Editorial Board: Emmet B. Keeffe, MD (Chair);

Anna Lok, MD; Brian McMahon, MD; Albert Min, MD; Myron Tong, MD; Naoky Tsai, MD; Bruce Tung, MD

HBV Watch™

Timely Information for Practicing Physicians

 

OCTOBER 2003

 

TOPIC REVIEW: Noninvasive Markers For Assessment of Hepatic Fibrosis in Chronic Viral Hepatitis

The traditional standard to establish the stage (fibrosis) and grade (inflammation) of disease in patients with chronic viral hepatitis is liver biopsy. Arguments in favor of routine pretreatment liver biopsy include (1) precise determination of the stage of fibrosis and urgency for therapy, (2) exclusion of unsuspected secondary diagnoses (uncommon), (3) prediction of response to therapy (in hepatitis B and C), and (4) information to help the patient decide on therapy and direct the aggressiveness of side-effect management during antiviral therapy (in chronic hepatitis C). Arguments against routine pretreatment liver biopsy in patients with chronic viral hepatitis include (1) risks and costs associated with biopsy, (2) sampling error and intra- and interobserver variance, (3) patient preference for therapy without biopsy (should not prohibit therapy) (4) mild histological changes found in the majority of patients with persistently normal aminotransferase levels (hepatitis B and C), and (5) 75-80% sustained virological response in patients with chronic hepatitis C and genotypes 2 or 3. There is a need for a simple, reliable, and inexpensive way to assess disease severity in patients with chronic viral hepatitis with high positive and negative predictive values. A number of studies have shown that a high AST/ALT ratio, low platelet count, or prolonged prothrombin time is an indicator of cirrhosis. Investigators in France have shown that a more complex formula of tests, including γ-glutamyltranspeptidase (GGT), total bilirubin, α2-macroglobulin, haptoglobin, and apolipoprotein A1 (Fibrotest), can achieve good prediction of either no or mild fibrosis (stage 0-1) or advanced fibrosis (stage 3-4) in patients with chronic hepatitis C virus (HCV) infection. In the U.S. preliminary studies using a panel of markers based on extracellular matrix and connective tissue proteins (FibroSpect) have shown similar utility in identifying HCV patients with either mild or advanced fibrosis. Fibrotest and FibroSpect overall have approximately an 80% sensitivity and 80% specificity in regard to agreement with liver histology. These two tests perform best in predicting those with mild or severe fibrosis but perform poorly in predicting those with moderate fibrosis. Other models have incorporated age, gender, alcohol consumption, and serum cholesterol in formulae predicting minor versus advanced fibrosis. The current tests undergoing study suggest that up to half of patients with chronic viral hepatitis may have their fibrosis stage accurately predicted by noninvasive testing, leaving the other half as candidates for liver biopsy for precise determination of fibrosis stage.

 

Biochemical Markers IN HBV PATIENTS

Prediction of histological lesions.  Robert Myers and associates in Paris investigated the use of aminotransferases and two other biochemical indices, Fibrotest and Actitest (Fibrotest plus ALT), to detect histological lesions in 209 patients with chronic hepatitis B.  Biopsies were analyzed using the METAVIR classification.  A2-A3 activity (moderate to severe necroinflammation) was detected in 41 patients (20%), and F2-F4 fibrosis (periportal fibrosis to cirrhosis) was detected in 61 patients (29%).  Multiple regression analysis identified only AST and GGT levels to be independent predictors of A2-A3 activity.  An AST (or ALT) value £ 30 IU/L excluded significant necroinflammatory activity with 96% certainty.  Fibrotest accurately predicted F2-F4 fibrosis: scores £ 0.20 had a negative predictive value of 92%, and scores > 0.80 had a positive predictive value of 92%.  These findings demonstrated that aminotransferase levels and biochemical indices are accurate markers of histologic lesions in patients with chronic hepatitis B.  In addition, restricting liver biopsies to patients with intermediate Fibrotest scores (> 0.20 to £ 0.80) may eliminate the need for liver biopsies in 46% of patients while maintaining 92% accuracy.  (Myers RP et al. J Hepatol 2003;39:222-230)

 

Adefovir Dipivoxil (ADV)

Development of an HBV polymerase mutation and clinical resistance.  Clinical studies have shown ADV reduces serum HBV DNA levels in most patients with chronic HBV infection and produces improvement in liver histology and ALT levels.  In contrast to lamivudine, no patients developed viral resistance to adefovir during the 48-week course of treatment in these studies.  A low rate of natural polymorphic mutations, which were not shown to confer drug resistance by in vitro phenotypic analysis of the mutant viruses, occurred in adefovir-treated patients.  These findings suggested that prolonged suppression of HBV replication without the emergence of resistance may be possible with adefovir.  Peter Angus and others now report a patient who developed resistance to adefovir following the emergence of a novel mutation in the HBV polymerase gene.  The patient initially responded to adefovir as manifested by a 2.4 log10 decrease in serum HBV DNA and normalization of ALT levels.  However, during the second year of therapy, serum HBV DNA progressively increased to near-pretreatment levels.  This change in serum HBV DNA level was associated with increasing ALT levels and worsening of liver function tests.  Polymerase chain reaction sequencing identified the development of a novel mutation of HBV polymerase (the substitution of threonine for asparagine at residue rt236 in domain D).  In vitro testing demonstrated that this mutation caused a marked reduction in susceptibility to adefovir.  The patient responded to subsequent lamivudine therapy.  This is the first documented case of the development of virologic and clinical resistance to adefovir dipivoxil therapy.  The emergence of resistance to adefovir dipivoxil appears to be infrequent and delayed in nature.  The subsequent response to treatment with lamivudine suggests that combination antiviral therapy may provide the greatest possibility for long-term suppression of viral replication.  (Angus P et al. Gastroenterology 2003;125:292-297)

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