Long-term outcome of primary non-responders to tenofovir therapy in HIV/HBV-co-infected patients: impact of HBV genotype G.

AIM: To evaluate the early virological response (EVR) to combined tenofovir-lamivudine or emtricitabine regimen in HBV/HIV-co-infected patients and the long-term efficacy of tenofovir. METHODS: In this retrospective monocentric study, among the 166 HIV/HBV-co-infected patients regularly followed from 2003 to 2008 at Bichat Claude Bernard Hospital, 61 patients had received, either de novo combination therapy with tenofovir and lamivudine or emtricitabine (group I, n = 15) or add-on tenofovir to lamivudine therapy (group II, n = 46). The HBV polymerase region was sequenced and analysed for all patients with available samples. RESULTS: All 15 group I patients achieved EVR vs 32 (82%) of group II patients (P = 0.15). Seven adherent group II patients met criteria for primary non-response, but achieved delayed response (DR) to therapy. In these seven patients, when compared with the 39 group II patients, there was a trend to longer duration of lamivudine pre-treatment and to higher rate of lamivudine-resistant mutants; and HBV genotype-G proportion was higher (P = 0.026). No virological breakthrough occurred after a median of 46 months follow up. CONCLUSION: In these HBV/HIV-co-infected patients, first-line HBV therapy with tenofovir and emtricitabine or lamivudine was associated with EVR. However, DR to tenofovir was observed in 15% of patients who added tenofovir to lamivudine therapy, of whom four of seven (57%) had genotype G-HBV infection. No resistance was evidenced after 46 months of therapy even in patients with DR to tenofovir. At last, a good renal safety profile of TDF was observed after a median follow-up of 4 years of therapy.

Bleeding in patients with Budd-Chiari syndrome.

BACKGROUND & AIMS: Anticoagulation therapy is recommended for patients with Budd-Chiari syndrome (BCS). This study aimed to assess the incidence, severity, and risk factors of major bleeding in patients with Budd-Chiari syndrome (BCS) receiving anticoagulation therapy. METHODS: We evaluated 94 consecutive BCS patients. Major bleeding required hospitalization, and/or transfusion of ≥ 2 red blood cell units, and/or was located intracranially, and/or retroperitoneally, and/or was fatal. RESULTS: After a median follow-up of 43 months, 47 patients had 92 major bleeding episodes (22.8 per 100 patient-years). Forty episodes were related to invasive therapy for BCS. The origin of the 52 other episodes was gastrointestinal in 26 (including 15 related to portal hypertension) and genital in 10; 26 were spontaneous and 26 provoked. Excess anticoagulation was identified in 13 (27%) out of 49 documented episodes. Bleeding was managed by interrupting or reducing anticoagulation in 34 episodes, surgery in 18, endoscopy in 12, and radiological intervention in 8. The presence of esophageal varices was an independent predictor of bleeding unrelated to invasive therapy for BCS. Bleeding contributed to death in five patients and caused neurological complications in two. These poor outcomes were associated with more severe liver disease at baseline. CONCLUSIONS: Major bleeding is common in BCS patients receiving anticoagulation therapy. Invasive procedures and portal hypertension are major factors, while excess anticoagulation plays a secondary role. Baseline BCS severity is the main determinant of prognosis at bleeding. Reducing anticoagulation intensity during invasive therapy and reinforced prophylaxis for portal hypertension could improve the benefit-risk ratio of anticoagulation.

Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin.

