Hepatocellular carcinoma risk in hepatitis C stage-3 fibrosis after sustained virological response with direct-acting antivirals.

BACKGROUND & AIMS: Patients with chronic hepatitis C and stage 3 fibrosis are thought to remain at risk of hepatocellular carcinoma after sustained virological response. We investigated this risk in a large cohort of patients with well-defined stage 3 fibrosis. METHODS: We performed a multicentre, ambispective, observational study of chronic hepatitis C patients with sustained virological response after treatment with direct-acting antivirals started between January and December 2015. Baseline stage 3 was defined in a two-step procedure: we selected patients with transient elastography values of 9.5-14.5 kPa and subsequently excluded those with nodular liver surface, splenomegaly, ascites or collaterals on imaging, thrombopenia or esophago-gastric varices. Patients were screened twice-yearly using ultrasound. RESULTS: The final sample comprised 506 patients (median age, 57.4 years; males, 59.9%; diabetes, 17.2%; overweight, 44.1%; genotype 3, 8.9%; HIV coinfection, 18.4%; altered liver values, 15.2%). Median follow-up was 33.7 (22.1-39.1) months. Five hepatocellular carcinomas and 1 cholangiocarcinoma were detected after a median of 29.4 months (95% CI: 26.8-39.3), with an incidence of 0.47/100 patients/year (95% CI: 0.17-1.01). In the multivariate analysis, only males older than 55 years had a significant higher risk (hazard ratio 7.2 [95% CI: 1.2-41.7; P = .029]) with an incidence of 1.1/100 patients/year (95% CI: 0.3-2.8). CONCLUSIONS: In a large, well-defined cohort of patients with baseline hepatitis C stage-3 fibrosis, the incidence of primary liver tumours was low after sustained virological response and far from the threshold for cost-effectiveness of screening, except in males older than 55 years.

A Model Based on Noninvasive Markers Predicts Very Low Hepatocellular Carcinoma Risk After Viral Response in Hepatitis C Virus-Advanced Fibrosis.

BACKGROUND AND AIMS: Patients with hepatitis C virus (HCV) and advanced fibrosis remain at risk of hepatocellular carcinoma (HCC) after sustained viral response (SVR) and need lifelong surveillance. Because HCC risk is not homogenous and may decrease with fibrosis regression, we aimed to identify patients with low HCC risk based on the prediction of noninvasive markers and its changes after SVR. APPROACH AND RESULTS: This is a multicenter cohort study, including patients with HCV and compensated advanced fibrosis that achieved SVR after direct antivirals. Clinical and transient elastography (TE) data were registered at baseline, 1 year, and 3 years after the end of treatment (EOT). All patients underwent liver ultrasound scan every 6 months. Patients with clinical evaluation 1 year after EOT were eligible. Univariate and multivariate Cox regression analysis were performed, and predictive models were constructed. HCC occurrence rates were evaluated by Kaplan-Meier. Nine hundred and ninety-three patients were eligible (56% male; 44% female; median age 62 years), 35 developed HCC (3.9%), and the median follow-up was 45 months (range 13-53). Baseline liver stiffness measurement (LSM) (HR 1.040; 95% CI 1.017-1.064), serum albumin (HR 0.400; 95% CI 0.174-0.923), 1-year DeltaLSM (HR 0.993; 95% CI 0.987-0.998), and 1-year FIB-4 score (HR 1.095; 95% CI 1.046-1.146) were independent factors associated with HCC. The TE-based HCC risk model predicted 0% of HCC occurrence at 3 years in patients with score 0 (baseline LSM ≤ 17.3 kPa, albumin >4.2 g/dL, and 1-year DeltaLSM > 25.5%) versus 5.2% in patients with score 1-3 (Harrell's C 0.779; log-rank 0.002). An alternative model with FIB-4 similarly predicted HCC risk. CONCLUSIONS: A combination of baseline and dynamic changes in noninvasive markers may help to identify patients with a very low risk of HCC development after SVR.

Reflex testing. A key tool for the elimination of hepatitis C.

Hepatitis C is a major cause of liver cirrhosis and hepatocellular carcinoma, as well as the primary indication for liver transplant in Europe. The highly effective direct-acting antivirals currently available make it possible to achieve the hepatitis C elimination targets set by the World Health Organization. For this, population screening and reflect testing are fundamental strategies.

