Dev Samarasinghe

Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index.

We sought to develop a clinically useful index comprising standard and physiologically relevant variables to predict the probability of significant hepatic fibrosis in subjects with chronic hepatitis C virus (HCV) infection. Fibrosis was graded as mild (stages F0 or F1) or significant (stages F2–F4). Thirty‐five clinical and laboratory parameters were analyzed initially in 176 patients with detectable HCV RNA to derive a fibrosis probability index (FPI) to predict significant fibrosis. This index then was validated in a second group of 126 subjects. Among 18 variables associated with severe fibrosis on univariate analysis, multiple logistic regression analysis identified age, aspartate aminotransferase (AST), total cholesterol level, insulin resistance (by homeostasis model), and past alcohol intake as independent predictors of significant fibrosis. The area under the receiver operating characteristic (ROC) curves was 0.84 for the initial cohort and 0.77 for the validation cohort. In the initial cohort, the sensitivity of the FPI based on these five predictors was 96%, and the negative predictive value was 93% at a score of ≥0.2. At scores ≥0.8, the FPI was 94% specific and had a positive predictive value of 87%. In conclusion, an FPI using routinely assessed markers and incorporating a measure of insulin resistance can reliably predict the probability of significant hepatic fibrosis in most patients with chronic HCV infection. Such an index should prove useful to guide decision making regarding the need for liver biopsy, and potentially for avoiding or deferring biopsy in a large proportion of patients with mild liver disease. (HEPATOLOGY 2004;39:1239–1247.)

Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection

Abstract Background: Hepatic steatosis is common in hepatitis C, but the relative importance of host and viral factors is controversial. In the present prospective study, we examined metabolic factors associated with non‐alcoholic fatty liver and viral genotype as predictors of steatosis and fibrosis in chronic hepatitis C infection.

Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus

BACKGROUND & AIMS Perinatal transmission of hepatitis B virus still occurs despite immunoprophylaxis in approximately 9% of children from highly viraemic mothers. Antiviral therapy in this setting has been suggested, however with limited evidence to direct agent choice. METHODS We conducted a multi-centre, prospective, opt-in observational study of antiviral safety and efficacy in pregnant women with high viral load (>7 log IU/ml); lamivudine was used from 2007 to 2010 and tenofovir disoproxil fumarate (TDF) from late 2010. Outcomes of treated and untreated cohorts were compared. RESULTS 120 women with 130 pregnancies used TDF (58), lamivudine (52 including four who switched due to TDF intolerance) and no therapy (20). 96% were HBeAg positive, with baseline viral load mean 7.8 log IU/ml (±0.72) and ALT median 25 U/L (18.75-33). Duration of antiviral theraphy before birth was mean 58 days (±19) TDF and 53 (±14) lamivudine. Viral load declined by 3.64 log IU/ml (±0.9) TDF and 2.81 log IU/ml (±1.33) lamivudine. Virologic failure (birth viral load >7 IU/ml) occurred in 3% and 18% respectively. Congenital abnormality rate and neonatal growth centiles were similar across cohorts. Perinatal transmission reduced significantly to 2% and 0% in TDF and lamivudine cohorts, compared with 20% in untreated. CONCLUSIONS TDF in this setting is safe, effective and more potent than lamivudine. Antiviral therapy did not adversely impact obstetric or infant parameters. More TDF intolerance occurred than expected. Perinatal transmission was significantly reduced in antiviral therapy cohorts.

Effects of Interferon Treatment Response on Liver Complications of Chronic Hepatitis C: 9-year Follow-Up Study

OBJECTIVES:Fibrotic severity, biochemical indices of poor liver function, and sporadic transmission are independent predictors of liver complications among people with chronic hepatitis C. After accounting for these factors, we tested whether interferon treatment or the treatment response reduces the rate of liver cancer, liver-related death or transplantation, and other liver complications during extended follow-up.METHODS:Liver clinic cohort of 455 patients with histologically proven chronic hepatitis C was followed prospectively for median 9 yr (IQ 6, 11 yr); 384 received interferon, 343 completed a treatment course. Liver complications were assessed in relation to treatment and treatment response in univariate and multivariate models, and survival to onset of liver-related complications was determined.RESULTS:The annual incidence of total liver complications was 1.5% in treated and 2.9% in untreated patients and appeared quasilinear throughout 9-yr follow-up. Interferon treatment did not influence the rate of liver complications. However, the rate of complications increased exponentially with transition of the treatment response from sustained viral response (SVR), through response-relapse to nonresponse (or no treatment). By univariate analysis, response to interferon treatment was a significant predictor of complications. After adjustment for fibrosis score, serum albumin concentration and mode of transmission in a multivariate model, treatment response just failed to reach significance (p = 0.058) as a predictor of outcome.CONCLUSIONS:Response to antiviral therapy, and particularly SVR, appears to reduce liver complications in chronic hepatitis C. However, in the absence of an antiviral treatment response, a course of interferon does not reduce risks of liver cancer or liver failure.

