Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Children With Chronic HCV: Part 2 of the DORA Study.

BACKGROUND AND AIMS: Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV-infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years. APPROACH AND RESULTS: Children with chronic HCV infection, genotype 1-6, with or without compensated cirrhosis, were divided into three cohorts by age-cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)-and given weight-based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady-state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug-related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults. CONCLUSIONS: A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV-infected children 3 to < 12 years old.

Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Adolescents With Chronic Hepatitis C Virus: Part 1 of the DORA Study.

The pangenotypic regimen of glecaprevir and pibrentasvir (G/P) is approved to treat adults with chronic hepatitis C virus (HCV) infection and has yielded high cure rates in adults in clinical trials. Approved treatment options for pediatrics may include ribavirin. A pangenotypic regimen for pediatric patients remains an unmet need. DORA is an ongoing phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics (PK), safety, and efficacy of G/P in pediatric patients with chronic HCV. This analysis includes Part 1 of the study, conducted in adolescent patients 12-17 years of age given the adult regimen of G/P (300 mg/120 mg) once daily for 8-16 weeks according to the indication durations used in adults. Patients were either treatment naïve or experienced with interferon-based regimens. The primary PK endpoint was steady-state exposures for glecaprevir and pibrentasvir; the primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). The secondary efficacy endpoints were on-treatment virologic failure, relapse, and reinfection. Safety and tolerability were monitored. Part 1 enrolled 48 adolescent patients infected with genotypes 1, 2, 3, or 4, of whom 47 were administered G/P. All 47 patients (100%) achieved SVR12. No on-treatment virologic failures or relapses occurred. PK exposures of glecaprevir and pibrentasvir were comparable to exposures in adults. No adverse events (AEs) led to treatment discontinuation, and no serious AEs occurred. Conclusion: Adolescent patients with chronic HCV infection treated with G/P achieved a comparable exposure to adults, 100% SVR12 rate, and safety profile consistent with that in adults. This pangenotypic regimen demonstrated 100% efficacy within the adolescent population in as little as 8 weeks of treatment.

Congenital Extrahepatic Portosystemic Shunts (Abernethy Malformation): An International Observational Study.

Congenital extrahepatic portosystemic shunt (CEPS) or Abernethy malformation is a rare condition in which splanchnic venous blood bypasses the liver draining directly into systemic circulation through a congenital shunt. Patients may develop hepatic encephalopathy (HE), pulmonary hypertension (PaHT), or liver tumors, among other complications. However, the actual incidence of such complications is unknown, mainly because of the lack of a protocolized approach to these patients. This study characterizes the clinical manifestations and outcome of a large cohort of CEPS patients with the aim of proposing a guide for their management. This is an observational, multicenter, international study. Sixty-six patients were included; median age at the end of follow-up was 30 years. Nineteen patients (28%) presented HE. Ten-, 20-, and 30-year HE incidence rates were 13%, 24%, and 28%, respectively. No clinical factors predicted HE. Twenty-five patients had benign nodular lesions. Ten patients developed adenomas (median age, 18 years), and another 8 developed HCC (median age, 39 years). Of 10 patients with dyspnea, PaHT was diagnosed in 8 and hepatopulmonary syndrome in 2. Pulmonary complications were only screened for in 19 asymptomatic patients, and PaHT was identified in 2. Six patients underwent liver transplantation for hepatocellular carcinoma or adenoma. Shunt closure was performed in 15 patients with improvement/stability/cure of CEPS manifestations. Conclusion: CEPS patients may develop severe complications. Screening for asymptomatic complications and close surveillance is needed. Shunt closure should be considered both as a therapeutic and prophylactic approach.

High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin.

BACKGROUND & AIMS: Pegylated interferon (PEG-IFN) alfa-2b plus ribavirin (RBV) is the standard of care for adults with chronic hepatitis C but was not approved for the treatment of children at the time of this study. The aim of this study was to evaluate the efficacy and safety of PEG-IFN alfa-2b plus RBV in children. METHODS: Children and adolescents ages 3-17 years were treated with PEG-IFN alfa-2b (60microg/m(2)/week) plus RBV (15mg/kg/day). The duration of therapy was 24 weeks for genotype (G) 2 and G3 patients with low viral load (<600,000IU/ml) and 48 weeks for G1, G4, and G3 with high viral load (>or=600,000IU/ml). The primary end point was sustained virologic response (SVR), defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of therapy. RESULTS: SVR was attained by 70 (65%) children. Genotype was the main predictor of response: G1, 53%; G2/3, 93%; G4, 80%. SVRs were similar in younger and older children. Baseline viral load was the main predictor of response in the G1 cohort. No new safety signals were identified, and adverse events (AEs) were generally mild or moderate in severity. Dose was modified because of AEs in 25% of children; 1 child discontinued because of an AE (thrombocytopenia). No serious AEs related to study drugs were reported. CONCLUSION: Therapy with PEG-IFN alfa-2b plus RBV in children and adolescents with chronic hepatitis C offers favorable efficacy, reduced injection frequency, and an acceptable safety profile.

Ombitasvir/Paritaprevir/Ritonavir With or Without Dasabuvir and With or Without Ribavirin for Adolescents With HCV Genotype 1 or 4.

In adults, treatment of hepatitis C virus (HCV) infection with ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) with or without dasabuvir (DSV) and ±ribavirin (RBV) results in high rates of sustained virologic response (SVR). However, these regimens have not been investigated in adolescents. This ongoing, open-label, phase 2/3 study evaluated the pharmacokinetics, safety, and efficacy of OBV/PTV/r+DSV±RBV treatment for 12 weeks in adolescents infected with HCV genotype (GT) 1 without cirrhosis (part 1) and the safety and efficacy of OBV/PTV/r±DSV±RBV treatment for 12 or 24 weeks in adolescents infected with GT1 or GT4 without cirrhosis or with compensated cirrhosis (parts 1 and 2). Patients were 12-17 years of age and treatment naive or interferon experienced. Treatment regimens were based on HCV GT and cirrhosis status. Endpoints were SVR at posttreatment week 12 (SVR12), adverse events (AEs), and pharmacokinetic parameters. Thirty-eight adolescents were enrolled, 66% were female patients, and 76% were White; 42%, 40%, and 18% of patients had HCV GT1a, GT1b, and GT4 infections, respectively. Median age was 15 years (range, 12-17 years), and 1 patient had cirrhosis. The SVR12 rate was 100% (38/38; 95% confidence interval [CI], 90.8%-100%). No treatment-emergent grade 3 or 4 laboratory abnormalities were reported. No serious AEs occurred on treatment, and no AEs led to study drug discontinuation. The most common AEs were headache (21%), fatigue (18%), nasopharyngitis (13%), pruritus (13%), and upper respiratory tract infection (11%). Intensive pharmacokinetic results showed OBV, PTV, DSV, and ritonavir drug exposures were comparable to those seen in adults. Conclusion: Treatment with OBV/PTV/r±DSV±RBV was well tolerated and highly efficacious in adolescents with HCV GT1 or GT4 infection.