A pilot single arm observational study of sofosbuvir/ledipasvir (200 + 45 mg) in 6- to 12- year old children.

BACKGROUND: No available data on the use of sofosbuvir/ledipasvir combination in treatment of hepatitis C virus (HCV) infection in children 6- to 12- year old. AIM: To assess the safety and efficacy of sofosbuvir plus ledipasvir in children 6- to 12- year old with chronic HCV genotype 4 infection. METHODS: This is a pilot prospective single arm observational open-label multicentre study. A total of 20 consecutive eligible chronic HCV infected children, aged from 6- to 12- years were included in this study and treated with a fixed sofosbuvir/ledipasvir combination in half the adult dose (200/45 mg) once daily for 12 weeks. Laboratory tests including virological markers were measured at baseline, 2, 4, 8 and 12 weeks (end of treatment [EOT]), and 12 weeks after end of treatment for sustained virological response 12 (SVR12). RESULTS: The intention-to-treat (ITT) SVR12 rate was 19/20 (95%; 95% CI: 76.4%-99.1%). SVR12 was not assessed in one patient who was lost to follow-up after showing viral negativity at the EOT12. All the remaining 19 patients (100%, 95% CI: 83.18%-100%) who completed the full protocol and follow-up visits achieved SVR12 with normal liver, haematological, and renal function tests and no side effects or fatalities. CONCLUSIONS: This pilot study demonstrated that the fixed dose sofosbuvir/ledipasvir combination could be safe and effective treatment in children 6- to 12- years with chronic hepatitis C genotype 4 infection. Our pilot results might encourage larger and multicentre studies in this age group.

The effectiveness and safety of ledipasvir plus sofosbuvir in adolescents with chronic hepatitis C virus genotype 4 infection: a real-world experience.

BACKGROUND: The combination of ledipasvir plus sofosbuvir was recently approved for treatment of adolescent (12-17 years) HCV genotype 1, 4, 5 & 6 patients. However, few clinical trials have been performed in genotype 1 patients. AIM: To investigate the effectiveness and safety of ledipasvir plus sofosbuvir in chronic HCV adolescent patients with genotype 4 in the real world. METHODS: This prospective multicentre (six centres) open-label study included 144 adolescent chronic HCV patients with genotype 4 (mean age 14 ± 2, 69% males). All patients received a combination tablet containing 400 mg sofosbuvir and 90 mg ledipasvir once daily for 12 weeks. Laboratory and virological markers were evaluated at baseline, week 4, week 8 and week 12 (EOT), and 12 weeks after end of treatment (SVR12). RESULTS: SVR12 was observed in 142/144 patients (99%). The relapsers occurred in previous naïve patients (n = 2/128, 2%), while the experienced patients showed 100% SVR12. SVR12 was 98% in F0/F1 patients in comparison to 100% in F2 patients (P = 0.552). No serious side effects were observed, nor was treatment discontinuation or death. Headache was the most common side effect in all patients (20%). In experienced patients, pruritus (31%, P = 0.007), diarrhoea (44%, P < 0.001) and skin rash (19%, P = 0.002) were higher than in naïve patients. CONCLUSIONS: A ledipasvir plus sofosbuvir regimen is well tolerated and effective, and can be used safely in treating adolescent patients with chronic hepatitis C genotype 4.

Fibronectin, platelet factor 4 and beta-thromboglobulin in endemic hepatosplenic schistosomiasis: relation to acute hematemesis.

