Jan Borovicka

Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study.

BACKGROUND & AIMS Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy. METHODS The analysis included 1362 individuals: 1015 with chronic hepatitis C and 347 who spontaneously cleared the virus (448 were coinfected with human immunodeficiency virus [HIV]). Responses to pegylated interferon alfa and ribavirin were assessed in 465 individuals. Associations between more than 500,000 single nucleotide polymorphisms (SNPs) and outcomes were assessed by multivariate logistic regression. RESULTS Chronic hepatitis C was associated with SNPs in the IL28B locus, which encodes the antiviral cytokine interferon lambda. The rs8099917 minor allele was associated with progression to chronic HCV infection (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.74-3.06; P = 6.07 x 10(-9)). The association was observed in HCV mono-infected (OR, 2.49; 95% CI, 1.64-3.79; P = 1.96 x 10(-5)) and HCV/HIV coinfected individuals (OR, 2.16; 95% CI, 1.47-3.18; P = 8.24 x 10(-5)). rs8099917 was also associated with failure to respond to therapy (OR, 5.19; 95% CI, 2.90-9.30; P = 3.11 x 10(-8)), with the strongest effects in patients with HCV genotype 1 or 4. This risk allele was identified in 24% of individuals with spontaneous HCV clearance, 32% of chronically infected patients who responded to therapy, and 58% who did not respond (P = 3.2 x 10(-10)). Resequencing of IL28B identified distinct haplotypes that were associated with the clinical phenotype. CONCLUSIONS The association of the IL28B locus with natural and treatment-associated control of HCV indicates the importance of innate immunity and interferon lambda in the pathogenesis of HCV infection.

Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C

BACKGROUND/AIMS While several risk factors for the histological progression of chronic hepatitis C have been identified, the contribution of HCV genotypes to liver fibrosis evolution remains controversial. The aim of this study was to assess independent predictors for fibrosis progression. METHODS We identified 1189 patients from the Swiss Hepatitis C Cohort database with at least one biopsy prior to antiviral treatment and assessable date of infection. Stage-constant fibrosis progression rate was assessed using the ratio of fibrosis Metavir score to duration of infection. Stage-specific fibrosis progression rates were obtained using a Markov model. Risk factors were assessed by univariate and multivariate regression models. RESULTS Independent risk factors for accelerated stage-constant fibrosis progression (>0.083 fibrosis units/year) included male sex (OR=1.60, [95% CI 1.21-2.12], P<0.001), age at infection (OR=1.08, [1.06-1.09], P<0.001), histological activity (OR=2.03, [1.54-2.68], P<0.001) and genotype 3 (OR=1.89, [1.37-2.61], P<0.001). Slower progression rates were observed in patients infected by blood transfusion (P=0.02) and invasive procedures or needle stick (P=0.03), compared to those infected by intravenous drug use. Maximum likelihood estimates (95% CI) of stage-specific progression rates (fibrosis units/year) for genotype 3 versus the other genotypes were: F0-->F1: 0.126 (0.106-0.145) versus 0.091 (0.083-0.100), F1-->F2: 0.099 (0.080-0.117) versus 0.065 (0.058-0.073), F2-->F3: 0.077 (0.058-0.096) versus 0.068 (0.057-0.080) and F3-->F4: 0.171 (0.106-0.236) versus 0.112 (0.083-0.142, overall P<0.001). CONCLUSIONS This study shows a significant association of genotype 3 with accelerated fibrosis using both stage-constant and stage-specific estimates of fibrosis progression rates. This observation may have important consequences for the management of patients infected with this genotype.

