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International audience; Various critical events, liver related or not, occur in patients with compensated cirrhosis, but their respective burden remains to be prospectively assessed. The aim of this prospective cohort study involving 35 French centers was to capture the whole spectrum of complications occurring in compensated viral cirrhosis (VC) using competing risks analyses. Inclusion criteria were: histologically proven cirrhosis resulting from hepatitis C virus (HCV) or hepatitis B virus (HBV); Child-Pugh A; and no previous hepatic complications. The cohort was considered as a multistate disease model, cumulative incidences (CumIs) of events were estimated in a competing risks framework. A total of 1,654 patients were enrolled from 2006 to 2012 (HCV, 1,308; HBV, 315; HCV-HBV, 31). During a median follow-up of 34 months, at least one liver nodule was detected in 271 patients, confirmed as hepatocellular carcinoma (HCC) in 128 (4-year cumI: 10.5%) and cholangiocarcinoma in 3. HCC incidence was higher in HCV (4-year cumI: 11.4% vs. 7.4%; P = 0.05). HCC fulfilled Milan criteria in 79.3%, leading to curative treatment in 70.4%. Liver decompensation occurred more frequently in HCV patients (4-year cumI: 10.8% vs. 3.6%; P = 0.0004). Virological eradication/control was achieved in 34.1% of HCV and 88.6% of HBV patients and was associated with a marked decrease in HCC, decompensation, and bacterial infection incidences. Survival was shorter in HCV patients (4-year cumI: 91.6% vs. 97.2%; P = 0.0002). Death (n = 102; missing data: 6) was attributed to liver disease in 48 (47%; liver cancer: n = 18; miscellaneous, n = 30) and extrahepatic causes in 48 (47%; bacterial infection: n = 13; extrahepatic cancers: n = 10; cardiovascular events: n = 5; miscellaneous, n = 20). CONCLUSION: After 3 years of follow-up, extrahepatic events still explained half of deaths in patients with compensated VC. A strong decrease in complications was linked to virological eradication/control. (Hepatology 2015;62:737-750)

Presence of clots in the stomach makes emergency endoscopy difficult in patients with upper gastrointestinal bleeding. We investigated whether the association of erythromycin infusion to gastric lavage could improve stomach cleansing before endoscopy.One hundred patients admitted for upper gastrointestinal bleeding were randomly assigned to receive either gastric lavage plus intravenous erythromycin (250 mg) or gastric lavage plus placebo before endoscopy in a double-blind study. The primary end point was the efficacy of intravenous erythromycin to improve stomach cleansing before endoscopy, assessed by both subjective and objective criteria.Characteristics of patients at admission were similar in both groups. Sixty-six patients had portal hypertension. The gastric mucosa was entirely visualized by the endoscopist in 65% of patients in the erythromycin group, versus 44% in the placebo group (p0.05). The quality of examination of the upper gastrointestinal tract, assessed by using a 10-cm visual analog scale, was better in the erythromycin group (4.2+/-2 vs. 3.3+/-2.2, p0.05). Clots were found in the stomach in 30% of patients in the erythromycin group, versus 52% in the placebo group (p0.05). However, ability to identify the source of bleeding, mean duration of endoscopy, and need for a second-look endoscopy, did not differ between the two groups. Similar results were observed in the subgroup of cirrhotic patients. Erythromycin was well tolerated by all patients.Intravenous erythromycin before endoscopy improves stomach cleansing and quality of endoscopic examination in patients with upper gastrointestinal bleeding, but the clinical benefit is limited.

Background HIV-infected patients with HAART-related lipodystrophy are frequently insulin resistant and at risk of non-alcoholic fatty liver disease (NAFLD) with steatohepatitis (NASH). The transcription factors, peroxisome proliferator activated receptors (PPARalpha, PPARgamma1/PPARgamma2) and sterol regulatory element binding proteins (SREBP-1) regulate liver lipid metabolism. Here, we examined whether their expression was modified and related to liver injury in HIV-infected patients. Methods Fourteen HAART-treated HIV patients (nine with and five without insulin resistance) who had liver biopsy because of unexplained elevated transaminases were compared with nine non-HIV age-and body mass index-matched patients with NAFLD and 10 controls without steatosis. Hepatic expression of PPARs and SREBP-1 was assessed by real time reverse transcriptase-polymerase chain reaction. Results Liver histology showed NASH in six of nine insulin-resistant lipodystrophic and two of five non-insulin-resistant HIV patients. Compared with NAFLD or control subjects, expression of SREBP-1 was significantly higher only in HIV-insulin-resistant patients (P = 0.04 and P = 0.02) whereas, compared to controls, HIV-insulin-resistant, HIV-non-insulin-resistant and NAFLD patients had lower expressions of PPARgamma1 (P = 0.03, P = 0.05 and P = 0.01) and PPARgamma2 (P = 0.04, P = 0.05 and P = 0.01). Among HIV patients, the percentage of steatosis was positively correlated with SREBP-1 expression (r = 0.62, P = 0.04) whereas the score of fibrosis was inversely correlated with PPARgamma1 and PPARgamma2 expression (r = -0.57, P = 0.03 and r = -0.6, P = 0.02, respectively). Conclusion Insulin-resistant lipodystrophic HIV-infected patients may develop NASH. Steatosis is associated with overexpression of SREBP-1 and fibrosis with decreased expression of PPARgamma1 and PPARgamma2. These results suggest that altered expression of SREBP-1 and PPARgamma could contribute to the pathogenesis of steatosis and fibronecrotic changes in insulin-resistant lipodystrophic patients.

Whether primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome requires immunosuppressive therapy in addition to ursodeoxycholic acid (UDCA) is a controversial issue.Seventeen patients with simultaneous form of strictly defined overlap were followed for 7.5 years. First-line treatment was UDCA alone (UDCA) in 11 and combination of immunosuppressors and UDCA (UDCA + IS) in 6.Characteristics at presentation were not significantly different between the 2 groups. In the UDCA + IS group (f-up 7.3 years), biochemical response in terms of AIH features (ALT2ULN and IgG16 g/L) was achieved in 4/6 and fibrosis did not progress. In the UDCA group, biochemical response was observed in three patients together with stable or decreased fibrosis (f-up 4.5 years) whereas the eight others were non-responders with increased fibrosis in four (f-up 1.6 years). Seven of these eight patients subsequently received combined therapy for 3 years. Biochemical response was obtained in 6/7 and no further increase of fibrosis was demonstrated. Overall, fibrosis progression in non-cirrhotic patients occurred more frequently under UDCA monotherapy (4/8) than under combined therapy (0/6) (P = 0.04).Combination of UDCA and immunosuppressors appears to be the best therapeutic option for strictly defined PBC-AIH overlap syndrome.

