Ingolf Schiefke

A Polymorphism Near IL28B Is Associated With Spontaneous Clearance of Acute Hepatitis C Virus and Jaundice

BACKGROUND & AIMS A single nucleotide polymorphism (SNP) upstream of the IL28B gene has been associated with response of patients with chronic hepatitis C to therapy with pegylated interferon and ribavirin and also with spontaneous clearance of acute hepatitis C in a heterogeneous population. We analyzed the association between IL28B and the clinical presentation of acute hepatitis C virus (HCV) infection in a homogeneous population. METHODS We analyzed the SNP rs12979860 in 190 women from the German anti-D cohort (infected with HCV genotype 1b via contaminated rhesus prophylaxis) and its association with spontaneous clearance. Clinical data were available in 136 women with acute infection who were also evaluated for IL28B genotype. Based on results of a TaqMan polymerase chain reaction assay, the rs12979860 SNP genotypes studied were C/C, C/T, or T/T. RESULTS Spontaneous clearance was more common in patients with the C/C genotype (43/67; 64%) compared with C/T (22/90; 24%) or T/T (2/33; 6%) (P < .001). Jaundice during acute infection was more common among patients with C/C genotype (32.7%) than non-C/C patients (with C/T or T/T) (16.1%; P = .032). In C/C patients, jaundice during acute infection was not associated with an increased chance of spontaneous clearance (56.3%) compared with those without jaundice (60.6%). In contrast, in non-C/C patients, jaundice was associated with a higher likelihood of spontaneous clearance (42.9%) compared with those without jaundice (13.7%). CONCLUSIONS The SNP rs12979860 upstream of IL28B is associated with spontaneous clearance of HCV. Women with the C/T or T/T genotype who did not develop jaundice had a lower chance of spontaneous clearance of HCV infection.

Non-Invasive Assessment of Hepatic Steatosis in Patients with NAFLD Using Controlled Attenuation Parameter and 1H-MR Spectroscopy

Introduction Non-invasive assessment of steatosis and fibrosis is of growing relevance in non-alcoholic fatty liver disease (NAFLD). 1H-Magnetic resonance spectroscopy (1H-MRS) and the ultrasound-based controlled attenuation parameter (CAP) correlate with biopsy proven steatosis, but have not been correlated with each other so far. We therefore performed a head-to-head comparison between both methods. Methods Fifty patients with biopsy-proven NAFLD and 15 healthy volunteers were evaluated with 1H-MRS and transient elastography (TE) including CAP. Steatosis was defined according to the percentage of affected hepatocytes: S1 5-33%, S2 34–66%, S3 ≥67%. Results Steatosis grade in patients with NAFLD was S1 36%, S2 40% and S3 24%. CAP and 1H-MRS significantly correlated with histopathology and showed comparable accuracy for the detection of hepatic steatosis: areas under the receiver-operating characteristics curves were 0.93 vs. 0.88 for steatosis ≥S1 and 0.94 vs. 0.88 for ≥S2, respectively. Boot-strapping analysis revealed a CAP cut-off of 300 dB/m for detection of S2-3 steatosis, while retaining the lower cut-off of 215 dB/m for the definition of healthy individuals. Direct comparison between CAP and 1H-MRS revealed only modest correlation (total cohort: r = 0.63 [0.44, 0.76]; NAFLD cases: r = 0.56 [0.32, 0.74]). For detection of F2–4 fibrosis TE had sensitivity and specificity of 100% and 98.1% at a cut-off value of 8.85 kPa. Conclusion Our data suggest a comparable diagnostic value of CAP and 1H-MRS for hepatic steatosis quantification. Combined with the simultaneous TE fibrosis assessment, CAP represents an efficient method for non-invasive characterization of NAFLD. Limited correlation between CAP and 1H-MRS may be explained by different technical aspects, anthropometry, and presence of advanced liver fibrosis.