Digestive units in the National Health System of the 21st century. Organizational and management standards for a patient-centered service.

The Spanish Society of Digestive Pathology has set a consensus document on the standards and recommendations for gastroenterology units (GU). These standards are considered as relevant in the organization and management of the unit to develop their activities with efficiency and quality. Four key groups of processes have been identified: a) care for the acutely ill adult patient; b) outpatient digestive endoscopy; c) in-hospital support to other services and outpatient clinics; and d) management of patients with chronic complex digestive pathology. Standards for organization and management of the unit were classified within the group of support processes, and training and research as strategic processes. Standards have also been developed for some functional and monographic units such as endoscopy, hepatology and inflammatory bowel disease; as well as for certain procedures including endoscopic retrograde cholangiopancreatography, colonoscopy and gastroscopy. The standards will be set for other units and procedures as they are developed. The standards developed must be reviewed within a maximum period of five years.

Clinical Outcome Event Adjudication in a 10-Year Prospective Study of Nucleos(t)ide Analogue Therapy for Chronic Hepatitis B.

Background and Aims: In the REALM (Randomized, Observational Study of Entecavir to Assess Long-Term Outcomes Associated with Nucleoside/Nucleotide Monotherapy for Patients with Chronic HBV Infection) study, 12,378 patients with chronic hepatitis B virus (HBV) infection received up to 10 years of randomized therapy with entecavir or another HBV nucleos(t)ide analogue. Monitored clinical outcome events (COEs) included malignant neoplasms, HBV disease progression events, and deaths. An external event adjudication committee (EAC) was convened to provide real-time review of reported COEs to optimize data quality, and minimize potential adverse effects of the large cohort, interdisciplinary outcome assessments, geographic scope, and long duration. Methods: The EAC comprised an international group of hepatologists and oncologists with expertise in diagnosis of targeted COEs. The EAC reviewed and adjudicated COEs according to prospectively defined diagnostic criteria captured in the EAC charter. Operational processes, including data collection and query procedures, were implemented to optimize efficiency of data recovery to maximize capture of adjudicated COEs, the primary study outcome measure. Results: A total of 1724 COEs were reported and 1465 of these events were adjudicated by the EAC as reported by the investigators (85.0% overall concordance). Concordance by COE type varied: deaths, 99.6%; hepatocellular carcinoma (HCC), 83.3%; non-HCC malignancies, 88.0%; non-HCC HBV disease progression, 68.2%. Reasons for lack of concordance were most commonly lack of adequate supporting data to support an adjudicated diagnosis or evidence that the event pre-dated the study. Conclusions: The REALM EAC performed a critical role in ensuring data quality and consistency; EAC performance was facilitated by well-defined diagnostic criteria, effective data capture, and efficient operational processes. Trial registration: ClinicalTrials.gov NCT00388674.

Higher levels of serum uric acid influences hepatic damage in patients with non-alcoholic fatty liver disease (NAFLD).

BACKGROUND: recent evidence suggests a causal link between serum uric acid and the metabolic syndrome, diabetes mellitus, arterial hypertension, and renal and cardiac disease. Uric acid is an endogenous danger signal and activator of the inflammasome, and has been independently associated with an increased risk of cirrhosis. AIM AND METHODS: six hundred and thirty-four patients from the nation-wide HEPAMET registry with biopsy-proven NAFLD (53% NASH) were analyzed to determine whether hyperuricemia is related with advanced liver damage in patients with non-alcoholic fatty liver disease (NAFLD). Patients were divided into three groups according to the tertile levels of serum uric acid and gender. RESULTS: the cohort was composed of 50% females, with a mean age of 49 years (range 19-80). Patients in the top third of serum uric acid levels were older (p = 0.017); they had a higher body mass index (p < 0.01), arterial blood pressure (p = 0.05), triglyceridemia (p = 0.012), serum creatinine (p < 0.001) and total cholesterol (p = 0.016) and lower HDL-cholesterol (p = 0.004). According to the univariate analysis, the variables associated with patients in the top third were more advanced steatosis (p = 0.02), liver fibrosis (F2-F4 vs F0-1; p = 0.011), NASH (p = 0.002) and NAS score (p = 0.05). According to the multivariate logistic regression analysis, the top third of uric acid level was independently associated with steatosis (adjusted hazard ratio 1.7; CI 95%: 1.05-2.8) and NASH (adjusted hazard ratio 1.8; CI 95%: 1.08-3.0) but not with advanced fibrosis (F2-F4) (adjusted hazard ratio 1.09; CI 95%: 0.63-1.87). CONCLUSION: higher levels of serum uric acid were independently associated with hepatocellular steatosis and NASH in a cohort of patients with NAFLD. Serum uric acid levels warrants further evaluation as a component of the current non-invasive NAFLD scores of histopathological damage.

