Mariano Cartier

Ciprofloxacin in primary prophylaxis of spontaneous bacterial peritonitis: A randomized, placebo-controlled study

BACKGROUND/AIMS Low protein concentration in ascitic fluid has been identified as a risk factor for spontaneous bacterial peritonitis (SBP). Until now, primary prophylaxis has not been recommended in these patients. The aim was to investigate the efficacy of long-term administration of ciprofloxacin to prevent SBP. METHODS One hundred cirrhotic patients with <1.5 g/dl of total protein in ascitic fluid were randomized prospectively, in a double blind fashion to receive ciprofloxacin 500 mg/day (n=50) or placebo (n=50) for 12 months. RESULTS Baseline data were similar in both groups. In the ciprofloxacin group, SBP occurred almost four times less frequently than in the placebo group but it was not statistically significant. The probability of survival at 12 months was significantly higher in patients receiving ciprofloxacin (86% versus 66%) (p<0.04). SBP and sepsis were the most frequent causes of death in the placebo group whereas gastrointestinal bleeding was responsible for the most deaths in the ciprofloxacin group. The probability of remaining free of bacterial infections was higher in patients receiving ciprofloxacin (80% versus 55%) (p=0.05). CONCLUSIONS Patients with cirrhosis and low protein concentration in ascitic fluid are candidates to receive long-term prophylaxis to reduce the risk of infections and improve survival.

Serum creatinine and bilirubin predict renal failure and mortality in patients with spontaneous bacterial peritonitis: a retrospective study

Background: Patients with spontaneous bacterial peritonitis (SBP) are at a high risk for renal failure and death despite successful treatment of infection. Intravenous (IV) albumin administration combined with antibiotic treatment has been shown to significantly decrease these risks. Clinical evidence is lacking on which patients are appropriate candidates for albumin treatment.

Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: A multicenter prospective study

BACKGROUND & AIM Retrospective studies show an association between proton pump inhibitor (PPI) therapy and spontaneous bacterial peritonitis (SBP). We investigate the relationship between PPI and SBP in decompensated cirrhotic patients in a large nationwide prospective study. METHODS Seven hundred seventy patients with a diagnosis of decompensated cirrhosis were admitted consecutively in 23 hospitals in Argentina from March 2011 to April 2012; the patients were carefully investigated for PPI consumption in the previous 3 months. In total, 251 patients were excluded because of active gastrointestinal hemorrhage, antibiotic use during the preceding weeks, HIV-positive status and immunosuppressive therapy. RESULTS Two hundred twenty-six out of 519 patients (43.5%) had received PPI therapy within the last 3 months. In 135 patients, PPIs were administered for longer than 2 weeks. A bacterial infection was shown in 255 patients (49.1%). SBP was diagnosed in 95 patients out of 394 patients with ascites (24.7%). There was no significant difference in the rate of PPI consumption between the infected and the non-infected patients (44.3% vs. 42.8%) or between the SBP patients and the patients with ascites without SBP (46% vs. 42%). In the SBP patients, the duration of PPI administration did not influence the rate of SBP occurrence. The type of bacteria and the origin of SBP infection were similar in the patients with and without PPI. CONCLUSION In the current large, multicenter, prospective study, PPI therapy, specifically evaluated at admission of consecutive cirrhotic patients, was not associated with a higher risk of SBP.

Immune dysfunction in cirrhosis: Distinct cytokines phenotypes according to cirrhosis severity.

