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.

Sofosbuvir plus daclatasvir with or without ribavirin in 551 patients with hepatitis C-related cirrhosis, genotype 4.

BACKGROUND: The Daclatasvir and Sofosbuvir combination therapy (SOF/DCV) has shown efficacy in patients with chronic hepatitis C in clinical trials. AIM: To investigate the efficacy and safety of SOF/DCV for treatment of patients with hepatitis C-related liver cirrhosis genotype 4. METHODS: Multicentre study involving 551 patients with liver cirrhosis genotype 4; 432 naïve patients and 119 treatment-experienced patients. All patients received SOF (400 mg) and DCV (60 mg) daily in addition to weight-based ribavirin (RBV) for 12 weeks and when RBV is contraindicated the treatment duration was extended to 24 weeks. RESULTS: Sustained virological response at 12 weeks after end of treatment (SVR12) rate was 92% in naïve cirrhotic patients and 87% in previous treated patients (by ITT analysis). Virological failure was infrequent, occurring in 42 patients (8%) overall. Thirty-two (6%) were non responders; and 10 (2%) cases were relapsers, 31 patients (7%) were CTP-A and 11 (13.3%) patients were CTP-B (by ITT analysis). The most common adverse events were anaemia, fatigue, headache, pruritus. Serious side effects were recorded mainly in CTP-B cirrhotic patients including HCC and hepatic encephalopathy. CONCLUSIONS: The SOF/DCV combination therapy has proven efficacy and safety in treating patients with hepatitis C-related liver cirrhosis genotype 4 in a large cohort of patients in the real world.

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.

A randomized trial of endoscopic variceal ligation versus cyanoacrylate injection for treatment of bleeding junctional varices.

BACKGROUND: There is scarcity of data concerning the management of bleeding junctional gastroesophageal varices. AIM: Our aim was to compare the efficacy and safety of endoscopic variceal ligation (EVL) with cyanoacrylate injection for the treatment of bleeding junctional varices. METHODS: One hundred fifty patients with bleeding junctional varices were included in the study. Patients were subjected after randomization to either EVL of junctional varices (group 1:75 patients) or cyanoacrylate injection (group 11:75 patients). Endoscopic sessions were continued till obliteration of the varices. Clinical as well as biochemical parameters and severity of liver disease were assessed in all patients. RESULTS: Control of active variceal bleeding was achieved in 61 patients (81%) in group I and in 68 patients (91%) in group II with no significant difference (p = 0.07). Re-bleeding was seen in 12 patients (16%) in group I and 5 patients in group II (6%). Junctional varix obliteration was achieved after one session in 33% of patients in group I and 52% of patients in group II, however after 2 sessions it was achieved in 67% in group I and 93 % in group II. After 3 sessions variceal obliteration was achieved in 99% in group 1. Fever, chest pain and dysphagia were observed more frequently in group II than in group I. Long term complications including spontaneous bacterial peritonitis, hepatic encephalopathy and hepatorenal syndrome were also observed more frequently group II than in group I. CONCLUSION: EVL may be a good alternative to cyanoacrylate injection in treatment of bleeding junctional varices.

Plasma met-enkephalin, beta-endorphin and leu-enkephalin levels in human hepatic encephalopathy.

To address the role of the opioid system in the pathogenesis of hepatic encephalopathy (HE) we measured plasma met-enkephalin, beta-endorphin and leu-enkephalin in patients with different grades of HE compared to control subjects and patients with cirrhosis. Plasma met-enkephalin levels were significantly higher in patients with cirrhosis and all grades of HE than controls. Plasma beta-endorphin levels were similar in the 3 groups. Plasma leu-enkephalin levels were significantly higher in HE grades II, III and IV than in controls, patients with cirrhosis and HE grade I patients. Our results support data on the involvement of met-enkephalin and leu-enkephalin in the pathogenesis of HE and provide a rationale for the use of opioid receptor antagonists in the treatment of HE.

Serum levels of astroglial S100-beta and neuron-specific enolase in hepatic encephalopathy patients.