UNLABELLED: A sustained virologic response (SVR) in patients with chronic hepatitis C receiving pegylated interferon (PEG-IFN) plus ribavirin is defined as undetectable serum HCV-RNA at 24 weeks (W+24) posttreatment follow-up. Viral load outcome in patients with virological relapse (VR) has not been explored. This study evaluated whether the assessment of serum HCV-RNA 12 weeks (W+12) after the end of treatment was as relevant as W+24 to evaluate SVR in 573 patients who received combination PEG-IFN and ribavirin and had a virological response at the end of treatment. Serum HCV-RNA was measured, using a new assay based on transcription-mediated amplification (TMA) with a lowest detection limit of 5-10 IU/mL, at W+12 and W+24 after the end of treatment. VR was defined as reappearance of detectable HCV-RNA at W+24 posttreatment follow-up. The positive predictive value (PPV) of undetectable serum HCV-RNA at W+12 was evaluated to identify patients with SVR, and the viral load outcome was measured in relapse patients. At the W+24 posttreatment follow-up, 408 (71%) patients had an SVR, 181 (71.2%) were treated with PEG-IFNalpha-2a and ribavirin, and 227 (71.1%) were treated with PEG-IFNalpha-2b and ribavirin. At W+12, serum HCV-RNA was undetectable in 409 patients, and 408 patients were SVR (PPV 99.7%, 95% confidence interval 99.1-100). In relapse patients, serum HCV-RNA levels were 5.623 +/- 0.748, 4.979 +/- 0.870, and 5.216 +/- 0.758 log(10) IU/mL at baseline, W+12, and W+24, respectively. CONCLUSION: Our results show that the assessment of serum HCV-RNA 12 weeks after the end of treatment, using the highly sensitive TMA assay (PPV 99.7%), is as relevant as after 24 weeks to predict SVR and make decisions on the management of treated patients, suggesting a new definition for SVR.

Quantification of hepatitis B surface antigen: a new concept for the management of chronic hepatitis B.

HBsAg is a very important clinical test that might not only indicate active hepatitis B virus (HBV) infection but might also be used to predict clinical and treatment outcome. Clearance of HBsAg in patients with chronic HBV infection is associated with a much better clinical outcome, although surveillance for early detection of hepatocellular carcinoma (HCC) should continue. HBV DNA quantification is currently used for selecting candidates for therapy, monitoring response to therapy and detecting the emergence of drug resistance. Assays for HBsAg quantification are less expensive than HBV DNA and fully automated with a high throughput capacity. HBsAg titering may be a useful tool to manage patients with chronic HBV, to more clearly define which patients may, and more importantly, may not, benefit from treatment. Baseline and on-treatment HBsAg quantification may help to refine future treatment algorithms for both immune-modulator therapy and nucleos(t)ide analogues. Both HBV markers provide complementary information on the status of HBV infection. However, the relevance of serum HBsAg levels and its use as a reliable replacement for both covalently closed circular DNA and HBV DNA remain unclear.

Danoprevir, an HCV NS3/4A protease inhibitor, improves insulin sensitivity in patients with genotype 1 chronic hepatitis C.

BACKGROUND/AIM: Insulin resistance (IR) is a major predictor of treatment failure in patients with hepatitis C virus (HCV) infection treated with peginterferon/ribavirin. The aim of this study was to evaluate the short-term effect of an HCV protease inhibitor monotherapy on IR in parallel with an antiviral effect. PATIENTS/METHODS: In a phase 1b placebo-controlled study, four cohorts of treatment-naïve patients with genotype 1 HCV received danoprevir (ITMN-191/RG7227), a protease inhibitor, or placebo (8/2 patients in each cohort respectively) in a gelatin capsule every 12 h (100, 200 mg) or 8 h (100, 200 mg) for 14 days. A fifth cohort including prior non-responders to peginterferon/ribavirin was similarly randomised to receive placebo or 300 mg danoprevir every 12 h. IR was assessed with the homeostasis model (HOMA-IR) at baseline and days 7, 14 and 15. RESULTS: Serum HCV-RNA and HOMA-IR correlated significantly (Spearman rho=0.379, p<0.0001). At baseline, mean±SD serum HCV-RNA level and mean±SD HOMA-IR score were 6.2±0.5 log(10) IU/ml and 3.8±1.9, respectively. At the end of 14 days of monotherapy the mean±SD decrease in viral load was 2.2±1.3 log(10) IU/ml (p<0.0001) in patients who received the active drug (n=40). In parallel, the mean±SD HOMA-IR score also decreased in these patients by 1.6±1.1 (p<0.0001), with a close correlation between the extent of HOMA-IR improvement and the decrease in viral load. By contrast, serum HCV-RNA and HOMA-IR remained unchanged in patients who received placebo (n=10; 6.3±0.5 log(10) IU/ml and 3.8±2.5, respectively). CONCLUSION: HCV protease inhibitor may restore insulin sensitivity in patients with genotype 1 HCV. The place of insulin sensitisers remains to be determined in the era of triple therapy.

Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) currently represents the major cause of liver-related death in patients with hepatitis C virus (HCV)-related cirrhosis. We assessed the influence of combination therapy on the risk of HCC, liver-related complications (ascites, variceal bleeding), and liver-related death (or liver transplantation). METHODS: Three hundred seven chronic hepatitis C patients with bridging fibrosis (n=127) or cirrhosis (n=180) were evaluated by Cox regression analysis. Sustained virological response (SVR) was defined as undetectable serum HCV RNA at 24 weeks after treatment. RESULTS: SVR developed in 33% of patients. The SVR rates were not different between patients with bridging fibrosis (37%) and those with cirrhosis (30%), p=0.186. During a median follow-up of 3.5 years (range 1-18 years) after the last treatment, the incidence rates per 100 person-years of HCC, liver-related complications, and liver-related death, were 1.24, 0.62, and 0.61 among SVR patients, respectively, and 5.85, 4.16, and 3.76 among non-SVR patients, respectively (log-rank test, p<0.001). According to multivariate analysis, non-SVR was an independent predictor of HCC (HR 3.06; 95% CI=1.12-8.39), liver-related complications (HR 4.73; 95% CI: 1.09-20.57), and liver-related death (HR 3.71; 95% CI=1.05-13.05). CONCLUSIONS: SVR is achieved in one-third of patients with HCV-related cirrhosis treated with peginterferon and ribavirin. SVR has a strong independent positive influence on the incidence of HCC and on the prognosis of these patients.

Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients.

UNLABELLED: Pegylated interferon alfa-2a (PEG-IFN) may induce sustained virological response (SVR) in 20% of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. In addition, loss of hepatitis B surface antigen (HBsAg) is achieved with a 10% yearly rate after treatment cessation in sustained responders. The aim of this study was to assess on-treatment serum HBsAg kinetics to predict SVR in HBeAg-negative patients treated with PEG-IFN. Forty-eight consecutive patients were treated with PEG-IFN (180 microg/week) for 48 weeks. Serum hepatitis B virus (HBV) DNA (COBAS TaqMan) and HBsAg (Abbott Architect HBsAg QT assay) were assessed at baseline, during treatment (weeks 12, 24, and 48), and during follow-up (weeks 72 and 96). SVR was defined as undetectable serum HBV DNA (<70 copies/mL) 24 weeks after treatment cessation. Twenty-five percent of patients achieved SVR. They were not different from those who failed treatment regarding age, sex, ethnicity, HBV genotype, baseline serum HBV DNA and HBsAg levels, or liver histology. During treatment, serum HBsAg levels decreased only in patients who developed SVR, with mean decreases of 0.8 +/- 0.5, 1.5 +/- 0.6, and 2.1 +/- 1.2 log(10) IU/mL at weeks 12, 24, and 48, respectively. A decrease of 0.5 and 1 log(10) IU/mL in serum HBsAg levels at weeks 12 and 24 of therapy, respectively, had high predictive values of SVR (negative predictive value [NPV] 90%, positive predictive value [PPV] 89% for week 12; NPV 97%, PPV 92% for week 24). HBsAg loss was observed in three patients, all with SVR. CONCLUSION: Early serum HBsAg drop has high predictive values of SVR to PEG-IFN in HBeAg-negative CHB patients. Serum quantitative HBsAg may be a useful tool to optimize the management of PEG-IFN therapy in these patients.