The long-term impact of tenofovir disoproxil fumarate (TDF) on hepatitis B virus (HBV) replication has not yet been studied in HIV-HBV-co-infected patients.We conducted a prospective study of HBV-DNA decay kinetics in 28 HIV-HBV-co-infected patients treated by TDF. HBV dynamics were studied using mixed linear models, and baseline factors affecting them were analysed using Cox models.The HBV-DNA load declined by a mean of 4.6 log copies/ml during follow-up (mean 71 weeks), and fell below the detection limit (200 copies/ml) in 21 patients. Inhibition of viral replication by TDF was associated with a decrease in alanine aminotransferase levels (125 versus 68 IU, P0.05). HBV-DNA decay was biphasic, with an rapid fall followed by a gradual decline. Baseline factors associated with a steeper first slope in the HBV-DNA decrease were high HBV load, positive hepatitis B e antigen (HBeAg) and YMDD mutations. Baseline factors increasing the time to reach an HBV-DNA level less than 200 copies/ml were high HBV load (150 days when HBV-DNA10 log, 316 days when HBV-DNA10 log) and positive HBeAg. Previous exposure to lamivudine or TDF-lamivudine did not modify HBV-DNA decrease under therapy in this population with a high prevalence of YMDD mutations.The long-term decline in HBV DNA under TDF is biphasic and is primarily influenced by the initial HBV load. However, the clinical significance of such an association remains moderate, and TDF can be efficiently included in the highly active antiretroviral therapy regimen of HIV-HBV-co-infected patients, regardless of HBV strains and their degree of replication.

Patients with obstructive sleep apnea (OSA) are at risk for the development of fatty liver as a result of being overweight. Several data suggest that OSA per se could be a risk factor of liver injury; ischemic hepatitis during OSA has been reported, and OSA is an independent risk factor for insulin resistance. Therefore, we investigated liver damage and potential mechanisms in 163 consecutive nondrinking patients with nocturnal polysomnographic recording for clinical suspicion of OSA. Serum levels of liver enzymes were measured in all patients. Liver biopsy was offered to patients with elevated liver enzymes. Intrahepatic hypoxia was assessed by the expression of vascular endothelial growth factor (VEGF) on liver biopsy specimens. Severe OSA (apnea-hypopnea index [AHI] > 50/hr) was seen in 27% of patients; 52% had moderate OSA (AHI 10-50/hr), and 21% had no OSA. Overall, 20% had elevated liver enzymes. Independent parameters associated with elevated liver enzymes were body mass index (BMI) (OR: 1.13; CI: 1.03-1.2) and severe OSA (OR: 5.9; CI: 1.2-29). Liver biopsy was performed in 18 of 32 patients with elevated liver enzymes and showed steatohepatitis in 12 cases, associated with fibrosis in 7 cases. Patients with severe OSA were more insulin-resistant according to homeostasis model assessment, had higher percentage of steatosis as well as scores of necrosis and fibrosis, despite similar BMI. Hepatic immunostaining used as an indirect marker of hypoxia was not different between patients with or without severe OSA. In conclusion, severe OSA is a risk factor for elevated liver enzymes and steatohepatitis independent of body weight. Promotion of insulin resistance is probably involved. Further studies are needed to determine whether hypoxia contributes directly to liver injury. (HEPATOLOGY 2005;41:1290–1296.)

OBJECTIVES: During the progression of chronic liver disease towards cirrhosis, morphological studies have shown a close association between parenchymal remodeling and obliterative lesions of intrahepatic small portal and hepatic veins. These lesions are highly suggestive of intrahepatic thrombotic events, which may have a key role in the pathogenesis of hepatic fibrosis. The aim of the study was to investigate thrombotic risk factors in chronic hepatitis C patients with different extent of liver fibrosis. METHODS: The following thrombotic factors were evaluated in 68 hepatitis C patients with prothrombin activity >/= 80% (34 consecutive patients with extensive fibrosis and/or cirrhosis compared with 34 consecutive patients without extensive fibrosis and/or cirrhosis): factor V Leiden, G20210A prothrombin mutation, antithrombin, protein C and S deficiencies, hyperhomocysteinemia, elevated factor VIII level, and lupus anticoagulant. RESULTS: Three thrombotic risk factors were significantly more frequent in patients with extensive fibrosis and/or cirrhosis than in those without extensive fibrosis: protein C deficiency present in 14 patients (41%) as compared with three patients (9%), p= 0.004; elevated factor VIII level present in 19 patients (56%) as compared with six patients (18%), p= 0.002; and hyperhomocysteinemia present in 10 patients (29%) as compared with two patients (6%), p= 0.023. The association of two or three prothrombotic factors was present in 19 patients (56%) with extensive fibrosis and/or cirrhosis as compared with one patient (3%) without extensive fibrosis and/or cirrhosis, p < 0.001. CONCLUSION: Multiple thrombotic risk factors coexist frequently in patients with extensive fibrosis and early stage of cirrhosis. Their association with local inflammation could favor thrombotic events in the liver micro-circulatory bed.

The aim of this retrospective study was to determine the potential reversibility of hepatitis C virus (HCV) cirrhosis with the combined antifibrotic effects of interferon-alpha and the increasing frequency of sustained virologic response. Sixty-four HCV-cirrhotic immunocompetent patients who underwent antiviral therapies (interferon-alpha with or without ribavirin) and pretreatment and posttreatment liver biopsies were included (group 1). Resolution of cirrhosis was defined as a decrease in the fibrosis score from 4 to 2 or less by the Metavir score after blinded analysis by 2 independent pathologists. An additional group of 4 HCV-infected dialysis patients (group 2) who had received antiviral treatment, among whom 3 underwent a combined renal and liver transplantation allowing the analysis of the whole liver, was also studied. In 5 (all stage Child A) of the 64 cirrhotic patients (7.8%), the final biopsy showed only F2 to portal and periportal fibrosis with rare fibrous septa without nodule formation. Four of these 5 were complete sustained responders (negative PCR and normal ALT), and 1 was a relapser. In group 2, reversibility of cirrhosis was observed in 3 of the 4 patients and was clearly shown in 2 patients by the analysis of the whole-liver examination at the time of the hepatectomy preceding the transplantation. In conclusion, long-lasting suppression of the necroinflammatory activity of liver disease and/or antifibrogenetic effects of interferon-alpha may allow regression of cirrhosis.