BACKGROUND/OBJECTIVES Cirrhosis associated immune dysfunction has been proposed to switch from a pro-inflammatory phenotype in stable cirrhosis to an immunodeficient one in patients with decompensated cirrhosis and acute-on-chronic liver failure. The aim of the present study was to compare serum cytokine levels between healthy patients, stable cirrhosis, and decompensated cirrhotic patients with and without development of acute-on-chronic liver failure (ACLF); and to explore whether any of the measured cytokines is associated with cirrhosis severity and prognosis in ACLF patients. METHODS Patients were enrolled from October 2013 to May 2014 in two hospitals located in Buenos Aires. Cirrhotic patients with an acute decompensating event were enrolled accordingly to the development of ACLF defined by the CANONIC study group. There were two control groups: healthy subjects (n=14) and stable cirrhotic patients (n=14). Demographic, clinical and biochemical data were obtained. Seventeen cytokines were measured using Bio-Plex Pro Human Cytokine 17-plex Assay. RESULTS Of the 49 decompensated cirrhotic patients enrolled, 18 (36.7%) developed ACLF. Leukocyte count, MELD score at admission, Clif-SOFA at admission and day 7 were significantly higher in the ACLF group (p=0.046, p<0.001, p<0.001, p<0.001 respectively) as well as short-term mortality (p<0.001) compared to stable and decompensated cirrhotic patients. In comparison with healthy controls, stable cirrhotic and decompensated cirrhotic patients showed increased levels of pro-inflammatory and anti-inflammatory cytokines: IL-6, IL-7, IL-8, IL-10, IL 12, and TNF-α. Decompensated cirrhotic patients with the development of ACLF showed a significant decrease of IL-7, IL-10, IL-12, TNF-α, MCP-1 and IFN-γ, but a sustained response of IL-6 and IL-8. When evaluating cirrhosis severity, IL-6 and IL-8 correlated positively with MELD score, whereas only IL-6 correlated positively with Clif-SOFA score at day 7; IL-2 correlated negatively with Clif-SOFA at admission. In comparison with all scores, leukocyte count showed positive correlation and IFN-γ negative correlation with disease severity. When evaluating survival, only MELD and Clif-SOFA scores had a significant association with mortality. CONCLUSIONS Pro-inflammatory cytokines and chemo-attractant elements are increased in cirrhosis in comparison with healthy subjects, and display higher values concomitantly with cirrhosis progression. However, in acute-on-chronic liver failure an opposite cytokine pattern that can be resumed as a combination of immune paresis and excessive inflammatory response was observed. Several pro-inflammatory cytokines (IL-2, IL-6, IL-8 and IFN-γ) showed correlation with disease severity; their utility as prognostic biomarkers needs to be further studied.

Ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin is safe and effective in HCV-infected patients in a real-life cohort from Latin America

Information about the use of ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin (OBV/PTV/r/DSV ± RBV) in real‐clinical practice in Latin America is scarce. We aimed to confirm safety and effectiveness of OBV/PTV/r/DSV ± RBV therapy in real‐world setting. We analyzed a cohort of patients with genotype 1 infection treated with OBV/PTV/r/DSV ± RBV. Data on demographics, clinical features, safety, and virological response were retrospectively collected from 21 centers in Latin America. A total of 96 patients received OBV/PTV/r/DSV, associated with RBV in 68% of the cases. Most were genotype 1b (80%), 56 (58%) had cirrhosis, and 45 (47%) failed prior HCV treatment. Adverse events occurred in 62% of patients. The most common adverse events were pruritus (21%), hyperbilirubinemia (17%), and asthenia (17%). Five patients discontinued therapy prematurely due to hepatic decompensation, three of them were Child‐Pugh B at baseline and one patient died due to multi‐organ failure. Follow up HCV‐RNA 12 weeks after completion of therapy was evaluated in all the patients and sustained virologic response rate was 97%. No virologic breakthrough was detected. Our study confirms that OBV/PTV/r/DSV treatment is highly effective in patients with chronic HCV without cirrhosis or with Child‐Pugh A cirrhosis in non‐European populations. Adverse events were often mild and rarely led to treatment discontinuation except for patients with Child‐Pugh B cirrhosis or with previous history of hepatic decompensation. These results can support the development of public strategies to expand the access of OBV/PTV/r + DSV and other DAAs combinations in order to reduce the burden of HCV infection in our region.