Some platelet alpha-granule contents were assessed in parallel with other markers of hemostatic imbalance in 50 patients with hepatosplenic schistosomiasis (15 patients with compensated hepatosplenomegaly, 15 patients with advanced hepatic fibrosis and ascites and 20 patients during an acute attack of hematemesis from ruptured esophageal varices). Platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), fibronectin (FN), prothrombin fragment 1 + 2, thrombin-antithrombin (TAT) complexes, fibrin degradation products (FbDP) and D-dimer were assessed in schistosomal patients compared to controls (15 healthy subjects). A significant increase in both thrombin (high TAT and prothrombin fragment 1 + 2 levels) and plasmin (high FbDP and D-dimer levels) generation was detected in decompensated patients establishing the presence of a steady state of low-grade disseminated intravascular coagulation, with and without overt bleeding, in these patients. A decrease in plasma FN concentration was found in diseased groups compared to controls. The reduction in plasma levels of FN paralleled the defective liver function and matched the relative decrease in tissue FN in liver specimens of decompensated patients suggesting that FN levels can be used to evaluate the pathological staging of the disease. A significant increase in beta-TG and PF4 levels was noted in decompensated patients with ascites and/or acute hematemesis compared both to controls and compensated patients reflecting platelet alpha-granule release and consequently increased in vivo platelet activation which may initiate and/or perpetuate the pathophysiological mechanisms of the hemostatic imbalance underlying the hemorrhagic diathesis in hepatosplenic schistosomiasis.

Hyperfibrinolysis in hepatosplenic schistosomiasis.

AIM: To evaluate the nature of accelerated fibrinolysis in hepatosplenic schistosomiasis. METHODS: The biological activity of plasminogen (Plg), plasminogen activators (PA), alpha 2-antiplasmin (alpha 2-AP) and plasminogen activator inhibitor-1 (PAI-1) was determined by photometric analysis in 15 compensated and 35 decompensated patients with endemic Egyptian hepatosplenomegaly. Quantitative measurement of plasma concentrations of tissue t-PA, t-PA-PAI-1 complex, alpha 2-antiplasmin-plasmin complex (alpha 2-APP), fibrinogen degradation products (FbDP), D-dimers (D-D), thrombin-antithrombin complex (TAT) and prothrombin fragment (F 1 + 2) complexes, using double antibody sandwich enzyme linked immunosorbent assays and grading of the degree of hepatic insufficiency according to the Child-Pugh classification, were also carried out. RESULTS: The progressive deterioration of liver function in schistosomal patients, which matched the severity of the disease, led to simultaneous defects in profibrinolytic (decreased Plg and increased PA and t-PA) and antifibrinolytic (decreased alpha 2-AP and PAI-1) factors-the latter defects being the most prominent-resulting in significant generation of plasmin (increased APP complexes) and therefore enhanced fibrinolysis (increased FbDP and D-dimer). The raised concentrations of FbDP, D-D, TAT and F 1 + 2 established its secondary nature. CONCLUSION: These findings suggest that the amount of PAI-1 available to bind and neutralise circulating t-PA may be a critical factor in the progress of hyperfibrinolysis observed in hepatosplenic schistosomiasis, and that the pronounced reduction in its plasma concentration may be regarded as a potential warning indicator of haemostatic imbalance in decompensated schistosomal patients at high risk of variceal bleeding.

Is the coagulopathy of hepatosplenic schistosomiasis immune-related?

Some of the soluble factors that affect haemostasis produced in the course of hepatosplenic schistosomiasis, including endotoxins (Ex), interleukin-1 alpha (IL-1 alpha) and tumour necrosis factor-alpha (TNF-alpha) were studied. Forty-one patients with hepatosplenic schistosomiasis were studied and classified into early hepatosplenic schistosomiasis (n = 12), hepatocellular decompensation (n = 14), vascular decompensation (n = 15) as well as twelve healthy controls. Thrombin-antithrombin complex (TAT), protein C and free protein S antigen and activity, endotoxin, IL-1 alpha and TNF-alpha levels were measured in all cases. Evidence of enhanced thrombin generation (elevated TAT levels) with reduced anticoagulant potential (reduced protein C and free protein S antigen and activity levels) could be demonstrated, thus reflecting decreased production and increased consumption of both coagulant and anticoagulant proteins. The association of high Ex, IL-1 alpha and TNF-alpha levels may suggest their possible implication in the causation of intravascular coagulation in hepatosplenic schistosomiasis.