Safety and Efficacy of Ledipasvir–Sofosbuvir With or Without Ribavirin for Chronic Hepatitis C in Children Ages 6‐11

Abstract

Currently, there are no interferon-free treatments available for hepatitis C virus (HCV)-infected patients younger than 12 years. We evaluated the safety and effectiveness of the all-oral regimen ledipasvir-sofosbuvir ± ribavirin in HCV-infected children aged 6 to<12 years. In an open-label study, patients aged 6 to <12 years received ledipasvir 45 mg-sofosbuvir 200 mg as two fixed-dose combination tablets 22.5/100 mg once daily, with or without ribavirin, for 12 or 24 weeks, depending on HCV genotype and cirrhosis status. The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Twelve patients underwent intensive pharmacokinetic sampling to confirm the appropriateness of the ledipasvir and sofosbuvir dosages. Ninety-two patients were enrolled (88 genotype 1, 2 genotype 3, and 2 genotype 4), with a median age of 9 years (range, 6-11). Most were perinatally infected (97%) and treatment-naive (78%). Two were confirmed to have cirrhosis, while the degree of fibrosis was unknown in 55 patients. The overall SVR12 rate was 99% (91/92; 95% confidence interval, 94%-100%). The single patient not reaching SVR relapsed 4 weeks after completing 12 weeks of treatment. The most common adverse events were headache and pyrexia. One patient had three serious adverse events, which were considered to be not related to study treatment: tooth abscess, abdominal pain, and gastroenteritis. The area under the concentration-time curve and maximum concentration values for sofosbuvir, its primary metabolite GS-331007, and ledipasvir were within predefined pharmacokinetic equivalence boundaries (50%-200%) compared to values in adults in phase 2/3 of the ledipasvir and sofosbuvir studies. Conclusion: Ledipasvir-sofosbuvir was well tolerated and highly effective in children 6 to <12 years old with chronic HCV.

Sofosbuvir and Ribavirin Therapy for Children Aged 3 to <12 Years With Hepatitis C Virus Genotype 2 or 3 Infection

“…In addition, no patient interrupted or modified ribavirin dosing because of an adverse event of low hemoglobin. In the study by Murray et al, 2 pediatric patients aged 6 to 11 years with GT3 infection who received ledipasvir‐sofosbuvir plus ribavirin similarly did not experience hematologic laboratory abnormalities despite treatment with ribavirin …”

Hepatitis C Guidance 2019 Update: American Association for the Study of Liver Diseases–Infectious Diseases Society of America Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection

“…A 12‐week course is recommended for patients without cirrhosis; 24 weeks is recommended for those with compensated cirrhosis. Three clinical trials supporting the approval of ledipasvir/sofosbuvir in the pediatric population aged ≥ 3 years demonstrated high SVR12 rates comparable to those observed in adults . Limited real‐world data further corroborate these findings …”

Treatment of Adolescents With Chronic Hepatitis C Virus Infection: New Regimen on the Block

“…So, what have we learned from the ZIRCON study and from the results of the other clinical trials on the use of DAAs in children and adolescents with chronic HCV infection? First, across the different studies the adult dosing for adolescents and, for sofosbuvir and ledipasvir, half the dose used in adults for children ages 6‐11 years, resulted in comparable plasma exposures to those found in the phase II and phase III clinical trials in adults with chronic HCV infection . Second, all of the studies showed excellent efficacy (SVR12) in children and adolescents with chronic HCV infection independently of age, treatment history, degree of liver fibrosis, and treatment duration .…”

“…First, across the different studies the adult dosing for adolescents and, for sofosbuvir and ledipasvir, half the dose used in adults for children ages 6‐11 years, resulted in comparable plasma exposures to those found in the phase II and phase III clinical trials in adults with chronic HCV infection . Second, all of the studies showed excellent efficacy (SVR12) in children and adolescents with chronic HCV infection independently of age, treatment history, degree of liver fibrosis, and treatment duration . Third, the safety profile of these treatments was excellent in children and adolescents …”

“…So far, results from specific age cohorts enrolled have been published. The safety and efficacy of sofosbuvir/ledipasvir for children (ages 6‐11 years) and adolescents (ages 12‐17 years), and sofosbuvir and ribavirin for adolescents, have been reported recently. In addition to industry‐driven clinical trials, few investigator‐initiated studies are available on the use of DAAs in children and adolescents with chronic HCV infection …”