Early identification of patients with severe (discriminant function ≥32) biopsy-proven alcoholic hepatitis (AH) who are not responding to corticosteroids would be clinically relevant. Our goal was to develop simple criteria that will help physicians to promptly identify nonresponders to corticosteroids. A total of 238 patients were included. We used 6 months survival as an end point because of the rule requiring 6 months for listing alcoholic patients for transplantation. Overall survival at 1 and 6 months was 85% ± 2.3% and 64.3% ± 3.3%, respectively. An early change in bilirubin levels (ECBL) at 7 days (defined as bilirubin level at 7 days lower than bilirubin level on the first day of treatment) was observed in 73% of patients. At 7 days, in patients with ECBL, bilirubin decreased (84 ± 75 μmol/L [4.94 ± 4.40 mg/dL]), whereas it increased in patients without ECBL (76.5 ± 77 μmol/L [4.50 ± 4.54 mg/dL], P < .0001). Ninety-five percent of patients with ECBL continued to have improved liver function during treatment. At 6 months, survival of patients with ECBL was significantly higher than that of patients without ECBL, 82.8% ± 3.3% versus 23% ± 5.8%, P < .0001. On multivariate analysis, ECBL, discriminant function and creatinine were independent prognostic variables, and ECBL had the most important prognostic value. In conclusion, ECBL is a very simple predictive factor for identifying nonresponders. A recommendation to discontinue corticosteroids after 7 days in patients without ECBL, suggested by our results, awaits additional confirmation. (Hepatology 2003;38:1363-1369.)

The aim of our multicenter study was to assess the efficacy of ursodeoxycholic acid (UDCA) on the survival of patients with alcohol-induced cirrhosis and jaundice. We included patients with histologically proven alcohol-induced cirrhosis and serum bilirubin >50 micromol/L. After randomization, patients received either UDCA (13-15 mg/kg/d) or a placebo for 6 months. Two hundred twenty-six patients (113 in each group) were included in 24 centers. There were 139 men and 87 women, mean age of 50.3 years. Seventy-four percent had associated alcohol-induced hepatitis, and 24% received a corticosteroid therapy. At inclusion, the 2 groups were comparable for the main clinical and biologic parameters, but serum bilirubin was higher in the UDCA group than in the placebo group (163 micromol/L vs. 145 micromol/L, P

Obesity and its comorbidities have reached dramatic worldwide epidemic proportions over the last decade leading to a growing attention raised by the politics and the medical community. Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome is widely observed in obese subjects. NAFLD encompasses a large spectrum of liver injuries ranging from simple steatosis to steatohepatitis (NASH) and cirrhosis with a risk of hepatocellular carcinoma [1]. In this setting, NAFLD has emerged as a major public health issue all over the world. However, its pathogenesis is still poorly understood and its relative treatments remain insufficient. Obstructive sleep apnea (OSA) that consists of upper airway obstruction leading to intermittent hypoxia (IH), affects 25–50% of the obese individuals [2]. Its severity is usually assessed by the level of apnea-hypopnea index (AHI) and the cumulative percentage of study time spent below a SaO2 of 90%. Correction of hypoxia with nasal continuous positive airway pressure (CPAP) is the standard non-surgical treatment. Through hypoxia and effects on insulin sensitivity, lipid metabolism and inflammation, OSA might play a role in the development of NAFLD/NASH and has received growing interest in the management of obesity. Several human studies have suggested a role of OSA and its hypoxia-relative consequences in the development of NAFLD [3–7]. In a large cohort of patients with OSA, Tanne et al. reported severe OSA as a risk factor of elevated transaminases independent of body mass index (BMI) [3]. Liver biopsy performed in a subgroup of patients with abnormal liver tests revealed NASH in 67% and positive relationship between the severity of liver injury and OSA. There was also a strong relationship independent of BMI, between OSA and insulin resistance assessed by HOMA index, a central actor in the development of NAFLD. Because of the limited number of patients with liver biopsy, we were unable

Background Interferon α (IFN-α) is thought to be responsible for cytochrome P450 (CYP)-dependent drug interactions mediated by a decrease in CYP activities. Objectives The objectives are to determine whether IFN-α and ribavirin can alter pretreatment CYP1A2, CYP2D6, CYP3A4 and N-acetyltransferase-2 activities after 1 month of treatment. Methods Enzymatic activities were determined among 14 patients with chronic active hepatitis C before IFN-α (3 · 106 U, 3 times a week) and ribavirin introduction and after 1 month of treatment. During both study periods, subjects received 80 mg dextromethorphan and 140 mg caffeine (1,3,7-trimethylxanthine [137X]). CYP3A4, CYP2D6, and NAT2 activities were assessed by use of urinary metabolic ratios of 3-methoxymorphinan/dextromethorphan, dextrorphan/dextromethorphan, and 5-acetylamino-6-formylamino-3-methyluracil (AFMU)/1-methylxanthine(1X). The plasma paraxanthine/caffeine ratio was used to measure CYP1A2 activity. Results CYP3A4 and CYP2D6 activities tended to increase after 1 month of antiviral therapy, but the change did not reach statistical significance. CYP1A2 and NAT2 activities were not significantly modified after 1 month of antiviral treatment. Pretreatment activities were significantly lower than those previously observed in healthy volunteers for CYP2D6 (mean ± SD, 148 ± 139 versus 759 ± 692; P = .0008) and CYP3A4 (0.18 ± 0.06 versus 0.52 ± 0.72; P = .0006). This difference was no longer statistically significant after 1 month of treatment, because CYP2D6 and CYP3A4 activities improved in 7 patients. Conclusion In patients with chronic hepatitis C, pretreatment CYP3A4 and CYP2D6 activities were significantly lower than those observed in healthy volunteers. These differences disappeared after 1 month of antiviral treatment because of the restoration of these CYP activities in about half of the patients. Clinical Pharmacology & Therapeutics (2002) 71, 488–495; doi: 10.1067/mcp.2002.124468

Hezode et al. recently reported the frequent occurrence of anemia and thrombocytopenia in the ANRS-CO20-CUPIC cohort of hepatitis C virus (HCV) cirrhotic experienced patients treated with pegylated-interferon (Peg-IFN), ribavirin (RBV), and telaprevir or boceprevir.1,2 Using frequent measurements of serum drug concentrations, hemoglobin, and platelet concentrations obtained in 15 patients of this cohort, we show how an on-treatment model-based approach could be used to individualize dose regimen and avoid the occurrence of RBV-induced anemia and Peg-IFN-induced thrombocytopenia.