Polyfunctional HCV-specific T-cell responses are associated with effective control of HCV replication

HCV infection has a severe course of disease in HIV/HCV co‐infection and in liver transplant recipients. However, the mechanisms involved remain unclear. Here, we evaluated functional profiles of HCV‐specific T‐cell responses in 86 HCV mono‐infected patients, 48 HIV/HCV co‐infected patients and 42 liver transplant recipients. IFN‐γ and IL‐2 production and ability of CD4 and CD8 T cells to proliferate were assessed after stimulation with HCV‐derived peptides. We observed that HCV‐specific T‐cell responses were polyfunctional in HCV mono‐infected patients, with presence of proliferating single IL‐2‐, dual IL‐2/IFN‐γ and single IFN‐γ‐producing CD4+ and dual IL‐2/IFN‐γ and single IFN‐γ‐producing CD8+ cells. In contrast, HCV‐specific T‐cell responses had an effector profile in HIV/HCV co‐infected individuals and liver transplant recipients with absence of single IL‐2‐producing HCV‐specific CD4+ and dual IL‐2/IFN‐γ‐producing CD8+ T cells. In addition, HCV‐specific proliferation of CD4+ and CD8+ T cells was severely impaired in HIV/HCV co‐infected patients and liver transplant recipients. Importantly, “only effector” T‐cell responses were associated with significantly higher HCV viral load and more severe liver fibrosis scores. Therefore, the present results suggest that immune‐based mechanisms may contribute to explain the accelerated course of HCV infection in conditions of HIV‐1 co‐infection and liver transplantation.

HCV-related advanced fibrosis/cirrhosis: randomized controlled trial of pegylated interferon alpha-2a and ribavirin.

Summary.  In patients with hepatitis C virus (HCV)‐related advanced fibrosis/cirrhosis, 30% of sustained HCV clearance has been reported with pegylated interferon α‐2a (PEG‐IFN) alone, but the efficacy and tolerability of the PEG‐IFN/ribavirin (RBV) combination remain poorly defined. A total of 124 treatment‐naïve patients with biopsy proved HCV‐related advanced fibrosis/cirrhosis (Ishak score F4–F6, Child–Pugh score ≤7) were randomized to 48 weeks of PEG‐IFN (180 μg sc weekly) and standard dose of RBV (1000/1200 mg po daily, STD) or PEG‐IFN (180 μg sc weekly) and low‐dose of RBV (600/800 mg po daily, LOW). Sustained virologic response (SVR) rates with PEG‐IFN/STD RBV (52%) were higher – albeit not significantly – than that with PEG‐IFN/LOW RBV (38%, P = 0.153). In multivariate analysis, genotype 2/3 and a baseline platelet count ≥150 × 109/L were independently associated with SVR. The likelihood of SVR was <7% if viraemia had not declined by ≥2 log or to undetectable levels after 12 weeks. Nine adverse events in the STD RBV and 15 in the LOW RBV group were classified as severe (including two deaths); dose reductions for intolerance were required in 78% and 57% (P = 0.013), and treatment was terminated early in 23% and 27% of patients (P = n.s.). The benefit/risk ratio of treating compensated HCV‐cirrhotics with STD PEG‐IFN/RBV is favourable.

Host- rather than virus-related factors reduce health-related quality of life in hepatitis C virus infection

Background: Hepatitis C virus (HCV) infection is associated with decreased health-related quality of life (HRQOL). Although HCV has been suggested to directly impair neuropsychiatric functions, other factors may also play a role. Patients and methods: In this cross-sectional study, we assessed the impact of various host-, disease- and virus-related factors on HRQOL in a large, unselected population of anti-HCV-positive subjects. All individuals (n = 1736) enrolled in the Swiss Hepatitis C Cohort Study (SCCS) were asked to complete the Short Form 36 (SF-36) and the Hospital Anxiety Depression Scale (HADS). Results: 833 patients (48%) returned the questionnaires. Survey participants had significantly worse scores in both assessment instruments when compared to a general population. By multivariable analysis, reduced HRQOL (mental and physical summary scores of SF-36) was independently associated with income. In addition, a low physical summary score was associated with age and diabetes, whereas a low mental summary score was associated with intravenous drug use. HADS anxiety and depression scores were independently associated with income and intravenous drug use. In addition, HADS depression score was associated with diabetes. None of the SF-36 or HADS scores correlated with either the presence or the level of serum HCV RNA. In particular, SF-36 and HADS scores were comparable in 555 HCV RNA-positive and 262 HCV RNA-negative individuals. Conclusions: Anti-HCV-positive subjects have decreased HRQOL compared to controls. The magnitude of this decrease was clinically important for the SF-36 vitality score. Host and environmental, rather than viral factors, seem to impact on HRQOL level.

