Rita Lin

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.

Interferon alfa-2b for chronic hepatitis C : effects of dose increment and duration of treatment on response rates. Results of the first multicentre Australian trial

Two hundred and thirty patients with histologically proven chronic hepatitis C were randomized to receive one of the following treatment protocols: (a) 3 million units of interferon alfa-2b thrice weekly for 6 months, (b) 5 million units thrice weekly for 6 months, or (c) 3 million units thrice weekly for 2 years. The short-term response to treatment was defined by normal alanine aminotransferase for at least 3 months and until the end of treatment, and was confirmed by loss of hepatitis C viraemia in 42 (91%) of 46 cases as determined by reverse transcription-polymerase chain reaction. Short-term response to interferon alfa-2b was independent of the incremental dose, being 64% for 5 million units and 58% for 3 million units. Long-term response to interferon alfa-2b was defined by continued normality of alanine aminotransferase levels for at least 6 months after treatment withdrawal. The long-term response rates among responders treated for 6 months and those treated for 2 years were 29% and 54%, respectively (p < 0.001). Among all 18 patients tested, serum HCV-RNA was negative at both 6 and 12 months of follow-up in all long-term responders, and none have subsequently relapsed. Improvement in hepatic necroinflammatory changes was confirmed by quantitative histology (Scheuer score) in responders at the end of interferon alfa-2b treatment. The changes were significantly greater among those who had been treated for 2 years compared with those treated for 6 months (p < 0.05 and p < 0.02, respectively, for portal and lobular inflammation scores). Several pretreatment characteristics could be correlated with a favourable response to interferon alfa-2b. Thus, absence of cirrhosis was associated with a short-term response of 75%, while only 42% of patients with cirrhosis had a short-term response (p < 0.001). The frequency of short-term response to interferon alfa-2b also differed according to mode of disease acquisition, being best for injecting drug use (71%), less favourable for blood transfusion (56%) and worst for sporadic cases (43%) (p < 0.01). This observed difference, however, was not independent of histology on multivariate analysis. In summary, a 5 million unit dose of interferon alfa-2b failed to improve the short-term or long-term response to interferon alfa-2b treatment, but prolongation of interferon alfa-2b treatment to 2 years resulted in substantially improved long-term response rate.

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.

Hepatocellular proliferation and development of hepatocellular carcinoma: A case-control study in chronic hepatitis C

Patients with hepatitis C have an increased risk of developing hepatocellular carcinoma (HCC). This is related to the stage of chronic liver disease, as characterized histologically by hepatic fibrosis and architectural distortion, but it is unclear whether histological markers can define the risk of developing HCC. We conducted a case-control immunohistochemical study of Ki-67, a marker for hepatocellular proliferation, in livers of 18 patients who had developed HCC more than 2 years after the biopsy specimen had been taken. Using conditional logistic regression analysis, the results were compared with 18 selected controls, who were age-matched patients with hepatitis C of similar histological stage who had not developed HCC. We also examined livers for cellular dysplasia, p53 mutations, and bcl-2 overexpression, and assessed whether the results could be correlated with demographic and disease-related variables, such as gender, region of birth, alcohol consumption, severity of liver disease, HCV genotype, and markers of hepatitis B virus (HBV) infection. Livers from patients who developed HCC were more often positive for Ki-67 (13 of 18 [72%] v 9 of 18 [50%]; P = .06) and tended to have higher mean Ki-67 scores (6 +/- 7.5 v 3 +/- 4.4; P = .10) compared with control cases. In the HCC-predisposed group, three livers showed large cell dysplasia, two were positive for p53 mutations, and two for bcl-2 overexpression. In contrast, in the non-HCC group, only one case had dysplasia, and none were positive for immunostaining for p53 or bcl-2 mutations. With the exception of one case, all livers with large cell dysplasia or p53 mutations and bcl-2 overexpression were also positive for Ki-67. Twelve (55%) of the 22 Ki-67-positive cases were anti-HBc-positive in the serum, in contrast to 2 of 14 (14%) patients in the Ki-67-negative group (P = .01). Patients with evidence of past infection with HBV were more often Ki-67 positive than those who had no evidence of past infection (85% [11 of 13] v 45% [10 of 22]; P = .02). There were no other associations between demographic or disease-related variables and Ki-67 expression. Increased hepatocellular proliferative activity, as assessed by Ki-67 expression, may be one factor indicative of an increased risk of developing HCC among patients with chronic hepatitis C. Furthermore, past infection with HBV appears to be an important correlate of increased hepatocellular proliferation in hepatitis C.