To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin (PegIFN/RBV) therapy could improve the efficacy of PegIFN/RBV in previously null-responder patients with chronic genotype 1 or 4 hepatitis C virus (HCV) infection.Genotype 1 or 4 HCV-infected patients with null response to previous PegIFN/RBV treatment and with hypovitaminosis D (30 ng/mL) prospectively received cholecalciferol 100000 IU per week for 4 wk [from week -4 (W-4) to W0], followed by 100000 IU per month in combination with PegIFN/RBV for 12 mo (from W0 to W48). The primary outcome was the rate of early virological response defined by an HCV RNA12 IU/mL after 12 wk PegIFN/RBV treatment.A total of 32 patients were included, 19 (59%) and 13 (41%) patients were HCV genotype 1 and 4, respectively. The median baseline vitamin D level was 15 ng/mL (range: 7-28). In modified intention-to-treat analysis, 29 patients who received at least one dose of PegIFN/RBV were included in the analysis. All patients except one normalized their vitamin D serum levels. The rate of early virologic response was 0/29 (0%). The rate of HCV RNA12 IU/mL after 24 wk of PegIFN/RBV was 1/27 (4%). The safety profile was favorable.Addition of vitamin D to PegIFN/RBV does not improve the rate of early virologic response in previously null-responders with chronic genotype 1 or 4 HCV infection.

Summary TNFα has been shown to play a role in hepatitis C virus (HCV)-induced insulin resistance (IR). Polymorphism of the IL28B gene that encodes IFN-lambda 3 may be associated with IR through modulation of TNFα. The aim of this study was to investigate the relationship between IL28B rs12979860 genotype, the level of TNFα activation and the degree of IR in patients with chronic hepatitis C. One hundred and thirty-three nondiabetic genotype 1 HCV-infected patients with biopsy proven noncirrhotic hepatitis C were investigated for IR (using HOMA index), IL28B rs12979860 genotype and fasting circulating levels of soluble receptor 1 of TNFα (sTNFR1) and adipokines: leptin, adiponectin and IL-6. The HOMA-IR was positively correlated with serum levels of leptin (r = 0.35, P

To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin.In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNAlower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients.Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups.The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4.NCT01125189.

OBJECTIVE The impact of early-untreated HIV infection on chronic hepatitis C was determined in a case-control study, aimed at limiting factors associated with the progression of immunodeficiency. METHODS HIV-infected patients attending for a medical examination during 1995-1996 were systematically screened for: previous intravenous drug use without other HIV or Hepatitis C virus (HCV) risk factor, CD4 cell count > 200/microl, no AIDS, no antiretroviral treatment, positive anti-HCV antibody, negative hepatitis B surface antigen, abnormal aminotransferase activity. Thirty-eight consecutive eligible HIV-infected patients (cases) were included. Thirty-eight HCV-infected patients without HIV infection whose unique risk factor was intravenous drug use (controls) were paired to cases according to age, sex, and duration of HCV infection. RESULTS Cases and controls had similar ages, sex ratios, duration of HCV infection, and alcohol intake. They were infected predominantly by genotypes 1 and 3. Viraemia was higher in cases than in controls. METAVIR histological scores of activity and fibrosis in cases versus controls were 2.2 +/- 0.8 versus 1.6 +/- 0.7 (P = 0.0008) and 1.8 +/- 1 versus 1.5 +/- 0.8 (P = 0.06), respectively. The percentage of cirrhosis was higher in cases, without reaching statistical difference. The progression rate of fibrosis was higher in cases. Age at contamination and METAVIR activity score were significantly associated with the progression of fibrosis in cases. CONCLUSION Early-untreated HIV infection is associated with higher HCV viraemia and more severe liver injury in intravenous drug users with chronic hepatitis C.

Sustained viral suppression using monotherapy with interferon alfa (IFN-alpha) or lamivudine can only be achieved in a small percentage of patients with chronic hepatitis B. The concomitant administration of lamivudine and IFN-alpha does not enhance efficacy. We postulated that the optimal timing of therapy might be sequential treatment with lamivudine and IFN-alpha. The aim of this study was therefore to assess the efficacy of sequential treatment in patients resistant to IFN-alpha alone. Fourteen male patients, with a median age of 40 years, nonresponders to IFN-alpha with hepatitis B virus (HBV) DNA100 pg/mL (branched DNA [bDNA] Chiron) and positive hepatitis B e antigen (HBeAg) in 11 of 14 patients, were treated with lamivudine 100 mg/d alone for 20 weeks, then with both IFN-alpha2b 5 MU 3 times per week and lamivudine for 4 weeks, and lastly with IFN-alpha alone for 24 weeks. At the end of lamivudine therapy, all patients had undetectable serum HBV DNA, and none exhibited an emergence of HBV polymerase mutant or breakthrough. Sustained serum HBV-DNA clearance 6 months after the end of sequential treatment was achieved in 8 of 14 patients, HBeAg-to-anti-HBe seroconversion in 5 of 11 patients, and HBeAg and hepatitis B surface antigen (HBsAg) seroconversions in 3 of 14 patients (anti-HBs100 IU/mL). All sustained responders had normalized their alanine transaminase (ALT) values and exhibited histologic improvements. In conclusion, the results of this pilot study suggest that sequential treatment with lamivudine and IFN-alpha can induce a sustained virologic response, including HBs seroconversion, in patients with chronic hepatitis B not responding to IFN-alpha alone, without the selection of drug-resistant mutants. This therapeutic schedule warrants further evaluation in clinical trials.

Background/Aims : Steatosis could be the result of HCV (hepatitis C virus)-induced hypobetalipoproteinemia in patients with chronic hepatitis C. The aim of this study was to assess serum levels of main constituents of betalipoproteins and their relationship with steatosis in patients with chronic hepatitis C without known risk factors for steatosis. Patients : One-hundred male patients with untreated biopsy proven non-cirrhotic chronic hepatitis C were included. Twenty-nine of these patients were further treated with interferon. Results : Cholesterol concentration was significantly lower in patients compared to three control groups: reference male population, patients with chronic hepatitis B or with non-alcoholic fatty liver. In multivariate analysis, low apolipoprotein B concentration was an independent factor related with the degree of steatosis. Hypobetalipoproteinemia and degree of steatosis were significantly associated with infection with genotype 3. Among treated patients, only sustained virological responders had a significant increase of cholesterol (5.6±1 vs. 4.7±1.3 mmol/l; P =0.03) and apolipoprotein B concentrations (113±19 vs. 75±14 mg/dl; P =0.05). Conclusion : In chronic hepatitis C, hypobetalipoproteinemia is prevalent and associated with steatosis, especially in patients infected with genotype 3. The correction of hypobetalipoproteinemia following HCV eradication suggests that HCV itself could induce hypobetalipoproteinemia and steatosis.