Cytomegalovirus-Induced Transient Protein-Losing Hypertrophic Gastropathy in an Immunocompetent Adult

Transient protein-losing hypertrophic gastropathy with similarity to Ménétrier’s disease is described. Acute infection with cytomegalovirus (CMV) could be shown to play a causative role. Immunodeficiency was ruled out. The 34-year-old patient had complete resolution of the disease without antiviral treatment. To our knowledge the present report is the first case of CMV-associated protein-losing hypertrophic gastropathy in an immunocompetent adult. To date, a similar disorder has only been described in children. CMV infection should be considered in patients with acute and symptomatic protein loss of gastrointestinal origin.

Laparoscopic mesh-augmented hiatoplasty as a treatment of gastroesophageal reflux disease and hiatal hernias–preliminary clinical and functional results of a prospective case series

BACKGROUND Because fundoplication-related side effects are frequent, we evaluated laparoscopic mesh-augemented hiatoplasty (LMAH) as a potential treatment option for gastroesophageal reflux disease and/or symptomatic hiatal herania. LMAH aims to prevent reflux solely by mesh-reinforced narrowing of the hiatus and lengthening of the intra-abdominal esophagus. METHODS Twenty-two consecutive patients with LMAH were evaluated prospectively using a modified Gastrointestinal Symptom Rating Scale questionnaire, pH measurement, manometry, and endoscopy. Follow-up was scheduled at 3 and 12 months after surgery. RESULTS Total reflux decreased from 16.3% before surgery to 3.5% 3 months after surgery (P = .001). The reflux score decreased from 3.8 before surgery to 2.1 1 year after surgery (P = .001). The respective values of the indigestion score were 3.4 and 2.0 (P < .001). After surgery, all patients were able to belch. Vomiting was impossible only for 2 patients, and 90% of patients assessed their results as good to excellent. CONCLUSIONS LMAH seems to be feasible, safe, and has no significant side effects.

Evaluation of delayed gastric emptying in diabetic patients with autonomic neuropathy by a new magnetic resonance imaging technique and radio-opaque markers

OBJECTIVE Our objective was to validate a new noninvasive magnetic resonance imaging (MRI) technique for diagnosis of delayed gastric emptying by using radio-opaque markers (ROMs) in diabetic patients with and without cardiovascular autonomic (CAN) and peripheral sensomotoric neuropathy (PSN). RESEARCH DESIGN AND METHODS Fifteen diabetic outpatients were recruited, eight with CAN and PSN (group A, age 28–61 years, mean diabetes duration 27 years) and seven without CAN (group B, age 28–60 years, mean diabetes duration 16 years). Gastric emptying and motility were assessed with ROMs and MRI in random order. After an overnight fast either a test meal (451 kcal) containing a capsule with 10 ROMs is eaten and a supine plain abdominal × ray is taken after 6 h or 500 ml intralipid 10% (550 kcal) is swallowed for the MRI study, using a 1.5 Tesla Gyroscan ACS II (Philips, Eindohoven, The Netherlands). Computer-assisted segmentation of images was used to measure gastric emptying (T1/2, min) over 125 min, contraction frequency (F, min−1), mean contraction amplitude (CA, % basal), and velocity (V, cm/s). Blood glucose was kept constant at 5.0–8.0 mmol/l. RESULTS In group A, 6.1 ± 1.36 ROMs (mean ± SE) were retained in the stomach after 6 h and 0 ROM in group B, indicating a significant delay of gastric emptying in patients with CAN. The MRI study revealed a significantly longer gastric emptying (P < 0.005) in group A (T1/2 = 124 ± 10 min) as compared with group B (T1/2 = 85 ± 18 min). There was no difference in F, CA, and V between the two groups: F 2.9 ± 0.07 and 2.7 ± 0.1 (min−1), CA 26.8 ± 1.2 and 29.6 ± 1.6 (% basal), V 0.43 ± 0.02 and 0.40 ± 0.02 (cm/s), respectively. CONCLUSIONS MRI offers the possibility of visualizing and examining exactly the mechanisms responsible for gastric emptying and is characterized by a high specificity but a lower sensitivity as compared with ROMs, which proved to be an ideal screening test for diagnosis of gastroparesis in clinical practice.

Multipurpose use of the over-the-scope-clip system (“Bear claw”) in the gastrointestinal tract: Swiss experience in a tertiary center

AIM To evaluate the outcome of over-the-scope-clip system (OTSC) for endoscopic treatment of various indications in daily clinical practice in Switzerland. METHODS This prospective, consecutive case series was conducted at a tertiary care hospital from September 2010 to January 2014. Indications for OTSC application were fistulae, anastomotic leakage, perforation, unroofed submucosal lesion for biopsy, refractory bleeding, and stent fixation in the gastrointestinal (GI) tract. Primary technical success was defined as the adequate deployment of the OTSC on the target lesion. Clinical success was defined as resolution of the problem; for instance, no requirement for surgery or further endoscopic intervention. In cases of recurrence, retreatment of a lesion with a second intervention was possible. Complications were classified into those related to sedation, endoscopy, or deployment of the clip. RESULTS A total of 28 OTSC system applications were carried out in 21 patients [median age 64 years (range 42-85), 33% females]. The main indications were fistulae (52%), mostly after percutaneous endoscopic gastrostomy tube removal, and anastomotic leakage after GI surgery (29%). Further indications were unroofed submucosal lesions after biopsy, upper gastrointestinal bleeding, or esophageal stent fixation. The OTSC treatments were applied either in the upper (48%) or lower (52%) GI tract. The mean lesion size was 8 mm (range: 2-20 mm). Primary technical success and clinical success rates were 85% and 67%, respectively. In 53% of cases, the suction method was used without accessories (e.g., twin grasper or tissue anchor). No endoscopy-related or OTSC-related complications were observed. CONCLUSION OTSC is a useful tool for endoscopic closure of various GI lesions, including fistulae and leakages. Future randomized prospective multicenter trials are warranted.

Effect of lintitript, a new CCK-A receptor antagonist, on gastric emptying of a solid-liquid meal in humans.

The role of cholecystokinin (CCK) in the regulation of gastric emptying of physiological meals containing solids and liquids in humans remains controversial. We studied the role of endogenous CCK in the emptying of a solid/liquid meal administering the new, highly specific and potent CCK-A receptor antagonist lintitript. Gastric emptying was assessed in nine healthy male volunteers using a randomized, double blind, two-period crossover design with oral lintitript (15 mg 1 h prior to meal intake) or placebo on two different days. After ingestion of a pancake (570 kcal) labelled with 500 microCi of 99mTc-sulfur colloid and 500 ml 10% dextrose containing 80 microCi. 111In-DTPA, subjects were studied in a sitting position, using a dual-headed gamma camera. Plasma CCK and pancreatic polypeptide (PP) were measured by a specific RIA. Lintitript distinctly accelerated gastric emptying of solids, while gastric emptying of liquids was not significantly altered. The lag period was shortened by 20% (P<0.05), AUC and half emptying time of solid emptying were lowered by 12% and 13%, respectively (P<0.03). Lintitript markedly increased postprandial plasma CCK release (P<0.001) while distinctly reducing postprandial PP levels (P<0.01) as compared to placebo. These data provide further evidence for a significant role of CCK in the regulation of gastric emptying of solids. The study demonstrates for the first time the marked gastrokinetic properties of the new CCK-A receptor antagonist lintitript in humans.