The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report.

Abstract Hepatitis C virus (HCV) genotypes 4, 5 and 6 represent >20% of all HCV cases worldwide. HCV-4 is mainly seen in Egypt, where it represents 90% of all HCV cases. Antischistosomal therapy was the main cause of contamination there, followed by procedures performed by informal providers and traditional healers such as dental care, wound treatment, circumcision, deliveries, excision and scarification. It is also highly prevalent in sub-Saharan Africa and in the Middle East. In Europe, its prevalence has recently increased particularly among intravenous drug users and in immigrants. HCV-5 is mainly found in South Africa, where it represents 40% of all HCV genotypes, but four pockets of HCV-5 were found in France, Spain, Syria and Belgium and sporadic cases were found elsewhere. The mode of transmission is mainly iatrogenic and transfusion. HCV-6 is found in Hong Kong, Vietnam, Thailand and Myanmar and also in American and Australian from Asian origin. The response to treatment in HCV-4 is intermediate between HCV-1 and HCV-2 and HCV-3. A sustained viral response is achieved in 43-70% with pegylated interferon and ribavirin. It is higher in Egyptians than Europeans and Africans and is negatively related to insulin resistance and to the severity of fibrosis. It increases to >80% with 24 weeks of therapy only if a rapid virological response is achieved. In HCV-5, a sustained virological response is achieved in >60% with 48 weeks of therapy. HCV-6 is also considered an easy-to-treat genotype, leading to a response in 60-85% of cases.

Metabolic disorders associated with chronic hepatitis C: impact of genotype and ethnicity.

BACKGROUND & AIM: Patients with hepatitis C virus (HCV) infection, especially those with genotypes 1 and 4, have an increased risk of developing metabolic disorders. The aim of this study was to evaluate the associations among metabolic disorders, ethnicity and genotype in a large cohort of patients with chronic hepatitis C (CHC). PATIENTS AND METHODS: All consecutive patients with CHC who were seen in our hepato-gastroenterology unit between January 2002 and September 2008 were included. Demographical data and variables related to the metabolic syndrome were collected. Insulin resistance was assessed using the homeostasis model for the assessment of insulin resistance test (HOMA-IR) test. RESULTS: Among the 454 CHC patients, the prevalence of the metabolic syndrome was 12.4%. The HOMA-IR test was performed in 140 patients, and 35.0% had insulin resistance. There were more Black Africans among the patients with genotypes 1/4 than among those with genotypes 2/3 (32.0 vs 1.2%, P<0.0001). Insulin resistance was more common in patients with genotypes 1/4 than in those with genotypes 2/3 (17 vs 1.7%, P=0.0001 and 43.3 vs 16.3%, P=0.001, respectively). Genotypes 1/4 were more frequently present in patients with insulin resistance than in those without insulin resistance (85.7 vs 60.5%, P=0.001). By logistic regression, genotypes 1/4 [odds ratio (OR)=2.79; 95% confidence interval (CI): 1.09-7.12, P=0.032] and older age (OR=1.03; 95% CI: 1.004-1.06, P=0.024) were independently associated with the presence of insulin resistance. CONCLUSIONS: In CHC, insulin resistance is independently associated with the presence of genotypes 1/4. Ethnicity is not independently associated with metabolic disorders in patients with CHC.

High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: a long-term follow-up study.