Effectiveness and safety of original and generic sofosbuvir for the treatment of chronic hepatitis C: A real world study

We report the first real‐world prospective multicenter cohort study that evaluated the effectiveness and safety of original or generic sofosbuvir‐based regimens in patients with chronic hepatitis C in Latin America. The main endpoints were assessment of sustained virological response and serious adverse events rates. A total of 321 patients with chronic hepatitis C treated with the following regimens were included: sofosbuvir plus daclatasvir for 12 (n = 34) or 24 (n = 135) weeks, sofosbuvir plus daclatasvir plus ribavirin for 12 (n = 84) or 24 (n = 56) weeks, or sofosbuvir plus ribavirin for 12 (n = 8) or 24 (n = 2) weeks. Patients received either original sofosbuvir (Sovaldi®, Gilead Sciences, n = 135) or generic sofosbuvir (Probirase®, Laboratorios RICHMOND, n = 184) which were randomly assigned by the National Ministry of Health. Overall, 292 (91%) patients had cirrhosis, 136 (42%) were treatment experienced, and 240 (75%) genotype 1. The overall sustained virological response was 90% (95% CI 86‐93%); 91% (95% CI 84‐95%) in patients who received Sovaldi®, and 89% (95% CI 84‐93%) in patients who received Probirase®. Anemia was the most common adverse event and was reported in 52 (17%) patients. Bacterial infection, gastrointestinal bleeding, worsening of ascites or encephalopathy occurred in less than 5% of the patients. During the study, seven (2%) patients died, four of whom died of cirrhosis‐related complications. In summary, we observed similar sustained virological response rates than prior studies, both in patients who received Sovaldi® or Probirase®. Serious adverse events were infrequent, in line with prior studies that included patients with cirrhosis treated with protease‐inhibitor‐free regimes.

T1178 Influence of Primary Sclerosing Cholangitis (PSC) On Ulcerative Colitis (UC) Disease Activity

