undiagnosed paediatric infection. Universal prenatal screening will aid identification of perinatally exposed newborns, but new strategies are needed to boost testing of exposed infants and at-risk adolescents. Postpartum treatment programmes can prevent subsequent vertical transmission but are hampered by low rates of linkage to care and treatment completion. These challenges may be avoided by DAA use in pregnancy, and this warrants continued study.

Paediatric HCV is now readily curable. Substantial clinical and public health effort is required to ensure widespread uptake of this therapeutic breakthrough.

In children with hematological malignancies, chronic hepatitis C virus (HCV) infection has been associated with more rapid liver disease progression and higher risk of malignancy relapse due to chemotherapy interruption. We evaluated the safety and efficacy of ledipasvir-sofosbuvir for 12weeks in these patients.

In a phase 2, open-label study, at one site in Egypt, patients ages 12-<18years with chronic HCV genotype 1 or 4 infection undergoing maintenance chemotherapy for hematological malignancies received ledipasvir-sofosbuvir (90 mg/400 mg) once daily for 12weeks. The efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). Safety was assessed by the incidence of adverse events and clinical and laboratory data, including HCV flares defined as alanine aminotransferase >3-fold increase from Day 1 and HCV RNA elevation >1 × log10 from Day 1.

Of the 19 adolescents enrolled and treated, median age was 14 years (range 12-17), 84% (16/19) were male, and all had HCV genotype 4 and were HCV treatment naive. All patients completed treatment and achieved SVR12 (19/19, 100%, 95% confidence interval, 82-100). Common adverse events were pyrexia (5/19, 26%), diarrhea (4/19, 21%), and headache (4/19, 21%). Three patients experienced serious adverse events of pneumonia (two patients), and osteoarthritis and diarrhea (one patient); none were considered related to study drug. No patient experienced HCV flares.

Ledipasvir-sofosbuvir was well-tolerated and efficacious in adolescents with chronic HCV genotype 4 and leukemia undergoing maintenance chemotherapy. These data support the use of this interferon and ribavirin-free regimen in adolescents with hematological malignancies.

Chronic hepatitis C virus (HCV) infection represents a crucial health problem in children that greatly influences their quality of life. Many efforts have been directed toward investing in effective drugs with a high safety profile and oral administration for better compliance.

This study aims to assess the safety of a fixed-dose combination of ledipasvir/sofosbuvir plus drug efficacy and sustained virologic response (SVR) at 12 weeks after treatment discontinuation.

One tablet (90 mg ledipasvir, 400 mg sofosbuvir) was administered to treatment-naïve children aged 12-18 years weighing at least 35 kg with chronic HCV infection for 6 months, genotype 4. Patients were divided into 2 groups, (1) without comorbidities (24 patients) and (2) with comorbidities (26 patients).

At the end of the therapy, all patients (100%) had SVR and a significant reduction of liver enzymes with mild tolerable side effects.

Ledipasvir/sofosbuvir fixed-dose combination is a safe and highly effective therapeutic option in Egyptian children aged ≥ 12 years, with chronic HCV infection, genotype 4, either without or with comorbidities.

Available real-world data on the efficacy and safety of ledipasvir/sofosbuvir (LDV/SOF) in pediatric patients are limited. In this prospective, open-label, single-center study, we aimed to present our real-life experience with a fixed dose of LDV/SOF (90/400 mg) for the treatment of chronic hepatitis C (CHC) genotypes 1 and 4 in children aged 12 to 17 years.

We analyzed intention-to-treat (ITT) and per-protocol (PP) rates of sustained virological response (SVR), defined as undetectable HCV viral load at posttreatment week 12, in 37 participants treated with LDV/SOF according to the HCV genotype, baseline liver fibrosis, duration of treatment, and experience of the previous ineffective antiviral treatment. There were 32 patients infected with genotype 1 and 5 with genotype 4. Fourteen (38%) participants were treatment-experienced, two were coinfected with HIV, and three were cirrhotic. Two patients qualified for 24 weeks of therapy, and the remaining 35 received 12 weeks of LDV/SOF treatment.

The overall ITT SVR12 rate was 36/37 (97%). One patient was lost to follow-up after week 4 of therapy when his HCV RNA was undetectable. All 36 patients who completed the full protocol achieved SVR (36/36, 100%). PP analyses of SVR12 rates according to the HCV genotype, baseline liver fibrosis, duration of the treatment, and previous ineffective treatment were all 100%. A significant decrease in aminotransferase serum levels was observed in the subsequent weeks of the treatment and at SVR assessment compared to baseline. No serious adverse events were reported.

The results of this study confirm previous observations of a suitable efficacy and safety profile of LDV/SOF for the treatment of CHC genotypes 1 and 4 in adolescents.

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.

Direct-acting antiviral (DAA) treatment for 8 weeks has a sustained virological response rate in adults with chronic hepatitis C. We have conducted a systematic review and meta-analysis to compare the efficacy and safety of the 8-week vs. 12/24-week DAA treatment in adolescents and children with CHC. The PubMed, Web of Science, and Cochrane databases were searched for the relevant articles from January 1, 2017 to August 28, 2020 and further screened for literature reviews on April 1, 2021. Pool proportions with 95% CIs for SVR12 were summarized with fixed/random effects models using Freeman-Tukey double arcsine transformation. Subgroup analysis was used to explore the source of heterogeneity. Thirty-six relevant publications were identified. For adolescents aged 12-17 years old, the pooled SVR12 and AE rate were 99.4% (95% CI: 98.7-99.9) and 34.7% (95% CI: 31.9-37.6). No one discontinued treatment due to drug intolerance. In addition, the SVR12 adolescents treated for 12 and 8/24 weeks were 99.3% (95% CI: 98.4-99.9) and 100%, respectively. The pooled SVR12 rate, AEs, and SAEs for children younger than 12 years were 98.9% (95% CI: 97.3-99.8), 51.6% (95% CI: 47.0-56.2), and 1.1% (95% CI: 0.4-2.5), respectively. The most common AE was fatigue (28.4%). The SVR12 was 98.8% (95% CI: 97.1-99.8) and 100% for the pediatric patients treated for 12 weeks and 8/24 weeks, respectively. Taken together, DAAs are generally effective against CHC and well-tolerated by the adolescents and children. A treatment duration of 8 weeks is equally effective and safe as 12/24 weeks in this demographic group.

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.

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.

To summarise the evidence on efficacy and safety of DAAs in children and adolescents with chronic HCV infection.

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.

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.

Children and adolescents with chronic HCV infection can be safely treated with DAAs with similar efficacy as reported in adults.