Ursodeoxycholic acid (UDCA) could potentiate the effect of interferon (IFN) in patients with chronic hepatitis C resistant to IFN. We compared the efficacy of IFN with that of a combination of IFN and UDCA. Patients were randomized to receive UDCA (13-15 mg/kg/day) (n = 47) or placebo (n = 44) plus interferon (3 MU three times weekly) for 6 months and were then followed up for 6 additional months. At entry 30% of patients had cirrhosis, and 70% had HCV genotype 1. Five and four patients withdrew from the combination and the monotherapy groups, respectively. At 6 months alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities were significantly lower (P < 0.001) in the combination group than in the monotherapy group; the differences were no longer significant at 1 year. At 6 months ALAT activities normalized in 10 and 8 patients in the combination and the monotherapy groups, respectively (P = 0.67). In 10 of them (5 in each group) HCV RNA levels became undetectable. At 1 year four versus one patient had a sustained normalization of ALAT, and in one patient the HCV RNA became negative. There was no difference in the histologic progression. In this setting, in contrast to chronic cholestasis, UDCA administration induced an increase in total serum bile acids and did not change primary bile acids. An IFN plus UDCA combination is more effective than IFN alone in terms of ALAT but not in terms of the virologic response. These results favor the hypothesis that UDCA has an effect on the biochemical indices of cellular injury independent of a change in primary bile acids

A placebo-controlled trial of pioglitazone in subjects with non-alcoholic steatohepatitis. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. Background/Aims No pharmacologic therapy has conclusively proved to be effective for the treatment of non-alcoholic steatohepatitis, which is characterized by insulin resistance, steatosis, and necroinflammation with or without centrilobular fibrosis. Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus. Methods We randomly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed non-alcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500kcal/d in relation to the calculated daily intake required to maintain body weight) plus pioglitazone (45mg daily) or a hypocaloric diet plus placebo. Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test ([ 14 C]glucose given with the oral glucose load and [ 3 H]glucose given by intravenous infusion). Results Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance ( P P =0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P P P =0.008). Administration of pioglitazone, as compared with placebo, was associated with improvement in histologic findings with regard to steatosis ( P =0.003), ballooning necrosis ( P =0.02), and inflammation ( P =0.008). Subjects in the pioglitazone group had a greater reduction in necroinflammation (85% vs. 38%, P =0.001), but the reduction in fibrosis did not differ significantly from that in the placebo group ( P =0.08). Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone; no other adverse events were observed. Conclusions In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with non-alcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. [Abstract reproduced by permission of N Engl J Med 2006;355:2297–2307]

The association of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) is thought to be rare, and its optimal treatment is unknown. Of 130 consecutive patients with a diagnosis of PBC, we identified 12 cases (9.2%) of overlap syndrome (10 females, 2 males; median age, 50 years) strictly defined by the presence of at least two of the three recognized biochemical, serological, and histological criteria of each disease. One patient had initially pure PBC and developed AIH characterized by a flare of alanine transaminase (ALT) (1,330 IU/L; N < 35), elevated immunoglobulin G (IgG) (42 g/L; N < 14.0), and presence of anti-smooth muscle antibodies (ASMA) after 20 months of ursodeoxycholic acid (UDCA) therapy. A complete clinical and biochemical remission was achieved under combination of corticosteroids and UDCA. Eleven patients had features of both diseases at presentation: high serum levels of alkaline phosphatase (AP) (median: 280 IU/L; N < 100), ALT (140 IU/L), and IgG (30.8 g/L), presence of mitochondrial antibodies (n = 9) or ASMA (n = 9), florid bile duct lesions (n = 8), and moderate or severe periportal or periseptal lymphocytic piecemeal necrosis (n = 11). UDCA (13-15 mg/kg/d) given alone in 5 patients induced a significant decrease in biochemical cholestasis but not in ALT levels, and liver fibrosis progressed in 3 patients. Corticosteroids given alone in 6 patients induced a significant decrease in ALT, IgG, and AP levels, but none had a biochemical normalization. The patients with persistently abnormal liver tests under either UDCA or corticosteroids received both UDCA and corticosteroids. A further marked biochemical improvement was observed, and all patients became asymptomatic. We conclude that, in patients with PBC: 1) overlap syndrome with AIH is not rare; 2) flares of AIH may occur either spontaneously or under UDCA; and 3) combination of UDCA and corticosteroids is required in most patients to obtain a complete biochemical response. Overlap syndrome may represent an important and unrecognized cause of resistance to UDCA in patients with PBC.

The aim of this study was to assess the incidence of decompensation (ascites, jaundice, variceal bleeding, and encephalopathy), hepatocellular carcinoma (HCC) and death or liver transplantation in patients with compensated hepatitis C virus (HCV)-related cirrhosis, taking into account the viral genotype and interferon (IFN) therapy. Between 1989 and 1994, 668 patients with no clinical evidence of decompensation were referred to our department for liver biopsy because of positivity for anti-HCV antibodies and elevated aminotransferase activity; 103 of these patients had cirrhosis. The median follow-up was 40 months. Fifty-nine patients were treated with IFN for a mean duration of 11 ± 6 months; 3 (5%) had a prolonged biochemical and virological response. Baseline characteristics of IFN-treated and untreated patients were not significantly different. HCV genotypes (InnoLiPa) were predominantly 1b (48%) and 3a (20%). During follow-up, complications of cirrhosis occurred in 26 patients, HCC in 11 patients, and decompensation not related to HCC in 19 patients. Sixteen patients died, 94% of liver disease. Three patients were transplanted for liver failure. The 4-year risk of HCC was 11.5% (annual incidence 3.3%) and that of decompensation was 20%. Survival probability was 96% and 84% at 2 and 4 years, respectively. In multivariate analysis, the absence of IFN therapy was the only independent factor predictive both for HCC and decompensation. A low albumin level at entry and the absence of IFN therapy were the two independent factors predictive of death or liver transplantation. Probability of survival at 2 and 4 years was significantly different between IFN-treated and untreated patients (respectively 97% and 92% vs 95% and 63%,P< .0001). In conclusion, in patients with compensated HCV-related cirrhosis: 1) complications of cirrhosis are frequent, whatever the viral genotype; and 2) the severity of cirrhosis and the absence of IFN therapy are independently predictive of bad outcome

Despite the incontestable benefits of telaprevir and boceprevir-based triple therapy in patients infected with genotype 1, the practitioner faces a number of new challenges. In daily clinical practice, a checklist approach may facilitate the management of triple therapy. Before initiation, several specific issues should be reviewed with the patient in order to optimize adherence and treatment outcome: potential drug to drug interaction, treatment duration and stopping rules, possible treatment outcomes, side effects, dose and administration with food advice, management of side effects. Because treatment failure is associated with the emergence of resistance-associated variants with reduced sensitivity to protease inhibitors, adherence is of major importance. In this setting, the role of educational nurse should be emphasized for the management of triple therapy in daily clinical practice.