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Evaluate the Efficacy, Safety, and Tolerability of Prucalopride in Men With Chronic Constipation

OBJECTIVES:Prucalopride is effective at alleviating symptoms of chronic constipation in women. The aim of this study was to assess the efficacy of 12 weeks of prucalopride treatment compared with placebo in men with chronic constipation.METHODS:This was a multicenter, stratified, randomized, parallel-group, double-blind, placebo-controlled, phase 3 study (ClinicalTrials.gov identifier: NCT01147926). The primary end point was the proportion of patients with a mean of three or more spontaneous complete bowel movements (SCBMs) per week across the treatment period. Efficacy end points were assessed using daily electronic diaries, global assessment of the severity of constipation and efficacy of treatment, and Patient Assessment of Constipation—Symptoms (PAC-SYM) and Patient Assessment of Constipation—Quality of Life (PAC-QOL) questionnaires.RESULTS:In total, 374 patients were enrolled in the study. Significantly more patients achieved a mean of three or more SCBMs per week in the prucalopride group (37.9%) than in the placebo group (17.7%, P<0.0001). The proportion of patients rating their constipation treatment as “quite a bit” to “extremely” effective at the final on-treatment visit was 46.7 and 30.4% in the prucalopride and placebo groups, respectively. The difference between treatment groups was statistically significant (P<0.0001). The proportion of patients with an improvement of at least 1 point in PAC-QOL satisfaction subscale score was 52.7 and 38.8% in the prucalopride and placebo groups, respectively (P=0.0035). Prucalopride had a good safety profile and was well tolerated.CONCLUSIONS:Prucalopride is effective, has a good safety profile, and is well tolerated for the treatment of men with chronic constipation.

The predictive value of IL28B gene polymorphism for spontaneous clearance in a single source outbreak cohort is limited in patients carrying the CCR5Δ32 mutation

BACKGROUND & AIMS The CCR5Δ32 mutation has been suspected to adversely affect outcomes of HCV infection, although reports have remained controversial. Here, we investigated the relative genetic contributions of the CCR5Δ32 deletion and the IL28B rs12979860 polymorphisms to spontaneous clearance of hepatitis C in a single-source outbreak. METHODS We retrieved 396 Caucasian women (119 women with spontaneous HCV clearance) who had been infected with HCV genotype 1-contaminated anti-D immunoglobulin in 1978, and determined their IL28B and CCR5 alleles. RESULTS IL28B CC, CT, and TT genotypes were found in 35.4%, 50%, and 14.6% of patients and corresponded to spontaneous clearance rates of 50%, 21.2%, and 12.1% (Chi(2)=38.7, p=5.0×10(-10)), respectively. CCR5 WT/WT, WT/Δ32, and Δ32/Δ32 genotypes were observed in 76%, 22.7%, and 1.3% of patients and corresponded to clearance rates of 33.2%, 21.2%, and 0% (Chi(2)=6.9, p=0.009), respectively. In a stepwise forward-conditional multivariate regression model both CCR5 (OR 2.1, p=0.01 for WT/WT) and IL28B genetic variants (OR 4.3, p=4.6×10(-10) for the C/C genotype) were identified as independent predictors of spontaneous HCV clearance. Importantly, favorable response rates were associated with the IL28B CC genotype only in CCR5 wild-type homozygous women, while HCV clearance in CCR5Δ32 carriers remained poor even in patients with the rs12979860 CC genotype. CONCLUSIONS Both IL28B rs1297860 and CCR5Δ32 allelic variants are independent genetic determinants of spontaneous HCV clearance. The variable relative distribution between IL28B rs1297860 and CCR5Δ32 allelic variants in different populations may have masked the role of the CCR5Δ32 mutation in some studies.

Risk Factors for Bleeding Complications after Endoscopic Variceal Ligation Therapy

BACKGROUND Bleeding from esophageal varices is a severe complication of portal hypertension. Endoscopic band ligation (EBL) is the treatment of choice for acute variceal bleeding. It is also performed for primary and secondary prophylaxis of bleeding from esophageal varices. After EBL, patients are at risk of postinterventional bleeding; the risk factors for this complication are poorly evaluated. METHODS We retrospectively analyzed data from patients who underwent EBL. We evaluated clinical data, laboratory and endoscopic findings. RESULTS 255 patients with 387 ligation sessions were included in the analysis. Patients with bleeding complications had a significantly higher severity of liver disease as measured by a higher Child-Pugh score (10.5 vs. 8, p = 0.002), lower albumin (26.5 vs. 31.9 [g/L], p = 0.0001) and lower prothrombin activity (46.5 vs. 70 [%], p = 0.0001). The incidence of bacterial infection was significantly higher in patients with postinterventional bleeding. As well, the white blood cell count was significantly higher in the bleeding group (9.5 vs. 6.5 [× 10 (9) /L], p = 0.030). In patients with bleeding events we observed an elevated heart rate compared to those without this complication (80 vs. 72 [bpm], p = 0.017). Furthermore, we found a lower hemoglobin level (5.9 vs. 6.4 [mmol/L], p = 0.028) and a lower hematocrit (0.280 vs. 0.314, p = 0.031) in the bleeding group. Younger patients suffered more often from postinterventional bleeding (52.5 vs. 58 [years], p = 0.012). CONCLUSION There are clinical data which can be ascertained easily in order to reflect the risk of bleeding complications after EBL.

