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 2005

BRIEF REVIEW: NONINVASIVE SURROGATE MARKERS OF HEPATITIS B VIRUS (HBV) FIBROSIS

The traditional standard to establish the stage (degree of fibrosis) and grade (degree of inflammation) of disease in patients with chronic viral hepatitis is liver biopsy. However, liver biopsy is limited by the potential for complications and sampling error. Thus, 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 aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, low platelet count, or prolonged prothrombin time is an indicator of cirrhosis. Investigators from France have shown that a complex formula based on results of a panel of tests including γ-glutamyltranspeptidase, total bilirubin, α₂-macroglobulin, haptoglobin, apolipoprotein A₁, and ALT (FibroTest-ActiTest [FT-AT, FibroSURE]) can help predict no or mild fibrosis (stage 0–1) or advanced fibrosis (stage 2–4) and degree of necroinflammatory activity. Although more widely studied in patients with chronic hepatitis C, FibroSURE was previously validated in one study of patients with chronic HBV infection (J Hepatol 2003;39:222–230). In the United States, preliminary studies using a panel of markers based on extracellular matrix and connective tissue proteins (FibroSpect) have shown similar utility in identifying chronic hepatitis C patients with mild or advanced fibrosis (J Hepatol 2004;41:935–942). FibroSURE and FibroSpect have an 80% sensitivity and 80% specificity in agreement with liver histology. Currently, noninvasive tests can only classify patients into 1 of 2 categories and are unable to provide actual grading or staging. Other models have incorporated age, gender, alcohol consumption, and serum cholesterol in formulae predicting minor versus advanced fibrosis. Current studies of these two noninvasive tests suggest that up to half of patients with chronic viral hepatitis may have their fibrosis stage accurately predicted, leaving the other half as candidates for biopsy to precisely determine the stage of fibrosis and grade of inflammation. These tests have not been validated in patients with nonalcoholic fatty liver disease.

NonInvasive Tests IN HBV PATIENTS

¹³C-caffeine breath test. The detection of significant hepatic fibrosis or cirrhosis in chronic HBV patients has both prognostic and therapeutic implications. While liver biopsy is regarded as the best method of grading hepatic fibrosis, this invasive procedure does not lend itself to being performed frequently over time and is associated with a risk of potential complications as well as sampling error. These limitations led Park and colleagues to study the use of the ¹³C-caffeine breath test as a noninvasive quantitative method to monitor liver function during lamivudine therapy. Among 48 patients with chronic HBV, the ¹³C-caffeine test results in patients with Metavir F0–1 fibrosis were similar to those in 24 healthy controls, but were decreased in patients with F2–3 fibrosis (P = 0.047) and cirrhosis (P = 0.001). In addition, the results of serial ¹³C-caffeine breath tests improved in responders to long-term lamivudine treatment and remained stable or worsened in patients with continued viremia and/or elevated ALT levels. These results demonstrate that the ¹³C-caffeine test identifies chronic HBV patients with significant hepatic fibrosis and detects improvement in liver function in patients responding to lamivudine. (Park G J-H, et al. Aliment Pharmacol Ther 2005;22:395–403.)

FT-AT. Poynard and coworkers conducted a prospective, longitudinal, multicenter study in which the FT-AT was used to noninvasively follow 298 patients with HBV after 6, 12, and 24 months of lamivudine therapy. The accuracy of FT-AT compared with liver biopsy was validated with the area under the receiver operating characteristic (ROC) curve for 283 evaluable patients (0.77 for bridging fibrosis and 0.75 for severe activity). A 3-phase kinetic profile in the improvement of the noninvasive serum markers was observed: a marked decrease during the first 6 months, a plateau phase of stability between 6 and 12 months, and another period of improvement between 12 and 24 months. These data suggest that FT-AT is a useful means of following patients with HBV noninvasively during lamivudine therapy. (Poynard T, et al. Am J Gastroenterol 2005;100:1970–1980.)

Natural History

Genotype C vs genotype B infection. Chu and Liaw studied the impact of genotype on the natural course of chronic HBV infection in 202 hepatitis B e antigen (HBeAg)-positive Taiwanese patients with normal ALT levels at baseline. A total of 150 genotype B– and 52 genotype C–infected patients were followed for an average of 10.8 years (range, 3 to 20 years). Genotype B disease was associated with an earlier and higher rate of HBeAg seroconversion. Reactivation of HBV infection was more common in patients with genotype C. Furthermore, multivariate analysis revealed genotype C disease and reactivation of HBV to be independent predictive factors for cirrhosis, while high HBV DNA levels were not predictive of cirrhosis. These data show that genotype C HBV infection is associated with a higher risk of HBV reactivation and progression to cirrhosis in patients with HBeAg-positive HBV. (Chu C-M and Liaw Y-F. J Hepatol 2005;43:411–417.)

Cohort study in northern Greece. Thrace, a region in northern Greece, is still considered to be endemic for HBV. As part of the Interreg I–II EC project, 263 chronic hepatitis B surface antigen (HBsAg)-positive carriers in Thrace were followed prospectively for a median of 5 years (range, 2 to 12 years). In this cohort study, the authors observed that: (1) the annual seroconversion rates for HBsAg and HBeAg were 1% and 10%, respectively, (2) 23.6% of patients had active liver disease and 39% had moderate fibrosis at presentation, (3) HBsAg carriers with serum HBV DNA levels <10⁴ copies/mL had normal ALT levels and unchanged liver histology over the follow-up period, and (4) an HBV DNA level of 7.1 × 10⁴ copies/mL was the minimum HBV DNA level associated with fluctuating ALT levels. (Zacharakis GH, et al. J Med Virol 2005;77:173–179.)

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