Upcoming pharmacological developments in chronic hepatitis B: can we glimpse a cure on the horizon?

BACKGROUND: Hepatitis B virus (HBV) chronic infection affects up to 240 million people in the world and it is a common cause of cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) plays an essential role in HBV persistence and replication. Current pharmacological treatment with nucleos(t)ide analogues (NA) may suppress HBV replication with little or no impact on cccDNA, hence lifelong treatment is required in the vast majority of patients. Clearances of intrahepatic cccDNA and/or HBsAg are critical endpoints for future antiviral therapy in chronic HBV. Recent promising developments targeting different molecular HBV life cycle steps are being pre-clinically tested or have moved forward in early clinical trials. METHODS: We review the current state of the art of these pharmacological developments, mainly focusing on efficacy and safety results, which are expected to lay the ground for future HBV eradication. An inclusive literature search on new treatments of HBV using the following electronic databases: Pubmed/MEDLINE, AMED, CINAHL and the Cochrane Central Register of Controlled Trials. Full-text manuscripts and abstracts published over the last 12 years, from 2005 to March 2011 were reviewed for relevance and reference lists were crosschecked for additional applicable studies regarding new HBV antiviral treatment. RESULTS: HBV entry inhibitors, HBV core inhibitors, HBV cccDNA transcripts RNA interference, HBV cell apoptosis inducers, HBV RNA, viral proteins and DNA knock down agents, HBV release inhibitors, anti-sense nucleosides, exogenous interferon stimulation, interferon response stimulation and HBV therapeutic vaccines were reviewed. CONCLUSION: This review will provide readers with an updated vision of current and foreseeable therapeutic developments in chronic hepatitis B.

Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. METHODS: Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. RESULTS: Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1-59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9-8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0-4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0-11.4) among those with cirrhosis (p=0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0-5.5) among patients <45years, 9.7% (95% CI 5.8-13.6) among patients from 45-60years, and 12.2% (95% CI 5.3-19.1) among patients >60years of age at start of therapy (p=0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8years 4.2% (95% CI 0.1-8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3-19.3) of patients with cirrhosis experienced clinical disease progression (p=0.007). CONCLUSIONS: Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. LAY SUMMARY: Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer.

Factores de riesgo de la enfermedad hepática grasa no alcohólica / Risk factors for non-alcoholic fatty liver disease

Prevalence of non-alcoholic fatty liver disease (NAFLD) may be 10%-15% worldwide, and these figures are even higher in obese and in type 2 diabetes mellitus patients. The most important risk factor is metabolic syndrome, especially central obesity. Even though the majority of patients with macrovesicular steatohepatitis will not progress to advanced liver disease, a subgroup of patients will evolve to non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. Independent risk factors associated with NASH are older age, type 2 diabetes mellitus and obesity. Patients with significant hepatocellular lesion, such as hepatocyte ballooning, Mallory hyalline or fibrosis, have a higher risk of cirrhosis and are more likely to have a high liver-related mortality, although higher global mortality has not been demonstrated. Although NASH related cirrhosis may have better prognosis compared to hepatitis C cirrhosis, recent series suggest that it may be the third cause of liver transplantation. Steatosis, NASH and cirrhosis recurrence post-liver transplantation is common. The risk of hepatocellular carcinoma (HCC) is increased in patients with NAFLD, and all patients with cryptogenic cirrhosis should be screened for HCC