BODY: The VMP1 gene was characterized by its early and strong expression during the acute phase of pancreatitis. VMP1 is necessary in autophagy and its expression induces the formation of autophagosomes. In order to analyze the function of VMP1 at a molecular level, the purpose of this work was to search for interacting proteins by the Two-Hybrid strategy. This in vivo system is based on putting in contact the protein of interest with each of the proteins that are expressed by a cell line. We amplified by PCR 4 fragments from the VMP1 hydrophilic domains and then subcloned them in the pSOS vector. Three independent Two-Hybrid experiments were performed with each of the VMP1 fragments using a HeLa cells library. The checked positive clones were amplified by PCR, purified and finally sequenced. Of the 94 positive clones that were obtained, 11 of them corresponded to interacting proteins: S100A10, ElF, EEF1G, FADD, HSPA5, AlphaL-1 Fucosidase, Ribosomal protein S10, Kinesin 2, TARBP2, LARP1 y USP9X. A bibliographic search was done for each of the interactors that were found and those related with the role of VMP1 were selected. We started studying the S100A10 protein because it’s over expressed in pancreatic tumors and it’s related with vesicular transport. By performing pull-down essays we could confirmed its interaction with VMP1. Besides this, it was analyzed by confocal microscopy the effect of the interaction between VMP1 and S100A10 on the formation of the autophagosome; the recruitment of the fusion fluorescent protein pRFP-LC3 was used as marker. We found that over expression of S100A10 reduced significantly the recruitment of LC3 induced by VMP1 over expression. In conclusion we were able to find out a group of genes that potentially interact with VMP1 in vivo and we demonstrated that the interaction VMP1S100A10 reduces the formation of autophagosomes. AUTOPHAGY MEDIATED BY VMP1 EXPRESSION IS A SURVIVAL MECHANISM INCAERULEIN-TREATED AR42J PANCREAS CELLS SACCHETTI MARIA L. GRASSO DANIEL, LO RÉ ANDREA, PARDO ROMINA, IOVANNA JUAN L, ROPOLO ALEJANDRO, VACCARO MARIA I 1. School of Medicine, University of Buenos Aires, Buenos Aires,Argentina. 2. Unite 624, INSERM, Marseille, France. ABSTRACT BODY: Autophagy is a degradation process of cytoplasmic cellular constituents, which serves as a survival mechanism in starving cells and it is characterized by sequestration of bulk cytoplasm and organelles in double-membrane vesicles called autophagosomes. Autophagy has been linked to a variety of pathological processes including human and experimental acute pancreatitis. We have recently characterized the Vacuole Membrane Protein 1 (VMP1), which is highly activated in acute pancreatitis, as a new autophagy-related protein that localizes in the membrane of pancreatitis-induced vacuoles. We have also shown that VMP1 is a novel autophagy related membrane protein that triggers autophagosome formation in mammalian cells. Our aim was to study the role of VMP1-induced autophagy in pancreas acinar cells. AR42J cells were cultured in nutrient and grown factor-replete conditions and treated with increasing doses of caerulein (Cae) in a time course scheme. We found that Cae treatment induces VMP1 expression in AR42J cells by RT-PCR and Western Blot analysis. We also found that Cae treatment induces autophagy; it was demonstrated by pRFP-LC3 recruitment and by Western Blot of endogenous LC3. Apart from that, using trypan blue and acrydine orange strategies, it was shown that Cae treatment eventually leads to cell death. Finally, in order to know whether VMP1 expression is directly involved in Cae-induced autophagy, VMP1 expression was silenced using two different specific VMP1-siRNAs. As a result we found out that Cae treatment failed to induce autophagy in VMP1-silenced cells and the effect was rescued after transfecting cells with a VMP1-expression plasmid. Moreover, silencing VMP1 expression decreased significantly AR42J cells survival under Cae treatment. Our results indicate that VMP1 is involved in caerulein-induced autophagy and suggest that VMP1-mediated autophagy is a survival mechanism in AR42J pancreas cells. GASTRIC ACID SUPPRESSION OF ORAL POWDER 20 mg OMEPRAZOLE. PILOT STUDY IN HEALTHY SUBJECTS SOIFER LUIS, PERALTA DANIEL ANGEL, CARUSO NORBERTO 2 1. UNIMOT (Unidad de Motilidad y Patología Funcional Digestiva) – Ciudad Autónoma de Buenos Aires, Argentina 2. Laboratorios Bagó S.A. – Medical Department Ciudad Autónoma de Buenos Aires, Argentina Background: since Omeprazol is acid labile, it is rapidly degraded by gastric acid secretion. The combination of Omeprazol plus sodium bicarbonate and alginic acid could protect Omeprazol from acid degradation and enhance the speediness of action of the proton pump inhibitor. The rapid neutralization of gastric acid produced by sodium bicarbonate activates the proton pumps, rendering them more susceptible to Omeprazol action. Aim: To assess, in healthy subjects, the acid suppression capacity and the speediness of action of an oral powder association (Omeprazol 20 mg plus sodium bicarbonate 1680 mg and alginic acid 250.08 mg) using 24 h pHmetry. Subjects and Method: prospective, open study in 13 healthy subjects (9 women) aged 36.69 ± 8.9 years. Gastric 24 h pHmetry with glass electrode located at 10 cm from lower esophageal sphincter was similarly performed on two different occasions in the same group of healthy subjects (day 0 and day 6). During the first pHmetry 6 subjects received no medication, and 7 took the powder association 2 h before the end of the procedure. The second study was performed with the subjects taking the medication for the six previous days, including the study day. For data comparison non-parametric Wilcoxon test was performed. Measurements: a) time with pH < 4, b) time to reach the maximum pH value, and c) peak pH after first drug administration. Results: the comparison between first and second study shows a significant reduction in gastric acidity. Percentage time pH < 4 Hours Day 0 72.02 ± 20.18 17.28 ± 4.8 Day 6 34.05 ± 20.50 8.17 ± 4.92 p < 0.01 Maximum pH obtained after the first drug administration was 6.98 ± 1.66, and the time to reach the peak was 18.34 ± 9.84 minutes. No adverse events were observed. Conclusion: The results of this study show that this oral powder combination induces significant, fast and intensive acid gastric suppression. This new formulation has a distinct pharmacokinetic and pharmacodynamic profile. Unlike delayed-release proton pump inhibitors, this product provides a rapid and sustained control of gastric acidity.