Red cell abnormalities characterized by ektacytometry in children with cholestasis.

BACKGROUND: Spur-cell anemia sometimes accompanies cholestasis. We postulated that even in the absence of spur-cells, cholestasis might alter red blood cell (RBC) osmotic fragility and deformability. Therefore, we assessed these RBC measures by ektacytometry in pediatric patients. METHODS: We conducted a single center, prospective, cross-sectional investigation of RBC membrane characteristics by ektacytometry in pediatric patients with intra- and extrahepatic cholestasis followed at Cincinnati Children's Hospital Medical Center. We measured red cell membrane fragility and deformability in 17 patients with cholestasis and 17 age-matched controls without cholestasis. RESULTS: Patients with cholestasis had decreased RBC osmotic fragility compared to controls, with a significant left shift in Omin, indicating increased RBC surface-to-volume ratio. One showed spur cell morphology. However, the other 16 had no spurring, indicating that ektacytometry is a sensitive method to detect RBC membrane abnormalities. Left shift of Omin positively correlated with serum conjugated bilirubin levels and even more negatively with serum vitamin E concentration. CONCLUSIONS: This study suggests that subclinical red blood cell membrane abnormalities exist in most pediatric patients with cholestasis, increasing risk for hemolysis when subjected to oxidative stress. Hence minimizing pro-oxidants exposure and maximizing antioxidant exposure is advisable for this group. GOV IDENTIFIER: NCT05582447 https://clinicaltrials.gov/ct2/show/NCT05582447?cond=Cholestasis&cntry=US&state=US%3AOH&city=Cincinnati&draw=2&rank=2 . IMPACT: Spur cell anemia due to decreased red cell osmotic fragility and decreased deformability has been reported among patients with cholestasis. Ektacytometry is a reliable, reproducible method to measure red cell osmotic fragility and deformability. Few data describe red cell osmotic fragility or deformability in patients with cholestasis who may or may not have spur cell anemia. Ektacytometry shows that red cell osmotic fragility and deformability are decreased in many children with cholestasis even when spur cell anemia has not yet occurred. Factors associated with decreased osmotic fragility include elevated serum bilirubin, elevated serum bile acids, and decreased serum vitamin E.

Sofosbuvir-velpatasvir in children 3-17 years old with hepatitis C virus infection.

BACKGROUND: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated. METHODS: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group. FINDINGS: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range. INTERPRETATION: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection.

Recent Increase in Incidence of Severe Acute Hepatitis of Unknown Etiology in Children is Associated with Infection with Adenovirus and Other Nonhepatotropic Viruses.

OBJECTIVE: To evaluate whether the nature and severity of non-A-E severe acute hepatitis in children noted by the World Health Organization from late 2021 through early 2022 was indeed increased in 2021-2022 compared with prior years. STUDY DESIGN: We performed a single-center, retrospective study to track the etiology and outcomes of children with non-A-E severe acute hepatitis in 2021-2022 compared with the prior 3-year periods (2018-2019, 2019-2020, and 2020-2021). We queried electronic medical records of children ≤16 years of age with alanine or aspartate aminotransferase levels of >500 IU. Data were analyzed for the periods of October 1, 2021, to May 1, 2022, and compared with the same time periods in 2018-2021. RESULTS: Of 107 children meeting entry criteria, 82 cases occurred from October to May of 2018-2022. The average annual case number was 16.3 in 2018-2021 compared with a 2-fold increase (to 33) in 2021-2022 (P = .0054). Analyses of etiologies showed that this increase was associated with a higher number of children who tested positive for viruses (n = 16) when compared with the average of 3.7 for 2018-2021 (P = .018). Adenovirus (26.1%) and severe acute respiratory syndrome coronavirus-2 (10.3%) were the most frequently detected viruses in 2021-2022. Despite evidence of acute liver failure in 37.8% of children in the entire cohort and in 47% of those with viral infection, the overall survival rate was high at 91.4% and 88.9%, respectively. CONCLUSIONS: The number of children with severe acute hepatitis in our center increased from 2021 to May 2022, with a greater frequency of cases associated with adenovirus, yet transplant-free survival remains high.