To find a reliable, noninvasive method for the diagnosis of cognitive impairment in patients with hepatic cirrhosis we measured serum levels of astroglial S100beta and neuron-specific enolase in cirrhotic patients with and without hepatic encephalopathy (HE). S100beta levels showed a significant increase in groups with HE stage 1 and 2 compared to both control and cirrhosis patients. However serum neuron-specific enolase levels were not significantly different between the studied groups. S100beta levels had a specificity of 91.3% and sensitivity of 51.7% for detection of HE from cirrhosis. Serum S100beta may be a useful surrogate marker for the diagnosis of mild cognitive impairment in cirrhotic patients before they progress to more advanced stages of HE.

Serum levels of astroglial S100-beta and neuron-specific enolase in hepatic encephalopathy patients

To find a reliable, noninvasive method for the diagnosis of cognitive impairment in patients with hepatic cirrhosis we measured serum levels of astroglial S100beta and neuron-specific enolase in cirrhotic patients with and without hepatic encephalopathy [HE]. S100beta levels showed a significant increase in groups with HE stage 1 and 2 compared to both control and cirrhosis patients. However serum neuron-specific enolase levels were not significantly different between the studied groups. S100beta levels had a specificity of 91.3% and sensitivity of 51.7% for detection of HE from cirrhosis. Serum S100beta may be a useful surrogate marker for the diagnosis of mild cognitive impairment in cirrhotic patients before they progress to more advanced stages of HE

Plasma met-enkephalin, beta-endorphin and leu-enkephalin levels in human hepatic encephalopathy

To address the role of the opioid system in the pathogenesis of hepatic encephalopathy [HE] we measured plasma met- enkephalin, beta -endorphin and leu- enkephalin in patients with different grades of HE compared to control subjects and patients with cirrhosis. Plasma met- enkephalin levels were significantly higher in patients with cirrhosis and all grades of HE than controls. Plasma beta levels were similar in the 3 groups. Plasma leu- enkephalin levels were significantly higher -endorphin in HE grades II, III and IV than in controls, patients with cirrhosis and HE grade I patients. Our results support data on the involvement of met- enkephalin and leu- enkephalin in the pathogenesis of HE and provide a rationale for the use of opioid receptor antagonists in the treatment of HE

Difference in the susceptibility to certain molluscicides and Schistosoma mansoni infection of three forms Egyptian Biomphalaria glabrata.

The first generation of 3 morphologically different forms of B. glabrata collected from Giza were compared for LC50 values susceptibility to bayluscide and copper sulphate (chemical molluscicides) and Anagallis arvensis and Calendula micrantha (plant molluscicides) and to Schistosoma mansoni infection. Form (2) as juvenile and adult were less sensitive to C. micrantha and A. arvensis. Form (3) as juvenile and form (1) as adult were least sensitive to CuSO4. Approximately the same susceptibility to bayluscide was observed in the 3 forms either as juvenile or adult. The sublethal concentrations of the molluscicides on B. glabrata 3 forms showed no significant difference in the growth or survival rate in between. Form (2) was significantly higher in the egg lying capacity. The total protein concentration was not affected except in certain cases where the increase was primarily due to the increase in the globulin concentrations which indicate with the marked increase observed in the urea concentration and marked increase or inhibition in the activity of either AST or ALT that the digestive gland of the 3 forms of snails is seriously affected by molluscicides. The 3 forms of B. glabrata showed low susceptibility to infection with the local strain of S. mansoni.

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.

Consanguineous matings in the Egyptian population.

A total of 26 554 Egyptians was ascertained to study the incidence of consanguineous marriages. They were of different ages, different socioeconomic standards, and from different areas. There were 7646 from urban areas, 11 280 from suburban areas, and 7628 from rural areas. The incidence of consanguineous matings in the general population was found to be 28.96% with an average inbreeding coefficient of 0.010, which could be considered high. The highest incidence was that in the rural areas. First cousin marriages occurred more often than the other types of consanguinity.