International audience; Background & AimsIn 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.Methods674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16.ResultsA 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

Background & Aims The combination of vaniprevir (a NS3/4A protease inhibitor) with peginterferon and ribavirin was shown to increase rates of sustained virologic response (SVR) significantly, compared with peginterferon and ribavirin alone, in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection without cirrhosis. We performed a blinded, randomized, controlled trial of the effects of vaniprevir with peginterferon and ribavirin in patients with cirrhosis who did not respond to prior therapy with peginterferon and ribavirin. Methods Treatment-experienced patients (88% white and 35% prior null responders) with HCV genotype 1 infection and compensated cirrhosis were assigned randomly to groups given vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 24 weeks (n = 16), vaniprevir (600 mg twice daily) for 24 weeks with peginterferon and ribavirin for 48 weeks (n = 14), vaniprevir (300 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), or placebo with peginterferon and ribavirin for 48 weeks (n = 14, control). Cirrhosis was documented by liver biopsy (84%) or noninvasive methods (16%). Before randomization, participants were stratified based on their historical response to peginterferon and ribavirin. Results In the primary analysis, SVR rates among patients in the respective vaniprevir groups were 9 of 15 (60.0%), 9 of 13 (69.2%), 8 of 15 (53.3%), and 10 of 13 (76.9%), compared with 2 of 14 (14.3%) in the control group (pairwise P values ≤ .016). Cirrhotic patients with null or partial responses to prior therapy achieved SVR less often than patients with prior breakthrough or relapse, although 42.1% of prior null responders in the vaniprevir groups achieved SVRs. Patients in the vaniprevir groups more frequently experienced mild-moderate nausea, vomiting, and diarrhea than controls; 5% developed grade 2 anemia compared with none in the control group (no patient developed grade 3 or 4 anemia). Among patients in the vaniprevir groups who experienced virologic failure, resistance-associated variants were detected predominantly at positions 155, 156, and 168 in the HCV protease gene. Conclusions In a controlled phase 2B trial, vaniprevir with peginterferon and ribavirin significantly increased rates of SVR among treatment-experienced patients with chronic HCV genotype 1 infection, compared with re-treatment with peginterferon and ribavirin alone. Vaniprevir generally was well tolerated for up to 48 weeks in patients with compensated cirrhosis. ClinicalTrials.gov number, NCT00704405.

BACKGROUND & AIMS: Chronic hepatitis C virus carriers may have repeatedly normal aminotransferase activity despite detectable viremia and histological hepatitis. The aim of this study was to determine the effect of interferon in this population. METHODS: Three million units of interferon alfa was administered 3 times weekly for 6 months in 10 patients with chronic hepatitis C virus infection, repeatedly normal alanine aminotransferase activity, and chronic hepatitis on liver biopsy. Serum hepatitis C virus RNA was detected by polymerase chain reaction and quantified by branched DNA before, at the end, and 1 year after treatment. A liver biopsy was performed 1 year after treatment withdrawal. RESULTS: At treatment withdrawal, hepatitis C virus RNA levels had significantly decreased, but RNA was still detectable by polymerase chain reaction in 8 of 10 patients. During the 1-year follow- up period, 6 of 9 patients had elevated aminotransferase activity on at least one occasion. One year after treatment withdrawal, RNA levels had returned to pretreatment values and no significant histological improvement was observed in the 7 patients who underwent liver biopsy. CONCLUSIONS: In patients with chronic hepatitis C and repeatedly normal aminotransferase activity, standard interferon therapy does not lead to sustained virological or histological responses despite a transient effect on hepatitis C virus replication. (Gastroenterology 1996 Jan;110(1):291-5)

Dieulafoy's ulcer is a particular form of gastric ulcer confined to a persistent caliber artery and may lead to severe hemorrhage. We report a case of fatal gastric bleeding in a woman with benign biclonal gammapathy. Autopsy found a typical Dieulafoy's ulcer centered by a persistent caliber artery which wall was thickened by AL-amyloid deposits. Amyloidosis involved the gastric wall, but also middle caliber arteries of the liver, the lung, the pancreas, the kidney and the myocardium. AL-amyloidosis is a rare and late complication of monoclonal gammapathy and may be asymptomatic. Pathogenesis of Dieulafoy's ulcer remains unclear. In our case, local ischemia may have facilitated gastric ulceration, and amyloid deposits may have contributed to arterial rupture.

In a cohort of 483 blood donors positive for antibody to hepatitis C virus on second-generation enzyme-linked immunosorbent, the confirmatory second-generation recombinant immunoblot assay (Ortho Diagnostic Systems) was positive in 172 cases (36%), indeterminate in 113 (23%), and negative in 198 (41%). We further studied 94 of the donors (recombinant immunoblot assay positive in 85, indeterminate in 6, and negative in 3). Alanine transaminase (ALT) activity, assayed on three occasions, was elevated in at least one assay in 85% of the 85 recombinant immunoblot assay-positive donors. Liver disease was present in 95% of these patients (chronic persistent hepatitis, 35%; chronic active hepatitis, 53%; cirrhosis, 7%). Ten of the 13 recombinant immunoblot assay-positive donors with normal ALT activity had liver disease; polymerase chain reaction testing for viral RNA was predictive of liver disease in most cases. Donors with cirrhosis differed significantly from cirrhosis-free donors in terms of age, sex ratio, ALT activity, and excessive alcohol consumption. Three of the 6 recombinant immunoblot assay-indeterminate donors (isolated C 22) who underwent histological examination had elevated ALT activity and liver disease. The 3 recombinant immunoblot assay-negative donors evaluated were free of liver disease. This study shows that anti-HCV second-generation enzyme-linked immunosorbent positivity is confirmed in fewer than 40% of blood donors by the second-generation recombinant immunoblot assay, and that liver disease is present in 95% of recombinant immunoblot assay-positive donors. Recombinant immunoblot assay positivity combined with viremia is frequently associated with the existence of liver disease, regardless of transaminase activity. Excessive alcohol consumption may be an important factor in the onset of cirrhosis in anti-HCV-positive blood donors.