Treatment of massive cecal bleeding in a 28-Year-old patient with homozygous factor V deficiency with activated factor VII.

Factor V deficiency is usually accompanied with recurrent epistaxis, menorrhagia and haemorrhages after trauma. So far, gastrointestinal bleeding has not been reported. We describe here the first case of severe cecal bleeding in a 28-year-old woman with homozygous factor V deficiency. As a reasonable alternative to large amounts of fresh frozen plasma, we indicated recombinant activated factor VII (rFVIIa), as supra-physiological concentrations directly activate factor X and prothrombin on the surface of activated platelets. With this regimen, the bleeding immediately stopped and the patient was discharged three days later. Rotation thromboelastometry studies showed a marked improvement in clot generation after rFVIIa infusion. We conclude that massive cecal mucosal bleeding is a possible manifestation of homozygous factor V deficiency and rFVIIa could be a successful therapy.

Eisenmangelanämie: Wann i.v. behandeln?

Eisenmangel und Anämie kommen bei zahlreichen Grunderkrankungen vor, z. T. mit gravierenden Auswirkungen auf Morbidität und Mortalität. Wie gehen Sie bei der Diagnostik vor? Wann sollte die Therapie oral, wann i.v. erfolgen?

929g Efficacy and safety of prucalopride in men with chronic constipation: a phase 3, randomized, double-blind, placebo-controlled trial

Introduction Prucalopride (PRU) is a high-affinity serotonin receptor (5-HT 4 ) agonist approved in Europe for the symptomatic treatment of chronic constipation (CC) in women. The aim of this study was to evaluate the efficacy and safety of PRU in men with CC. Method This was a phase 3, multicentre, parallel-group, double-blind trial (NCT01147926). Men aged ≥ 18 years with CC who had ≤ 2 spontaneous complete bowel movements (SCBMs)/week were randomised to receive placebo (PLA) or PRU 2 mg (starting dose of 1 mg for patients aged ≥ 65 years) once daily for 12 weeks. The primary endpoint was the proportion of men achieving a mean of ≥ 3 SCBMs/week over 12 weeks. Secondary endpoints included Patient Assessment of Constipation-Symptoms (PAC-SYM) and Patient Assessment of Constipation-Quality of Life (PAC-QOL) questionnaire scores. Safety was assessed throughout the study. Results Overall, 374 patients were randomised. More men in the PRU group than in the PLA group (37.9% vs. 17.7%, respectively; p p = 0 .0743) and ≥ 1 SBM/week (65.5% vs. 43.1%; p p = 0 .3152) or abdominal (39.1% vs. 35.1%; p = 0 .4874) or rectal (34.9% vs. 29.2%; p = 0 .2759) subscale scores. However, there was a significant difference in stool symptoms score (53.3% vs. 36.3%; p = 0 .0005). The proportion of men with an improvement of ≥ 1 in total PAC-QOL score was higher with PRU (40.2%) than PLA (32.7%; p = 0 .0755). PRU had a good safety profile and was well tolerated, consistent with previous studies. The incidences of serious adverse events and ischaemic cardiovascular adverse events were low and similar in both treatment groups. Conclusion Results from this study demonstrate that PRU is effective, has a good safety profile and is well tolerated in men with CC, similar to the findings for women with CC. Disclosure of interest Y. Yiannakou Grant/ Research Support from: Shire, Consultant for: Shire, M. Bouchoucha: None Declared, I. Schiefke: None Declared, H. Piessevaux Conflict with: Shire, R. Filip: None Declared, L. Gabalec: None Declared, D. Stephenson Employee of: Shire, R. Kerstens Employee of: Shire, K. Etherson Conflict with: Shire, A. Levine Employee of: Shire.