BACKGROUND/AIMS: To assess the HBsAg seroconversion rate and its impact on the long-term outcome in chronic hepatitis B patients treated with conventional interferon, and to analyze the serum HBsAg concentration prior to seroconversion. METHODS: Ninety-seven HBeAg-positive patients were retrospectively evaluated. Sustained virological response (SVR) was defined as HBeAg seroconversion and undetectable serum HBV-DNA 48 weeks after treatment discontinuation. HBsAg level was assessed at yearly intervals until seroconversion in SVRs. RESULTS: Twenty-five patients (26%) achieved SVR. By multivariate analysis, SVR was associated with low serum HBV DNA level and severe liver fibrosis. During a median follow-up of 14 years (range, 5-20 years), 28 patients (29%) developed HBsAg seroconversion including 16 SVRs (64%) and 12 non-SVRs (16%), p < 0.001. HBsAg quantification showed a major decrease (median = 46%, range = 19-100%) in the first year after interferon starting in SVR patients. Six patients developed hepatocellular carcinoma, none of them had undergone HBsAg seroconversion. Liver fibrosis improved in 70% of patients with HBsAg seroconversion compared to 30% of those without HBsAg seroconversion (p < 0.01). CONCLUSIONS: HBsAg seroconversion is achieved with a high steady rate in patients responding to interferon, and associated with excellent outcome. Prospective studies are needed to clarify the utility of on-treatment quantitative serum HBsAg in interferon-based therapy.

Pregnancy in women with known and treated Budd-Chiari syndrome: maternal and fetal outcomes.

BACKGROUND/AIMS: Budd-Chiari syndrome (BCS) mainly affects women of childbearing age. We aimed to clarify whether pregnancy, a thrombotic risk factor, should be contraindicated in patients with known and treated BCS. METHODS: A retrospective study of pregnancy in women with known and treated BCS. RESULTS: Sixteen women had 24 pregnancies. Nine women had undergone surgical or radiological treatment. Anticoagulation was administered during 17 pregnancies. Seven fetuses were lost before gestation week 20. Deliveries occurred between week 20 and 31 in two patients, week 32 and 36 in eleven and after week 37 in four. There was one stillbirth, but 16 infants did well. Factor II gene mutation was a factor for a poor outcome of pregnancies. In two patients, symptomatic thrombosis recurred during pregnancy or postpartum. All patients were alive after a median follow-up of 34 months after the last delivery. Bleeding at delivery, although non-lethal, occurred only on anticoagulation therapy. CONCLUSIONS: When known and treated BCS is well controlled, pregnancy should not be contraindicated as maternal outcome, and fetal outcome beyond gestation week 20, are good. The risk-benefit ratio of anticoagulant therapy needs to be further clarified. Patients should be fully informed of the persistent risks of such pregnancies.

Virological response at 4 weeks to predict outcome of hepatitis C treatment with pegylated interferon and ribavirin.

BACKGROUND: Viral kinetics during therapy provides information on how to individualize treatment. To determine the benefit of assessing positive predictive values (PPVs) and negative predictive values (NPVs) of rapid virological responses (RVRs) and early virological responses (EVRs), on-treatment outcomes in chronic hepatitis C patients were examined. METHODS: A total of 408 patients (221 treatment-naive) treated with pegylated interferon-alpha2b and ribavirin were included. Hepatitis C virus (HCV) RNA was measured at baseline, 4 weeks and 12 weeks. RVR was defined as undetectable HCV RNA at 4 weeks and EVR as >/=2 log(10) decrease in HCV RNA at 12 weeks. The additive value of RVR on predicting sustained virological response (SVR) was assessed with receiver operating characteristic (ROC) curves. RESULTS: SVR, RVR and EVR were observed in 46%, 23% and 78% of patients, respectively. PPVs of RVR were 96%, 100% and 100% in treatment-naive patients, relapsers and non-responders, respectively. NPVs of failure to achieve EVR were 97%, 75% and 91%, in treatment-naive patients, relapsers and non-responders, respectively. At 4 weeks, patients with RVR had the highest probability to achieve SVR (odds ratio 44.98 in the entire population and 32.95 in treatment-naive patients). ROC curves showed the area under the ROC curve to be 0.758 versus 0.832 in the entire population and 0.795 versus 0.858 in treatment-naive patients at baseline versus week 4, respectively. CONCLUSIONS: RVR is a strong predictor of SVR (PPV>96%) and failure to achieve EVR is a strong predictor of non-SVR (NPV>75%), independent of patients' pretreatment status. Added to baseline characteristics, RVR increased the accuracy to predict SVR. The combination of RVR and EVR provided complementary information, and thus provides a key opportunity to individualize treatment and improve the benefit/risk ratio of therapy.