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.

Virus and host factors are both important determinants of response to interferon treatment among patients with chronic hepatitis C

SUMMARY. Virus and host factors have both been linked to the response to interferon treatment among patients with chronic hepatitis C but their relative importance and potential interactions are unclear. Hepatitis C virus genotype and level of viraemia were determined in pretreatment sera from 65 Australian patients treated with interferon‐α2b (IFN‐α2b). 3 MU tiw for 6 months. Hepatitis C viraemia was quantitated by a competitive reverse transcription‐polymerase chain reaction (RT‐PCR) method and genotype was determined by a line probe assay. By univariate analysis, there were positive associations between initial (short‐term) responses to IFN treatment and younger age (P= 0.004). absence of cirrhosis (P= 0.01). and injecting drug use as risk factor for infection (P= 0.05) but not gender, duration of infection, or level of viraemia. Genotype appeared to be important (P= 0.06) but failed to reach statistical significance. By multivariate analysis, absence of cirrhosis was the only significant independent predictor of treatment response (P= 0.01). Among initial responders, the factors associated with long‐term response were the pretreatment HCV RNA titre and the duration of infection. There was a close association between viral genotype, but not viral load, and the severity of liver disease. An interplay of factors determines the outcome of a 6‐month course of interferon treatment for hepatitis C. Severity of liver disease, but not the viral load, is the most crucial determinant of initial response to interferon, and histological severity appeared to be influenced by the viral genotype. The level of hepatitis C virus (HCV) viraemia and the duration of infection are independent determinants of long‐term response by affecting the relapse rate after interferon treatment.

Epidemiology of hepatitis C virus infection in Australia

The geographical distribution of chronic hepatitis C virus (HCV) infection appears to be one of high and low prevalence regions. Australia resembles the USA, UK and other parts of northern Europe in being a low prevalence region, and thereby differs from southern Europe, the middle-east, south-eastern Asia and Japan. However, the high levels of recent immigration from areas with high prevalence of chronic HCV infection makes Australia an interesting place for epidemiological studies of hepatitis C. In particular, it is possible to examine different pathways of viral transmission and any pathobiological differences liver disease related to the source of infection. A further implication of recent immigration is that the genetic diversity of the Australian population is increasing. Thus 24% of the present population were born outside Australia, including in southern European, middle-eastern and southeast Asian countries. This has allowed us to reexamine the proposed relationships between HCV infection and autoimmune chronic active hepatitis within a genetically heterogeneous community. In the present minireview, we have examined the published as well as preliminary unpublished data concerning the prevalence of chronic HCV infection in Australia. In particular, we discuss the risks of viral infection according to parenteral and nonparenteral modes of spread, the relationship of these and other demographic factors to the severity of associated hepatic pathology, and the serological and virological correlates of autoimmune and hepatitis C-related liver disease.

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.

Effects of hepatitis G virus coinfection on severity of hepatitis C: Relationship to risk factors and response to interferon treatment

The aims of the present study were to identify characteristics that are more often associated with hepatitis G virus (HGV) coinfection in Australian patients infected with the hepatitis C virus (HCV) and to investigate the effects of HGV on the histological and functional severity of chronic hepatitis C. Serum samples from 209 patients with chronic hepatitis C were tested for HGV‐RNA using single‐round reverse transcriptase—polymerase chain reaction to primers directed at the NS5 region of the HGV genome. Hepatitis G virus RNA was detected in 40 cases (19%). Hepatitis G virus‐coinfected patients tended to be younger and parenteral risks could be identified in all but six. Although country of birth did not differ significantly between the coinfected and HCV‐alone groups, HGV‐positive patients appeared to be less likely to have originated from Asia. On logistic regression analysis, HCV genotype 3a was found in a significantly higher proportion of patients with HGV coinfection than other genotypes (P<0.01). Liver histology and response to interferon were similar in the HGV‐coinfected and HCV‐alone groups and liver‐related complications appeared to occur less frequently in patients with both HGV and HCV. On univariate analysis, antipyrine clearance was found to be higher in the coinfected group (P<0.05), implying better preservation of hepatic metabolic function, but this difference was lost when adjusted for HCV genotype. In conclusions coinfection with HGV was more commonly associated with HCV genotype 3a, a genotype associated with injection drug use in younger patients. However, the presence of HGV coinfection did not adversely affect liver disease or the response to interferon treatment in patients with chronic hepatitis C.