La enfermedad hepática grasa no alcohólica puede afectar al 15%-25% de la población, con cifras mayores en pacientes obesos y con diabetes mellitus tipo 2. El principal factor de riesgo es el síndrome metabólico, especialmente la obesidad central. Aunque la mayoría de los pacientes con esteatosis macrovacuolar simple no presentan progresión de su enfermedad, existe un subgrupo que progresa a esteatohepatitis no alcohólica, y aunque se desconocen los factores de riesgo para esta progresión, la mayoría de los estudios reconocen la edad, la presencia de diabetes mellitas tipo 2 y la obesidad como predictores de riesgo independientes de EHNA. La presencia de lesión hepatocelular significativa, como el abalonamiento hepatocitario o la hialina de Mallory y la fibrosis, incrementan significativamente el riesgo de cirrosis. Los pacientes que tienen esta lesión histopatológica presentan una mortalidad de causa hepática superior, si bien no se ha demostrado una mortalidad global aumentada. Aunque la cirrosis secundaria a esteatohepatitis no alcohólica parece tener un pronóstico ligeramente mejor que la secundaria a hepatitis C, en muchas series es la tercera causa de trasplante ortotópico de hígado. La recurrencia postrasplante de la esteatosis, de la esteatohepatitis no alcohólica y de la cirrosis es frecuente. Existe un aumento del riesgo de hepatocarcinoma en pacientes con enfermedad hepática grasa no alcohólica. En la actualidad se recomienda el seguimiento para la detección precoz de este tumor en todos los pacientes con cirrosis criptogénica

Labour productivity losses caused by premature death associated with hepatitis C in Spain.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) infection places a huge burden on healthcare systems. There is no study assessing the impact of HCV infection on premature deaths in Spain. The aim of this study was to estimate productivity losses because of premature deaths attributable to hepatitis C occurring in Spain during 2007-2011. MATERIALS AND METHODS: We use data from several sources (Registry of Deaths, Labour Force Survey and Wage Structure Survey) to develop a simulation model based on the human capital approach and to estimate the flows in labour productivity losses in the period considered. The attributable fraction method was used to estimate the numbers of deaths associated with HCV infection. Two sensitivity analyses were developed to test the robustness of the results. RESULTS: Our model shows total productivity losses attributable to HCV infection of 1054.7 million euros over the period analysed. The trend in productivity losses is decreasing over the period. This result is because of improvements in health outcomes, reflected in the reduction of the number of years of potential productive life lost. Of the total estimated losses, 18.6% were because of hepatitis C, 24.6% because of hepatocellular carcinoma, 30.1% because of cirrhosis, 15.9% because of other liver diseases and 10.7% because of HIV-HCV coinfection. CONCLUSION: The results show that premature mortality attributable to hepatitis C involves significant productivity losses. This highlights the need to extend the analysis to consider other social costs and obtain a more complete picture of the actual economic impact of hepatitis C infection.

A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells.

The multikinase inhibitor sorafenib is the only effective drug in advanced cases of hepatocellular carcinoma (HCC). However, response differs among patients and effectiveness only implies a delay. We have recently described that sorafenib sensitizes HCC cells to apoptosis. In this work, we have explored the response to this drug of six different liver tumor cell lines to define a phenotypic signature that may predict lack of response in HCC patients. Results have indicated that liver tumor cells that show a mesenchymal-like phenotype, resistance to the suppressor effects of transforming growth factor beta (TGF-ß) and high expression of the stem cell marker CD44 were refractory to sorafenib-induced cell death in in vitro studies, which correlated with lack of response to sorafenib in nude mice xenograft models of human HCC. In contrast, epithelial-like cells expressing the stem-related proteins EpCAM or CD133 were sensitive to sorafenib-induced apoptosis both in vitro and in vivo. A cross-talk between the TGF-ß pathway and the acquisition of a mesenchymal-like phenotype with up-regulation of CD44 expression was found in the HCC cell lines. Targeted CD44 knock-down in the mesenchymal-like cells indicated that CD44 plays an active role in protecting HCC cells from sorafenib-induced apoptosis. However, CD44 effect requires a TGF-ß-induced mesenchymal background, since the only overexpression of CD44 in epithelial-like HCC cells is not sufficient to impair sorafenib-induced cell death. In conclusion, a mesenchymal profile and expression of CD44, linked to activation of the TGF-ß pathway, may predict lack of response to sorafenib in HCC patients.

