Should antiviral treatment be extended to patients with chronic hepatitis B and mildly elevated alanine aminotransferase?

The availability of seven approved therapies, including five oral drugs, for chronic hepatitis B has expanded the indications for treatment. The decision to initiate treatment is easy in patients with liver failure, but there continues to be debate regarding when treatment should be initiated in patients with precirrhotic liver disease.1,2 Recognizing that liver biopsy is not performed on all patients with chronic hepatitis B, the guidelines of the American Association for the Study of Liver Diseases (AASLD)3,4 and the Asian Pacific Association for the Study of the Liver (APASL)5 primarily rely on alanine aminotransferase (ALT) levels to guide treatment decisions. The AASLD and APASL guidelines recommend treatment for patients with an ALT level higher than 2 times the upper limit of normal (ULN) range and liver biopsy to guide treatment decisions for patients with an ALT level 1 to 2 times ULN, particularly if they are above the age of 40 years. The guidelines of the European Association for the Study of the Liver place more emphasis on liver histology; they recommend treatment for patients with at least a Metavir activity grade of A2 (range 0-3) or a Metavir fibrosis score of F2 (range 0-4).6 All three guidelines recommend that patients who are deemed not to be treatment candidates at presentation be monitored so that treatment can be initiated later when the liver disease becomes more active. Many investigators have challenged the recommendation to defer treatment in patients with normal or mildly elevated ALT levels. These experts cite recent studies finding that up to 50% of hepatitis B carriers with normal levels of ALT may have histologically significant liver disease; however, many of the studies involved small numbers of patients, most studies monitored ALT on only one or two occasions over a 6-month period prior to biopsy, and all but one study failed to report the number of patients with normal levels of ALT that were not biopsied. Thus, the findings of these studies may not be generalized to patients with persistently normal levels of ALT. For example, Kumar et al.7 reported that 21% of hepatitis B e antigen (HBeAg)–negative patients with persistently normal ALT levels and hepatitis B virus (HBV) DNA levels below 5 log10 copies/mL had histologically active liver disease, but only 29 of 75 patients (39%) who met the ALT and HBV DNA criteria underwent liver biopsy. Furthermore, the conclusion that a fair proportion of “inactive carriers” had histologically significant liver disease was based on the findings of six patients who had a maximum fibrosis score of 1 (in a range of 0-4) and a maximum histology activity index of 5 (in a range of 0-18). In another study, 59 patients who had normal levels of ALT on at least two occasions 6 months apart underwent liver biopsy; 18% had significant fibrosis (Metavir score F2), and 34% had significant inflammation (Metavir score A2).8 It should be noted that only patients with HBV DNA levels 4 log10 copies/mL were biopsied, and age 40 years was an important predictor of significant liver disease. In a third study, 24 of 69 patients (35%) with ALT levels 1 to 2 times ULN had significant liver disease as defined by a fibrosis stage 2 (range 0-4) or fibrosis stage 1 and an inflammation grade 2 (range 0-4).9 Age 35 years, male gender, and increasing ALT levels were predictors of significant liver disease. Studies that have focused on patients in the immunetolerant phase have shown that hepatic inflammation and fibrosis are negligible to mild in most patients with minimal or no progression after 5 years. In one study of 40 patients, 20 had a Metavir fibrosis score of F0, and 20 had a score of F1; 9 had a Metavir activity score of A0, 29 had a score of A1, and only 2 had a score of A2.10 In another study of 57 patients, 19 had an Ishak fibrosis score of 0 (range 0-6), and 38 had stage 1 fibrosis.11 Follow-up biopsies after a mean of 5 years revealed no changes in the fibrosis scores for 42 of 48 patients who remained in the immune-tolerant phase. These findings indicate that significant liver disease can be found in HBV carriers with normal ALT levels, but the Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; APASL, Asian Pacific Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; ULN, upper limit of normal. Address reprint requests to: Anna S. Lok, M.D., University of Michigan Health System, 3912 Taubman Center, SPC 5362, 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail: aslok@umich.edu; fax: 734-936-7024. Copyright © 2009 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.23496 Potential conflict of interest: Dr. Lok is a consultant for and received grants from Bristol-Myers Squibb, Gilead, and Roche. She also received grants from GlaxoSmithKline, Novartis, and Schering-Plough.