Levels and initial course of serum alanine aminotransferase can predict outcome of patients with Budd-Chiari syndrome.

BACKGROUND & AIMS: Patients with Budd-Chiari syndrome can present with acute, subacute, or chronic disease; the definitions and significance of these variants have been disputed. An increased level of serum alanine aminotransferase (ALT) is an objective marker for acute liver injury. We analyzed the significance of changes in ALT levels in Budd-Chiari syndrome patients. METHODS: We performed a retrospective analysis of data from 96 consecutive Budd-Chiari syndrome patients. RESULTS: A threshold peak ALT level that was 5-fold the upper limit of normal distinguished 2 groups of patients: patients with high levels of ALT (40% of patients) presented with more severe liver disease, less frequent liver fibrosis, and more frequent liver cell necrosis, compared with those with ALT levels below this threshold. Patients with levels of ALT that started out high but slowly declined (<50% of starting concentration within 3 days) had significantly lower odds of survival than those with a rapid decline and those with low levels of ALT (40 months transplantation-free survival, 31%, 63%, and 71%, respectively). When ALT level and the velocity of its decline are used as criterion, these data add significant prognostic information to Child-Pugh, to Clichy, and to Rotterdam Budd-Chiari syndrome scores. CONCLUSIONS: Determination of ALT levels at patient presentation allows 2 variants of Budd-Chiari syndrome to be distinguished. High levels of ALT reflect acute, severe, but potentially reversible, ischemic liver cell necrosis. High levels of ALT that decrease slowly predict a poor outcome for patients and might justify rapid aggressive management.

Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C.

BACKGROUND & AIMS: It is unclear whether hepatitis C virus (HCV) is eradicated in patients with chronic hepatitis C who achieved a sustained virologic response (SVR). METHODS: In this long-term follow-up study, including chronic hepatitis C patients who achieved SVR after interferon-based therapy, the presence of residual HCV RNA in serum, liver, and peripheral blood mononuclear cells (PBMCs) was assessed, using transcription-mediated amplification (sensitivity, <9.6 IU/mL). The benefit of SVR on liver fibrosis was evaluated using the METAVIR score. RESULTS: A total of 344 patients were followed up for a median duration of 3.27 years (range, 0.50-18 y; interquartile range [IQR], 1.68-5.35 y). A total of 114 patients had a posttreatment liver tissue (median, 0.50 y; range, 0-14 y; IQR, 0-3.5 y) and a total of 156 had one PBMC (median, 3.0 y; range, 0.50-18 y; IQR, 1.25-5.50 y). Serum HCV RNA remained undetectable (1300 samples), indicating that none of the patients had a relapse. HCV RNA was detectable in 2 of 114 (1.7%) liver specimens, and in none of 156 PBMC specimens. Histologic analysis of 126 paired pretreatment and posttreatment liver biopsy specimens (median, 0.50 y; range, 0-14 y; IQR, 0-3.5 y) showed that fibrosis stage was improved in 56%, stable in 32%, deteriorated in 12%. Regression of cirrhosis was observed in 9 of 14 (64%) (95% confidence interval, 39-89) patients. No cirrhosis decompensation was observed, and 3 patients developed hepatocellular carcinoma. CONCLUSIONS: In this large cohort of chronic hepatitis C patients, SVR was durable up to 18 years after treatment cessation, in addition to fibrosis stability/improvement (88%) and cirrhosis regression (64%). The presence of residual HCV RNA was observed only in liver tissue (1.7%). This result strongly suggests that SVR may be considered to show eradication of HCV infection.

Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis.

BACKGROUND & AIMS: Our study was designed to test the association between insulin resistance (IR) and hepatitis C virus (HCV) genotypes, serum HCV RNA level and liver fibrosis stage in a large prospective cohort of chronic hepatitis C (CHC) patients. METHODS: Six hundred consecutive patients (CHC, n = 500; chronic hepatitis B (CHB), n = 100) were evaluated on the day of liver biopsy. IR (Homeostasis Model for Assessment of Insulin Resistance) and all components of the metabolic syndrome were assessed. By logistic regression, independent factors associated with IR and those associated with significant fibrosis were assessed in nondiabetic and noncirrhotic CHC, respectively. Parameters of IR were compared between hepatitis B and 240 CHC matched by epidemiologic, metabolic, and histologic features. RESULTS: IR was present in 32.4% of the 462 nondiabetic CHC and associated with the metabolic syndrome, genotypes 1 and 4, significant fibrosis, and severe steatosis. IR was diagnosed in 15% of 145 CHC without metabolic syndrome or significant fibrosis, and associated with genotypes 1 and 4, high serum HCV RNA level, and moderate-severe necroinflammation. Significant fibrosis was present in 51.1% of the 454 noncirrhotic CHC patients and associated with male sex, age >40 years, IR, moderate-severe necroinflammation, and severe steatosis. IR was less frequent in CHB than in matched CHC (5% vs 35%, respectively, P < .001). CONCLUSIONS: IR is a specific feature of CHC, associated with genotypes 1 and 4 and high serum HCV RNA level. Significant fibrosis is associated with IR independent from steatosis.

Prognostic indices for Budd-Chiari syndrome: valid for clinical studies but insufficient for individual management.

OBJECTIVES: Several prognostic indices (PIs) have been proposed for Budd-Chiari syndrome (BCS). However, patient characteristics, causal factors, and treatment outcomes have changed since these indices have been elaborated. Validation in a recent patient population and comparison of predictive accuracy between these PIs are needed. METHODS: A database of 96 BCS patients diagnosed between 1995 and 2005 was analyzed. Cox survival models were fitted with time to liver transplantation or death, and time to invasive therapy or death, as end points. The prognostic values of known indices (Child-Pugh score, model for end-stage liver disease (MELD), Clichy, Rotterdam BCS index, New Clichy, and BCS-TIPS (transjugular intrahepatic portosystemic shunt)) at diagnosis were assessed in Cox models using the chi-square test, the Kent and O'Quigley measure of dependence, and unrestricted bootstrapping analysis. Areas under receiver operating characteristic curves (AUROCs) were built for both end points and compared. RESULTS: All prognostic indices, except BCS-TIPS, were significant predictors of transplant-free and invasive therapy-free survival. However, only 31 and 37% of the variance in transplant-free and invasive therapy-free survival, respectively, were explained by the best performing indices. For transplant-free survival, AUROCs were < 0.70. For invasive therapy-free survival, AUROCs were < 0.80. For both end points, BCS-TIPS PI AUROCs were significantly lower than others. CONCLUSIONS: Most PIs are valid for transplant-free survival and invasive therapy-free survival in a population of current BCS patients, and thus can be used for stratification in clinical studies. However, predictive accuracy is insufficient to be used for individual patients.

Sustained virological response is associated with clearance of hepatitis C virus RNA and a decrease in hepatitis C virus antibody.

