Hepatitis B Virus Immunotolerant Patients: Need to Differentiate Patients With or Without Liver Disease

Abstract

We read with great interest the response by Andreani et al1Andreani T. Serfaty L. Poupon R. et al.Need to strictly define hepatitis B virus (HBV) immunotolerant patients to avoid unnecessary liver biopsy.Gastroenterology. 2008; 135: 2155-2156Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar to our study regarding virologic and histologic features of chronic hepatitis B virus (HBV)-infected asymptomatic patients with persistently normal alanine aminotransferase (PNALT).2Kumar M. Sarin S.K. Hissar S. et al.Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT.Gastroenterology. 2008; 134: 1376-1384Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar We appreciate their concurring with us that among HBeAg-negative chronic HBV-infected patients, the so-called inactive carriers may have significant fibrosis and histologic activity, whatever the level of viral DNA. Andreani et al have raised an interesting issue with regard to chronically HBV-infected patients considered to be in the immunotolerant phase of infection. The definition of the immune tolerance phase is persistence of HBeAg-positive chronic HBV infection without significant ongoing necroinflammatory disease of the liver.3Kao J.H. Chen D.S. Critical analysis of the immune tolerance phase of chronic HBV infection: natural history and diagnosis.Curr Hepatitis Rep. 2008; 7: 5-11Crossref Scopus (4) Google Scholar What should be the cutoff HBV DNA levels for considering the patients to be in the immunotolerant phase of infection, and how to predict histology without liver biopsy, based on ALT and HBV DNA levels? In the 2 studies mentioned by Andreani et al,4Hui C.K. Leung N. Yuen S.T. et al.Natural history and disease progression in Chinese chronic hepatitis B patients in immunetolerant phase.Hepatology. 2007; 46: 395-401Crossref PubMed Scopus (206) Google Scholar, 5Andreani T. Serfaty L. Mohand D. et al.Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome.Clin Gastroenterol Hepatol. 2007; 5: 636-641Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar consisting of HBeAg-positive patients with normal ALT and HBV DNA >107 copies/ml, including 57 and 40 Asian patients, liver biopsy showed only mild disease in all, and no patient had a histologic score of fibrosis of >1. We agree that our study included all patients with HBeAg and normal transaminases, whatever the HBV DNA level. However, as suggested by Andreani et al, we analyzed the data according to the HBV DNA levels. Among 73 HBeAg-positive patients with PNALT, 23 had HBV DNA levels of >107 copies/ml and 50 had HBV DNA levels of <107 copies/ml. The median (range) of fibrosis scores among HBeAg-positive patients with PNALT was comparable between patients with HBV DNA levels >107 copies/ml (1.0 [0.0–3.0]) and HBV DNA levels of <107 copies/ml (1.0 [0.0–4.0]; P = .649). We constructed a ROC curve to determine whether there is an HBV DNA level that could differentiate patients with fibrosis from without any fibrosis on liver biopsy, and we found that the area under the curve was 0.424; that is, HBV DNA is a poor surrogate for fibrosis on liver biopsy. We agree that, although we found a significant positive correlation between histologic stage of fibrosis and serum HBV DNA level in our entire cohort of 1387 patients with normal or elevated transaminases, there was no such correlation among HBeAg-positive patients with PNALT (Spearman correlation coefficient, 0.020; P = .864), but we did not find an inverse relationship between fibrosis and HBV DNA in HBeAg-positive patients with PNALT. Thus, the issue whether to biopsy every HBeAg-positive patient with normal ALT is tricky. The decision to do biopsy or not in these patients cannot be based on HBV DNA levels alone. More important than defining the immune tolerant phase is to identify patients with histologic evidence of liver disease. Furthermore, recent studies have found an association between even low levels of HBV DNA and chronic hepatitis B complications, especially in Asian patients who acquire the virus early in life.6Yuen M.F. Yuan H.J. Wong D.K. et al.Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications.Gut. 2005; 54: 1610-1614Crossref PubMed Scopus (316) Google Scholar Large-scale studies focusing particularly on HBeAg-positive chronically HBV-infected patients with PNALT should be done to define the immune tolerant phase accurately. An algorithm-based approach, possibly using noninvasive markers of fibrosis or quantitative liver function tests, would help to justify the rationale for performing liver biopsies.