Anti-viral therapy for prevention of perinatal HBV transmission: extending therapy beyond birth does not protect against post-partum flare

Antepartum anti‐viral therapy (AVT) is often administered to prevent perinatal transmission of hepatitis B virus (HBV) infection. Little is known about the effect of AVT on post‐partum flare rates and severity.

Changes in Antipyrine Clearance and Platelet Count, but Not Conventional Liver Tests, Correlate With Fibrotic Change in Chronic Hepatitis C: Value for Predicting Fibrotic Progression

OBJECTIVE:We tested whether fibrotic progression in chronic hepatitis C could be predicted by liver tests, antipyrine clearance, or platelet count.METHODS:In 58 patients (6 untreated, 52 interferon-treated), a second liver biopsy was taken median 4.5 yr after first histologic diagnosis. We used receiver operating characteristic curves to determine whether changes in conventional liver tests, antipyrine clearance, or platelet count were predictive of altered hepatic fibrosis score.RESULTS:Apart from a weak association with change in ALT, conventional liver tests (albumin, bilirubin, prothrombin time) failed to correlate with changes (Δ) in hepatic fibrosis, but there were significant correlations between Δantipyrine clearance or Δplatelet count and Δfibrosis score (p < 0.01). As indicated by areas under the receiver operating characteristic curves, the diagnostic accuracy of Δantipyrine clearance for fibrotic progression was 68%; for Δplatelet count it was 80%. With defined cut-off values (−0.05 ml/min/kg for Δantipyrine clearance; −41 × 109/L for Δplatelet count), the negative predictive values for fibrotic progression were 85% with antipyrine clearance and 89% with platelet count. Corresponding positive predictive values were 48% and 91%, respectively.CONCLUSIONS:Changes in antipyrine clearance and platelet count are more sensitive than conventional tests for indicating fibrotic change in chronic hepatitis C. Both could be used to reliably identify those who do not have fibrotic progression, and platelet count also has a high positive predictive value for disease progression.

Changes in serum albumin during treatment of chronic hepatitis B with lamivudine: effects of response and emergence of drug resistance.

OBJECTIVES:In chronic hepatitis B patients treated with lamivudine, the incidence of drug resistance increases with the duration of therapy. The effect of drug resistance on hepatic synthetic function is not well defined. The aim of the present study was to assess the effect of lamivudine therapy on hepatic synthetic function in patients with moderately severe chronic hepatitis B and, particularly, to determine the effect of drug resistance.METHODS:Hepatic synthetic function was assessed using serial measurements of serum albumin in 38 patients (26 with cirrhosis) in an open-label treatment program.RESULTS:An initial antiviral response (hepatitis B virus [HBV] DNA undetectable by hybridization assay) occurred in all patients, and nine of 22 (41%) hepatitis B e antigen–positive cases underwent hepatitis B e antigen seroconversion. Among 29 patients with undetectable serum HBV DNA at the end of observation, the mean serum albumin concentration rose from 39.9 ± 0.7 to 43.2 ± 0.6 g/L, corresponding to a yearly increase of 1.85 g/L (p < 0.001). This was largely attributable to an increase among cirrhotic patients. Nine patients (24%) developed resistance to lamivudine, all after 12 months of treatment. Among them, the mean serum albumin concentration had increased from 39.6 ± 1.2 to 42.9 ± 0.8 g/L before resistance emerged, but then decreased to 39.3 ± 1.7 g/L (p = 0.01) at the time of reappearance of HBV DNA.CONCLUSION:Suppression of viral replication by lamivudine improves hepatic synthetic function in chronic hepatitis B patients, but emergence of drug resistance is associated with a rapid decline in serum albumin, at least to pretreatment levels.

Endoscopic palliation of oesophageal carcinoma with Atkinson prosthesis

Abstract To assess the degree of palliation, the associated morbidity and mortality and to compare our results with other published series, we reviewed our use of the Atkinson prosthesis in 100 consecutive patients for the palliation of unresectable oesophageal carcinoma. The group had a mean age of 71.2 ± 2.3 years. All prostheses were placed by the pulsion method. Intubation was successful in 91%. Improvement in swallowing was seen in 82.1%. Major early procedure‐related morbidity was high at 23% with 11 perforations (11%). Procedure‐related mortality was 12%. Those aged 70 years or more had a 34.5% risk of morbidity and 15.5% risk of dying from the procedure. Late procedure‐related complications requiring further endoscopic procedures occurred in 27%. Our 7 day mortality was 14.7% (14 patients) and 31 patients (32.6%) had died within 30 days, usually from the disease itself. Those surviving the procedure (> 7 days) had a mean survival of 105 (range 9–735) days.

Culture of sinusoidal endothelial cells from rat liver

culture of stellate cells from both normal animals and experimental models of liver injury provide us with a powerful medium in which to investigate the processes involved in the initiation of stellate cell activation and the development of hepatic fibrosis. In addition, these techniques may assist in the evaluation of pathways involved in reversing the activated phenotype, resulting in the regression of fibrosis, possibly through the development of new therapeutic technologies.