Lysosomal acid lipase deficiency manifestations in children and adults: Baseline data from an international registry.

BACKGROUND AND AIMS: Lysosomal acid lipase deficiency (LAL-D) is a rare, autosomal recessive disease involving lysosomal accumulation of cholesteryl esters and triglycerides. The International Lysosomal Acid Lipase Deficiency Registry (NCT01633489), established in 2013 to understand LAL-D natural history and long-term outcomes, is accessible to centres caring for patients diagnosed by deficient LAL activity and/or biallelic pathogenic LIPA variants. We describe the registry population enrolled through 2 May 2022. METHODS: In this prospective observational study, we analysed demographic and baseline clinical characteristics of children (ages ≥6 months to <18 years) and adults diagnosed with LAL-D. RESULTS: Of 228 patients with confirmed disease, 61% were children; 202/220 (92%) with data on race were white. Median age was 5.5 years at sign/symptom onset and 10.5 years at diagnosis; median time from sign/symptom onset to diagnostic testing was 3.3 years. The most common manifestations raising suspicion of disease were elevated alanine (70%) and aspartate aminotransferase levels (67%) and hepatomegaly (63%). Among 157 with reported LIPA mutations, 70 were homozygous and 45 were compound heterozygous for the common exon 8 splice junction pathogenic variant (E8SJM-1). Seventy percent (159/228) of patients had dyslipidaemia. Among 118 with liver biopsies, 63% had microvesicular steatosis exclusively, 23% had mixed micro- and macrovesicular steatosis and 47% had lobular inflammation. Of 78 patients with fibrosis-stage data, 37% had bridging fibrosis and 14% had cirrhosis. CONCLUSIONS: Although LAL-D signs/symptoms occur early, diagnosis is often delayed. Abnormal transaminase levels associated with hepatomegaly and dyslipidaemia should raise suspicion and prompt earlier diagnosis of LAL-D. TRIAL REGISTRATION NUMBER: NCT01633489.

Ledipasvir-Sofosbuvir for 12 Weeks in Children 3 to <6 Years Old With Chronic Hepatitis C.

For children under 12 years of age who have chronic hepatitis C virus (HCV) infection, there are currently no approved treatments with direct-acting antiviral agents. We therefore evaluated the safety and efficacy of ledipasvir-sofosbuvir in HCV-infected children aged 3 to <6 years. In an open-label study, patients 3 to <6 years old chronically infected with HCV genotype 1 (n = 33) or 4 (n = 1) received weight-based doses of combined ledipasvir-sofosbuvir as granules (33.75 mg/150 mg for weights <17 kg or 45 mg/200 mg for weights ≥17 kg) for 12 weeks. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12). For the first 14 patients, intensive pharmacokinetic sampling was done on day 10 of treatment. All patients had been infected through perinatal transmission and were treatment naïve. No patients had known cirrhosis. Ten patients (29%) weighed <17 kg. SVR12 was achieved in 97% of patients (33 of 34); the patient who did not achieve SVR12 was 3 years old and discontinued treatment after 5 days because of an adverse event "abnormal drug taste." The most common adverse events were vomiting (24% of patients), cough (21%), and pyrexia (21%). No patients experienced a serious adverse event. Intensive pharmacokinetic analysis of 13 patients for whom data were evaluable confirmed that the doses selected were appropriate. Conclusion: Ledipasvir-sofosbuvir was well tolerated and highly effective in children 3 to <6 years old with chronic HCV infection.

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

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.

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

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 in adolescents 12-17 years old with hepatitis C virus genotype 2 or 3 infection.

Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with hepatitis C virus genotype 2 or 3 (ClinicalTrials.gov NCT02175758). Fifty-two patients received sofosbuvir 400 mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS-331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). The median age of patients was 15 years, and 75% had genotype 3. Eighty-three percent of patients were treatment-naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% confidence interval, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in phase 2 and 3 sofosbuvir studies, the area under the curve and maximum concentration for sofosbuvir and GS-331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%-200%. CONCLUSION: Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic hepatitis C virus genotype 2 or 3 infection. (Hepatology 2017;66:1102-1110).

The safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12-17 years old with hepatitis C virus genotype 1 infection.

No all-oral, direct-acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a phase 2, multicenter, open-label study to evaluate the efficacy and safety of ledipasvir-sofosbuvir in adolescents with chronic HCV genotype 1 infection. One hundred patients aged 12-17 years received a combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. On the tenth day following initiation of dosing, 10 patients underwent an intensive pharmacokinetic evaluation of the concentrations of sofosbuvir, ledipasvir, and the sofosbuvir metabolite GS-331007. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at 12 weeks posttreatment. Median age of patients was 15 years (range 12-17). A majority (80%) were HCV treatment-naive, and 84% were infected through perinatal transmission. One patient had cirrhosis, and 42 did not; in 57 patients the degree of fibrosis was unknown. Overall, 98% (98/100; 95% confidence interval 93%-100%) of patients reached sustained virologic response at 12 weeks. No patient had virologic failure. The 2 patients who did not achieve sustained virologic response at 12 weeks were lost to follow-up either during or after treatment. The three most commonly reported adverse events were headache (27% of patients), diarrhea (14%), and fatigue (13%). No serious adverse events were reported. Area under the concentration-time curve (tau) and maximum concentration values for sofosbuvir, ledipasvir, and GS-331007 were within the predefined pharmacokinetic equivalence boundaries of 50%-200% when compared with adults from phase 2 and 3 studies of ledipasvir and sofosbuvir. CONCLUSION: Ledipasvir-sofosbuvir was highly effective at treating adolescents with chronic HCV genotype 1 infection; the dose of ledipasvir-sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile. (Hepatology 2017;66:371-378).

Health-related Quality of Life in Adolescent Patients With Hepatitis C Genotype 1 Treated With Sofosbuvir and Ledipasvir.

OBJECTIVE: The aim of the study was to assess the effect of treatment with ledipasvir/sofosbuvir (LDV/SOF) on the health-related quality of life (HRQL) of pediatric patients with chronic hepatitis C virus (HCV) infection. METHODS: Adolescents (12-17 years) with HCV were treated with LDV/SOF (90/400 mg daily) for 12 weeks. HRQL was assessed using the PedsQLv4.0-SF15 completed by the children and caregivers before, during, and after treatment. RESULTS: We included 100 adolescents with HCV genotype 1 infection (14.7 ±â€Š2.0 years, 1% known cirrhosis, 80% treatment-naïve, 97% sustained virologic response-12). At baseline, HRQL the caregiver- perceived HRQL scores were lower than adolescents' self-reported scores (by 6.7-7.9 points, all P < 0.01). At the end of 12 weeks of treatment, however, the caregiver-reported HRQL scores showed a significant improvement (+all P < 0.04), whereas the adolescents' self-reported scores did not change from the baseline. HRQL scores reported by caregivers remained higher than baseline (by +4.7-+7.5, P < 0.01) through 12 weeks after treatment, as did the adolescents' self-reported Emotional Functioning scores (+4.3 from baseline, P = 0.0009); observed improvements were sustained after 24 weeks of follow-up (all P < 0.04). Multivariate analysis showed that, after adjustment for location, age, and sex, having a history of anxiety and panic disorders were consistent predictors of impaired HRQL in adolescents with HCV infection (P < 0.05). CONCLUSIONS: Treatment of HCV in adolescents with LDV/SOF is associated with some improvement in HRQL. Caregivers' reports of HRQL in adolescents with HCV significantly increased with treatment and were similar to the adolescent self-reported HRQL after sustained virologic response-12.