Prevention of hepatocellular carcinoma in patients with chronic hepatitis B.

Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma (HCC). Globally, over half a million people each year are diagnosed with HCC, with marked geographical variations. Despite overwhelming evidence for a causal role of hepatitis B virus (HBV) infection in the development of HCC and a well-established relationship between high baseline hepatitis B viral load and cumulative risk of HCC, the molecular basis for this association has not been fully elucidated. In addition, a beneficial role for antiviral therapy in preventing the development of HCC has been difficult to establish. This review examines the biological and molecular mechanisms of HBV-related hepatocarcinogenesis, recent results on the effect of modern nucleos(t)ides on the rate of HCC development in high risk HBV cohorts and the potential mechanisms by which long-term antiviral therapy with potent inhibitors of HBV replication might reduce the risk of HCC in patients with chronic hepatitis B. Although evidence from randomized controlled trials shows the favourable effects of antiviral agents in achieving profound and durable suppression of HBV DNA levels while improving liver function and histology, robust evidence of other long-term clinical outcomes, such as prevention of HCC, are limited.

[Impact of antiviral therapy on the natural history of hepatitis C virus]. / Impacto del tratamiento antiviral en la historia natural del virus de la hepatitis C.

Chronic hepatitis C virus infection affects around 150 million persons, and 350,000 persons worldwide die of this disease each year. Although the data on its natural history are incomplete, after the acute infection, most patients develop chronic forms of hepatitis C with variable stages of fibrosis. In these patients, continual inflammatory activity can cause significant fibrosis, cirrhosis, decompensation of the liver disease, or hepatocarcinoma. In the next few years, it is expected that hepatitis C virus infection and its complications will significantly increase, as will the incidence of hepatocarcinoma in Spain. This review presents the data on the natural history of hepatitis C virus infection and discusses the potential impact of antiviral therapy on the distinct stages of the disease.

NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.

A role for the NADPH oxidases NOX1 and NOX2 in liver fibrosis has been proposed, but the implication of NOX4 is poorly understood yet. The aim of this work was to study the functional role of NOX4 in different cell populations implicated in liver fibrosis: hepatic stellate cells (HSC), myofibroblats (MFBs) and hepatocytes. Two different mice models that develop spontaneous fibrosis (Mdr2(-/-)/p19(ARF-/-), Stat3(Δhc)/Mdr2(-/-)) and a model of experimental induced fibrosis (CCl(4)) were used. In addition, gene expression in biopsies from chronic hepatitis C virus (HCV) patients or non-fibrotic liver samples was analyzed. Results have indicated that NOX4 expression was increased in the livers of all animal models, concomitantly with fibrosis development and TGF-ß pathway activation. In vitro TGF-ß-treated HSC increased NOX4 expression correlating with transdifferentiation to MFBs. Knockdown experiments revealed that NOX4 downstream TGF-ß is necessary for HSC activation as well as for the maintenance of the MFB phenotype. NOX4 was not necessary for TGF-ß-induced epithelial-mesenchymal transition (EMT), but was required for TGF-ß-induced apoptosis in hepatocytes. Finally, NOX4 expression was elevated in patients with hepatitis C virus (HCV)-derived fibrosis, increasing along the fibrosis degree. In summary, fibrosis progression both in vitro and in vivo (animal models and patients) is accompanied by increased NOX4 expression, which mediates acquisition and maintenance of the MFB phenotype, as well as TGF-ß-induced death of hepatocytes.

Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli.