BACKGROUND/AIM: Viral eradication in chronic hepatitis C patients with sustained virological response (SVR) after interferon (IFN) therapy remains controversial. METHODS: During a long-term follow-up study, 157 patients with SVR to IFN-alpha-2b-based therapy were investigated with a transcription-mediated amplification (TMA) assay in serum. The hepatitis C virus (HCV) antibody was assessed by measuring the optical density (OD) (Axsym HCV v3.0) and the semiquantitative titres (RIBA HCV v3.0) of the HCV antibodies directed against the core, NS3, NS4 and NS5 proteins. A control group included 23 untreated patients with persistently normal serum alanine aminotransferase and detectable serum HCV-RNA. RESULTS: The median duration of follow-up was 4.0 (0-10) years. Serum HCV-RNA remained undetectable in all patients. The mean HCV antibody OD were 93 +/- 19 and 45 +/- 21 before therapy and in the last available serum sample respectively (P=0.001). There was a marked decrease in the HCV antibodies directed against the NS3, NS4 and NS5 proteins (P=0.001), while the core protein titre remained strongly positive. The 23 control patients were followed for a median of 5 (2-14) years. The mean HCV antibody OD were 65 +/- 14 and 64 +/- 19 in the first and the last measurements, respectively (NS), and HCV antibody titres for structural and non-structural proteins remained unchanged. CONCLUSION: This long-term study evaluating 157 patients demonstrated that SVR assessed by TMA is durable, and HCV antibodies were markedly decreased (mainly those directed against the non-structural proteins), emphasizing an absence of ongoing infection. These results strongly suggest that HCV infection cured in patients who achieve an SVR.

Interferon therapy for chronic hepatitis B.

This article summarizes the results obtained with interferon alfa and pegylated interferon alfa, as monotherapy and in combination with lamivudine, in the treatment of chronic hepatitis B.

Acute hepatitis E with severe jaundice: report of three cases.

Hepatitis E virus (HEV) is the main cause of enterically transmitted non-A hepatitis worldwide. Infection is endemic in developing countries. Disease course is benign, and severe jaundice is rarely reported. Three patients presented to our department with symptomatic acute hepatitis. Two of them had recently travelled to endemic areas. Jaundice was very marked in all patients. HEV infection was documented by HEV antibodies and by HEV-RNA detection in serum and stools. In the autochthonous case, immunoglobulin-M was absent, and diagnosis was established on HEV-RNA amplification by real-time reverse transcriptase-PCR. Comprehensive investigation for concomitant causes of liver disease was negative in all patients. Histological features showed marked cholestasis with multiple bile plugs in dilated canaliculi. In conclusion, acute hepatitis E may be autochthonous in developed countries and patients may present with severe jaundice. HEV-RNA detection by real-time reverse transcriptase-PCR is a very efficacious diagnostic tool in anti-HEV immunoglobulin-M-negative cases.

[Steatosis during chronic hepatitis C: the role of insulin resistance and viral factors]. / Stéatose au cours de l'hépatite chronique C: rôle de l'insulino-résistance et des facteurs viraux.

Liver steatosis is frequent in patients with chronic hepatitis C. Two main types are described: (1) "viral steatosis" induced by the virus, especially genotype 3, which probably inhibits the "Microsomal Triglyceride Transfer Protein", thus decreasing "Very Low Density Lipoprotein" secretion and leading to triglyceride accumulation within hepatocytes; (2) "metabolic steatosis" which is a feature of the metabolic syndrome and insulin resistance, a systemic disorder associated with a high risk of cardiovascular disease and diabetes mellitus. Insulin resistance induces intrahepatic triglyceride accumulation due to excess free fatty acid flux from increased adipose tissue lipolysis as well as increased intrahepatic lipogenesis through activation of the "Sterol Response Element Binding Protein". Hepatitis C Virus itself can also be responsible for insulin resistance, possibly through impairment of the insulin signalling pathway because of increased"Tumor Necrosis Factor Alpha" levels and/or upregulated "Cytokine Signalling Suppressor" expression. Insulin resistance and steatosis, appear to be associated with fibrosis progression and impairment of sustained response to antiviral treatment.