Quantification of HBsAg and HBV-DNA during Therapy with Peginterferon alpha-2b plus Lamivudine and Peginterferon alpha-2b Alone in a German Chronic Hepatitis B Cohort

BACKGROUND Peginterferon alpha-2b (PEG-IFNa2b) and lamivudine are efficient treatment options for chronic hepatitis B virus (HBV) infection. We assumed that a combination therapy of PEG-IFNα-2b plus lamivudine will be more effective than PEG-IFNα-2b alone concerning loss of HBV-DNA, HBeAg seroconversion, and HBsAg reduction. PATIENTS AND METHODS Patients with chronic hepatitis B were randomised to nine months treatment with PEG-IFNα-2b 1.5 µg/kg o. i. w. or PEG- IFNα-2b plus lamivudine 100 mg/d. The study was designed with 60 patients per treatment arm. The primary endpoint was defined as loss of HBV-DNA (< 400 copies/mL) 24 weeks after the end of therapy. HBV-DNA (PCR), HBsAg (Architect, Abbott), and HBeAg (Axsym, Abbott) were determined prior to and at the end of treatment as well as at follow-up. HBV-genotypes were determined by Innolipa (Innogenetics). RESULTS Only 32 patients were randomised to combination therapy and 27 individuals to monotherapy due to low recruitment rates. On treatment reduction of HBV-DNA was significantly higher during combination therapy compared to PEG-IFNa-2b monotherapy (- 4.60 ± 2.71 vs. - 2.41 ± 2.17 log; p = 0.003). However, there was no difference in the number of cases achieving HBV-DNA < 400 copies/mL, ALT normalisation, or HBeAg seroconversion at follow-up. None of the parameters was significantly related to HBV-genotypes. In a post-hoc analysis serum HBsAg levels were analysed as an additional prognostic parameter for treatment response (n = 29). Combination therapy showed a stronger, but not significant HBsAg decline during (- 0.7 ± 1.17 log IU/mL vs. - 0.26 ± 0.61 log IU/mL; p = 0.35) and after therapy (- 0.68 ± 1.29 log IU/mL vs. - 0.24 ± 0.56 log IU/mL; p = 0.82). Two of three cases with a 2-log HBsAg decline to HBsAg levels < 100 IU/mL eliminated HBsAg during long-term follow-up. CONCLUSION The study was underpowered with respect to the primary endpoint due to low recruitment rates. However, in the post-hoc analysis HBsAg decline was over two-fold stronger at the end of treatment and follow-up after combination therapy and did not rebound after lamivudine withdrawal. These results may indicate the usefulness of future combination therapies without discontinuation of nucleos(t)ide analogues.

Usage characteristics and adverse event rates of the direct puncture and pull techniques for percutaneous endoscopic gastrostomy in patients with malignant tumors of the upper aerodigestive tract

Background and study aims  Patients with malignant tumors of the upper gastrointestinal tract are at risk of weight loss. Early supportive nutrition therapy is therefore recommended and usually requires placement of a percutaneous endoscopic gastrostomy (PEG). The aim of this study was to compare adverse events and usage characteristics of the direct puncture technique with those of the traditional pull technique when used in patients with endoscopically passable tumors. The primary endpoint was the rate of inflammatory adverse events (AEs) at the gastrostomy fistula. The secondary endpoint was the long-term rate of puncture-site metastases. Patients and methods  One hundred twenty patients (median age 56; IQR 36, 86 years) were randomized and treated per protocol in this prospective open randomized single-center study. Follow-ups were conducted on the third and seventh post-interventional days, after 1, 3 and 6 months and the last follow-up 5 years after intervention. Results  Within the short-term follow-up period of 6 months after PEG placement, AEs were noted in 47 patients (39.2 %). These included 22 inflammations and 16 device dislocations and were mainly found in the puncture group (33 vs. 14 in the pull group) with a significantly increased incidence in the first month after PEG insertion ( P  = 0.001). Evaluation of the 5-year data did not reveal any significant differences. The gastrostomy tube was used in 101 patients (84.2 %) (range 18 days to 5 years). Conclusions  Our results favor the pull technique for patients with endoscopically passable tumors of the upper gastrointestinal tract due to less short-term adverse events. Both systems contributed equally to secure long-term use.