Sorafenib increases survival rate of patients with advanced hepatocellular carcinoma (HCC). The mechanism underlying this effect is not completely understood. In this work we have analyzed the effects of sorafenib on autocrine proliferation and survival of different human HCC cell lines. Our results indicate that sorafenib in vitro counteracts autocrine growth of different tumor cells (Hep3B, HepG2, PLC-PRF-5, SK-Hep1). Arrest in S/G2/M cell cycle phases were observed coincident with cyclin D1 down-regulation. However, sorafenib's main anti-tumor activity seems to occur through cell death induction which correlated with caspase activation, increase in the percentage of hypodiploid cells, activation of BAX and BAK and cytochrome c release from mitochondria to cytosol. In addition, we observed a rise in mRNA and protein levels of the pro-apoptotic "BH3-domain only" PUMA and BIM, as well as decreased protein levels of the anti-apoptotic MCL1 and survivin. PUMA targeting knock-down, by using specific siRNAs, inhibited sorafenib-induced apoptotic features. Moreover, we obtained evidence suggesting that sorafenib also sensitizes HCC cells to the apoptotic activity of transforming growth factor-ß (TGF-ß) through the intrinsic pathway and to tumor necrosis factor-α (TNF) through the extrinsic pathway. Interestingly, sensitization to sorafenib-induced apoptosis is characteristic of liver tumor cells, since untransformed hepatocytes did not respond to sorafenib inducing apoptosis, either alone or in combination with TGF-ß or TNF. Indeed, sorafenib effectiveness in delaying HCC late progression might be partly related to a selectively sensitization of HCC cells to apoptosis by disrupting autocrine signals that protect them from adverse conditions and pro-apoptotic physiological cytokines.

Influence of occult hepatitis B virus infection in chronic hepatitis C outcomes.

Persistence of hepatitis B virus-DNA in the sera, peripheral blood mononuclear cells or in the liver of hepatitis B surface antigen (HBsAg)-negative patients with or without serological markers of previous exposure (antibodies to HBsAg and/or to HB-core antigen) defines the entity called occult hepatitis B infection (OBI). Co-infection with hepatitis B and hepatitis C viruses is frequent in highly endemic areas. While this co-infection increases the risk of liver disease progression, development of cirrhosis and hepatocellular carcinoma and also increases the rate of therapeutic failure to interferon-based treatments than either virus alone, a potentially negative effect of OBI on clinical outcomes and of therapeutic response to current antiviral regimes of patients with chronic hepatitis C remains inconclusive.

Peginterferon plus ribavirin and sustained virological response in HCV-related cirrhosis: outcomes and factors predicting response.

OBJECTIVES: Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response. METHODS: Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS: Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1-81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353-7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752-5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418-6.927); baseline viral load <6 × 10(5) (OR=2.597; 95% CI: 1.583-4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26-3.39). No patient with a HCV-RNA decline <1 log(10) at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32-5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81-5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546-4). Improved outcome was more evident in responders with less advanced disease at baseline. CONCLUSIONS: SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.

Environmental risk factors in inflammatory bowel diseases. Investigating the hygiene hypothesis: a Spanish case-control study.

OBJECTIVE: Environmental factors have been implicated in the etiology of inflammatory bowel disease (IBD), but evidence for the hygiene hypothesis is unclear. We investigated the relationship between early-life infection-related exposures and risk of IBD. PATIENTS AND METHODS: A hospital-based case-control study was carried out. A total of 124 cases of Crohn's disease (CD) and 146 of ulcerative colitis (UC) were compared with 235 and 278 well-matched control subjects, respectively. A multi-item questionnaire on familial history of IBD, childhood circumstances and familial socioeconomic status was carried out. RESULTS: In a multivariate model, living in urban areas (odds ratio (OR) 4.58 (95% CI 2.17-10)), high educational level (OR 1.83 (95% CI 14-2.95)) and social status (OR 1.68 (95% CI 1.2-2.35)) were risk factors for CD, whereas childhood respiratory infections (OR 0.35 (95% CI 0.23-0.52)) and gastroenteritis (OR 0.55 (95% CI 0.36-0.85)) were protective factors. Living in urban areas (OR 4.6 (95% CI 2.29-9.9)), a high educational level (OR 10.3 (95% CI 2.54-42.1)) and social status (OR 2.042 (95% CI 1.31-3.17)) were also risk factors for UC, whereas respiratory infections (OR 0.42 (95% CI 0.29-0.6)) and gastroenteritis (OR: 0.6 (95% CI 0.42-0.86)) were protective factors. Appendectomy (OR 0.173 (95% CI 0.06-0.52)) and current smoking (OR 0.75 (95% CI 0.59-0.96)) were also protective for UC. CONCLUSION: These results further support the hypothesis that better living conditions during childhood are associated with an increased risk for IBD, and reinforce the negative association between smoking and appendectomy and the risk of UC.