Hepatitis B e antigen-negative patients with persistently normal alanine aminotransferase levels and hepatitis B virus DNA &gt; 2000 IU/mL
Authors: Chia-Yen Dai, Wan-Long Chuang, Jee-Fu Huang, Ming-Lung Yu
Journal: Hepatology (2008)

We read with great interest the article by Papatheodoridis et al. published in HEPATOLOGY.1 The authors enrolled 434 hepatitis B e antigen (HBeAg)–negative patients and reported higher proportions of histological indication for treatment (grading score ≥ 7 and/or stage ≥ 2 in Ishak's classification) in chronic hepatitis B patients with higher serum hepatitis B virus (HBV) DNA levels. The authors concluded that HBeAg-negative chronic HBV patients with increased alanine aminotransferase (ALT) and HBV DNA ≥ 20,000 IU/mL almost always require therapeutic intervention, but histological indications for treatment are also present in the majority of such patients with HBV DNA < 20,000 and even HBV DNA < 2000 IU/mL. In contrast, the majority of HBeAg-negative patients with persistently normal alanine aminotransferase (PNALT) and HBV DNA > 2000 IU/mL have minimal histological lesions, and they may not require immediate liver biopsy and treatment. Some concerns have to be addressed. First, the authors defined the 35 HBeAg-negative patients with PNALT and HBV DNA > 2000 IU/mL as inactive carriers in this study. This is different from the diagnostic criteria for the inactive carrier state in the practice guideline of the American Association for the Study of Liver Diseases, which uses HBV DNA < 2000 IU/mL.2 Second, the 35 patients defined as inactive carriers all had HBV DNA levels not only >2000 IU/mL but also <20,000 IU/mL. Kumar et al.3 recently reported that in HBeAg-negative patients with PNALT, the median (range) HBV DNA was 4.29 (2.78-9.20) log10 copies/mL; 55.3% (64/116) and 35.3% (41/116) had HBV DNA ≥ 4 and 5 log10 copies/mL, respectively. Previous studies from France4 (85 cases) and Taiwan5 (414 cases) on HBeAg-negative patients with PNALT showed that 18.8% and 55.8% had a level > 4 log10 copies/mL, and 2.4% and 31.6% had an HBV DNA level > 5 log10 copies/mL. Accordingly, 64.1%,3 12.5%,4 and 56.7%5 of HBeAg-negative patients with PNALT and an HBV DNA level > 4 log10 copies/mL had an HBV DNA level > 5 log10 copies/mL. The lack of patients with PNALT and HBV DNA ≥ 20,000 IU/mL in the study1 raises the concern of possible selection bias. Third, a histological indication for treatment according to the definition of Papatheodoridis et al.1 was present in 17% (6/35) of their inactive carriers by the presence of stage 2 fibrosis but without active necroinflammation (grading score of 2-4 in all six cases).1 Kumar et al. reported that 41.4% (24/58) of patients with PNALT had active liver disease with significant activity (histologic activity index score ≥ 3) and/or significant fibrosis (stages 2-4). They reported that 32.4% (11/34) of patients with histologically inactive disease and 75% (18/24) of patients with active disease had HBV DNA > 5 log10 copies/mL. In other words, 20.7% (6/29) of patients with PNALT and HBV DNA < 5 log10 copies/mL had active liver disease.3 This implies that the histological characteristics of these patients are a heterogeneous group. Lastly, Feld et al.6 reported in their follow-up study that 10.7% and 20% of HBeAg-negative patients with normal ALT and HBV DNA from 4 to 5 log10 copies/mL experienced a rise in ALT by 6 and 12 months of follow-up, respectively. Additionally, Zacharakis et al.7 reported that four (2.1%) patients who had PNALT and serum HBV DNA levels > 2000 IU/mL exhibited HBV reactivation with increased ALT levels; there was a yearly incidence of 0.4% in their follow-up study. Considering all this, we completely agree with the authors that HBeAg-negative patients with persistently or transiently increased ALT and HBV DNA ≥ 20,000 IU/mL always require therapeutic intervention, as suggested by the recommendation of the guidelines of the American Association for the Study of Liver Diseases,2 and we appreciate and are sympathetic to contributions from Papatheodoridis et al. on strengthening this concept from the histological point of view. Nevertheless, we think the conclusion that HBeAg-negative patients with PNALT and HBV DNA > 2000 IU/mL may not require immediate liver biopsy and treatment requires a more careful reappraisal because of the limitations of the study. HBeAg-negative patients with normal aminotransferase levels and HBV DNA > 2000 IU/mL seem to be one of the patient groups currently overlooked in recent guidelines,2, 8 so more efforts to develop strategies for optimizing treatment outcomes for this group of patents are mandatory. Chia-Yen Dai* , Wan-Long Chuang* , Jee-Fu Huang §, Ming-Lung Yu* , * Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, § Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan.