Patrick Hillon

Propranolol for Prevention of Recurrent Gastrointestinal Bleeding in Patients with Cirrhosis: A Controlled Study

It has been suggested that because propranolol decreases portal venous pressure, it may prevent gastrointestinal bleeding associated with portal hypertension. We randomly assigned 74 patients with cirrhosis, who were admitted because of gastrointestinal bleeding, to either oral propranolol given in doses that reduced the heart rate by 25 per cent (38 patients) or to a placebo (36 patients). The proportion of patients free of recurrent gastrointestinal bleeding one year after inclusion in this study was 96 per cent in the propranolol group and 50 per cent in the placebo group (P less than 0.0001). We conclude that continuous administration of propranolol by mouth is effective in preventing recurrent gastrointestinal bleeding in patients with cirrhosis.

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) – NCT01514890

BACKGROUND & AIMS In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C

BACKGROUND/AIMS Our aims were to investigate the host and viral specific factors associated with diabetes mellitus (DM) and insulin resistance in chronic hepatitis C patients. METHODS One hundred and three hepatitis C virus (HCV)-infected were studied to assess the effects of HCV genotype, hepatic iron content, steatosis, hepatic fibrosis, body mass index (BMI) and family history of DM on the occurrence of DM. Insulin resistance (HOMA IR) was studied in 81 non-diabetic patients to determine the mechanism associated with insulin resistance in this subgroup. RESULTS Sixteen of the 123 were diabetic (13.0%). The variables predictive of DM were METAVIR fibrosis score 4 (OR, 13.16; P = 0.012), family history of diabetes (OR, 16.2; P = 0.0023), BMI (OR, 1.37; P = 0.017) and age (OR, 1.09; P = 0.002). In non-diabetic HCV-infected patients, HOMA-IR of METAVIR fibrosis score 0 and 1 patients were significantly different than score 2 and score 3/4 patients. CONCLUSIONS Our findings indicate that older age, obesity, severe liver fibrosis and family history of diabetes help identify those HCV patients who might have potential risk factors for development of DM. We observed that insulin resistance in non-diabetic HCV-infected patients was related to grading of liver fibrosis, and occurs already at an early stage in the course of HCV infection.

Early Administration of Vapreotide for Variceal Bleeding in Patients with Cirrhosis

BACKGROUND In patients with cirrhosis, pharmacologic or endoscopic treatment may control variceal bleeding. However, the effects of early administration of a somatostatin analogue followed by endoscopic treatment are unknown. METHODS We studied the effects of treatment with vapreotide, a somatostatin analogue, begun before endoscopic treatment in 227 patients with cirrhosis who were hospitalized for acute upper gastrointestinal bleeding. The patients were randomly assigned to receive vapreotide (a 50-microg intravenous bolus followed by an infusion at a rate of 50 microg per hour for five days) or placebo within a mean (+/-SD) of 2.3+/-1.5 hours after admission. All the patients received endoscopic treatment a mean of 2.6+/-3.3 hours after the infusion was begun. After the exclusion of 31 patients whose bleeding was not caused by portal hypertension, there were 98 patients in each group. RESULTS At the time of endoscopy, active bleeding was evident in 28 of 91 patients in the vapreotide group (31 percent), as compared with 43 of 93 patients in the placebo group (46 percent) (P=0.03). During the five-day infusion, the primary objective--survival and control of bleeding--was achieved in 65 of 98 patients in the vapreotide group (66 percent) as compared with 49 of 98 patients in the placebo group (50 percent) (P=0.02). The patients in the vapreotide group received significantly fewer blood transfusions (2.0+/-2.2 vs. 2.8+/-2.8 units, P=0.04). Overall mortality rates at 42 days were not significantly different in the two groups. CONCLUSIONS In patients with cirrhosis and variceal bleeding, the combination of vapreotide and endoscopic treatment is more effective than endoscopic treatment alone as a method of controlling acute bleeding. However, the use of combination therapy does not affect mortality rates at 42 days.

Quantification of Liver Fat Content: Comparison of Triple-Echo Chemical Shift Gradient-Echo Imaging and in Vivo Proton MR Spectroscopy

PURPOSE To validate a triple-echo gradient-echo sequence for measuring the fat content of the liver, by using hydrogen 1((1)H) magnetic resonance (MR) spectroscopy as the reference standard. MATERIALS AND METHODS This prospective study was approved by the appropriate ethics committee, and written informed consent was obtained from all patients. In 37 patients with type 2 diabetes (31 men, six women; mean age, 56 years), 3.0-T single-voxel point-resolved (1)H MR spectroscopy of the liver (Couinaud segment VII) was performed to calculate the liver fat fraction from the water (4.7 ppm) and methylene (1.3 ppm) peaks, corrected for T1 and T2 decay. Liver fat fraction was also computed from triple-echo (consecutive in-phase, opposed-phase, and in-phase echo times) breath-hold spoiled gradient-echo sequence (flip angle, 20 degrees), by estimating T2* and relative signal intensity loss between in- and opposed-phase values, corrected for T2* decay. Pearson correlation coefficient, Bland-Altman 95% limit of agreement, and Lin concordance coefficient were calculated. RESULTS Mean fat fractions calculated from the triple-echo sequence and (1)H MR spectroscopy were 10% (range, 0.7%-35.6%) and 9.7% (range, 0.2%-34.1%), respectively. Mean T2* time was 14.7 msec (range, 5.4-25.4 msec). Pearson correlation coefficient was 0.989 (P < .0001) and Lin concordance coefficient was 0.988 (P < .0001). With the Bland-Altman method, all data points were within the limits of agreement. CONCLUSION A breath-hold triple-echo gradient-echo sequence with a low flip angle and correction for T2* decay is accurate for quantifying fat in segment VII of the liver. Given its excellent correlation and concordance with (1)H MR spectroscopy, this triple-echo sequence could replace (1)H MR spectroscopy in longitudinal studies.

Visceral fat area is an independent predictive biomarker of outcome after first-line bevacizumab-based treatment in metastatic colorectal cancer

Background Adipose tissue releases angiogenic factors that may promote tumour growth. Objective To determine whether body mass index (BMI), subcutaneous fat area (SFA) and visceral fat area (VFA) are associated with outcomes in patients given first-line bevacizumab-based treatment for metastatic colorectal cancer (MCC). Patients CT was used to measure SFA and VFA in 120 patients with MCC who received bevacizumab-based treatment (bevacizumab group, n=80) or chemotherapy alone (chemotherapy group, n=40) as first-line treatment. Associations linking BMI, SFA and VFA to tumour response, time-to-progression (TTP) and overall survival (OS) were evaluated. Results In the bevacizumab group, median follow-up lasted for 24 months (3–70). BMI, SFA and VFA values above the median (ie, high BMI, high VFA and high SFA) were significantly associated with absence of a response. TTP was shorter in patients with high BMI (9 vs 12 months; p=0.01) or high VFA (9 vs 14 months; p=0.0008). High VFA was associated with shorter OS (p=0.0493). By multivariate analysis, high VFA was independently associated with response, TTP and OS (HR=7.18, p=0.008, HR=5.79, p=0.005 and HR=2.88, p=0.027, respectively). In the chemotherapy group, median follow-up lasted for 30 months (4–84). BMI, SFA and VFA were not associated with response, TTP or OS. In the whole population, interaction between VFA and bevacizumab administration was significant for response (OR=3.31, p=0.005) and TTP (HR=1.64, p=0.022), thereby confirming the results. Conclusion This study provides the first evidence that high VFA independently predicts a poorer outcome in patients given first-line bevacizumab-based treatment for MCC. However, this predictive biomarker needs to be validated in a different dataset.

Hepatitis C virus-associated hypobetalipoproteinemia is correlated with plasma viral load, steatosis, and liver fibrosis

OBJECTIVES:A relationship between chronic hepatitis C virus (HCV) infection and lipid metabolism has recently been suggested. The aim of this study was to determine the correlation between lipid profile and virology, histologic lesions, and response to α interferon therapy in noncirrhotic, nondiabetic patients with hepatitis C.METHODS:A total of 109 consecutive untreated chronic hepatitis C patients were studied to assess the following: 1) the effects of HCV genotype, viral load, steatosis, hepatic fibrosis, and body mass index (BMI) on lipid profile; and 2) whether lipid parameters could predict response to antiviral therapy.RESULTS:The control group showed a significantly higher apolipoprotein B (apoB) concentration compared with patients with chronic hepatitis C. Hypobetalipoproteinemia (apo B <0.7 g/L) was found in 27 (24.7%) chronic HCV patients and in five (5.3%) control subjects (p = 0.0002). Levels of apo B were negatively correlated with steatosis and HCV viral load (r= − 0.22; p = 0.03). This last correlation was strong for non-1 genotype and genotype 3 (r= − 0.48; p = 0.0005, and r= − 0.47; p = 0.007, respectively) but was not found in genotype 1. In multivariate analysis, low apo B concentration was significantly associated with fibrosis grade 2 or 3 versus grade 0 or 1 (p < 0.001), steatosis >5% (p < 0.001), low body mass index (p < 0.001), and high HCV viral load (p < 0.014). No correlation was found in the 76 treated patients between apo B and response to interferon therapy.CONCLUSION:In chronic HCV patients, hypobetalipoproteinemia occurs already in the early stages of HCV infection before the development of liver cirrhosis. The correlation between apo B levels and HCV viral load seems to confirm the interaction between hepatitis C infection and β-lipoprotein metabolism.

Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data.

The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single‐nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta‐analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model = 1.77; 95% confidence interval [CI]: 1.42‐2.19; P = 2.78 × 10−7). This association was more pronounced in ALD (OR = 2.20; 95% CI: 1.80‐2.67; P = 4.71 × 10−15) than in CHC patients (OR = 1.55; 95% CI: 1.03‐2.34; P = 3.52 × 10−2). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development. (Hepatology 2014;59:2170–2177)

Association between Insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing antiretroviral therapy

Summary: Insulin resistance (IR) in the context of highly active antiretroviral therapy (HAART) is becoming more common in HIV‐infected patients. Patients with chronic hepatitis C virus (HCV) infection have an increased risk of IR and type 2 diabetes mellitus. A cross‐sectional study was performed to investigate whether chronic HCV infection constitutes a risk factor for IR in HIV‐HCV‐coinfected patients undergoing HAART. Inclusion criteria were positive HCV viremia and a sustained increase of alanine aminotransferase of at least twice the normal value. A total of 29 HIV‐HCV patients, 76 HIV patients, and 121 HCV controls were tested for IR and body mass index (BMI). IR was measured using the homeostasis model assessment. In HIV‐HCV and HIV patients, fat redistribution and lipid profile were assessed. There was no significant difference in age, CD4 cell count, HIV viral load, or duration of HAART between the HIV‐HCV and HIV groups. HIV‐HCV patients and HCV controls had a significant increase in IR when compared with HIV patients (0.25 ± 0.28 and 0.21 ± 0.34 versus 0.04 ± 0.37; p = .01 and p = .003, respectively). Lipoatrophy was observed more frequently in HIV‐HCV patients in comparison with HIV patients (41% versus 14%; p = .003). In HIV‐HCV patients, total cholesterol and triglyceride levels were significantly lower than in HIV patients. In multivariate analysis, IR, BMI, triglyceride levels, and peripheral fat wasting were the independent variables associated with HCV infection. Our findings suggest that chronic HCV infection is a significant factor associated with the development of metabolic abnormalities and with modifications in body composition in HIV patients receiving antiretroviral treatment.

Visceral fat area as a new independent predictive factor of survival in patients with metastatic renal cell carcinoma treated with antiangiogenic agents.

Purpose. A better identification of patients who are more likely to benefit from vascular endothelial growth factor-targeted therapy is warranted in metastatic renal cell carcinoma (mRCC). As adipose tissue releases angiogenic factors, we determined whether parameters such as visceral fat area (VFA) were associated with outcome in these patients. Experimental Design. In 113 patients with mRCC who received antiangiogenic agents (bevacizumab, sunitinib, or sorafenib) (n = 64) or cytokines (n = 49) as first-line treatment, we used computed tomography to measure VFA and subcutaneous fat area (SFA). We evaluated associations linking body mass index (BMI), SFA, and VFA to time to progression (TTP) and overall survival (OS). Results. High SFA and VFA values were significantly associated with shorter TTP and OS. By multivariate analysis, high VFA was independently associated with shorter TTP and OS. These results were internally validated using bootstrap analysis. By contrast, VFA was not associated with survival in the cytokine group. In the whole population, interaction between VFA and treatment group was significant for TTP and OS, thereby confirming the results. Conclusion. Our study provides the first evidence that high VFA could be a predictive biomarker from shorter survival in patients given first-line antiangiogenic agents for mRCC.