Colorectal cancer is the third and second most common cancer among men and women, respectively, in France. Interest in the chemoprevention of colorectal cancer has increased over the last two decades. Experimental data strongly suggest that ursodeoxycholic acid (UDCA) may have chemopreventative actions in colorectal cancer. UDCA is able to inhibit tumor development in azoxymethane and in dextran-related colitis models. In high-risk populations such as subjects with previous colorectal adenoma removal or inflammatory bowel disease, five out of 10 published studies suggested beneficial effects with UDCA on colonic carcinogenesis. In the azoxymethane model, UDCA inhibited tumor development by counteracting the tumor-promoting effects of secondary bile acids such as deoxycholic acid (DCA). The opposing effects of UDCA and DCA on lipid raft composition may be central to their effects on colonic tumorigenesis. Differential effects of DCA and UDCA on growth factor and inflammatory signals involved in colorectal carcinogenesis, such as epidermal growth factor receptor (EGFR) signaling and COX-2 expression, very likely mediate their opposing effects on colonic tumor promotion and tumor inhibition, respectively.

The standard therapeutic approach currently recommended for patients infected with genotype 1 hepatitis C virus (HCV) is the triple therapy combining pegylated interferon (PEG-IFN), ribavirin (RBV)and NS3/NS4 protease inhibitors, boceprevir or telaprevir [1]. Protease inhibitors (PIs) are direct acting antiviral drugs (DAA) which, when added to PEG-IFN and RBV, are able to achieve a significant gain in terms of sustained virological response (SVR), both in naive and treatment-experienced patients [2–5]. The use of these new molecules, despite its in contestable benefits, reveals on the other hand new challenges: the emergence of variants with reduced sensitivity to PIs, the development of new or higher rate of side effects, drug to drug interactions, and significant increase in the overall cost of antiviral therapy. Among the two DAAs commonly used in combination with PEG-IFN and RBV (PEG-IFN/RBV) for the treatment of genotype 1 HCV patients, boceprevir has been licensed with a lead-in phase, while telaprevir has been licensed without. EMA approved regimens of both drugs are reported in Figs. 1 and 2. The lead-in phase represents an initial period of 4 weeks of dual therapy with PEG-IFN/RBV, in standard doses, followed by triple therapy. The concept of lead-in phase was initiated by the Schering–Plough company in order to improve efficacy of boceprevir-based triple therapy. Indeed, by lowering HCV RNA level, a short course of PEG-IFN/RBV may theoretically reduce the risk of viral breakthrough or resistance. However, there is still much controversy regarding the utility of the lead-in phase, some authors advocating its role in improving, and/or predicting triple therapy effectiveness, while others view it as a useless complication of the therapeutic regimen, its chief disadvantage being the inconvenience to the patient.

Item does not contain fulltext OBJECTIVE: Insulin resistance is a predictor of poor response to peginterferon/ribavirin in patients infected with the chronic hepatitis C virus (HCV). There are no data on direct-acting antivirals. This exploratory analysis assessed the effect of metabolic factors and insulin resistance, measured by homoeostatic model assessment (HOMA), on virological response to telaprevir in Study C208. DESIGN: Overall, 161 HCV genotype 1-infected, treatment-naive patients received 12 weeks of telaprevir plus peginterferon/ribavirin, then 12/36 weeks of peginterferon/ribavirin depending on on-treatment response criteria. The prognostic significance of several factors, including HOMA-insulin resistance (HOMA-IR), on virological response at weeks 4 and 12, end of treatment and 24 weeks after treatment was explored by multiple regression analysis. RESULTS: Baseline HOMA-IR data were available for 147 patients; baseline characteristics were consistent with the overall population. Baseline HOMA-IR 4 was seen in 54%, 30% and 16% of patients, respectively. Neither response rates (any time point) nor week 4 viral load decline were significantly influenced by baseline HOMA-IR. In multivariate analyses, fibrosis stage and low-density lipoprotein cholesterol level were predictive of sustained virological response (OR 0.47 and 1.02, respectively). After the end of treatment, HOMA-IR was significantly lower in patients with sustained virological response than in those without (0.61 vs 1.34 for relapsers and 1.15 for non-responders; p

Direct acting antiviral agents for the management of chronic hepatitis C infection have recently been licensed. These new protease inhibitors are combined with pegylated interferon and ribavirin and markedly increase the proportion of patients who respond to antiviral therapy. The protease inhibitors may be used with a ‘lead-in’ phase of pegylated interferon and ribavirin and the value of this approach has been much debated with those supporting ‘lead in’ citing the advantages of assessing the early response to therapy before commencing the direct acting antiviral agent. Those opposed to the ‘lead-in’ phase cite the complexity of the regime and the lack of robust evidence showing an improvement in clinical outcome in those treated in this fashion.

Summary. The impact of antiretroviral drug exposure and associated lipodystrophy and/or insulin resistance (IR) on advanced liver fibrosis in HIV/HCV-coinfected patients is not fully documented. We determined the prevalence of advanced liver fibrosis (defined by hepatic stiffness ≥9.5 kPa) and associated factors, focusing on the impact of highly active antiretroviral therapy and its major adverse effects (lipodystrophy and IR), in 671 HIV/HCV-coinfected patients included in the ANRS CO13 HEPAVIH cohort. One hundred ninety patients (28.3%) had advanced liver fibrosis. In univariate analysis, advanced liver fibrosis was significantly associated with male sex, higher body mass index, HCV infection through intravenous drug use, a lower absolute CD4 cell count, a longer history of antiretroviral treatment, longer durations of protease inhibitors, non-nucleoside reverse transcriptase inhibitors and NRTI exposure, lipodystrophy, diabetes, and a high homeostasis model assessment method (HOMA) value. The only antiretroviral drugs associated with advanced liver fibrosis were efavirenz, stavudine and didanosine. In multivariate analysis, male sex (OR 2.0, 95% CI 1.1–3.5; P = 0.018), HCV infection through intravenous drug use (OR 2.0, 95% CI 1.1–3.6; P = 0.018), lipodystrophy (OR 2.0, 95% CI 1.2–3.3; P = 0.01), median didanosine exposure longer than 5 months (OR 1.7, 95% CI 1.0–2.8; P = 0.04) and a high HOMA value (OR 1.1, 95% CI 1.0–1.2; P = 0.005) remained significantly associated with advanced liver fibrosis. Mitochondrial toxicity and IR thus appear to play a key role in liver damage associated with HIV/HCV-coinfection, and this should be taken into account when selecting and optimizing antiretroviral therapy. Antiretroviral drugs with strong mitochondrial toxicity (e.g. didanosine) or a major effect on glucose metabolism should be avoided.

International audience; BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease associated with increased morbidity and mortality. Ursodeoxycholic acid (UDCA) may have antioxidant, anti-inflammatory, and antifibrotic properties and may reduce liver injury in NASH. To date, no studies have assessed the efficacy and safety of high-dose UDCA (HD-UDCA) in patients with NASH. METHODS: We conducted a 12-month, randomized, double-blind, placebo-controlled multicenter trial to evaluate the efficacy and safety of HD-UDCA (28-35 mg/kg per day) in 126 patients with biopsy-proven NASH and elevated alanine aminotransferase (ALT) levels. The primary study end point was reduction in ALT levels from baseline in patients treated with HD-UDCA compared with placebo. Secondary study end points were the proportion of patients with ALT normalization, relative reduction in the scores of serum markers of fibrosis and hepatic inflammation, and safety and tolerability. RESULTS: HD-UDCA significantly reduced mean ALT levels -28.3% from baseline after 12 months compared with -1.6% with placebo (p

NAFLD encompasses a spectrum of liver diseases including simple steatosis and nonalcoholic steatohepatitis (NASH), which is characterized by inflammation and hepatocyte ballooning on a background of steatosis. NAFLD, the hepatic manifestation of the metabolic syndrome, has become one of the most common causes of chronic liver diseases over the last decade in developed countries as well as in low and middle-income regions owing to dramatic epidemic proportions of obesity and diabetes worldwide. While simple steatosis has mostly a benign course, NASH can lead to fibrosis, cirrhosis and hepatocellular carcinoma. Insulin resistance is considered as the cornerstone in the development of NAFLD/NASH. Liver biopsy remains the gold standard for the diagnosis of NASH. However, non-invasive markers of NASH and fibrosis represent interesting tools to identify patients with severe liver injuries. Even if insulin sensitizers and hepatoprotective agents are promising drugs, no medication has been currently approved for the treatment of NASH. Diet, exercise and control of the metabolic disorders still represent crucial therapeutic options for the management of NAFLD/NASH.

Studies of blood donors positive for antibody to hepatitis C virus on enzyme-linked immunosorbent assay are probably biased by the large number of false-positive results. We evaluated the epidemiological and biological characteristics of 177 such donors with regard to the confirmatory secondgeneration RIBA test (Ortho Diagnostic Systems) and have compared the results to those from an age- and sex-matched control group of 177 donors negative for antibody to hepatitis C virus on enzyme-linked immunosorbent assay. Second-generation recombinant immunoblot assay was positive in 38% of cases, indeterminate in 6% and negative in 56%. The case-control study showed a significantly higher frequency of intravenous drug abuse (27% vs. 0%), blood transfusion (22% vs. 9%), history of jaundice (21% vs. 7%), elevated ALT level (49% vs. 4%) and HBc antibody positivity (32% vs. 7%) in second-generation recombinant immunoblot assay–positive donors. No such differences were found between the second-generation recombinant immunoblot assay–negative donors and their controls. The 35 second-generation recombinant immunoblot assay–positive donors without histories of transfusion or intravenous drug abuse had a significantly higher frequency of surgery with major blood loss or prolonged stays in areas of hepatitis B virus endemicity than did their controls (20% vs. 0% and 49% vs. 26%, respectively). In conclusion, at least one risk factor for HCV infection was identified in 82% of the secondgeneration recombinant immunoblot assay–positive donors, 91% of whom could have been identified on the basis of these risk factors, ALT level and presence of HBc antibody. (HEPATOLOGY 1993;17:183–187.)

Item does not contain fulltext BACKGROUND & AIMS: Recent studies have shown that 12 weeks of treatment with telaprevir, administered every 8 hours (q8h), combined with pegylated interferon (peginterferon) alfa-2a plus ribavirin significantly increased the rate of hepatitis C virus (HCV) eradication (sustained virologic response [SVR]) in patients infected with HCV genotype 1 compared with approved therapy. We investigated the efficacy, safety, tolerability, and pharmacokinetics of telaprevir given q8h or every 12 hours (q12 h) in combination with peginterferon alfa-2a or alfa-2b. METHODS: Treatment-naive patients (n = 161) infected with HCV genotype 1 were randomly assigned to groups that were given open-label telaprevir (750 mg q8 h or 1125 mg q12 h) in combination with standard doses of peginterferon alfa-2a (180 mug/wk) and ribavirin (1000-1200 mg/day) or peginterferon alfa-2b (1.5 mug.kg(-1).wk(-1)) and ribavirin (800-1200 mg/day). Patients received triple therapy for 12 weeks, followed by 12 or 36 additional weeks of treatment with peginterferon alfa and ribavirin, based on virologic response. RESULTS: Baseline characteristics were similar for all groups. SVR rates were 81.0% to 85.0% among groups; most patients received 24 weeks of therapy (68.0%). There were no significant differences in SVR rates (intent-to-treat analysis) among groups (P >/= .787), between the pooled q8 h and q12 h groups (P = .997), or between the pooled peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin groups (P = .906). The safety profile was similar among all groups. CONCLUSIONS: A high proportion (>80%) of patients achieved an SVR regardless of the telaprevir dosing frequency (q8 h or q12 h) or type of peginterferon alfa used (alfa-2a or alfa-2b).

Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element-binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism.

Aims: The aim of this study was to determine whether serum levels of adipokines, including the ratio of serum adiponectin to leptin (A/L) levels could predict the severity of liver injury in patients with non-alcoholic fatty liver disease (NAFLD). Patients and methods: Fifty-seven patients with biopsy-proven non-alcoholic steatohepatitis (NASH) (mean age 51±12, sex ratio 1), 17 with simple steatosis (mean age 47±12, sex ratio 1.4) and 10 controls without steatosis (mean age 51±11, sex ratio 4) were investigated. In all subjects, serum concentrations of triglycerides, ultrasensitive C reactive protein, leptin, adiponectin, soluble tumour necrosis factor receptor 1, interleukin (IL)-6 and Homeostasis Model Assessment Method (HOMA) were measured. Hepatic expression of adiponectin and its two receptors was assessed by quantitative reverse transcriptase polymerase chain reaction. Results: Body mass index (BMI) and HOMA were correlated positively with leptin levels (r=0.44 and 0.28 respectively) and negatively with the A/L ratio (r=0.51 and 0.41 respectively). Independent parameters associated with NASH vs steatosis were HOMA>3 [odds ratio (OR)=6.9] and A/L ratio